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Professor Clare Verrill has recently been appointed the lead of workstream 4 (Technology and Informatics) within the National Cancer Research Institute (NCRI) initiative, CM-Path (Cellular Molecular Pathology initiative).
Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials.
BACKGROUND: Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. METHODS: We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). FINDINGS: Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p<0·0001) and death from breast cancer (0·67, 0·61 to 0·73; p<0·0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9·0% (95% CI 7·4 to 10·7; p<0·0001) and 10-year breast cancer mortality was reduced by 6·4% (4·9 to 7·8; p<0·0001), with a 6·5% reduction (5·0 to 8·0; p<0·0001) in all-cause mortality, and no increase in death without recurrence (0·4%, -0·3 to 1·1; p=0·35). The proportional reduction in recurrence was largest in years 0-1 after randomisation (0·53, 99% CI 0·46 to 0·61), with benefits persisting through years 2-4 (0·73, 0·62 to 0·85) and 5-9 (0·80, 0·64 to 1·01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5·7% [95% CI 3·1 to 8·3], 6·8% [4·7 to 9·0], and 10·7% [7·7 to 13·6] in N0, N1-3, and N4+ disease). INTERPRETATION: Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics. FUNDING: Cancer Research UK, UK Medical Research Council.
Effects of pre‐operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study
We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care.
Validation of grading of non-invasive urothelial carcinoma by digital pathology for routine diagnosis
Abstract Background Pathological grading of non-invasive urothelial carcinoma has a direct impact upon management. This study evaluates the reproducibility of grading these tumours on glass slides and digital pathology. Methods Forty eight non-invasive urothelial bladder carcinomas were graded by three uropathologists on glass and on a digital platform using the 1973 WHO and 2004 ISUP/WHO systems. Results Consensus grades for glass and digital grading gave Cohen’s kappa scores of 0.78 (2004) and 0.82 (1973). Of 142 decisions made on the key therapeutic borderline of low grade versus high grade urothelial carcinoma (2004) by the three pathologists, 85% were in agreement. For the 1973 grading system, agreement overall was 90%. Conclusions Agreement on grading on glass slide and digital screen assessment is similar or in some cases improved, suggesting at least non-inferiority of DP for grading of non-invasive urothelial carcinoma.
WHO/ISUP grading of clear cell renal cell carcinoma and papillary renal cell carcinoma; validation of grading on the digital pathology platform and perspectives on reproducibility of grade.
BACKGROUND: There are recognised potential pitfalls in digital diagnosis in urological pathology, including the grading of dysplasia. The World Health Organisation/International Society of Urological Pathology (WHO/ISUP) grading system for renal cell carcinoma (RCC) is prognostically important in clear cell RCC (CCRCC) and papillary RCC (PRCC), and is included in risk stratification scores for CCRCC, thus impacting on patient management. To date there are no systematic studies examining the concordance of WHO/ISUP grading between digital pathology (DP) and glass slide (GS) images. We present a validation study examining intraobserver agreement in WHO/ISUP grade of CCRCC and PRCC. METHODS: Fifty CCRCCs and 10 PRCCs were graded (WHO/ISUP system) by three specialist uropathologists on three separate occasions (DP once then two GS assessments; GS1 and GS2) separated by wash-out periods of at least two-weeks. The grade was recorded for each assessment, and compared using Cohen's and Fleiss's kappa. RESULTS: There was 65 to 78% concordance of WHO/ISUP grading on DP and GS1. Furthermore, for the individual pathologists, the comparative kappa scores for DP versus GS1, and GS1 versus GS2, were 0.70 and 0.70, 0.57 and 0.73, and 0.71 and 0.74, and with no apparent tendency to upgrade or downgrade on DP versus GS. The interobserver kappa agreement was less, at 0.58 on DP and 0.45 on GS. CONCLUSION: Our results demonstrate that the assessment of WHO/ISUP grade on DP is noninferior to that on GS. There is an apparent slight improvement in agreement between pathologists on RCC grade when assessed on DP, which may warrant further study.
PURPOSE: A shortage of suitable donor livers is driving increased use of higher risk livers for transplantation. However, current biomarkers are not sensitive and specific enough to predict posttransplant liver function. This is limiting the expansion of the donor pool. Therefore, better noninvasive tests are required to determine which livers will function following implantation and hence can be safely transplanted. This study assesses the temperature sensitivity of proton density fat fraction and relaxometry parameters and examines their potential for assessment of liver function ex vivo. METHODS: Six ex vivo human livers were scanned during static cold storage following normothermic machine perfusion. Proton density fat fraction, T1 , T2 , and T 2 ∗ were measured repeatedly during cooling on ice. Temperature corrections were derived from these measurements for the parameters that showed significant variation with temperature. RESULTS: Strong linear temperature sensitivities were observed for proton density fat fraction (R2 = 0.61, P < .001) and T1 (R2 = 0.78, P < .001). Temperature correction according to a linear model reduced the coefficient of repeatability in these measurements by 41% and 36%, respectively. No temperature dependence was observed in T2 or T 2 ∗ measurements. Comparing livers deemed functional and nonfunctional during normothermic machine perfusion by hemodynamic and biochemical criteria, T1 differed significantly: 516 ± 50 ms for functional versus 679 ± 60 ms for nonfunctional, P = .02. CONCLUSION: Temperature correction is essential for robust measurement of proton density fat fraction and T1 in cold-stored human livers. These parameters may provide a noninvasive measure of viability for transplantation.
Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse
Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.
Deep EHR Spotlight: a Framework and Mechanism to Highlight Events in Electronic Health Records for Explainable Predictions.
The wide adoption of Electronic Health Records (EHR) has resulted in large amounts of clinical data becoming available, which promises to support service delivery and advance clinical and informatics research. Deep learning techniques have demonstrated performance in predictive analytic tasks using EHRs yet they typically lack model result transparency or explainability functionalities and require cumbersome pre-processing tasks. Moreover, EHRs contain heterogeneous and multi-modal data points such as text, numbers and time series which further hinder visualisation and interpretability. This paper proposes a deep learning framework to: 1) encode patient pathways from EHRs into images, 2) highlight important events within pathway images, and 3) enable more complex predictions with additional intelligibility. The proposed method relies on a deep attention mechanism for visualisation of the predictions and allows predicting multiple sequential outcomes.
Development of ex situ normothermic reperfusion as an innovative method to assess pancreases after preservation.
Static cold storage (SCS) is the standard method for pancreas preservation prior to transplantation; however, it does not permit organ assessment. Normothermic reperfusion (NR) is utilized clinically for other organs to assess viability. Our aim was to develop NR using normothermic machine perfusion technique to simulate reperfusion at the time of transplantation, enabling evaluation of oxygenated hypothermic machine perfusion (HMPO2) as a newer strategy to optimize pancreas preservation. 13 porcine pancreases procured after circulatory death were divided into 3 groups: 4 pancreases preserved using SCS, and 2 groups preserved by HMPO2 (n = 4 and n = 5, differing by type of preservation solution). Duration of perfusion or cold storage was 6 hours before the 1-hour assessment using NR. Outcome measures were perfusion characteristics, biochemistry and change in tissue water mass as oedema assessment. During NR, the HMPO2 groups demonstrated better perfusion characteristics, normal macroscopic appearances, decreased water mass and one HMPO2 group demonstrated a response to glucose stimulation. Conversely, the SCS group showed an increased water mass and developed early macroscopic appearances of oedema, interstitial haemorrhage and minimal portal outflow. This study suggests that ex situ assessment of pancreases by NR is promising, and that HMPO2 may be better than SCS.
Association of Age With 10-Year Outcomes After Coronary Surgery in the Arterial Revascularization Trial.
BACKGROUND: The association of age with the outcomes of bilateral internal thoracic arteries (BITAs) versus single internal thoracic arteries (SITAs) for coronary bypass grafting (CABG) remains to be determined. OBJECTIVES: The purpose of this study was to evaluate the association between age and BITA versus SITA outcomes in the Arterial Revascularization Trial. METHODS: The primary endpoints were all-cause mortality and a composite of major adverse events, including all-cause mortality, myocardial infarction, or stroke. Secondary endpoints were bleeding complications and sternal wound complications up to 6 months after surgery. Multivariable fractional polynomials analysis and log-rank tests were used. RESULTS: Age did not affect any of the explored outcomes in the overall BITA versus SITA comparison in the intention-to-treat analysis and in the analysis based on the number of arterial grafts received. However, when the intention-to-treat analysis was restricted to the populations of patients between age 50 and 70 years, younger patients in the BITA arm had a significantly lower incidence of major adverse events (p = 0.03). CONCLUSIONS: Our results suggest that BITA may improve long-term outcome in younger patients, although more randomized data are needed to confirm this hypothesis.
Hypertension affects an estimated 1.4 billion people and is a major cause of morbidity and mortality worldwide. Early diagnosis and intervention can potentially decrease cardiovascular events later in life. However, blood pressure (BP) measurements take time and require training for health care professionals. The measurements are also inconvenient for patients to access, numerous daily variables affect BP values, and only a few BP readings can be collected per session. This leads to an unmet need for an accurate, 24-h continuous, and portable BP measurement system. Electrocardiograms (ECGs) have been considered as an alternative way to measure BP and may meet this need. This review summarizes the literature published from January 1, 2010, to January 1, 2020, on the use of only ECG wave morphology to monitor BP or identify hypertension. From 35 articles analyzed (9 of those with no listed comorbidities and confounders), the P wave, QTc intervals and TpTe intervals may be promising for this purpose. Unfortunately, with the limited number of articles and the variety of participant populations, we are unable to make conclusions about the effectiveness of ECG-only BP monitoring. We provide 13 recommendations for future ECG-only BP monitoring studies and highlight the limited findings in pregnant and pediatric populations. With the advent of convenient and portable ECG signal recording in smart devices and wearables such as watches, understanding how to apply ECG-only findings to identify hypertension early is crucial to improving health outcomes worldwide.
COVIDTrach; the outcomes of mechanically ventilated COVID-19 patients undergoing tracheostomy in the UK: Interim Report
AbstractCOVIDTrach is a UK multidisciplinary collaborative project that aims to evaluate the outcomes of tracheostomy in COVID-19 patients. An invitation to participate in an online survey tool (REDCap) was disseminated to all UK NHS departments involved in tracheostomy in mechanically ventilated COVID-19 patients. Fifty-two percent (n=219/465) of patients who had undergone tracheostomy and were still alive, had been successfully weaned from mechanical ventilation at the point of completing the survey. The all cause in-hospital mortality following tracheostomy was 12% (n=62/530), with 3% of these (n=2/62) due to tracheostomy related complications and the remaining deaths due to COVID-19 related complications. Amongst 400 cases submitting data two weeks after the tracheostomy, no instance of COVID-19 infection amongst operators was recorded. This interim report highlights early outcomes following tracheostomy in mechanically ventilated COVID-19 patients. Future reporting from COVIDTrach will include more detailed analysis at later timepoints using comparator groups in order to provide a more comprehensive assessment of tracheostomy in COVID-19.