Search

Lung cancer is the leading cause of cancer death worldwide. The absence of symptoms in early-stage (I/II) disease, when curative treatment is possible, results in >70% of cases being diagnosed at late stage (III/IV), when treatment is rarely curative. This contributes greatly to the poor prognosis of lung cancer, which sees only 16.2% of individuals diagnosed with the disease alive at 5 years. Early detection is key to improving lung cancer survival outcomes. As a result, there has been longstanding interest in finding a reliable screening test. After little success with chest radiography and sputum cytology, in 2011 the United States National Lung Screening Trial demonstrated that annual low-dose computed tomography (LDCT) screening reduced lung cancer-specific mortality by 20%, when compared with annual chest radiography. In 2020, the NELSON study demonstrated an even greater reduction in lung cancer-specific mortality for LDCT screening at 0, 1, 3 and 5.5 years of 24% in men, when compared to no screening. Despite these impressive results, a call to arms in the 2017 European position statement on lung cancer screening (LCS) and the widespread introduction across the United States, there was, until recently, no population-based European national screening programme in place. We address the potential barriers and outstanding concerns including common screening foes, such as false-positive tests, overdiagnosis and the negative psychological impact of screening, as well as others more unique to LDCT LCS, including appropriate risk stratification of potential participants, radiation exposure and incidental findings. In doing this, we conclude that whilst the evidence generated from ongoing work can be used to refine the screening process, for those risks which remain, appropriate and acceptable mitigations are available, and none should serve as barriers to the implementation of national unified LCS programmes across Europe and beyond.

Background Lung cancer is the leading cause of cancer death in the world. A significant minority of lung cancer patients have never smoked (14% in the UK, and ranging from 10% to 25% worldwide). Current evidence suggests that never-smokers encounter delays during the diagnostic pathway, yet it is unclear how their experiences and reasons for delayed diagnoses differ from those of current and former smokers. This rapid review assessed literature about patient experiences in relation to symptom awareness and appraisal, help-seeking, and the lung cancer diagnostic pathway, comparing patients with and without a smoking history. Methods MEDLINE, PsychINFO and Google Scholar were searched for studies (2010-2020) that investigated experiences of the pathway to diagnosis for patients with and without a smoking history. Findings are presented using a narrative synthesis. Results Analysis of seven quantitative and three qualitative studies revealed that some delays during symptom appraisal and diagnosis are unique to never-smokers. Due to the strong link between smoking and lung cancer, and low awareness of non-smoking related lung cancer risk factors and symptoms, never-smokers do not perceive themselves to be at risk. Never-smokers are also likely to evaluate their experiences in comparison with other non-smoking related cancers, where prognosis is likely better, potentially leading to lower satisfaction with healthcare. Conclusion Never-smokers appear to have different experiences in relation to symptom appraisal and diagnosis. However, evidence in relation to help-seeking, and what is driving diagnostic delays for never-smoker patients specifically is lacking.

INTRODUCTION: Low-dose CT (LDCT) screening reduces lung cancer specific mortality. Several countries, including the UK, are evaluating the clinical impact and cost-effectiveness of LDCT screening using the latest evidence. In this paper we report baseline screening performance from five UK-based lung cancer screening programmes.METHODS: Data was collected at baseline from each screening programme. Measures of performance included prevalence of screen detected lung cancer, rate of surveillance imaging for indeterminate findings and surgical resection rates. Screening related harms were assessed by measuring false positive rates, number of invasive tests with associated complications in individuals without lung cancer and benign surgical resection rates.RESULTS: A total of 11,148 individuals had a baseline LDCT scan during the period of analysis (2011 to 2020). Overall, 84.7% (n = 9,440) of baseline LDCT scans were categorised as negative, 11.1% (n = 1,239) as indeterminate and 4.2% (n = 469) as positive. The prevalence of screen detected lung cancer was 2.2%, ranging between 1.8% and 4.4% for individual programmes. The surgical resection rate was 66% (range 46% to 83%) and post-surgical 90-day mortality for those with lung cancer 1.2% (n = 2/165). The false positive rate was 2% (n = 219/10,898) and of those with a positive result, one in two had lung cancer diagnosed (53.3%). An invasive test was required in 0.6% (n = 61/10,898) of screening attendees without lung cancer; there were no associated major complications or deaths. The benign surgical resection rate was 4.6% (n = 8/173), equating to 0.07% of the screened population.DISCUSSION: The performance of UK-based lung cancer screening programmes, delivered within or aligned to the National Health Service, compares favourably to published clinical trial data. Reported harms, including false positive and benign surgical resection rates are low. Ongoing monitoring of screening performance is vital to ensure standards are maintained and harms minimised.

Mesothelioma Most mesotheliomas originate in the pleura and are due to asbestos exposure. The incidence is decreasing somewhat with asbestos remediation, but mortality remains high in part because ...

Background: Programmed death-ligand 1 (PD-L1) expression on cancer cells is a clinically important biomarker to select patients with non-small cell lung cancer (NSCLC) for treatment with programmed death-1/PD-L1 inhibitors. Clinical trials of immunotherapy in patients with NSCLC have required histologic evidence for PD-L1 testing; in clinical practice, cytologic samples commonly are acquired in patients with advanced disease. Research Question: This study aims to investigate whether endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples are adequate for PD-L1 testing in NSCLC. Study Design and Methods: This study investigates the sampling adequacy of EBUS-TBNA for PD-L1 testing when compared with other methods. Furthermore, the relationship between clinicopathologic characteristics and PD-L1 expression in the study population have been examined. Five hundred seventy-seven NSCLC specimens were analyzed from consecutive patients with NSCLC across six centers in the United Kingdom and one center in the United States between January 2015 and December 2016. Results: In the EBUS-TBNA group (189 specimens), the overall percentage of patients with successful PD-L1 testing was 94.7%. There was no significant difference in sampling adequacy with other methods of tissue acquisition. Older patients had higher failure rates of PD-L1 testing (OR, 1.06; P =.008). In multivariate analysis, advanced N-stage (P =.048) and presence of brain metastasis (P

The Lung Screen Uptake Trial tested a novel invitation strategy to improve uptake and reduce socioeconomic and smoking-related inequalities in lung cancer screening (LCS) participation. It provides one of the first UK-based ‘real-world’ LCS cohorts. Of 2012 invited, 1058 (52.6%) attended a ‘lung health check’. 768/996 (77.1%) in the present analysis underwent a low-dose CT scan. 92 (11.9%) and 33 (4.3%) participants had indeterminate pulmonary nodules requiring 3-month and 12-month surveillance, respectively; 36 lung cancers (4.7%) were diagnosed (median follow-up: 1044 days). 72.2% of lung cancers were stage I/II and 79.4% of non-small cell lung cancer had curative-intent treatment.

Background The risks from potential exposure to coronavirus disease 2019 (COVID-19), and resource reallocation that has occurred to combat the pandemic, have altered the balance of benefits and harms that informed current (pre-COVID-19) guideline recommendations for lung cancer screening and lung nodule evaluation. Consensus statements were developed to guide clinicians managing lung cancer screening programs and patients with lung nodules during the COVID-19 pandemic. Methods An expert panel of 24 members, including pulmonologists (n = 17), thoracic radiologists (n = 5), and thoracic surgeons (n = 2), was formed. The panel was provided with an overview of current evidence, summarized by recent guidelines related to lung cancer screening and lung nodule evaluation. The panel was convened by video teleconference to discuss and then vote on statements related to 12 common clinical scenarios. A predefined threshold of 70% of panel members voting agree or strongly agree was used to determine if there was a consensus for each statement. Items that may influence decisions were listed as notes to be considered for each scenario. Results Twelve statements related to baseline and annual lung cancer screening (n = 2), surveillance of a previously detected lung nodule (n = 5), evaluation of intermediate and high-risk lung nodules (n = 4), and management of clinical stage I non–small-cell lung cancer (n = 1) were developed and modified. All 12 statements were confirmed as consensus statements according to the voting results. The consensus statements provide guidance about situations in which it was believed to be appropriate to delay screening, defer surveillance imaging of lung nodules, and minimize nonurgent interventions during the evaluation of lung nodules and stage I non–small-cell lung cancer. Conclusions There was consensus that during the COVID-19 pandemic, it is appropriate to defer enrollment in lung cancer screening and modify the evaluation of lung nodules due to the added risks from potential exposure and the need for resource reallocation. There are multiple local, regional, and patient-related factors that should be considered when applying these statements to individual patient care.

Rationale: Individuals eligible for lung cancer screening (LCS) by low-dose computed tomography (LDCT) are also at risk of chronic obstructive pulmonary disease (COPD) due to age and smoking exposure. Whether the LCS episode is useful for early detection of COPD is not well established. Objectives: To explore associations between symptoms, comorbidities, spirometry, and emphysema in participants enrolled in the Lung Screen Uptake Trial. Methods: This cross-sectional study was a prespecified analysis nested within Lung Screen Uptake Trial, which was a randomized study testing the impact of differing invitation materials on attendance of 60- to 75-year-old smokers and ex-smokers to a “lung health check” between November 2015 and July 2017. Participants with a smoking history ≥30 pack-years and who quit ≤15 years ago, or meeting a lung cancer risk of ≥1.51% via the Prostate Lung Colorectal Ovarian model or ≥2.5% via the Liverpool Lung Project model, were offered LDCT. COPD was defined and classified according to the GOLD (Global Initiative for Obstructive Lung Disease) criteria using prebronchodilator spirometry. Analyses included the use of descriptive statistics, chi-square tests to examine group differences, and univariable and multivariable logistic regression to explore associations between symptom prevalence, airflow limitation, and visually graded emphysema. Results: A total of 560 of 986 individuals included in the analysis (57%) had prebronchodilator spirometry consistent with COPD; 67% did not have a prior history of COPD and were termed “undiagnosed.” Emphysema prevalence in those with known and “undiagnosed” COPD was 73% and 68%, respectively. A total of 32% of those with “undiagnosed COPD” had no emphysema on LDCT. Inhaler use and symptoms were more common in the “known” than the “undiagnosed” COPD group (63% vs. 33% with persistent cough [P

Background MSCTRAIL is a cell-based therapy consisting of human allogeneic umbilical cord-derived MSCs genetically modified to express the anti-cancer protein TRAIL. Though cell-based therapies are typically designed with a target tissue in mind, delivery is rarely assessed due to a lack of translatable non-invasive imaging approaches. In this preclinical study, we demonstrate 89Zr-oxine labelling and PET-CT imaging as a potential clinical solution for non-invasively tracking MSCTRAIL biodistribution. Future implementation of this technique should improve our understanding of MSCTRAIL during its evaluation as a therapy for metastatic lung adenocarcinoma. Methods MSCTRAIL were radiolabelled with 89Zr-oxine and assayed for viability, phenotype, and therapeutic efficacy post-labelling. PET-CT imaging of 89Zr-oxine-labelled MSCTRAIL was performed in a mouse model of lung cancer following intravenous injection, and biodistribution was confirmed ex vivo. Results MSCTRAIL retained the therapeutic efficacy and MSC phenotype in vitro at labelling amounts up to and above those required for clinical imaging. The effect of 89Zr-oxine labelling on cell proliferation rate was amount- and time-dependent. PET-CT imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer up to 1 week post-injection, validated by in vivo bioluminescence imaging, autoradiography, and fluorescence imaging on tissue sections. Conclusions 89Zr-oxine labelling and PET-CT imaging present a potential method of evaluating the biodistribution of new cell therapies in patients, including MSCTRAIL. This offers to improve understanding of cell therapies, including mechanism of action, migration dynamics, and inter-patient variability.

Tobacco smoking causes lung cancer1–3, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA4,5. The profound effects of tobacco on the genome of lung cancer cells are well-documented6–10, but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4–14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0–6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis. Whole-genome sequencing of normal bronchial epithelium from 16 individuals shows that tobacco smoking increases genomic heterogeneity, mutational burden and driver mutations, whereas stopping smoking promotes replenishment of the epithelium with near-normal cells.

BackgroundLung squamous cell carcinoma (LUSC) accounts for a significant proportion of cancer deaths worldwide, and is preceded by the appearance of progressively disorganised pre-invasive lesions in the airway epithelium. Yet the biological mechanisms underlying progression of pre-invasive lesions into invasive LUSC are not fully understood. LRIG1 (leucine-rich repeats and immunoglobulin-like domains 1) is downregulated in pre-invasive airway lesions and invasive LUSC tumours and this correlates with decreased lung cancer patient survival.Methods and resultsUsing an Lrig1 knock-in reporter mouse and human airway epithelial cells collected at bronchoscopy, we show that during homeostasis LRIG1 is heterogeneously expressed in the airway epithelium. In basal airway epithelial cells, the suspected cell of origin of LUSC, LRIG1 identifies a subpopulation of progenitor cells with higher in vitro proliferative and self-renewal potential in both the mouse and human. Using the N-nitroso-tris-chloroethylurea (NTCU)-induced murine model of LUSC, we find that Lrig1 loss-of-function leads to abnormally high cell proliferation during the earliest stages of pre-invasive disease and to the formation of significantly larger invasive tumours, suggesting accelerated disease progression.ConclusionTogether, our findings identify LRIG1 as a marker of basal airway progenitor cells with high proliferative potential and as a regulator of pre-invasive lung cancer progression. This work highlights the clinical relevance of LRIG1 and the potential of the NTCU-induced LUSC model for functional assessment of candidate tumour suppressors and oncogenes.

P100 Table 1Factors influencing reduced utilisation of healthcare services during the covid-19 pandemicConclusions40% of individuals in a cohort at high risk of lung cancer and respiratory comorbidities reported reduced utilisation of health care services due to the COVID-19 pandemic.Limitations to our data include the lung health check questions not distinguishing between primary and secondary care or routine and urgent visits, and self-reported co-morbidity data limited to selected respiratory conditions. Nevertheless, we provide evidence for the scale of the problem and highlight that individuals with chronic respiratory conditions are particularly likely to be impacted.Please refer to page A193 for declarations of interest related to this abstract.

[No Abstract Available], Wellcome Trust [209553/Z/17/Z]; UCLH Biomedical Research Centre, This study was supported by Wellcome Trust grant 209553/Z/17/Z and the UCLH Biomedical Research Centre. Funding information for this article has been deposited with the Crossref Funder Registry.

Targeting early-stage lung cancer is vital to improve overall survival. We previously identified Toll-like receptor 2 (TLR2) as a regulator of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP), both key for tumor suppression. Here, we demonstrate that TLR2 is widely expressed in human lung tumor epithelium where it correlates with improved survival and clinical regression. Using genetically engineered mouse models of lung cancer we have shown that Tlr2 is a tumor suppressor in lung cancer initiation via regulation of proliferation and the SASP. The SASP is integral in the regulation of immune surveillance of premalignant cells, and we observe impaired myeloid derived immune surveillance following Tlr2 loss. Lastly, we show that administration of a synthetic Tlr2 agonist significantly reduces preinvasive lung tumor growth. Our data highlight an unexpected tumor surveillance pathway in early-stage lung cancer with therapeutic potential.Statement of significanceLung cancer is a major cancer of unmet need. This study identifies a novel tumor suppressor mechanism in lung cancer. Not only does this highlight a potential therapeutic target for early-stage disease but also multiple secreted candidate biomarkers that could be exploited to augment lung cancer screening approaches.

BACKGROUND: Whole-body MRI (WB-MRI) could be an alternative to multimodality staging of colorectal cancer, but its diagnostic accuracy, effect on staging times, number of tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in colorectal cancer.METHODS: The Streamline C trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed colorectal cancer. Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or polyp cancer. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs), and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN43958015, and is complete.FINDINGS: Between March 26, 2013, and Aug 19, 2016, 1020 patients were screened for eligibility. 370 patients were recruited, 299 of whom completed the trial; 68 (23%) had metastasis at baseline. Pathway sensitivity was 67% (95% CI 56 to 78) for WB-MRI and 63% (51 to 74) for standard pathways, a difference in sensitivity of 4% (-5 to 13, p=0·51). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (95% [95% CI 92-97]) and standard pathways (93% [90-96], p=0·48). Agreement with the multidisciplinary team's final treatment decision was 96% for WB-MRI and 95% for the standard pathway. Time to complete staging was shorter for WB-MRI (median, 8 days [IQR 6-9]) than for the standard pathway (13 days [11-15]); a 5-day (3-7) difference. WB-MRI required fewer tests (median, one [95% CI 1 to 1]) than did standard pathways (two [2 to 2]), a difference of one (1 to 1). Mean per-patient staging costs were £216 (95% CI 211-221) for WB-MRI and £285 (260-310) for standard pathways.INTERPRETATION: WB-MRI staging pathways have similar accuracy to standard pathways and reduce the number of tests needed, staging time, and cost.FUNDING: UK National Institute for Health Research.

Background: Type 2 alveolar epithelial cells (AEC2) are stem cells of the lung alveoli. Impaired renewal capacity of AEC2, the persistence of extracellular matrix producing myofibroblasts and the highly dysregulated cross-talk between these two cell types are key drivers in idiopathic pulmonary fibrosis (IPF). The potent profibrotic mediator TGFβ1 has been widely implicated in IPF pathogenesis. We have recently reported a key role for rapamycin-insensitive mTORC1 (mechanistic target of rapamycin complex 1) signalling in mediating TGFβ1-induced collagen deposition in primary human lung fibroblasts (pHLF), providing evidence supporting ATP-competitive mTOR inhibition (mTORi) as an anti-fibrotic strategy. Aims: To investigate the potential impact of mTORi on the alveolar epithelium and on epithelial regenerative capacity in the IPF lung. Methods and Results: We used a 3D in vitro model in which human alveolospheres were co-cultured with pHLF. When AEC2 were seeded with pHLFs pre-treated with TGFβ1 alone (p=0.0145), with the partial mTOR1 inhibitor rapamycin (100 nM) with (pl0.0001) or without (pl0.0001) TGFβ1, or with TGFβ1+mTORi (1 µM) (pl0.0001), significantly fewer alveolospheres were formed compared with AEC2 seeded with unstimulated pHLF. Repeated treatment of AEC2 and pHLF co-cultures with mTORi at days 1, 2.5, 5 and 10 post-seeding completely prevented alveolosphere formation at 1 µM and 300 nM, and significantly reduced their number at 100nM (pl0.0001). Treatment of mature alveolospheres at day 14 post-seeding did not impact alveolosphere numbers. Conclusions: These data suggest that fine modulation of TGFβ1-mTOR inhibition may be required in order to reduce collagen deposition without negatively impacting the regenerative capacity of the alveolar epithelium in IPF.

BackgroundNational targets for timely diagnosis and management of a potential cancer are driven in part by the perceived risk of disease progression during avoidable delays. However, it is unclear to what extent time-to-treatment impacts prognosis for patients with non-small cell lung cancer, with previous reviews reporting mixed or apparently paradoxical associations. This systematic review focuses on potential confounders in order to identify particular patient groups which may benefit most from timely delivery of care.MethodsMedline, EMBASE and Cochrane databases were searched for publications between January 2012 and October 2020, correlating timeliness in secondary care pathways to patient outcomes. The protocol is registered with PROSPERO (the International Prospective Register of Systematic Reviews; ID 99239). Prespecified factors (demographics, performance status, histology, stage and treatment) are examined through narrative synthesis.ResultsThirty-seven articles were included. All but two were observational. Timely care was generally associated with a worse prognosis in those with advanced stage disease (6/8 studies) but with better outcomes for patients with early-stage disease treated surgically (9/12 studies). In one study, patients with squamous cell carcinoma referred for stereotactic ablative radiotherapy benefited more from timely care, compared with patients with adenocarcinoma. One randomised controlled trial supported timeliness as being advantageous in those with stage I–IIIA disease.ConclusionThere are limitations to the available evidence, but observed trends suggest timeliness to be of particular importance in surgical candidates. In more advanced disease, survival trends are likely outweighed by symptom burden, performance status or clinical urgency dictating timeliness of treatment.

Lung cancer screening is effective if offered to people at increased risk of the disease. Currently, direct contact with potential participants is required for evaluating risk. A way to reduce the number of ineligible people contacted might be to apply risk-prediction models directly to digital primary care data, but model performance in this setting is unknown.MethodThe Clinical Practice Research Datalink, a computerised, longitudinal primary care database, was used to evaluate the Liverpool Lung Project V.2 (LLPv2) and Prostate Lung Colorectal and Ovarian (modified 2012) (PLCOm2012) models. Lung cancer occurrence over 5–6 years was measured in ever-smokers aged 50–80 years and compared with 5-year (LLPv2) and 6-year (PLCOm2012) predicted risk.ResultsOver 5 and 6 years, 7123 and 7876 lung cancers occurred, respectively, from a cohort of 842 109 ever-smokers. After recalibration, LLPV2 produced a c-statistic of 0.700 (0.694–0.710), but mean predicted risk was over-estimated (predicted: 4.61%, actual: 0.9%). PLCOm2012 showed similar performance (c-statistic: 0.679 (0.673–0.685), predicted risk: 3.76%. Applying risk-thresholds of 1% (LLPv2) and 0.15% (PLCOm2012), would avoid contacting 42.7% and 27.4% of ever-smokers who did not develop lung cancer for screening eligibility assessment, at the cost of missing 15.6% and 11.4% of lung cancers.ConclusionRisk-prediction models showed only moderate discrimination when applied to routinely collected primary care data, which may be explained by quality and completeness of data. However, they may substantially reduce the number of people for initial evaluation of screening eligibility, at the cost of missing some lung cancers. Further work is needed to establish whether newer models have improved performance in primary care data.

Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1. Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1-positive explants compared with 0% in BRCA1/MAD2L1-negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.

Introduction Lung cancer remains the leading cause of cancer related death globally. Low-dose CT (LDCT) screening of high-risk individuals reduces lung cancer specific mortality. An important requirement for any screening programme is to minimise harms, especially in those who do not have cancer. Data from randomised controlled trials is often used as the primary source from which to extrapolate risks of harm but they do not reflect modern, real-world practice. In this paper we present cumulative data on screening harms from five UK-based lung cancer screening programmes. Methods In the UK, several implementation pilots and research studies have demonstrated that screening can be successfully delivered within or aligned to the NHS. These include: UK Lung Cancer Screening Trial (UKLS), Lung Screen Uptake Trial, Manchester Lung Health Checks, Liverpool Healthy Lung Project and Nottingham Lung Health MOT.Most sites used BTS nodule management guidelines. Positive results were defined as those referred for more than a repeat LDCT. False positives were those positive screens without an eventual diagnosis of lung cancer. Harms were categorised according to the need for further imaging, invasive investigations and/or surgery. Complications were categorised as per the National Lung Screening Trial (NLST). Results A total of 11,815 screening LDCTs were performed across the five programmes (2016–2020). Overall, 85.5% of screening scans were categorised as negative, 10.5% as indeterminate and 4% as positive. Lung cancer detection was 2.1%, ranging from 1.7% to 4.4% across sites. The surgical resection rate was 66.0%. Details of the cumulative reported harms are summarised in table 1. Discussion This collaborative work provides up-to-date data on lung cancer screening performance and harms. The rate of positive (4%) and false positive (1.9%) screening results were significantly lower than NLST and the majority of European screening trials. Harms from investigation and treatment of non-malignant disease was minimised with no reported major complications or deaths. This provides reassurance that with the use of evidence-based practice and experienced MDTs, harms from false positive results can be minimised within screening. This information is important in the planning of larger scale implementation of lung cancer screening within the UK and beyond.

Introduction The SUMMIT Study aims to assess the implementation of Low-Dose Computed Tomography (LDCT) for lung cancer screening in a high-risk population and to validate a multi-cancer early detection blood test. LDCT results are communicated to participants and their GPs by standardised letter. We aim to evaluate the turnaround time from the scan report to the subsequent management and communication of results via letter. Methods Results are automatically sent to participants and GPs according to pre-defined management plans based on findings collected via proformatised radiology report. Possible outcomes from these reports are: urgent referrals for suspicious findings, nodule surveillance LDCT at 3 months, 12 month surveillance LDCT, or suitable for randomisation at Year 1 to annual or biennial LDCT (see figure 1). Participants with suspicious findings are reviewed by the study clinicians. Where appropriate an urgent referral to the participant’s local hospital is completed manually after discussion with the participant; the automated letters in these cases are delayed until contact is made with the participant and a clinical plan confirmed. Results We report outcomes from the first 11,551 SUMMIT Study participants with completed baseline LDCT reports. We aim to action results within 5 days: 11,319 (98.0%) of all results letters were mailed to participants and 11,423 (98.9%) to their GPs within 5 days. 645 (5.6%) participants required further review and consideration of an urgent referral. For these, 84.6% of results letters were mailed within 5 days, and 95.5% within 12 days. As expected, increased mailing times were observed in cases that were more complex, requiring liaison with an external clinical team or review of imaging at our internal weekly radiology meeting. Discussion Timely reporting of results is crucial in establishing wider roll-out of lung cancer screening in the UK. The vast majority of results are automated and are reliably sent as programmed. A minority require further clinical input and image review, prior to completion of an onwards referral. We demonstrate a scalable and feasible approach to feeding back results following LDCT.

Introduction Recent work has shown that tobacco smoke exposure increases the mutational burden and cell-to-cell mutational heterogeneity of the normal bronchial epithelium. However, smoking cessation allows the preferential expansion of low-mutant epithelial cells, which could be responsible for the decline in lung cancer risk on quitting smoking. Although less is understood about the nasal epithelium, the incidence of squamous cell cancer (SCC) in the nose is much lower than in the bronchi. Whether a difference in function or mutational burden underlies this variation is unknown. Methods Nasal brushings and endobronchial biopsies were enzymatically dissociated and underwent initial analysis by flow cytometry for expression of CK5, ITGA6, PDPN and NGFR (basal cell markers). Subsequently, single bronchial (n=152) and nasal epithelial (n=47) cells were flow-sorted and cultured from an ex-smoker to permit more detailed study of regional inter-cell variability and functionality. Index sorting was performed on the most relevant basal cell subpopulation marker PDPN. Single cells were clonally expanded in vitro and colony-forming efficiency and colony size were calculated. After expansion, DNA and RNA were isolated for downstream analysis. Results Flow cytometric analysis showed that CK5-positive basal cells constituted a similar proportion of the epithelial cell population in the nose and the bronchus (35% v. 30%, respectively, p=0.8). CK5-positive nasal basal cells compared with CK5-positive bronchial basal cells differed most in their expression of PDPN (6% v. 64% PDPN-positive, respectively, p=0.2). This was coupled with a lower median intensity of PDPN expression in nasal basal cells compared with bronchial basal cells (2437 v. 8434, respectively). Nasal epithelial cells showed lower colony-forming efficiency (15%) than bronchial epithelial cells (35%). In addition, the nasal clones that grew were significantly smaller in area than the bronchial clones (9.84 mm2 v. 13.26 mm2, respectively, p=0.0002). Conclusions The lower colony-forming efficiency, smaller colony size and lower expression of PDPN in the nasal epithelial population suggests nasal basal cells may have a lower stem cell capacity than their bronchial counterparts. Analysis of the mutational burden and transcriptomic profile of both populations is a crucial next step to understand the difference in incidence of SCC in these compartments.

Background Lung cancer is the leading cause of cancer related deaths worldwide. The value of targeting early stage disease has been widely recognised to improve survival. Oncogene-induced senescence (OIS) is a stress response instigated following the activation of oncogenes and is a well-known tumour suppressor mechanism. OIS is abundant in pre-invasive lesions in murine lung cancer models, however is lost during the progression to malignancy. We previously identified a regulatory role for Toll-like receptor 2 (TLR2) in OIS and expression of the senescence-associated secretory phenotype (SASP), however the functional relevance of this has yet to be established. Methods We used genetically engineered mouse (GEM) models of lung cancer (KrasLSL-G12D/+ and KrasLSL-G12D/+;TP53fl/fl) on both wild-type and Tlr2 null backgrounds. Lung specific activation of mutant KrasG12D and TP53 loss was achieved upon intranasal infection with Cre-recombinase expressing adenovirus. Tumour burden, senescence markers and SASP expression were assessed by immunohistochemistry. Immune cell recruitment was measured using flow cytometry on whole lung single cell suspensions from tumour bearing mice. The expression of Tlr2 and associated SASP components were measured in human pre-invasive lung cancer samples that either progressed to invasive malignancy or regressed to normal epithelium. Results Tlr2 loss was associated with an increased tumour burden and reduced survival in our GEM model. Furthermore, Tlr2 loss caused significantly reduced epithelial expression of key senescence markers and SASP factors. However, immune cell recruitment was not affected suggesting this effect was cell intrinsic. Inhalational administration of a synthetic TLR2 agonist (Pam2CSK4) significantly reduced tumour burden in our GEM model. Molecular profiling of bronchoscopic biopsies of human pre-invasive lung lesions revealed increased TLR2 and SASP expression in samples that did not progress to invasive malignancy, suggesting a tumour suppressor role for TLR2-SASP signalling in human lung cancer. Conclusions We have identified TLR2 as a potential tumour suppressor in lung cancer via regulation of the SASP. Furthermore, we have highlighted a novel therapeutic strategy for the treatment of early stage lung cancer. SASP factors are released into the bloodstream and are ideal candidate biomarkers of pre-invasive disease and thus could potentially aid in stratifying lung cancer screening populations.

Background Development of therapeutic approaches for rare respiratory diseases is hampered by the lack of systems that allow medium-to-high-throughput screening of fully differentiated respiratory epithelium from affected patients. This is a particular problem for primary ciliary dyskinesia (PCD), a rare genetic disease caused by mutations in genes that adversely affect ciliary movement and consequently mucociliary transport. Primary cell culture of basal epithelial cells from nasal brush biopsies followed by ciliated differentiation at the air–liquid interface (ALI) has proven to be a useful tool in PCD diagnostics but the technique's broader utility, including in pre-clinical PCD research, has been restricted by the limited number of basal cells that can be expanded from such biopsies. Methods We describe an immunofluorescence screening method, enabled by extensive expansion of basal cells from PCD patients and the directed differentiation of these cells into ciliated epithelium in miniaturised 96-well transwell format ALI cultures. As proof-of-principle, we performed a personalised investigation in a patient with a rare and severe form of PCD (reduced generation of motile cilia), in this case caused by a homozygous nonsense mutation in the MCIDAS gene. Results Initial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures. The screening system in our proof-of-principal investigation allowed drugs that induce translational readthrough to be evaluated alone or in combination with nonsense-mediated decay inhibitors. We observed restoration of basal body formation but not the generation of cilia in the patient's nasal epithelial cells in vitro. Conclusion Our study provides a platform for higher throughput analyses of airway epithelia that is applicable in a range of settings and suggests novel avenues for drug evaluation and development in PCD caused by nonsense mutations., Primary cell culture of nasal epithelial cells (including differentiation to multiciliated cells) from patients with primary ciliary dyskinesia enabled immunofluorescence-based screening in miniaturised air–liquid interface cultures https://bit.ly/3rjoxBF

The National Heart, Lung, and Blood Institute of the National Institutes of Health, together with the Longfonds BREATH consortium, convened a working group to review the field of lung regeneration and suggest avenues for future research. The meeting took place on May 22, 2019, at the American Thoracic Society 2019 conference in Dallas, Texas, United States, and brought together investigators studying lung development, adult stem-cell biology, induced pluripotent stem cells, biomaterials, and respiratory disease. The purpose of the working group was 1) to examine the present status of basic science approaches to tackling lung disease and promoting lung regeneration in patients and 2) to determine priorities for future research in the field.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Background: Idiopathic pulmonary fibrosis (IPF) and pleuroparenchymal fibroelastosis (PPFE) are known to have poor outcomes but detailed examinations of prognostic significance of an association between these morphologic processes are lacking. Methods: Retrospective observational study of independent derivation and validation cohorts of IPF populations. Upper-lobe PPFE extent was scored visually (vPPFE) as categories of absent, moderate, marked. Computerised upper-zone PPFE extent (cPPFE) was examined continuously and using a threshold of 2.5% pleural surface area. vPPFE and cPPFE were evaluated against 1-year FVC decline (estimated using mixed-effects models) and mortality. Multivariable models were adjusted for age, gender, smoking history, antifibrotic treatment and diffusion capacity for carbon monoxide. Findings: PPFE prevalence was 49% (derivation cohort, n = 142) and 72% (validation cohort, n = 145). vPPFE marginally contributed 3-14% to variance in interstitial lung disease (ILD) severity across both cohorts. In multivariable models, marked vPPFE was independently associated with 1-year FVC decline (derivation: regression coefficient 18.3, 95 CI 8.47-28.2%; validation: 7.51, 1.85-13.2%) and mortality (derivation: hazard ratio [HR] 7.70, 95% CI 3.50-16.9; validation: HR 3.01, 1.33-6.81). Similarly, continuous and dichotomised cPPFE were associated with 1-year FVC decline and mortality (cPPFE > 2.5% derivation: HR 5.26, 3.00-9.22; validation: HR 2.06, 1.28-3.31). Individuals with cPPFE > 2.5% or marked vPPFE had the lowest median survival, the cPPFE threshold demonstrated greater discrimination of poor outcomes at two and three years than marked vPPFE. Interpretation: PPFE quantification supports distinction of IPF patients with a worse outcome independent of established ILD severity measures. This has the potential to improve prognostic management and elucidate separate pathways of disease progression. Funding: This research was funded in whole or in part by the Wellcome Trust [209,553/Z/17/Z] and the NIHR UCLH Biomedical Research Centre, UK. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), Wellcome Trust [209553/Z/17/Z]; NIHR UCLH Biomedical Research Centre, UK; NIHR South-ampton Biomedical Research Centre; EPSRC [EP/M020533/1], This research was funded in whole or in part by the Wellcome Trust [209553/Z/17/Z]. For the purpose of open access, the author has applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission. This project, JJ, EG and SMJ were also supported by the NIHR UCLH Biomedical Research Centre, UK. MGJ and CB acknowledge the support of the NIHR South-ampton Biomedical Research Centre. EPSRC grant EP/M020533/1 helped support this work.

Image depicting all tumour‐derived components that can be detected in blood. Produced using BioRender., Lung cancer survival statistics are sobering with survival ranking among the poorest of all cancers despite the addition of targeted therapies and immunotherapies. However, improvements in tools for early detection hold promise. The Nederlands–Leuvens Longkanker Screenings Onderzoek (NELSON) trial recently corroborated the findings from the previous National Lung Screening Trial low‐dose Computerised Tomography (NLST) screening trial in reducing lung cancer mortality. Biomarker research and development is increasing at pace as the molecular life histories of lung cancers become further unravelled. Low‐dose CT screening (LDCT) is effective but targets only those at the highest risk and is burdensome on healthcare. An optimally designed CT screening programme at best will only detect a low proportion of overall lung cancers as only those at very high‐risk meet screening criteria. Biomarkers that help risk stratify suitable patients for LDCT screening, and those that assist in determining which LDCT detected nodules are likely to represent malignant disease are needed. Some biomarkers have been proposed as standalone lung cancer diagnosis tools. Bronchoscopy technology is improving, with better capacity to identify and obtain samples from early lung cancers. Clinicians need to be aware of each early lung cancer detection method’s inherent limitations. We anticipate that the future of early lung cancer diagnosis will involve a synergistic, multimodal approach, combining several early detection methods.

IntroductionLung cancer is the world’s leading cause of cancer death. Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the US National Lung Screening Trial. Here, we present the Yorkshire Lung Screening Trial (YLST), which will address key questions of relevance for screening implementation.Methods and analysisUsing a single-consent Zelen’s design, ever-smokers aged 55–80 years registered with a general practice in Leeds will be randomised (1:1) to invitation to a telephone-based risk-assessment for a Lung Health Check or to usual care. The anticipated number randomised by household is 62 980 individuals. Responders at high risk will be invited for LDCT scanning for lung cancer on a mobile van in the community. There will be two rounds of screening at an interval of 2 years. Primary objectives are (1) measure participation rates, (2) compare the performance of PLCOM2012(threshold ≥1.51%), Liverpool Lung Project (V.2) (threshold ≥5%) and US Preventive Services Task Force eligibility criteria for screening population selection and (3) assess lung cancer outcomes in the intervention and usual care arms. Secondary evaluations include health economics, quality of life, smoking rates according to intervention arm, screening programme performance with ancillary biomarker and smoking cessation studies.Ethics and disseminationThe study has been approved by the Greater Manchester West research ethics committee (18-NW-0012) and the Health Research Authority following review by the Confidentiality Advisory Group. The results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and on the YLST website.Trial registration numbersISRCTN42704678andNCT03750110.

Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the lungs with few treatment options. We recently reported loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptors 4 (DR4) and 5 (DR5). Using tissue microarray (TMAs) of tumour samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptors.BAP1knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wild-typeBAP1, but not catalytically-inactive mutantBAP1, reduced promoter activities ofDR4andDR5, suggesting deubiquinase activity plays an important role in the regulation of gene expression. Co-IP studies demonstrated direct binding of BAP1 and the transcription factor Ying Yang 1 (YY1) and ChIP assays revealed BAP1 and YY1 to be enriched in the promoter regions ofDR4andDR5. Notably, shRNA knockdown ofYY1also increased DR4 and DR5 expression, and sensitivity to TRAIL. These results demonstrate that BAP1 and YY1 together negatively regulate transcriptional activity of TRAIL receptors. BAP1 and YY1 may both therefore be strong therapeutic targets to enhance the efficacy of TRAIL-induced apoptosis.Statement of significanceWe describe how the most-frequently mutated tumour suppressor gene in mesothelioma regulates the response to TNF-related apoptosis-inducing ligand (TRAIL). These findings will accelerate a biomarker-driven cancer therapy.

Lung cancer kills an estimated 35 000 people in the UK every year. Despite the improvements in treating late-stage disease, lung cancer outcomes have changed little in the last 40 years. Low-dose CT (LDCT) screening for lung cancer reduces lung cancer mortality by 20%–24% and all-cause mortality by 7%.1 2 Lung cancer screening (LCS) however remains contentious, particularly how to implement it in an efficient and efficacious way. This contention extends to the potential costs of screening—financial to the National Health Service (NHS), and physical and psychological harms to patients. These concerns are particularly relevant to how we manage both the findings we aim to detect through screening (pulmonary nodules) and those we pick up inadvertently (incidental findings). The SUMMIT Study is the largest CT screening study in Europe and a key endpoint is detailing the feasibility of delivering CT screening across a complete population within the NHS. We present here SUMMIT’s approach to nodule and incidental findings management, a pragmatic model that is neither overly burdensome nor unsafe and provides a practical solution to some of the challenges of LDCT LCS. The SUMMIT study (ClinicalTrials.gov NCT03934866) is an LCS study recruiting individuals 55–77 years old at high risk of lung and other smoking-related cancers to LDCT screening. Its twin aims are to examine the performance of delivering an LDCT screening service for lung cancer to a high-risk population and to validate a cell-free nucleic acid blood test for detection of multiple cancers. The study began enrolment in April 2019 after the development of protocols for the management of pulmonary nodules and incidental findings that enabled a consistent approach to management across the entirety of the study (target recruitment of 25 000). The study aims to deliver a programme of LCS that is pragmatic, evidence-based, and practically deliverable by …

Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27–CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. Significance: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer. See related commentary by Krysan et al., p. 1442. This article is highlighted in the In This Issue feature, p. 1426

Summary Tobacco smoking causes lung cancer1–3, driven by the 60+ carcinogens in cigarette smoke that directly damage and mutate DNA4,5. The profound effects of tobacco on the lung cancer genome have been well documented6–10, but we lack equivalent data for normal bronchial cells. We sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutation burden, adding 1000-10,000+ mutations/cell, massively increasing both within-subject and between-subject variance, and generating several distinct signatures of substitutions and indels. A population of cells in subjects with smoking history had mutation burdens equivalent to that expected for never-smokers: these cells had less damage from tobacco-specific mutational processes, were four-fold more frequent in ex-smokers than current smokers, and had significantly longer telomeres than their more mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged never-smokers. In current smokers, ≥25% of cells carried driver mutations and 0-6% cells had 2 or even 3 drivers. Thus, tobacco smoking increases mutation burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.

Development of therapeutic approaches for rare respiratory diseases is hampered by the lack of systems that allow medium-to-high-throughput screening of fully differentiated respiratory epithelium from affected patients. This is a particular problem for primary ciliary dyskinesia (PCD), a rare genetic disease caused by mutations in genes that adversely affect ciliary movement and consequently mucociliary transport. Primary cell culture of basal epithelial cells from nasal brush biopsies, followed by ciliated differentiation at air-liquid interface (ALI) has proven to be a useful tool in PCD diagnostics but the technique’s broader utility, including in pre-clinical PCD research, has been limited by the number of basal cells that it is possible to expand from such biopsies. Here, we describe a high-content, imaging-based screening method, enabled by extensive expansion of PCD patient basal cells and their culture into differentiated human respiratory epithelium in miniaturised 96-well transwell format ALI cultures. Analyses of ciliary beat pattern, beat frequency and ultrastructure indicate that a range of different PCD defects are retained in these cultures. We perform a proof-of-principle personalized investigation in reduced generation of motile cilia (RGMC), a rare and very severe form of PCD, in this case caused by a homozygous nonsense mutation (c.441C>A; p.Cys147*) in theMCIDASgene. The screening system allowed multiple drugs inducing translational readthrough to be evaluated alone or in combination with inhibitors of nonsense-mediated decay. Restoration of basal body formation in the patient’s nasal epithelial cells was seenin vitro, suggesting a novel avenue for drug evaluation and development in PCD.SummaryWe describe primary cell culture of nasal epithelial cells from patients with primary ciliary dyskinesia including differentiatiation of these to a ciliary phenotype and high-content screening in miniaturised air-liquid interface cultures.

Introduction: Whole body magnetic resonance imaging (WB-MRI) may be more efficient in staging cancers, but can be harder for patients to tolerate. We examined predictors of patient preference for WB-MRI vs. CT/ PET-CT for staging colorectal or lung cancer. Methods: Patients recruited prospectively to two multicenter trials comparing diagnostic accuracy of WB-MRI with standard staging scans were sent two questionnaires: the first, administered at trial registration, captured demographics, educational level, and comorbidities; the second, administered after staging completion, measured emotional distress (GHQ-12), positive mood (PANAS), perceived scan burden, patients’ beliefs about WB-MRI, and preference for either WB-MRI or CT (colorectal trial), WB-MRI or PET-CT (lung trial). Preference for WB-MRI or CT / PET-CT were analysed using logistic regression. Results: Baseline and post-staging questionnaires were completed by 97 and 107 patients respectively. Overall, 56/107 (52%) preferred WB-MRI over standard scans, and were more likely to have no additional comorbidities, higher positive mood, greater awareness of potential benefits of WB-MRI, and lower levels of perceived WB-MRI scan burden. In adjusted analyses, only awareness of potential WB-MRI benefits remained a significant predictor (OR: 1.516, 95% CIs 1.006 to 2.284, p=0.047). Knowledge that WB-MRI does not use radiation predicted preference (adjusted OR: 3.018, 95% CIs 1.099 to 8.288, p=0.032), yet only 45/107 (42%) patients were aware of this attribute. Conclusions: A small majority of patients undergoing staging of colorectal or lung cancer prefer WB-MRI to CT/ PET-CT. Raising awareness of the potential benefits of WB-MRI, notably lack of ionising radiation, could influence preference.

Two large-scale RCTs have shown Computed Tomography (CT) lung cancer screening to be efficacious in reducing lung cancer mortality (8-24% in men, versus 26-59% in women). However, implementation is likely to be limited, slow and of variable quality throughout Europe, because of important remaining uncertainties, which have been incompletely addressed or not at all so far. Our 4-IN-THE-LUNG-RUN (TOWARDS INDIVIDUALLY TAILORED INVITATIONS, SCREENING INTERVALS, AND INTEGRATED CO-MORBIDITY REDUCING STRATEGIES IN LUNG CANCER SCREENING) proposal is the first multi-centered implementation trial on volume CT lung cancer screening amongst 26,000 males and females, at high risk for developing lung cancer, across five European countries. Main objective is to assess whether lung cancer stage I/II is comparable between personalized screening (biennial) and annual screening in baseline test negatives (24,000; 1:1). We envisage that with the answers to key questions established by this trial, many European citizens will swiftly benefit from this high-quality screening technology, others will face less harms than previously anticipated, and health care costs will be reduced to a large extent. 4-IN-THE-LUNG-RUN is performed by a multidisciplinary consortium of leading experts in the field of population-based cancer screening (NELSON, UKLS, ITALUNG, LUSI), CT imaging, biomarkers, treatment, modelling, and understanding health behaviour, and in both new and existing high quality centres. Aim of the presentation is to introduce the study design, the eligibility for participating in the trial and mentioning the challenges in the recruitment, smoking cessation, and CAC research.

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non–small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. Significance: This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution. This article is highlighted in the In This Issue feature, p. 2355

Molecular characterization of non-small cell lung cancer (NSCLC) and implications for treatment and prognosis are increasingly important. Selection of molecularly targeted systemic therapy is commonly based on clonal oncogenic drivers of which epidermal growth factor receptor ( EGFR ) and the fusion gene echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase ( EMLA4-ALK ) are examples established in clinical practice. The former, found in approximately 10–15% of patients with NSCLC in the western world, is more prevalent in adenocarcinoma, non/light smokers, younger females, and patients of far eastern descent (1). Patients with EMLA4-ALK translocated tumors share similar clinical characteristics but are less prevalent (2). Several other rarer candidate driver mutations, including ROS proto-oncogene 1, receptor tyrosine kinase ( ROS-1 ), are also implicated in NSCLC (3).

Purpose To describe the radiological findings of radiation-induced lung damage (RILD) present on CT imaging of lung cancer patients 12 months after radical chemoradiation. Material and methods Baseline and 12-month CT scans of 33 patients were reviewed from a phase I/II clinical trial of isotoxic chemoradiation (IDEAL CRT). CT findings were scored in three categories derived from eleven sub-categories: (1) parenchymal change, defined as the presence of consolidation, ground-glass opacities (GGOs), traction bronchiectasis and/or reticulation; (2) lung volume reduction, identified through reduction in lung height and/or distortions in fissures, diaphragm, anterior junction line and major airways anatomy, and (3) pleural changes, either thickening and/or effusion. Results Six patients were excluded from the analysis due to anatomical changes caused by partial lung collapse and abscess. All remaining 27 patients had radiological evidence of lung damage. The three categories, parenchymal change, shrinkage and pleural change were present in 100%, 96% and 82% respectively. All patients had at least two categories of change present and 72% all three. GGOs, reticulation and traction bronchiectasis were present in 44%, 52% and 37% of patients. Conclusions Parenchymal change, lung shrinkage and pleural change are present in a high proportion of patients and are frequently identified in RILD. GGOs, reticulation and traction bronchiectasis are common at 12 months but not diagnostic.

The results of the Dutch-Belgian low-dose CT (LDCT) screening trial (NELSON) have been eagerly awaited since the US National Lung Screening Trial (NLST), published in 2011, demonstrated annual LDCT screening of the chest led to a 20% decrease in lung cancer mortality compared with chest X-ray screening.1 While the US Preventative Service Task Force approved lung cancer screening in 2014,2 Europe and the rest of the globe have been paralysed by fear of implementation costs and the feasibility of introducing national LDCT screening programmes. The consensus from healthcare payers outside of the USA has been that we should wait for the results of the NELSON trial which, while smaller in size, would give us the confidence of a second randomised controlled trial and proof of effect in a population outside of the US healthcare system. Indeed, a recent Health Technology Assessment of LDCT screening in the UK specifically named the NELSON trial as an important source of future information and explicitly stated the results were required in order to make a decision about its efficacy and cost-effectiveness.3 It was on this background of hope and perhaps, dare we say it, healthcare payer fear that the NELSON trial preliminary results were released at the World Conference on Lung Cancer in Toronto in October. Despite NELSON being smaller in size than NLST and having a preponderance of male participants, the results were clear: LDCT screening compared with no screening leads to a statistically significant lung cancer mortality reduction of 26% for men and numbers hint that the benefit could be even greater in women (between 40% and 60%). With this new data the UK, and indeed the world outside of the USA, now needs to cast aside concerns over efficacy, as well as procrastination over implementation, and concentrate more …

Objectives/hypothesis Despite surgical advances, childhood tracheal stenosis is associated with high morbidity and mortality. Various tracheal scaffold strategies have been developed as the basis for bioengineered substitutes, but there is no consensus on which may be superior in vivo. We hypothesized that there would be no difference in morbidity and mortality between three competing scaffold strategies in rabbits. Study design Pilot preclinical study. Methods Tracheal scaffolds were prepared by three methods that have been applied clinically and reported: preserved cadaveric ("Herberhold") allografts, detergent-enzymatically decellularized allografts, and synthetic scaffolds (nanocomposite polymer [polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU)]). Scaffolds were implanted into cervical trachea of New Zealand White rabbits (n = 4 per group) without cell seeding. Control animals (n = 4) received autotransplanted tracheal segments using the same technique. Animals underwent bronchoscopic monitoring of the grafts for 30 days. Macroscopic evaluation of tissue integration, graft stenosis, and collapsibility and histological examinations were performed on explants at termination. Results All surgical controls survived to termination without airway compromise. Mild to moderate anastomotic stenosis from granulation tissue was detected, but there was evidence suggestive of vascular reconnection with minimal fibrous encapsulation. In contrast, three of the four animals in the Herberhold and POSS-PCU groups, and all animals receiving decellularized allografts, required early termination due to respiratory distress. Herberhold grafts showed intense inflammatory reactions, anastomotic stenoses, and mucus plugging. Synthetic graft integration and vascularization were poor, whereas decellularized grafts demonstrated malacia and collapse but had features suggestive of vascular connection or revascularization. Conclusions There are mirror-image benefits and drawbacks to nonrecellularized, decellularized, and synthetic grafts, such that none emerged as the preferred option. Results from prevascularized and/or cell-seeded grafts (as applied clinically) may elucidate clearer advantages of one scaffold type over another. Level of evidence NA. Laryngoscope, 127:E449-E457, 2017.

Background: \ud Among patients with non–small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.\ud \ud Methods: \ud In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.\ud \ud Results: \ud We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10−4), which remained significant in multivariate analysis.\ud \ud Conclusions: \ud Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601.)

Tracheal replacement for the treatment of end-stage airway disease remains an elusive goal. The use of tissue-engineered tracheae in compassionate use cases suggests that such an approach is a viable option. Here, a stem cell-seeded, decellularized tissue-engineered tracheal graft was used on a compassionate basis for a girl with critical tracheal stenosis after conventional reconstructive techniques failed. The graft represents the first cell-seeded tracheal graft manufactured to full good manufacturing practice (GMP) standards. We report important preclinical and clinical data from the case, which ended in the death of the recipient. Early results were encouraging, but an acute event, hypothesized to be an intrathoracic bleed, caused sudden airway obstruction 3 weeks post-transplantation, resulting in her death. We detail the clinical events and identify areas of priority to improve future grafts. In particular, we advocate the use of stents during the first few months post-implantation. The negative outcome of this case highlights the inherent difficulties in clinical translation where preclinical in vivo models cannot replicate complex clinical scenarios that are encountered. The practical difficulties in delivering GMP grafts underscore the need to refine protocols for phase I clinical trials.

Introduction The NLST and NELSON studies demonstrated lung cancer mortality reduction from low-dose CT (LDCT) lung cancer screening. Local implementation pilots of ‘Lung Health Checks’ indicate feasibility in the NHS. NHS England will now fund 10 aligned projects for a national Lung Health Check pilot as a major centre-piece of the early diagnosis agenda of the NHS Long Term Plan. We report on methodological approaches to deliver this project and progress towards deployment. Methods Sites selected from Clinical Commissioning Groups in 10 Cancer Alliances had highest incidence and mortality from lung cancer, excluding those where screening pilots or research projects were already underway. Approximately 600,000 individuals will be invited with an expected 200,000 scans over the next four years, including baseline and 24 month incident round scanning. To support quality and governance, NHS England published a National Protocol (January 2019), are developing a Quality Assurance Framework, minimum dataset, Incidental Findings Protocol and Research Standard (assisted by CRUK). NHSE are supported by the CT Screening Advisory Committee, a sub-group of the Clinical Expert Group for Lung Cancer, NHSE. Cancer Alliances are being assisted in developing detailed delivery plans by the National Cancer Programme team. Results Detailed delivery plans have been provided by all regions. 47 radiologists will attend a national education program with clearly defined metrics for a national quality assurance training standard including volumetry and computer-aided detection. Standard participant materials are in production and QA evaluator appointed. Data on infrastructure readiness, progress against delivery milestones and final supporting documents relating to quality and governance will be presented. Conclusions The Lung Health Check program will be a major national flagship for respiratory medicine and a key component of the Long Term Plan aspirations to achieve early stage diagnosis in 75% of cancer cases. The program will inform the international literature on implementation of potentially revolutionary lung cancer screening but careful adherence to QA and demonstration of efficacy through appropriate evaluation is critical. Potential barriers include participant uptake; workforce capacity and data flow/information governance. The Standard Protocol is already being used by several European countries as a template for local protocol development. On behalf of the CT Screening Advisory Group, Clinical Expert Group for Lung Cancer and NHS England National Cancer Team.

Before squamous cell lung cancer develops, pre-cancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. While recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of pre-cancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in-situ lesions harbour more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, TGF-beta signalling is overactive, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the CIS lesions as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. This study identifies mechanisms by which pre-cancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early stage lung cancer.

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 5 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., While low-dose CT is now preferred for lung cancer screening, our randomised trial of smokers with COPD showed that a proposed sequential policy using sputum testing to select who receives low-dose CT and autofluorescence bronchoscopy was ineffective http://bit.ly/2JZujnx

PurposeMSCTRAIL is a new stem cell-based therapy for lung cancer, currently in phase I evaluation (ClinicalTrials.gov ref: NCT03298763). Biodistribution of cell therapies is rarely assessed in clinical trials, despite cell delivery to the target site often being critical to presumed mechanism of action. This preclinical study demonstrates that MSCTRAIL biodistribution dynamics can be detected non-invasively using 89Zr-oxine labelling and PET imaging, thus supporting use of this cell tracking technology in phase II evaluation.MethodsMSCTRAIL were radiolabelled with a range of 89Zr-oxine doses, and assayed for cell viability, phenotype and therapeutic efficacy post-labelling. Cell biodistribution was imaged in a mouse model of lung cancer using PET imaging and bioluminescence imaging (BLI) to confirm cell viability and location in vivo up to 1 week post-injection.ResultsMSCTRAIL retained therapeutic efficacy and MSC phenotype at doses up to and above those required for clinical imaging. The effect of 89Zr-oxine labelling on cell proliferation rate was dose and time-dependent. PET imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer, with PET signal correlating with the presence of viable cells as assessed by bioluminescence imaging, ex vivo autoradiography and matched fluorescence imaging on lung tissue sections. Human dosimetry estimates were produced using simulations and preclinical biodistribution data.Conclusion89Zr-oxine labelling and PET imaging present an attractive method of evaluating the biodistribution of new cell-therapies, such as MSCTRAIL. This offers to improve understanding of mechanism of action, migration dynamics and interpatient variability of MSCTRAIL and other cell-based therapies.