ABSTRACT
INTRODUCTION: Lung cancer is the most common cause of cancer death globally. In 2022 the UK National Screening Committee recommended the implementation of a national targeted lung cancer screening programme, aiming to improve early diagnosis and survival rates. Research studies and services internationally consistently observe socioeconomic and smoking-related inequalities in screening uptake. Pathway navigation (PN) is a process through which a trained pathway navigator guides people to overcome barriers to accessing healthcare services, including screening. This nested randomised controlled trial aims to determine whether a PN intervention results in more individuals participating in lung cancer screening compared with the usual written invitation within a previous non-responder population as part of the Yorkshire Lung Screening Trial (YLST). METHODS AND ANALYSIS: A two-arm randomised controlled trial and process evaluation nested within the YLST. Participants aged 55-80 (inclusive) who have not responded to previous postal invitations to screening will be randomised by household to receive PN or usual care (a further postal invitation to contact the screening service for a lung health check) between March 2023 and October 2024. The PN intervention includes a postal appointment notification and prearranged telephone appointment, during which a pathway navigator telephones the participant, following a four-step protocol to introduce the offer and conduct an initial risk assessment. If eligible, participants are invited to book a low-dose CT (LDCT) lung cancer screening scan. All pathway navigators receive training from behavioural psychologists on motivational interviewing and communication techniques to elicit barriers to screening attendance and offer solutions. COPRIMARY OUTCOMES: The number undergoing initial telephone assessment of lung cancer risk. The number undergoing an LDCT screening scan.Secondary outcomes include demographic, clinical and risk parameters of people undergoing telephone risk assessment; the number of people eligible for screening following telephone risk assessment; the number of screen-detected cancers diagnosed; costs and a mixed-methods process evaluation.Descriptive analyses will be used to present numbers, proportions and quantitative components of the process evaluation. Primary comparisons of differences between groups will be made using logistic regression. Applied thematic analysis will be used to interpret qualitative data within a conceptual framework based on the COM-B framework. A health economic analysis of the PN intervention will also be conducted. ETHICS AND DISSEMINATION: The study is approved by the Greater Manchester West Research Ethics Committee (18-NW-0012) and the Health Research Authority following the Confidentiality Advisory Group review. Results will be shared through peer-reviewed scientific journals, conference presentations and on the YLST website. TRIAL REGISTRATION NUMBERS: ISRCTN42704678 and NCT03750110.
Subject(s)
Early Detection of Cancer , Lung Neoplasms , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/diagnostic imaging , Early Detection of Cancer/methods , Aged , Middle Aged , Male , Female , Patient Navigation , Aged, 80 and over , Randomized Controlled Trials as Topic , United Kingdom , Mass Screening/methods , Patient Acceptance of Health Care/statistics & numerical data , Health Services AccessibilityABSTRACT
BACKGROUND: Up to 50% of those attending for low-dose computed tomography screening for lung cancer continue to smoke and co-delivery of smoking cessation services alongside screening may maximise clinical benefit. Here we present data from an opt-out co-located smoking cessation service delivered alongside the Yorkshire Lung Screening Trial (YLST). METHODS: Eligible YLST participants were offered an immediate consultation with a smoking cessation practitioner (SCP) at their screening visit with ongoing smoking cessation support over subsequent weeks. RESULTS: Of 2150 eligible participants, 1905 (89%) accepted the offer of an SCP consultation during their initial visit, with 1609 (75%) receiving ongoing smoking cessation support over subsequent weeks. Uptake of ongoing support was not associated with age, ethnicity, deprivation or educational level in multivariable analyses, although men were less likely to engage (adjusted OR (ORadj) 0.71, 95% CI 0.56-0.89). Uptake was higher in those with higher nicotine dependency, motivation to stop smoking and self-efficacy for quitting. Overall, 323 participants self-reported quitting at 4â weeks (15.0% of the eligible population); 266 were validated by exhaled carbon monoxide (12.4%). Multivariable analyses of eligible smokers suggested 4-week quitting was more likely in men (ORadj 1.43, 95% CI 1.11-1.84), those with higher motivation to quit and previous quit attempts, while those with a stronger smoking habit in terms of cigarettes per day were less likely to quit. CONCLUSIONS: There was high uptake for co-located opt-out smoking cessation support across a wide range of participant demographics. Protected funding for integrated smoking cessation services should be considered to maximise programme equity and benefit.
Subject(s)
Smoking Cessation , Tobacco Use Disorder , Male , Humans , Smoking Cessation/methods , Community Health Services , Lung , TomographyABSTRACT
OBJECTIVES: To evaluate psychological, social, and financial outcomes amongst individuals undergoing a non-contrast abdominal computed tomography (CT) scan to screen for kidney cancer and other abdominal malignancies alongside the thoracic CT within lung cancer screening. SUBJECTS AND METHODS: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding a non-contrast abdominal CT scan to the thoracic CT within lung cancer screening. A total of 500 participants within the YKST, comprising all who had an abnormal CT scan and a random sample of one-third of those with a normal scan between 14/03/2022 and 24/08/2022 were sent a questionnaire at 3 and 6 months. Outcomes included the Psychological Consequences Questionnaire (PCQ), the short-form of the Spielberger State-Trait Anxiety Inventory, and the EuroQoL five Dimensions five Levels scale (EQ-5D-5L). Data were analysed using regression adjusting for participant age, sex, socioeconomic status, education, baseline quality of life (EQ-5D-5L), and ethnicity. RESULTS: A total of 380 (76%) participants returned questionnaires at 3 months and 328 (66%) at 6 months. There was no difference in any outcomes between participants with a normal scan and those with abnormal scans requiring no further action. Individuals requiring initial further investigations or referral had higher scores on the negative PCQ than those with normal scans at 3 months (standardised mean difference 0.28 sd, 95% confidence interval 0.01-0.54; P = 0.044). The difference was greater in those with anxiety or depression at baseline. No differences were seen at 6 months. CONCLUSION: Screening for kidney cancer and other abdominal malignancies using abdominal CT alongside the thoracic CT within lung cancer screening is unlikely to cause significant lasting psychosocial or financial harm to participants with incidental findings.
Subject(s)
Early Detection of Cancer , Lung Neoplasms , Tomography, X-Ray Computed , Humans , Male , Female , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/psychology , Middle Aged , Aged , Early Detection of Cancer/psychology , Feasibility Studies , Quality of Life , Surveys and Questionnaires , Radiography, Thoracic , Radiography, Abdominal , Anxiety , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/psychologyABSTRACT
OBJECTIVE: As lung cancer screening is rolled-out, there is a need to develop an effective quality assurance (QA) framework around radiology reporting to ensure optimal implementation. Here, we report a structured QA process for low-dose CT (LDCT) scans performed in the Yorkshire Lung Screening Trial. METHODS: Negative LDCT scans were single read after using computer-aided detection software. The radiology QA process included reviewing 5% of negative scans selected at random, and all cases with a subsequent diagnosis of extrapulmonary cancer or interval lung cancer not detected on the baseline scan. Radiologists were not informed of the reason for review and original radiology reports were scored as either "satisfactory", "satisfactory with learning points", or "unsatisfactory". RESULTS: From 6650 participants undergoing LDCT screening, 208 negative scans were reviewed alongside 11 cases with subsequent extrapulmonary cancer and 10 cases with interval lung cancer. Overall, only three reports were ultimately judged "unsatisfactory", 1% of randomly selected negative scans (n = 2/208) and one interval lung cancer scan (n = 1/10). Four out of a total of five cases judged "satisfactory with learning points" were related to oesophageal abnormalities where the participant was subsequently diagnosed with oesophageal cancer. CONCLUSION: The described process attempts to minimise bias in retrospective review of screening scans, and may represent a framework for future QA of national screening programmes. ADVANCES IN KNOWLEDGE: This study describes a structured QA process for a lung cancer screening programme, involving blinded second-read of LDCT screening scans to ensure fair, constructive audit of clinical performance.
Subject(s)
Lung Neoplasms , Radiology , Humans , Lung Neoplasms/diagnostic imaging , Early Detection of Cancer , Lung , Tomography, X-Ray Computed , Mass ScreeningABSTRACT
PURPOSE: The naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA. METHODS: A panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models. RESULTS: Genetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours. CONCLUSION: Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Eicosapentaenoic Acid/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antineoplastic Agents/administration & dosage , Aspirin/administration & dosage , Aspirin/pharmacology , Celecoxib/pharmacology , Cell Line, Tumor , Colorectal Neoplasms/pathology , Cyclooxygenase 2 Inhibitors/administration & dosage , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase Inhibitors/administration & dosage , Cyclooxygenase Inhibitors/pharmacology , Drug Resistance, Neoplasm , Eicosapentaenoic Acid/administration & dosage , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Xenograft Model Antitumor AssaysABSTRACT
Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis is associated with, and exacerbated by, obesity and the concomitant-elevated free fatty acid concentrations typically found in these patients. Hyperglycaemia and hyperlipidaemia together contribute to a decline in insulin-producing ß-cell mass through activation of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-κB and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF-κB and STAT1 activation is currently poorly defined. Using high-density microarray analysis of the ß-cell transcritptome, we have identified those genes and proteins most sensitive to glucose and fatty acid environment. Our data show that of those potentially able to activate STAT1 or NF-κB pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-κB activity in ß-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-κB activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death.
Subject(s)
CD40 Antigens/metabolism , Glucose/toxicity , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Lipids/toxicity , NF-kappa B/metabolism , STAT1 Transcription Factor/metabolism , Animals , Cell Death/drug effects , Gene Expression Regulation/drug effects , Humans , Insulin-Secreting Cells/drug effects , Mice, Inbred C57BL , Signal Transduction/drug effects , Signal Transduction/geneticsABSTRACT
Secretory granule exocytosis is a tightly regulated process requiring granule targeting, tethering, priming, and membrane fusion. At the heart of this process is the SNARE complex, which drives fusion through a coiled-coil zippering effect mediated by the granule v-SNARE protein, VAMP2, and the plasma membrane t-SNAREs, SNAP-25 and syntaxin-1A. Here we demonstrate that in pancreatic ß-cells the SNAP-25 accessory protein, snapin, C-terminal H2 domain binds SNAP-25 through its N-terminal Sn-1 domain. Interestingly whilst snapin binds SNAP-25, there is only modest binding of this complex with syntaxin-1A under resting conditions. Instead synataxin-1A appears to be recruited in response to secretory stimulation. These results indicate that snapin plays a role in tethering insulin granules to the plasma membrane through coiled coil interaction of snapin with SNAP-25, with full granule fusion competency only resulting after subsequent syntaxin-1A recruitment triggered by secretory stimulation.
Subject(s)
Exocytosis , Insulin-Secreting Cells/metabolism , SNARE Proteins/metabolism , Secretory Vesicles/metabolism , Synaptosomal-Associated Protein 25/metabolism , Vesicular Transport Proteins/metabolism , Animals , Cell Line , Insulin/metabolism , Insulin-Secreting Cells/cytology , Protein Binding , Protein Structure, Tertiary , Rats , Synaptosomal-Associated Protein 25/analysis , Syntaxin 1/analysis , Syntaxin 1/metabolism , Vesicular Transport Proteins/analysisABSTRACT
Myeloperoxidase (MPO) is associated with risk in acute coronary syndromes. However, the precise role it plays in ST-elevation myocardial infarction (STEMI) remains unclear. In this study we tested the hypothesis that levels of MPO in plasma after a myocardial infarction are affected by its ability to bind to the endothelium and there is local release of the enzyme at the culprit lesion. We measured plasma MPO in systemic circulation and throughout the coronary circulation in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). MPO levels at the femoral artery were higher (p <0.001) in patients with STEMI (n = 67, median 45 ng/ml, interquartile range 34 to 83) compared to control patients (n = 12, 25 ng/ml, 19 to 30) with chronic stable angina undergoing elective PCI. After administration of the anticoagulant bivalirudin in 13 patients with STEMI, plasma MPO was increased only at the culprit coronary artery lesion before PCI (178 ng/ml, 91 to 245) versus all other sites (femoral artery 86 ng/ml, 54 to 139, p = 0.019). Administration of heparin caused a marked increase of plasma MPO. Even so, it was still possible to detect an increase of plasma MPO at culprit lesion in patients with STEMI (n = 54, 171 ng/ml, 122 to 230) versus controls (n = 12, 136 ng/ml, 109 to 151, p <0.05) after heparin and before PCI. MPO levels were higher at the culprit lesion in patients with STEMI who presented early and in those with restricted flow (p <0.05). In conclusion, our results demonstrate that, in addition to a systemic increase of MPO in patients presenting early with STEMI, levels of this leukocyte enzyme are increased at the culprit coronary lesion before PCI.
Subject(s)
Myocardial Infarction/enzymology , Peroxidase/blood , Adult , Aged , Aged, 80 and over , Angioplasty, Balloon, Coronary , Anticoagulants/administration & dosage , Coronary Circulation , Endothelium, Vascular/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Heparin/administration & dosage , Humans , Linear Models , Male , Middle Aged , Myocardial Infarction/therapy , Neutrophils/metabolism , Statistics, NonparametricABSTRACT
Diabetes is characterized by high blood glucose which eventually impairs the secretion of insulin. Glucose directly affects cholesterol biosynthesis and may in turn affect cellular structures that depend on the sterol, including lipid rafts that help organize the secretory apparatus. Here, we investigated the long-term effects of glucose upon lipid rafts and secretory granule dynamics in pancreatic beta-cells. Raft fractions, identified by the presence of GM1 and flotillin, contained characteristically high levels of cholesterol and syntaxin 1A, the t-SNARE which tethers granules to the plasma membrane. Seventy-two hours exposure to 28mM glucose resulted in approximately 30% reduction in membrane cholesterol, with consequent redistribution of raft markers and syntaxin 1A throughout the plasma membrane. Live cell imaging indicated loss of syntaxin 1A from granule docking sites, and fewer docked granules. In conclusion, glucose-mediated inhibition of cholesterol biosynthesis perturbs lipid raft stability, resulting in a loss of syntaxin 1A from granule docking sites and inhibition of insulin secretion.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Exocytosis , Hyperglycemia/metabolism , Insulin/metabolism , Membrane Microdomains/metabolism , Syntaxin 1/metabolism , Animals , Cell Line , Cholesterol/biosynthesis , Diabetes Mellitus, Type 2/etiology , Glucose/metabolism , Glucose/pharmacology , Hyperglycemia/complications , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , RatsABSTRACT
Type 2 diabetes is characterised by elevated blood glucose and fatty acid concentrations, and aberrant expression of exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Restoration of normoglycaemia is often accomplished through use of the thiazolidinedione drug rosiglitazone (RSG), although little is known of its actions on the pancreas. Here we report that high glucose resulted in 96.6+/-0.2% inhibition of secretagogue-stimulated insulin secretion and 44.9+/-6.2% reduction in beta-cell insulin content. High glucose and lipid resulted in altered target-SNARE expression, syntaxin 1 becoming barely detectable whilst SNAP-25 was greatly up-regulated. RSG intervention further increased the expression of SNAP-25, but did not up-regulate syntaxin 1 expression. In summary, high glucose results in almost total attenuation of stimulated insulin secretion, partial depletion of beta-cell insulin stores and dysregulation of SNARE protein expression. RSG up-regulates SNAP-25 expression, but crucially not syntaxin 1 and hence fails to enhance insulin secretion.
Subject(s)
Insulin-Secreting Cells/metabolism , Insulin/metabolism , Thiazolidinediones/pharmacology , Animals , Cells, Cultured , Glucose/toxicity , Insulin Secretion , Insulin-Secreting Cells/drug effects , Oleic Acid/toxicity , Palmitic Acid/toxicity , Rats , Rosiglitazone , SNARE Proteins/biosynthesisABSTRACT
Calpain-10 (CAPN10) is the first type 2 diabetes susceptibility gene to be identified through a genome scan, with polymorphisms being associated with altered CAPN10 expression. Functional data have been hitherto elusive, but we report here a corresponding increase between CAPN10 expression level and regulated insulin secretion. Pancreatic beta-cell secretory granule exocytosis is mediated by the soluble N-ethylmaleimide-sensitive fusion protein attachment receptor protein complex of synaptosomal-associated protein of 25 kDa (SNAP-25), syntaxin 1, and vesicle-associated membrane protein 2. We report, for the first time, direct binding of a calpain-10 isoform with members of this complex. Furthermore, SNAP-25 undergoes a Ca2+-dependent partial proteolysis during exocytosis, with calpain protease inhibitor similarly suppressing both insulin secretion and SNAP-25 proteolysis. Based upon these findings, we postulate that an isoform of calpain-10 is a Ca2+-sensor that functions to trigger exocytosis in pancreatic beta-cells.