266 results found
Barnett JL, Maher TM, Quint JK, et al., 2023, Combination of Bronchoalveolar Lavage and CT Differentiates Progressive and Non-Progressive Fibrotic Lung Diseases., Am J Respir Crit Care Med
RATIONALE: Identifying patients with pulmonary fibrosis (PF) at risk of progression can guide management. We explore the utility of combining baseline bronchoalveolar lavage (BAL) and CT in differentiating progressive and non-progressive PF. METHODS: The derivation cohort consisted of incident cases of PF, for whom BAL was performed as part of diagnostic work-up. A validation cohort were prospectively recruited with identical inclusion criteria. Baseline thoracic CTs were scored for fibrosis extent and UIP pattern. BAL lymphocyte proportion was recorded. Annualized forced vital capacity decline >10% or death within one year defined disease progression. Multivariable logistic regression identified determinants of outcome. Optimum binary thresholds (maximal Wilcoxon rank statistic) at which CT fibrosis extent and BAL lymphocyte proportion could distinguish disease progression were identified. RESULTS: BAL lymphocyte proportion, UIP pattern and fibrosis extent were significantly and independently associated with disease progression in the derivation cohort (n=240 individuals). Binary thresholds for raised BAL lymphocyte proportion and extensive fibrosis were identified as 25% and 20% respectively. Raised BAL lymphocyte proportion was rare in patients with a UIP pattern (8/135[5.9%]) or with extensive fibrosis (7/144[4.9%]). In the validation cohort (n=290 subjects), a raised BAL lymphocyte proportion was associated with a significantly lower probability of disease progression in patients with non-extensive fibrosis or a non-UIP pattern. CONCLUSIONS: BAL lymphocytosis is rare in patients with extensive fibrosis or a UIP pattern on CT. In patients without a UIP pattern or with limited fibrosis, a BAL lymphocyte proportion of ≥ 25% was associated with a lower likelihood of progression.
Tisi S, Creamer AW, Dickson J, et al., 2023, Prevalence and clinical characteristics of non-malignant CT detected incidental findings in the SUMMIT lung cancer screening cohort., BMJ Open Respir Res, Vol: 10
BACKGROUND: Pulmonary and extrapulmonary incidental findings are frequently identified on CT scans performed for lung cancer screening. Uncertainty regarding their clinical significance and how and when such findings should be reported back to clinicians and participants persists. We examined the prevalence of non-malignant incidental findings within a lung cancer screening cohort and investigated the morbidity and relevant risk factors associated with incidental findings. We quantified the primary and secondary care referrals generated by our protocol. METHODS: The SUMMIT study (NCT03934866) is a prospective observational cohort study to examine the performance of delivering a low-dose CT (LDCT) screening service to a high-risk population. Spirometry, blood pressure, height/weight and respiratory history were assessed as part of a Lung Health Check. Individuals at high risk of lung cancer were offered an LDCT and returned for two further annual visits. This analysis is a prospective evaluation of the standardised reporting and management protocol for incidental findings developed for the study on the baseline LDCT. RESULTS: In 11 115 participants included in this analysis, the most common incidental findings were coronary artery calcification (64.2%) and emphysema (33.4%). From our protocolised management approach, the number of participants requiring review for clinically relevant findings in primary care was 1 in 20, and the number potentially requiring review in secondary care was 1 in 25. CONCLUSIONS: Incidental findings are common in lung cancer screening and can be associated with reported symptoms and comorbidities. A standardised reporting protocol allows systematic assessment and standardises onward management.
Denton CP, Goh NS, Humphries SM, et al., 2023, Extent of fibrosis and lung function decline in patients with systemic sclerosis and interstitial lung disease: data from the SENSCIS trial, Rheumatology, Vol: 62, Pages: 1870-1876, ISSN: 1462-0324
OBJECTIVE: To assess associations between the extent of fibrotic interstitial lung disease (ILD) and forced vital capacity (FVC) at baseline and change in FVC over 52 weeks in patients with systemic sclerosis-associated ILD (SSc-ILD) in the SENSCIS trial. METHODS: We used generalised additive models, which involve few assumptions and allow for interaction between non-linear effects, to assess associations between the extent of fibrotic ILD on high-resolution computed tomography (HRCT), and the interplay of extent of fibrotic ILD on HRCT and FVC % predicted, at baseline and FVC decline over 52 weeks. RESULTS: In the placebo group (n = 288), there was weak evidence of a modest association between a greater extent of fibrotic ILD at baseline and a greater decline in FVC % predicted at week 52 (r: -0.09 [95% CI -0.2, 0.03]). Higher values of both the extent of fibrotic ILD and FVC % predicted at baseline tended to be associated with greater decline in FVC % predicted at week 52. In the nintedanib group (n = 288), there was no evidence of an association between the extent of fibrotic ILD at baseline and decline in FVC % predicted at week 52 (r: 0.01 [95% CI: -0.11, 0.12]) or between the interplay of extent of fibrotic ILD and FVC % predicted at baseline and decline in FVC % predicted at week 52. CONCLUSION: Data from the SENSCIS trial suggest that patients with SSc-ILD are at risk of ILD progression and benefit from nintedanib largely irrespective of their extent of fibrotic ILD at baseline. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02597933.
O'Dowd EL, Lee RW, Akram AR, et al., 2023, Defining the road map to a UK national lung cancer screening programme., Lancet Oncol, Vol: 24, Pages: e207-e218
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.
Martínez-Ruiz C, Black JRM, Puttick C, et al., 2023, Genomic-transcriptomic evolution in lung cancer and metastasis., Nature, Vol: 616, Pages: 543-552
Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
Abbosh C, Frankell AM, Harrison T, et al., 2023, Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA., Nature, Vol: 616, Pages: 553-562
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.
Al-Sawaf O, Weiss J, Skrzypski M, et al., 2023, Body composition and lung cancer-associated cachexia in TRACERx., Nat Med, Vol: 29, Pages: 846-858
Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.
Al Bakir M, Huebner A, Martínez-Ruiz C, et al., 2023, The evolution of non-small cell lung cancer metastases in TRACERx., Nature, Vol: 616, Pages: 534-542
Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.
Karasaki T, Moore DA, Veeriah S, et al., 2023, Evolutionary characterization of lung adenocarcinoma morphology in TRACERx., Nat Med, Vol: 29, Pages: 833-845
Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.
A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.
Frankell AM, Dietzen M, Al Bakir M, et al., 2023, The evolution of lung cancer and impact of subclonal selection in TRACERx., Nature, Vol: 616, Pages: 525-533
Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.
Ng KW, Boumelha J, Enfield KSS, et al., 2023, Antibodies against endogenous retroviruses promote lung cancer immunotherapy., Nature, Vol: 616, Pages: 563-573
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
Dintakurti SH, Kamath S, Mahon C, et al., 2023, Pulmonary hypertension: the hallmark of acute COVID-19 microvascular angiopathy?, ERJ Open Research, Vol: 9, Pages: 1-4, ISSN: 2312-0541
Williams PJ, Philip KEJ, Gill NK, et al., 2023, Immediate, remote smoking cessation intervention in participants undergoing a targeted lung health check: quit smoking lung health intervention trial, a randomized controlled trial, Chest, Vol: 163, Pages: 455-463, ISSN: 0012-3692
BACKGROUND: Lung cancer screening programs provide an opportunity to support people who smoke to quit, but the most appropriate model for delivery remains to be determined. Immediate face-to-face smoking cessation support for people undergoing screening can increase quit rates, but it is not known whether remote delivery of immediate smoking cessation counselling and pharmacotherapy in this context also is effective. RESEARCH QUESTION: Does an immediate telephone smoking cessation intervention increase quit rates compared with usual care among a population enrolled in a targeted lung health check (TLHC)? STUDY DESIGN AND METHODS: In a single-masked randomized controlled trial, people 55 to 75 years of age who smoke and attended a TLHC were allocated by day of attendance to receive either immediate telephone smoking cessation intervention (TSI) support (starting immediately and lasting for 6 weeks) with appropriate pharmacotherapy or usual care (UC; very brief advice to quit and signposting to smoking cessation services). The primary outcome was self-reported 7-day point prevalence smoking abstinence at 3 months. Differences between groups were assessed using logistic regression. RESULTS: Three hundred fifteen people taking part in the screening program who reported current smoking with a mean ± SD age of 63 ± 5.4 years, 48% of whom were women, were randomized to TSI (n = 152) or UC (n = 163). The two groups were well matched at baseline. Self-reported quit rates were higher in the intervention arm, 21.1% vs 8.9% (OR, 2.83; 95% CI, 1.44-5.61; P = .002). Controlling for participant demographics, neither baseline smoking characteristics nor the discovery of abnormalities on low-dose CT imaging modified the effect of the intervention. INTERPRETATION: Immediate provision of an intensive telephone-based smoking cessation intervention, delivered within a targeted lung screening context, is associated with incr
Bhamani A, Horst C, Bojang F, et al., 2023, The SUMMIT Study: Utilising a written 'Next Steps' information booklet to prepare participants for potential lung cancer screening results and follow-up, LUNG CANCER, Vol: 176, Pages: 75-81, ISSN: 0169-5002
Dickson JL, Hall H, Horst C, et al., 2023, Uptake of invitations to a lung health check offering low-dose CT lung cancer screening among an ethnically and socioeconomically diverse population at risk of lung cancer in the UK (SUMMIT): a prospective, longitudinal cohort study., Lancet Public Health, Vol: 8, Pages: e130-e140
BACKGROUND: Lung cancer screening with low-dose CT reduces lung cancer mortality, but screening requires equitable uptake from candidates at high risk of lung cancer across ethnic and socioeconomic groups that are under-represented in clinical studies. We aimed to assess the uptake of invitations to a lung health check offering low-dose CT lung cancer screening in an ethnically and socioeconomically diverse cohort at high risk of lung cancer. METHODS: In this multicentre, prospective, longitudinal cohort study (SUMMIT), individuals aged 55-77 years with a history of smoking in the past 20 years were identified via National Health Service England primary care records at practices in northeast and north-central London, UK, using electronic searches. Eligible individuals were invited by letter to a lung health check offering lung cancer screening at one of four hospital sites, with non-responders re-invited after 4 months. Individuals were excluded if they had dementia or metastatic cancer, were receiving palliative care or were housebound, or declined research participation. The proportion of individuals invited who responded to the lung health check invitation by telephone was used to measure uptake. We used univariable and multivariable logistic regression analyses to estimate associations between uptake of a lung health check invitation and re-invitation of non-responders, adjusted for sex, age, ethnicity, smoking, and deprivation score. This study was registered prospectively with ClinicalTrials.gov, NCT03934866. FINDINGS: Between March 20 and Dec 12, 2019, the records of 2 333 488 individuals from 251 primary care practices across northeast and north-central London were screened for eligibility; 1 974 919 (84·6%) individuals were outside the eligible age range, 7578 (2·1%) had pre-existing medical conditions, and 11 962 (3·3%) had opted out of particpation in research and thus were not invited. 95 297 individuals were eligible for invitation
Sheeka A, Singaravelou A, Bartlett E, et al., 2023, COVID-protected pathways for image-guided lung cancer intervention during the COVID-19 pandemic: A cohort study., Br J Radiol, Vol: 96
OBJECTIVES: To compare the experience of COVID-protected and mixed cohort pathways in COVID-19 transmission at a tertiary referral hospital for elective CT-guided lung biopsy and ablation during the COVID-19 pandemic. METHODS: From September 2020 to August 2021, patients admitted for elective thoracic intervention were treated at a tertiary hospital (Site 1). Site 1 received patients for extracorporeal membrane oxygenation (ECMO) and invasive ventilation in the treatment of COVID-19. Shared imaging, theater, and hallway facilities were used.From April 2020 to August 2020, patients admitted for elective thoracic intervention were treated at a COVID-protected hospital (Site 2). No patients with suspected or confirmed COVID-19 were treated at Site 2.Patients were surveyed for clinical and laboratory signs of COVID-19 infection up to 30 days post-procedure. RESULTS: At Sites 1 and 2, patients (2.4%) were tested positive for COVID-19 at 10 and 14 days post-procedure.At Site 2, there were no COVID-19 positive cases within 30 days of undergoing elective thoracic intervention. CONCLUSION: A mixed-site method for infection control could represent a pragmatic approach to the management of elective procedures during the COVID-19 pandemic or for similar illnesses. ADVANCES IN KNOWLEDGE: Mixed-cohort infection control is possible in the prevention of nosocomial COVID-19 infection.
Hunter B, Chen M, Ratnakumar P, et al., 2022, A radiomics-based decision support tool improves lung cancer diagnosis in combination with the Herder score in large lung nodules, EBioMedicine, Vol: 86, ISSN: 2352-3964
Background:Large lung nodules (≥15 mm) have the highest risk of malignancy, and may exhibit important differences in phenotypic or clinical characteristics to their smaller counterparts. Existing risk models do not stratify large nodules well. We aimed to develop and validate an integrated segmentation and classification pipeline, incorporating deep-learning and traditional radiomics, to classify large lung nodules according to cancer risk.Methods:502 patients from five U.K. centres were recruited to the large-nodule arm of the retrospective LIBRA study between July 2020 and April 2022. 838 CT scans were used for model development, split into training and test sets (70% and 30% respectively). An nnUNet model was trained to automate lung nodule segmentation. A radiomics signature was developed to classify nodules according to malignancy risk. Performance of the radiomics model, termed the large-nodule radiomics predictive vector (LN-RPV), was compared to three radiologists and the Brock and Herder scores.Findings:499 patients had technically evaluable scans (mean age 69 ± 11, 257 men, 242 women). In the test set of 252 scans, the nnUNet achieved a DICE score of 0.86, and the LN-RPV achieved an AUC of 0.83 (95% CI 0.77–0.88) for malignancy classification. Performance was higher than the median radiologist (AUC 0.75 [95% CI 0.70–0.81], DeLong p = 0.03). LN-RPV was robust to auto-segmentation (ICC 0.94). For baseline solid nodules in the test set (117 patients), LN-RPV had an AUC of 0.87 (95% CI 0.80–0.93) compared to 0.67 (95% CI 0.55–0.76, DeLong p = 0.002) for the Brock score and 0.83 (95% CI 0.75–0.90, DeLong p = 0.4) for the Herder score. In the international external test set (n = 151), LN-RPV maintained an AUC of 0.75 (95% CI 0.63–0.85). 18 out of 22 (82%) malignant nodules in the Herder 10–70% category in the test set were identified as high risk by the decision-support tool, and may have been referred for earl
Tisi S, Dickson JL, Horst C, et al., 2022, Detection of COPD in the SUMMIT Study lung cancer screening cohort using symptoms and spirometry., Eur Respir J, Vol: 60
BACKGROUND: COPD is a major comorbidity in lung cancer screening (LCS) cohorts, with a high prevalence of undiagnosed COPD. Combining symptom assessment with spirometry in this setting may enable earlier diagnosis of clinically significant COPD and facilitate increased understanding of lung cancer risk in COPD. In this study, we wished to understand the prevalence, severity, clinical phenotype and lung cancer risk of individuals with symptomatic undiagnosed COPD in a LCS cohort. METHODS: 16 010 current or former smokers aged 55-77 years attended a lung health check as part of the SUMMIT Study. A respiratory consultation and spirometry were performed alongside LCS eligibility assessment. Those with symptoms, no previous COPD diagnosis and airflow obstruction were labelled as undiagnosed COPD. Baseline low-dose computed tomography (LDCT) was performed in those at high risk of lung cancer (PLCOm2012 score ≥1.3% and/or meeting USPSTF 2013 criteria). RESULTS: Nearly one in five (19.7%) met criteria for undiagnosed COPD. Compared with those previously diagnosed, those undiagnosed were more likely to be male (59.1% versus 53.2%; p<0.001), currently smoking (54.9% versus 47.6%; p<0.001) and from an ethnic minority group (p<0.001). Undiagnosed COPD was associated with less forced expiratory volume in 1 s impairment (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1 and 2: 85.3% versus 68.4%; p<0.001) and lower symptom/exacerbation burden (GOLD A and B groups: 95.6% versus 77.9%; p<0.001) than those with known COPD. Multivariate analysis demonstrated that airflow obstruction was an independent risk factor for lung cancer risk on baseline LDCT (adjusted OR 2.74, 95% CI 1.73-4.34; p<0.001), with a high risk seen in those with undiagnosed COPD (adjusted OR 2.79, 95% CI 1.67-4.64; p<0.001). CONCLUSIONS: Targeted case-finding within LCS detects high rates of undiagnosed symptomatic COPD in those most at risk. Individuals with und
Creamer AW, Horst C, Dickson JL, et al., 2022, Growing small solid nodules in lung cancer screening: safety and efficacy of a 200 mm(3) minimum size threshold for multidisciplinary team referral, THORAX, ISSN: 0040-6376
George PM, Reed A, Desai SR, et al., 2022, A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae., Science Translational Medicine, Vol: 14, Pages: 1-16, ISSN: 1946-6234
Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.
Woznitza N, Ghimire B, Devaraj A, et al., 2022, Impact of radiographer immediate reporting of X-rays of the chest from general practice on the lung cancer pathway (radioX): a randomised controlled trial, THORAX, ISSN: 0040-6376
Dickson JL, Hall H, Horst C, et al., 2022, Utilisation of primary care electronic patient records for identification and targeted invitation of individuals to a lung cancer screening programme, LUNG CANCER, Vol: 173, Pages: 94-100, ISSN: 0169-5002
Heriot DA, Stock CJW, Mumtaz Z, et al., 2022, IMPACT OF HIATUS HERNIA IN HYPERSENSITIVITY PNEUMONITIS - EXPERIENCE AT A TERTIARY CENTRE, Publisher: BMJ PUBLISHING GROUP, Pages: A94-A94, ISSN: 0040-6376
Nwankwo L, Periselneris J, Gilmartin D, et al., 2022, Predictors of adverse outcome in sarcoidosis complicated by chronic pulmonary aspergillosis, Publisher: OXFORD UNIV PRESS, Pages: 157-+, ISSN: 1369-3786
Rennison-Jones C, Gerry S, Gupta G, et al., 2022, The Brainomix automated e-ILD CT algorithm outperforms forced vital capacity in predicting outcomes for patients with idiopathic pulmonary fibrosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Batta R, Tornling G, Bengtsson T, et al., 2022, Non-interventional, retrospective, multi-center, follow-up study evaluating the effect of the angiotensin II type 2 receptor agonist C21 on lung pathology in subjects previously hospitalised with COVID-19, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Parris W, Philip K, Kaur-Gill N, et al., 2022, Effect of an immediate, remote smoking cessation intervention vs usual care among participants enrolled in lung health check: QuLIT2 study., Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Leahy TA, Chauhan A, Nicholas V, et al., 2022, Responder status and long term outcomes of critically ill patients with ARDS receiving high dose steroids as rescue therapy in a specialist acute respiratory failure centre, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Zhang YZ, Nicholson AG, Ly F, et al., 2022, Prediction of Clinically Significant Pathological Upstaging in Resected Lung Cancer: Insight from COVID-19 Pandemic (1st wave), Publisher: ELSEVIER SCIENCE INC, Pages: S112-S114, ISSN: 1556-0864
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