Progress and priorities in reducing the time to cancer diagnosis

Key developments in early diagnosis research and policy since the publication of the highly cited BJC review “Is increased time to diagnosis and treatment associated with poorer outcomes?” by Neal et al. in 2015 are summarised. Progress achieved since 2015 is described and priorities for further research identified

Easily missed? Bladder cancer in women

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Public preferences for using quantitative faecal immunochemical test (FIT) vs colonoscopy (CC) as diagnostic test for colorectal cancer: Evidence from an online survey

Background: There has been interest in using the non-invasive, home-based quantitative faecal immunochemical test (FIT) to rule out colorectal cancer (CRC) in high-risk symptomatic patients. Aim: To elicit public preferences for FIT versus colonoscopy (CC) and its delivery in primary care. Design & setting: A cross-sectional online survey in England. Method: A total of 1057 adults (without CRC symptoms and diagnosis) aged 40–59 years were invited from an English online survey panel. Responders were asked to imagine they had been experiencing CRC symptoms that would qualify them for a diagnostic test. Participants were presented with choices between CC and FIT in ascending order of number of CRCs missed by FIT (from 1–10%). It was measured at what number of missed CRCs responders preferred CC over FIT. Results: While 150 participants did not want either of the tests when both missed 1% CRCs, the majority (n = 741, 70.0%) preferred FIT to CC at that level of accuracy. However, this preference reduced to 427 (40.4%) when FIT missed one additional cancer. Women were more likely to tolerate missing CRC when using FIT. Having lower numeracy and perceiving a higher level of risk meant participants were less likely to tolerate a false negative test. Most of those who chose FIT preferred to return it by mail (62.2%), to be informed about normal test results by letter (42.1%), and about abnormal test results face to face (32.5%). Conclusion: While the majority of participants preferred FIT over CC when both tests had the same sensitivity, tolerance for missed CRCs was low

The diagnostic accuracy of a single CEA blood test in detecting colorectal cancer recurrence: Results from the FACS trial

Objective: To evaluate the diagnostic accuracy of a single CEA (carcinoembryonic antigen) blood test in detecting colorectal cancer recurrence. Background: Patients who have undergone curative resection for primary colorectal cancer are typically followed up with scheduled CEA testing for 5 years. Decisions to investigate further (usually by CT imaging) are based on single test results, reflecting international guidelines. Methods: A secondary analysis was undertaken of data from the FACS trial (two arms included CEA testing). The composite reference standard applied included CT-CAP imaging, clinical assessment and colonoscopy. Accuracy in detecting recurrence was evaluated in terms of sensitivity, specificity, likelihood ratios, predictive values, time-dependent area under the ROC curves, and operational performance when used prospectively in clinical practice are reported. Results: Of 582 patients, 104 (17.9%) developed recurrence during the 5 year follow-up period. Applying the recommended threshold of 5µg/L achieves at best 50.0% sensitivity (95% CI: 40.1-59.9%); in prospective use in clinical practice it would lead to 56 missed recurrences (53.8%; 95% CI: 44.2-64.4%) and 89 false alarms (56.7% of 157 patients referred for investigation). Applying a lower threshold of 2.5µg/L would reduce the number of missed recurrences to 36.5% (95% CI: 26.5-46.5%) but would increase the false alarms to 84.2% (924/1097 referred). Some patients are more prone to false alarms than others – at the 5µg/L threshold, the 89 episodes of unnecessary investigation were clustered in 29 individuals. Conclusion: Our results demonstrated very low sensitivity for CEA, bringing to question whether it could ever be used as an independent triage test. It is not feasible to improve the diagnostic performance of a single test result by reducing the recommended action threshold because of the workload and false alarms generated. Current national and international guidelines merit re-evaluation and options to improve performance, such as making clinical decisions on the basis of CEA trend, should be further assessed

Early detection of multiple myeloma in primary care using blood tests: a case-control study in primary care

This is the final version. Available on open access from Royal College of General Practitioners via the DOI in this recordBACKGROUND: Multiple myeloma is a haematological cancer characterised by numerous non-specific symptoms leading to diagnostic delay in a large proportion of patients. AIM: To identify which blood tests are useful in suggesting or excluding a diagnosis of myeloma. DESIGN AND SETTING: A matched case-control study set in UK primary care using routinely collected data from the Clinical Practice Research Datalink. METHOD: Symptom prevalence and blood tests were analysed up to 5 years before diagnosis in 2703 cases and 12 157 matched controls. Likelihood ratios (LR) were used to classify tests or their combinations as useful rule-in tests (LR+ = ≥5), or rule-out tests (LR- = ≤0.2). RESULTS: Raised plasma viscosity (PV) had an LR+ = 2.0, 95% confidence interval [CI] = 1.7 to 2.3; erythrocyte sedimentation rate (ESR) 1.9, 95% CI = 1.7 to 2.0; and C-reactive protein (CRP) 1.2, 95% CI = 1.1 to 1.4. A normal haemoglobin had an LR- = 0.42, 95% CI = 0.39 to 0.45; calcium LR- = 0.81, 95% CI = 0.78 to 0.83; and creatinine LR- = 0.80, 95% CI = 0.77 to 0.83. The test combination with the lowest LR- was all normal haemoglobin with calcium and PV, which had an LR- = 0.06, 95% CI = 0.02 to 0.18, though the LR- for normal haemoglobin and PV together was 0.12 (95% CI = 0.07 to 0.23). CONCLUSION: Plasma viscosity and ESR are better for both ruling in and ruling out the disease compared with C-reactive protein. A combination of a normal ESR or PV and normal haemoglobin is a simple rule-out approach for patients currently being tested in primary care.This manuscript presents work carried out as part of a DPhil scholarship awarded to Constantinos Koshiaris funded by the Primary Care Research Trust, the University of Oxford, and National Institute for Health Research (NIHR) Oxford CLAHRC. This article presents independent research funded by the NIHR

At what times during infection is SARS-CoV-2 detectable and no longer detectable using RT-PCR-based tests? A systematic review of individual participant data

Background: Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity. / Methods: We conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites. / Results: Of 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from − 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset. / Conclusions: RT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated

A single, one-off measure of depression and anxiety predicts future symptoms, higher healthcare costs, and lower quality of life in coronary heart disease patients: Analysis from a multi-wave, primary care cohort study

To determine whether a one-off, baseline measure of depression and anxiety in a primary care, coronary heart disease (CHD) population predicts ongoing symptoms, costs, and quality of life across a 3-year follow-up.Longitudinal cohort study.16 General Practice surgeries across South-East London.803 adults (70% male, mean age 71 years) contributing up to 7 follow-up points.Ongoing reporting of symptoms, health care costs, and quality of life.At baseline, 27% of the sample screened positive for symptoms of depression and anxiety, as measured by the Hospital Anxiety and Depression Scale (HADS). The probability of scoring above the cut-off throughout the follow-up was 71.5% (p<0.001) for those screening positive at baseline, and for those screening negative, the probability of scoring below the cut-off throughout the follow-up was 97.6% (p<0.001). Total health care costs were 39% higher during follow-up for those screening positive (p<0.05). Quality of life as measured by the SF-12 was lower on the mental component during follow-up for those screening positive (-0.75, CI -1.53 to 0.03, p = 0.059), and significantly lower on the physical component (-4.99, CI -6.23 to -.376, p<0.001).A one-off measure for depression and anxiety symptoms in CHD predicts future symptoms, costs, and quality of life over the subsequent three-years. These findings suggest symptoms of depression and anxiety in CHD persist throughout long periods and are detrimental to a patient's quality of life, whilst incurring higher health care costs for primary and secondary care services. Screening for these symptoms at the primary care level is important to identify and manage patients at risk of the negative effects of this comorbidity. Implementation of screening, and possible collaborative care strategies and interventions that help mitigate this risk should be the ongoing focus of researchers and policy-makers

Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1

Introduction We have previously reported that induction of epidermal growth factor receptor and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth-inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study, we have investigated whether induction of ErbB3 and/or ErbB4 may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines. Methods MCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for seven days, and effects on ErbB3/4 expression and signalling, as well as on cell growth, were assessed. Effects of heregulin β1 (HRGβ1) were also examined in the absence and presence of fulvestrant to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation. Results Fulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand HRGβ1 with enhanced ErbB3/4-driven signalling activity, reexpression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 HRGβ1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by HRGβ1 in all four cell lines. Conclusions These findings suggest that although antihormones such as fulvestrant may have potent acute growth-inhibitory activity in ER-positive breast cancer cells, their ability to induce and sensitise cells to growth factors may serve to reduce and ultimately limit their inhibitory activity

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

Peer reviewedPublisher PD

Cognitive domains affected post-COVID-19; a systematic review and meta-analysis

\ua9 2024 The Authors. European Journal of Neurology published by John Wiley &amp; Sons Ltd on behalf of European Academy of Neurology.Background and purpose: This review aims to characterize the pattern of post-COVID-19 cognitive impairment, allowing better prediction of impact on daily function to inform clinical management and rehabilitation. Methods: A systematic review and meta-analysis of neurocognitive sequelae following COVID-19 was conducted, following PRISMA-S guidelines. Studies were included if they reported domain-specific cognitive assessment in patients with COVID-19 at &gt;4 weeks post-infection. Studies were deemed high-quality if they had &gt;40 participants, utilized healthy controls, had low attrition rates and mitigated for confounders. Results: Five of the seven primary Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cognitive domains were assessed by enough high-quality studies to facilitate meta-analysis. Medium effect sizes indicating impairment in patients post-COVID-19 versus controls were seen across executive function (standardised mean difference (SMD) −0.45), learning and memory (SMD −0.55), complex attention (SMD −0.54) and language (SMD −0.54), with perceptual motor function appearing to be impacted to a greater degree (SMD −0.70). A narrative synthesis of the 56 low-quality studies also suggested no obvious pattern of impairment. Conclusions: This review found moderate impairments across multiple domains of cognition in patients post-COVID-19, with no specific pattern. The reported literature was significantly heterogeneous, with a wide variety of cognitive tasks, small sample sizes and disparate initial disease severities limiting interpretability. The finding of consistent impairment across a range of cognitive tasks suggests broad, as opposed to domain-specific, brain dysfunction. Future studies should utilize a harmonized test battery to facilitate inter-study comparisons, whilst also accounting for the interactions between COVID-19, neurological sequelae and mental health, the interplay between which might explain cognitive impairment