ABSTRACT
Lung cancer screening with low-dose CT was recommended by the UK National Screening Committee (UKNSC) in September, 2022, on the basis of data from trials showing a reduction in lung cancer mortality. These trials provide sufficient evidence to show clinical efficacy, but further work is needed to prove deliverability in preparation for a national roll-out of the first major targeted screening programme. The UK has been world leading in addressing logistical issues with lung cancer screening through clinical trials, implementation pilots, and the National Health Service (NHS) England Targeted Lung Health Check Programme. In this Policy Review, we describe the consensus reached by a multiprofessional group of experts in lung cancer screening on the key requirements and priorities for effective implementation of a programme. We summarise the output from a round-table meeting of clinicians, behavioural scientists, stakeholder organisations, and representatives from NHS England, the UKNSC, and the four UK nations. This Policy Review will be an important tool in the ongoing expansion and evolution of an already successful programme, and provides a summary of UK expert opinion for consideration by those organising and delivering lung cancer screenings in other countries.
Subject(s)
Lung Neoplasms , State Medicine , Humans , Lung Neoplasms/diagnostic imaging , Early Detection of Cancer , England , LungABSTRACT
INTRODUCTION: Although lung cancer screening is being implemented in the UK, there is uncertainty about the optimal invitation strategy. Here, we report participation in a community screening programme following a population-based invitation approach, examine factors associated with participation, and compare outcomes with hypothetical targeted invitations. METHODS: Letters were sent to all individuals (age 55-80) registered with a general practice (n=35 practices) in North and East Manchester, inviting ever-smokers to attend a Lung Health Check (LHC). Attendees at higher risk (PLCOm2012NoRace score≥1.5%) were offered two rounds of annual low-dose CT screening. Primary care recorded smoking codes (live and historical) were used to model hypothetical targeted invitation approaches for comparison. RESULTS: Letters were sent to 35 899 individuals, 71% from the most socioeconomically deprived quintile. Estimated response rate in ever-smokers was 49%; a lower response rate was associated with younger age, male sex, and primary care recorded current smoking status (adjOR 0.55 (95% CI 0.52 to 0.58), p<0.001). 83% of eligible respondents attended an LHC (n=8887/10 708). 51% were eligible for screening (n=4540/8887) of whom 98% had a baseline scan (n=4468/4540). Screening adherence was 83% (n=3488/4199) and lung cancer detection 3.2% (n=144) over 2 rounds. Modelled targeted approaches required 32%-48% fewer invitations, identified 94.6%-99.3% individuals eligible for screening, and included 97.1%-98.6% of screen-detected lung cancers. DISCUSSION: Using a population-based invitation strategy, in an area of high socioeconomic deprivation, is effective and may increase screening accessibility. Due to limitations in primary care records, targeted approaches should incorporate historical smoking codes and individuals with absent smoking records.
Subject(s)
Early Detection of Cancer , Lung Neoplasms , Humans , Male , Middle Aged , Aged , Aged, 80 and over , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/epidemiology , Smokers , Smoking/epidemiology , Mass Screening , Socioeconomic FactorsABSTRACT
BACKGROUND: Screening with low-dose computed tomography (LDCT) reduces lung cancer mortality; however, the most effective strategy for optimising participation is unknown. Here we present data from the Yorkshire Lung Screening Trial, including response to invitation, screening eligibility and uptake of community-based LDCT screening. METHODS: Individuals aged 55-80â years, identified from primary care records as having ever smoked, were randomised prior to consent to invitation to telephone lung cancer risk assessment or usual care. The invitation strategy included general practitioner endorsement, pre-invitation and two reminder invitations. After telephone triage, those at higher risk were invited to a Lung Health Check (LHC) with immediate access to a mobile CT scanner. RESULTS: Of 44 943 individuals invited, 50.8% (n=22 815) responded and underwent telephone-based risk assessment (16.7% and 7.3% following first and second reminders, respectively). A lower response rate was associated with current smoking status (adjusted OR 0.44, 95% CI 0.42-0.46) and socioeconomic deprivation (adjusted OR 0.58, 95% CI 0.54-0.62 for the most versus the least deprived quintile). Of those responding, 34.4% (n=7853) were potentially eligible for screening and offered a LHC, of whom 86.8% (n=6819) attended. Lower uptake was associated with current smoking status (adjusted OR 0.73, 95% CI 0.62-0.87) and socioeconomic deprivation (adjusted OR 0.78, 95% CI 0.62-0.98). In total, 6650 individuals had a baseline LDCT scan, representing 99.7% of eligible LHC attendees. CONCLUSIONS: Telephone risk assessment followed by a community-based LHC is an effective strategy for lung cancer screening implementation. However, lower participation associated with current smoking status and socioeconomic deprivation underlines the importance of research to ensure equitable access to screening.
Subject(s)
Early Detection of Cancer , Lung Neoplasms , Humans , Early Detection of Cancer/methods , Lung Neoplasms/diagnostic imaging , Tomography, X-Ray Computed/methods , Mass Screening , LungABSTRACT
OBJECTIVES: Although some evidence to suggest an association between preoperative anemia and reduced overall survival exists, contemporary studies investigating the impact of preoperative anemia on outcomes after resection for primary lung cancer are lacking. DESIGN: A multicenter retrospective review. SETTING: Two tertiary cardiothoracic surgery centers in the Northwest of England. PARTICIPANTS: A total of 5,029 patients between 2012 and 2018. INTERVENTIONS: All patients underwent lung resection for primary lung cancer. Patients were classified as anemic based on the World Health Organization definition. Men with hemoglobin <130 g/L and women with hemoglobin <120 g/L were considered to be anemic. MEASUREMENTS AND MAIN RESULTS: Outcomes assessed included perioperative mortality, 90-day mortality, and overall survival. Multivariate logistic and Cox regression analyses were used to assess the impact of preoperative anemia on 90-day mortality and overall survival, respectively. Overall, preoperatively, 24.0% (n = 1207) of patients were anemic. The 90-day mortality for anemic and nonanemic patients was 5.6% and 3.1%, respectively (p < 0.001). After multivariate adjustment, preoperative anemia was not associated with increased 90-day mortality. However, a log-rank analysis demonstrated reduced overall survival for anemic patients (p < 0.001). After multivariate adjustment, preoperative anemia was found to be independently associated with reduced overall survival (hazard ratio 1.287, 95% confidence interval 1.141-1.451, p < 0.001). CONCLUSIONS: Although anemia was not an independent predictor of short-term outcomes, it was independently associated with significantly reduced survival for patients undergoing resection for lung cancer. Further work is required to understand why anemia reduces long-term survival and whether pathways for anemic patients can be adapted to improve long-term outcomes.
Subject(s)
Anemia , Lung Neoplasms , Anemia/complications , Anemia/diagnosis , Anemia/epidemiology , Cohort Studies , Female , Hemoglobins , Humans , Lung , Lung Neoplasms/complications , Lung Neoplasms/surgery , Male , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND: COPD is a major cause of morbidity and mortality in populations eligible for lung cancer screening. We investigated the role of spirometry in a community-based lung cancer screening programme. METHODS: Ever smokers, age 55-74, resident in three deprived areas of Manchester were invited to a 'Lung Health Check' (LHC) based in convenient community locations. Spirometry was incorporated into the LHCs alongside lung cancer risk estimation (Prostate, Lung, Colorectal and Ovarian Study Risk Prediction Model, 2012 version (PLCOM2012)), symptom assessment and smoking cessation advice. Those at high risk of lung cancer (PLCOM2012 ≥1.51%) were eligible for annual low-dose CT screening over two screening rounds. Airflow obstruction was defined as FEV1/FVC<0.7. Primary care databases were searched for any prior diagnosis of COPD. RESULTS: 99.4% (n=2525) of LHC attendees successfully performed spirometry; mean age was 64.1±5.5, 51% were women, 35% were current smokers. 37.4% (n=944) had airflow obstruction of which 49.7% (n=469) had no previous diagnosis of COPD. 53.3% of those without a prior diagnosis were symptomatic (n=250/469). After multivariate analysis, the detection of airflow obstruction without a prior COPD diagnosis was associated with male sex (adjOR 1.84, 95% CI 1.37 to 2.47; p<0.0001), younger age (p=0.015), lower smoking duration (p<0.0001), fewer cigarettes per day (p=0.035), higher FEV1/FVC ratio (<0.0001) and being asymptomatic (adjOR 4.19, 95% CI 2.95 to 5.95; p<0.0001). The likelihood of screen detected lung cancer was significantly greater in those with evidence of airflow obstruction who had a previous diagnosis of COPD (adjOR 2.80, 95% CI 1.60 to 8.42; p=0.002). CONCLUSIONS: Incorporating spirometry into a community-based targeted lung cancer screening programme is feasible and identifies a significant number of individuals with airflow obstruction who do not have a prior diagnosis of COPD.
Subject(s)
Airway Obstruction/epidemiology , Lung Neoplasms/complications , Lung Neoplasms/diagnosis , Pulmonary Disease, Chronic Obstructive/complications , Spirometry , Aged , Early Detection of Cancer , Feasibility Studies , Female , Humans , Male , Middle Aged , Prevalence , Smoking , United KingdomABSTRACT
INTRODUCTION: Low-dose CT (LDCT) screening of high-risk smokers reduces lung cancer (LC) specific mortality. Determining screening eligibility using individualised risk may improve screening effectiveness and reduce harm. Here, we compare the performance of two risk prediction models (PLCOM2012 and Liverpool Lung Project model (LLPv2)) and National Lung Screening Trial (NLST) eligibility criteria in a community-based screening programme. METHODS: Ever-smokers aged 55-74, from deprived areas of Manchester, were invited to a Lung Health Check (LHC). Individuals at higher risk (PLCOM2012 score ≥1.51%) were offered annual LDCT screening over two rounds. LLPv2 score was calculated but not used for screening selection; ≥2.5% and ≥5% thresholds were used for analysis. RESULTS: PLCOM2012 ≥1.51% selected 56% (n=1429) of LHC attendees for screening. LLPv2 ≥2.5% also selected 56% (n=1430) whereas NLST (47%, n=1188) and LLPv2 ≥5% (33%, n=826) selected fewer. Over two screening rounds 62 individuals were diagnosed with LC; representing 87% (n=62/71) of 6-year incidence predicted by mean PLCOM2012 score (5.0%). 26% (n=16/62) of individuals with LC were not eligible for screening using LLPv2 ≥5%, 18% (n=11/62) with NLST criteria and 7% (n=5/62) with LLPv2 ≥2.5%. NLST eligible Manchester attendees had 2.5 times the LC detection rate than NLST participants after two annual screens (≈4.3% (n=51/1188) vs 1.7% (n=438/26 309); p<0.0001). Adverse measures of health, including airflow obstruction, respiratory symptoms and cardiovascular disease, were positively correlated with LC risk. Coronary artery calcification was predictive of LC (adjOR 2.50, 95% CI 1.11 to 5.64; p=0.028). CONCLUSION: Prospective comparisons of risk prediction tools are required to optimise screening selection in different settings. The PLCOM2012 model may underestimate risk in deprived UK populations; further research focused on model calibration is required.
Subject(s)
Early Detection of Cancer , Lung Neoplasms/diagnosis , Lung Neoplasms/etiology , Patient Selection , Aged , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Risk Assessment , Smoking , Tomography, X-Ray Computed , United KingdomABSTRACT
OBJECTIVES: Stereotactic ablative radiotherapy (SABR) is a well-established treatment for medically inoperable peripheral stage I nonsmall cell lung cancer (NSCLC). Previous nonrandomised evidence supports SABR as an alternative to surgery, but high-quality randomised controlled trial (RCT) evidence is lacking. The SABRTooth study aimed to establish whether a UK phase III RCT was feasible. DESIGN AND METHODS: SABRTooth was a UK multicentre randomised controlled feasibility study targeting patients with peripheral stage I NSCLC considered to be at higher risk of surgical complications. 54 patients were planned to be randomised 1:1 to SABR or surgery. The primary outcome was monthly average recruitment rates. RESULTS: Between July 2015 and January 2017, 318 patients were considered for the study and 205 (64.5%) were deemed ineligible. Out of 106 (33.3%) assessed as eligible, 24 (22.6%) patients were randomised to SABR (n=14) or surgery (n=10). A key theme for nonparticipation was treatment preference, with 43 (41%) preferring nonsurgical treatment and 19 (18%) preferring surgery. The average monthly recruitment rate was 1.7 patients against a target of three. 15 patients underwent their allocated treatment: SABR n=12, surgery n=3. CONCLUSIONS: We conclude that a phase III RCT randomising higher risk patients between SABR and surgery is not feasible in the National Health Service. Patients have pre-existing treatment preferences, which was a barrier to recruitment. A significant proportion of patients randomised to the surgical group declined and chose SABR. SABR remains an alternative to surgery and novel study approaches are needed to define which patients benefit from a nonsurgical approach.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Radiosurgery , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/radiotherapy , Carcinoma, Non-Small-Cell Lung/surgery , Feasibility Studies , Humans , Lung Neoplasms/pathology , Lung Neoplasms/radiotherapy , Lung Neoplasms/surgery , Neoplasm Staging , Treatment OutcomeABSTRACT
Lung cancer is the most common cause of cancer-related mortality worldwide, characterized by late clinical presentation (49-53% of patients are diagnosed at stage IV) and consequently poor outcomes. One challenge in identifying biomarkers of early disease is the collection of samples from patients prior to symptomatic presentation. We used blood collected during surgical resection of lung tumors in an iTRAQ isobaric tagging experiment to identify proteins effluxing from tumors into pulmonary veins. Forty proteins were identified as having an increased abundance in the vein draining from the tumor compared to "healthy" pulmonary veins. These protein markers were then assessed in a second cohort that utilized the mass spectrometry (MS) technique: Sequential window acquisition of all theoretical fragment ion spectra (SWATH) MS. SWATH-MS was used to measure proteins in serum samples taken from 25 patients <50 months prior to and at lung cancer diagnosis and 25 matched controls. The SWATH-MS analysis alone produced an 11 protein marker panel. A machine learning classification model was generated that could discriminate patient samples from patients within 12 months of lung cancer diagnosis and control samples. The model was evaluated as having a mean AUC of 0.89, with an accuracy of 0.89. This panel was combined with the SWATH-MS data from one of the markers from the first cohort to create a 12 protein panel. The proteome signature developed for lung cancer risk can now be developed on further cohorts.
Subject(s)
Biomarkers, Tumor/blood , Early Detection of Cancer/methods , Lung Neoplasms/blood , Proteomics , Aged , Female , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/pathology , Machine Learning , Male , Middle Aged , Neoplasm Staging , Proteome/genetics , Tandem Mass Spectrometry/methodsABSTRACT
Manchester's 'Lung Health Check' pilot utilised mobile CT scanners in convenient retail locations to deliver lung cancer screening to socioeconomically disadvantaged communities. We assessed whether screening location was an important factor for those attending the service. Location was important for 74.7% (n=701/938) and 23% (n=216/938) reported being less likely to attend an equivalent hospital-based programme. This preference was most common in current smokers (27% current smokers vs 19% former smokers; AdjOR 1.46, 95% CI 1.03 to 2.08, p=0.036) and those in the lowest deprivation quartile (25% lowest quartile vs 17.6% highest quartile; AdjOR 2.0, 95% CI 1.24 to 3.24, p=0.005). Practical issues related to travel were most important in those less willing to attend a hospital-based service, with 83.3% citing at least one travel related barrier to non-attendance. A convenient community-based screening programme may reduce inequalities in screening adherence especially in those at high risk of lung cancer in deprived areas.
Subject(s)
Delivery of Health Care/organization & administration , Early Detection of Cancer/methods , Lung Neoplasms/diagnostic imaging , Patient Preference/statistics & numerical data , Aged , Community Health Services/organization & administration , Early Detection of Cancer/statistics & numerical data , England , Female , Health Services Accessibility/statistics & numerical data , Humans , Male , Mass Screening/organization & administration , Middle Aged , Mobile Health Units/organization & administration , Patient Acceptance of Health Care/statistics & numerical data , Pilot Projects , Smoking/psychology , Socioeconomic Factors , Tomography, X-Ray ComputedABSTRACT
We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.
Subject(s)
Community Health Services/organization & administration , Early Detection of Cancer/methods , Lung Neoplasms/diagnostic imaging , Poverty Areas , Aged , Community Health Services/methods , England/epidemiology , Female , Health Services Accessibility , Humans , Lung Neoplasms/epidemiology , Lung Neoplasms/etiology , Male , Mass Screening/methods , Middle Aged , Mobile Health Units , Pilot Projects , Prevalence , Smoking/adverse effects , Tomography, X-Ray ComputedABSTRACT
We report results from the second annual screening round (T1) of Manchester's 'Lung Health Check' pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.
Subject(s)
Early Detection of Cancer/methods , Lung Neoplasms/diagnosis , Mass Screening/methods , Public Health , Smoking/adverse effects , Tomography, X-Ray Computed/methods , Aged , Female , Humans , Incidence , Lung Neoplasms/epidemiology , Male , Middle Aged , Pilot Projects , Smoking/epidemiology , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5â years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.
Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Small Cell/pathology , Early Detection of Cancer/methods , Lung Neoplasms/pathology , Sputum/cytology , Adenocarcinoma of Lung/complications , Adenocarcinoma of Lung/diagnostic imaging , Adenocarcinoma of Lung/pathology , Bronchoscopy , Carcinoma, Large Cell/complications , Carcinoma, Large Cell/diagnostic imaging , Carcinoma, Large Cell/pathology , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Small Cell/complications , Carcinoma, Small Cell/diagnostic imaging , Carcinoma, Squamous Cell/complications , Carcinoma, Squamous Cell/diagnostic imaging , Carcinoma, Squamous Cell/pathology , Cytological Techniques , Female , Humans , Lung Neoplasms/complications , Lung Neoplasms/diagnostic imaging , Male , Middle Aged , Neoplasm Staging , Optical Imaging , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/physiopathology , Risk Assessment , Sensitivity and Specificity , Tomography, X-Ray Computed , United KingdomABSTRACT
BACKGROUND: In the United States, lung cancer screening aims to detect cancer early in nonsymptomatic current and former smokers. A lung screening pilot service in an area of high lung cancer incidence in the United Kingdom has been designed based on United States trial evidence. However, our understanding of acceptability and reasons for lung screening uptake or decline in a United Kingdom nontrial context are currently limited. OBJECTIVE: To explore with ever smokers the acceptability of targeted lung screening and uptake decision-making intentions. DESIGN: Qualitative study using semistructured focus groups and inductive thematic analysis to explore acceptability and uptake decision-making intentions with people of similar characteristics to lung screening eligible individuals. SETTING AND PARTICIPANTS: Thirty-three participants (22 ex-smokers; 11 smokers) men and women, smokers and ex-smokers, aged 50-80 were recruited purposively from community and health settings in Manchester, England. RESULTS: Lung screening was widely acceptable to participants. It was seen as offering reassurance about lung health or opportunity for early detection and treatment. Participant's desire to know about their lung health via screening was impacted by perceived benefits; emotions such as worry about a diagnosis and screening tests; practicalities such as accessibility; and smoking-related issues including perceptions of individual risk and smoking stigma. DISCUSSION: Decision making was multifaceted with indications that current smokers faced higher participation barriers than ex-smokers. Reducing participation barriers through careful service design and provision of decision support information will be important in lung screening programmes to support informed consent and equitable uptake.
Subject(s)
Decision Making , Intention , Lung Neoplasms/diagnosis , Mass Screening/psychology , Smokers/psychology , Aged , Aged, 80 and over , Early Detection of Cancer , Female , Focus Groups , Humans , Male , Middle Aged , Qualitative ResearchABSTRACT
BACKGROUND: Preinvasive squamous cell cancer (PSCC) are local transformations of bronchial epithelia that are frequently observed in current or former smokers. Their different grades and sizes suggest a continuum of dysplastic change with increasing severity, which may culminate in invasive squamous cell carcinoma (ISCC). As a consequence of the difficulty in isolating cancerous cells from biopsies, the molecular pathology that underlies their histological variability remains largely unknown. METHOD: To address this issue, we have employed microdissection to isolate normal bronchial epithelia and cancerous cells from low- and high-grade PSCC and ISCC, from paraffin embedded (FFPE) biopsies and determined gene expression using Affymetric Human Exon 1.0 ST arrays. Tests for differential gene expression were performed using the Bioconductor package limma followed by functional analyses of differentially expressed genes in IPA. RESULTS: Examination of differential gene expression showed small differences between low- and high-grade PSCC but substantial changes between PSCC and ISCC samples (184 vs 1200 p-value <0.05, fc ±1.75). However, the majority of the differentially expressed PSCC genes (142 genes: 77%) were shared with those in ISCC samples. Pathway analysis showed that these shared genes are associated with DNA damage response, DNA/RNA metabolism and inflammation as major biological themes. Cluster analysis identified 12 distinct patterns of gene expression including progressive up or down-regulation across PSCC and ISCC. Pathway analysis of incrementally up-regulated genes revealed again significant enrichment of terms related to DNA damage response, DNA/RNA metabolism, inflammation, survival and proliferation. Altered expression of selected genes was confirmed using RT-PCR, as well as immunohistochemistry in an independent set of 45 ISCCs. CONCLUSIONS: Gene expression profiles in PSCC and ISCC differ greatly in terms of numbers of genes with altered transcriptional activity. However, altered gene expression in PSCC affects canonical pathways and cellular and biological processes, such as inflammation and DNA damage response, which are highly consistent with hallmarks of cancer.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Neoplasm Proteins/metabolism , Transcription Factors/metabolism , Transcriptome , Aged , Cells, Cultured , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Laser Capture Microdissection , Male , Middle Aged , Neoplasm Invasiveness , Tumor Cells, CulturedABSTRACT
The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Disease Progression , Lung Neoplasms/genetics , Antigens, Neoplasm , Biomarkers, Tumor/analysis , Drug Resistance, Neoplasm , Humans , Longitudinal Studies , Neoplasm Metastasis , Treatment OutcomeABSTRACT
This audit examined key performance indices related to endobronchial ultrasound (EBUS)-guided mediastinal lung cancer staging before and after the introduction of defined quality standards, at four independent EBUS centres in one cancer network. Data from 642 procedures were prospectively collected and analysed. The introduction of standards was associated with a significant increase (p<0.001) in sampling of key mediastinal lymph node stations (4R, 4L and 7) and a reduction in the variability of staging sensitivity between centres. These data reinforce the requirement for an appropriate regulatory framework for EBUS-transbronchial needle aspiration provision that includes quality assurance and performance monitoring.
Subject(s)
Bronchoscopy , Carcinoma, Non-Small-Cell Lung/pathology , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Mediastinal Neoplasms/pathology , Bronchoscopy/methods , Carcinoma, Non-Small-Cell Lung/diagnosis , Endoscopic Ultrasound-Guided Fine Needle Aspiration/standards , England , Humans , Mediastinal Neoplasms/diagnosis , Medical Audit , Neoplasm Staging , Predictive Value of Tests , Prospective Studies , Sensitivity and SpecificityABSTRACT
A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available.
Subject(s)
Antineoplastic Agents/therapeutic use , B7-H1 Antigen/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/diagnosis , Lung Neoplasms/diagnosis , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , B7-H1 Antigen/drug effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Humans , Immunohistochemistry , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Nivolumab , Programmed Cell Death 1 Receptor/drug effects , Programmed Cell Death 1 Receptor/metabolism , Quality ControlABSTRACT
BACKGROUND: Whilst there has been no clear consensus on the potential for earlier diagnosis of lung cancer, recent research has suggested that the time between symptom onset and consultation can be long enough to plausibly affect prognosis. In this article, we present findings from a qualitative study involving in-depth interviews with patients who had been diagnosed with lung cancer (n = 11), and people who were at heightened risk of developing the disease (n = 14). METHODS: A grounded theory methodology was drawn upon to conduct thematic and narrative based approaches to analysis. RESULTS: The paper focuses on three main themes which emerged from the study: i) fatalism and resignation in pathways to help-seeking and the process of diagnosis; ii) Awareness of smoking risk and response to cessation information and advice. iii) The role of social and other networks on help-seeking. Key findings included: poor awareness among participants of the symptoms of lung cancer; ambivalence about the dangers of smoking; the perception of lung cancer as part of a homogenisation of multiple illnesses; close social networks as a key trigger in help-seeking. CONCLUSIONS: We suggest that future smoking cessation and lung cancer awareness campaigns could usefully capitalise on the influence of close social networks, and would benefit from taking a 'softer' approach.
Subject(s)
Awareness , Health Knowledge, Attitudes, Practice , Lung Neoplasms , Patient Acceptance of Health Care , Smoking Cessation , Smoking Prevention , Social Environment , Aged , Female , Humans , Lung Neoplasms/etiology , Male , Middle Aged , Qualitative Research , Referral and Consultation , Smoking/adverse effects , Smoking Cessation/methodsABSTRACT
INTRODUCTION: Targeted low-dose CT lung cancer screening reduces lung cancer mortality. England's Targeted Lung Health Check programme uses risk prediction tools to determine eligibility for biennial screening among people with a smoking history aged 55-74. Some participants initially ineligible for lung cancer screening will later become eligible with increasing age and ongoing tobacco exposure. It is, therefore, important to understand how many people could qualify for reinvitation, and after how long, to inform implementation of services. METHODS: We prospectively predicted future risk (using Prostate, Lung, Colorectal and Ovarian trial's risk model (PLCOm2012) and Liverpool Lung Project version 2 (LLPv2) risk models) and time-to-eligibility of 5345 participants to estimate how many would become eligible through the course of a Lung Health Check screening programme for 55-74 years. RESULTS: Approximately a quarter eventually become eligible, with those with the lowest baseline risks unlikely to ever become eligible. Time-to-eligibility is shorter for participants with higher baseline risk, increasing age and ongoing smoking status. At a PLCOm2012 threshold ≥1.51%, 68% of those who continue to smoke become eligible compared with 18% of those who have quit. DISCUSSION: Predicting which participants may become eligible, and when, during a screening programme can help inform reinvitation strategies and service planning. Those with risk scores closer to the eligibility threshold, particularly people who continue to smoke, will reach eligibility in subsequent rounds while those at the lowest risk may be discharged from the programme from the outset.
Subject(s)
Early Detection of Cancer , Lung Neoplasms , Humans , Lung Neoplasms/diagnosis , Middle Aged , Male , Aged , Early Detection of Cancer/methods , Female , Tomography, X-Ray Computed , Prospective Studies , England/epidemiology , Smoking/epidemiology , Smoking/adverse effects , Risk Assessment , Eligibility Determination , Mass Screening/methods , Risk FactorsABSTRACT
BACKGROUND: Although previous studies have implicated tissue CD4(+) T cells in the development and maintenance of the inflammatory response in asthmatic patients, little is known about the role of CD8(+) T cells. There is now accumulating evidence that microRNAs and other noncoding RNAs are important regulators of T-cell function. OBJECTIVES: We sought to use transcriptomics to determine the activation state of circulating CD4(+) and CD8(+) T cells in patients with nonsevere and severe asthma. METHODS: mRNA and noncoding RNA expression in circulating T cells was measured by means of microarray, quantitative real-time PCR, or both. RESULTS: Comparison of mRNA expression showed widespread changes in the circulating CD8(+) but not CD4(+) T cells from patients with severe asthma. No changes were observed in the CD4(+) and CD8(+) T cells in patients with nonsevere asthma versus those in healthy control subjects. Bioinformatics analysis showed that the changes in CD8(+) T-cell mRNA expression were associated with multiple pathways involved in T-cell activation. As with mRNAs, we also observed widespread changes in expression of noncoding RNA species, including natural antisense, pseudogenes, intronic long noncoding RNAs (lncRNAs), and intergenic lncRNAs in CD8(+) T cells from patients with severe asthma. Measurement of the microRNA expression profile showed selective downregulation of miR-28-5p in CD8(+) T cells and reduction of miR-146a and miR-146b in both CD4(+) and CD8(+) T cells. CONCLUSIONS: Severe asthma is associated with the activation of circulating CD8(+) T cells but not CD4(+) T cells. This response is correlated with the downregulation of miR-146a/b and miR-28-5p, as well as changes in the expression of multiple species of lncRNA that might regulate CD8(+) T-cell function.