Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial.

BACKGROUND: There are limited data from randomized trials regarding whether volume-based, low-dose computed tomographic (CT) screening can reduce lung-cancer mortality among male former and current smokers. METHODS: A total of 13,195 men (primary analysis) and 2594 women (subgroup analyses) between the ages of 50 and 74 were randomly assigned to undergo CT screening at T0 (baseline), year 1, year 3, and year 5.5 or no screening. We obtained data on cancer diagnosis and the date and cause of death through linkages with national registries in the Netherlands and Belgium, and a review committee confirmed lung cancer as the cause of death when possible. A minimum follow-up of 10 years until December 31, 2015, was completed for all participants. RESULTS: Among men, the average adherence to CT screening was 90.0%. On average, 9.2% of the screened participants underwent at least one additional CT scan (initially indeterminate). The overall referral rate for suspicious nodules was 2.1%. At 10 years of follow-up, the incidence of lung cancer was 5.58 cases per 1000 person-years in the screening group and 4.91 cases per 1000 person-years in the control group; lung-cancer mortality was 2.50 deaths per 1000 person-years and 3.30 deaths per 1000 person-years, respectively. The cumulative rate ratio for death from lung cancer at 10 years was 0.76 (95% confidence interval [CI], 0.61 to 0.94; P = 0.01) in the screening group as compared with the control group, similar to the values at years 8 and 9. Among women, the rate ratio was 0.67 (95% CI, 0.38 to 1.14) at 10 years of follow-up, with values of 0.41 to 0.52 in years 7 through 9. CONCLUSIONS: In this trial involving high-risk persons, lung-cancer mortality was significantly lower among those who underwent volume CT screening than among those who underwent no screening. There were low rates of follow-up procedures for results suggestive of lung cancer. (Funded by the Netherlands Organization of Health Research and Development and others; NELSON Netherlands Trial Register number, NL580.).

Clinical research study implementation of case-finding strategies for heart failure and chronic obstructive pulmonary disease in the elderly with reduced exercise tolerance or dyspnea: A cluster randomized trial.

BACKGROUND: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) often remain undiagnosed in older individuals, although both disorders inhibit functionality and impair health. The aim of the study was to assess the effectiveness of a case-finding strategy of these disorders. METHODS: This is a clustered randomized trial; 18 general practices from the vicinity of Utrecht, the Netherlands, were randomly allocated to a case-finding strategy or usual care. Multimorbid community subjects (≥65 years) with dyspnea or reduced exercise tolerance were eligible for inclusion. The case-finding strategy consisted of history taking, physical examination, blood tests, electrocardiography, spirometry, and echocardiography. Subsequent treatment decisions were at the discretion of the general practitioner. Questionnaires regarding health status and functionality were filled out at baseline and after 6 months of follow-up. Information regarding changes in medication and health care use during the 6 months follow-up was extracted. RESULTS: A total of 829 participants were randomized: 389 in the case-finding strategy group and 440 in the usual care group. More patients in the case-finding group received a new diagnosis of HF or COPD than the usual care group (cumulative incidence 34% vs 2% and 17% vs. 2%, respectively). Scores for health status, functionality, and health care use were similar between the 2 strategies after 6 months of follow-up. CONCLUSIONS: A case-finding strategy applied in primary care to multimorbid older people with dyspnea or reduced exercise tolerance resulted in a number of new diagnoses of HF and COPD but did not result in short-term improvement of health status compared to usual care.

Patients' perspectives on the COPD-GRIP intervention, a new nursing care intervention for COPD.

BACKGROUND: The nurse-led chronic obstructive pulmonary disease-Guidance Research on Illness Perception (COPD-GRIP) intervention was developed to incorporate illness perceptions into COPD care with the intention to improve the health-related quality of life of COPD patients. This individualized intervention focuses on identifying, discussing and evaluating illness perceptions and consists of three consultations with a practice nurse. The aim of this study is to explore patients' experiences regarding the COPD-GRIP intervention. METHODS: A qualitative interview study nested in a cluster randomized trial in primary care. One-time semi-structured individual interviews with COPD patients who were guided with the COPD-GRIP intervention were conducted. During data collection, the constant comparative approach was used. All interviews were recorded, transcribed, anonymized and uploaded to MAXQDA. To identify themes, the transcripts were independently coded by two researchers. RESULTS: Sixteen patients were interviewed. All patients were positive and experienced an additional value of the COPD-GRIP intervention in different areas. Three main themes were identified and show that taking part in this intervention made the patients feel 'listened to and acknowledged', improved their awareness of the disease and its management and helped them to make lifestyle changes. Some patients suggested that the individualized care plan could be improved and to start the intervention immediately after being informed of the COPD diagnosis. All patients recommended this intervention. CONCLUSION: The results of this study indicate that patients acknowledge that the COPD-GRIP intervention is a useful and promising tool for providing individualized COPD care.

Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.

BACKGROUND: In the USA annual lung cancer screening is recommended. However, the optimal screening strategy (eg, screening interval, screening rounds) is unknown. This study provides results of the fourth screening round after a 2.5-year interval in the Dutch-Belgian Lung Cancer Screening trial (NELSON). METHODS: Europe's largest, sufficiently powered randomised lung cancer screening trial was designed to determine whether low-dose CT screening reduces lung cancer mortality by ≥25% compared with no screening after 10 years of follow-up. The screening arm (n=7915) received screening at baseline, after 1 year, 2 years and 2.5 years. Performance of the NELSON screening strategy in the final fourth round was evaluated. Comparisons were made between lung cancers detected in the first three rounds, in the final round and during the 2.5-year interval. RESULTS: In round 4, 46 cancers were screen-detected and there were 28 interval cancers between the third and fourth screenings. Compared with the second round screening (1-year interval), in round 4 a higher proportion of stage IIIb/IV cancers (17.3% vs 6.8%, p=0.02) and higher proportions of squamous-cell, bronchoalveolar and small-cell carcinomas (p=0.001) were detected. Compared with a 2-year interval, the 2.5-year interval showed a higher non-significant stage distribution (stage IIIb/IV 17.3% vs 5.2%, p=0.10). Additionally, more interval cancers manifested in the 2.5-year interval than in the intervals of previous rounds (28 vs 5 and 28 vs 19). CONCLUSIONS: A 2.5-year interval reduced the effect of screening: the interval cancer rate was higher compared with the 1-year and 2-year intervals, and proportion of advanced disease stage in the final round was higher compared with the previous rounds. TRIAL REGISTRATION NUMBER: ISRCTN63545820.

Computed tomographic findings in subjects who died from respiratory disease in the National Lung Screening Trial.

We evaluated the prevalence of significant lung abnormalities on computed tomography (CT) in patients who died from a respiratory illness other than lung cancer in the National Lung Screening Trial (NLST).In this retrospective case-control study, NLST participants in the CT arm who died of respiratory illness other than lung cancer were matched for age, sex, pack-years and smoking status to a surviving control. A chest radiologist and a radiology resident blinded to the outcome independently scored baseline CT scans visually and qualitatively for the presence of emphysema, airway wall thickening and fibrotic lung disease. The prevalence of CT abnormalities was compared between cases and controls by using chi-squared tests.In total, 167 participants died from a respiratory cause other than lung cancer. The prevalence of severe emphysema, airway wall thickening and fibrotic lung disease were 28.7% versus 4.8%, 26.9% versus 13.2% and 18.6% versus 0.5% in cases and controls, respectively. Radiological findings were significantly more prevalent in deaths compared with controls (all p<0.001).CT-diagnosed severe emphysema, airway wall thickening and fibrosis were much more common in NLST participants who died from respiratory disease, and CT may provide an additional means of identifying these diseases.

Proteomic profiling of peripheral blood neutrophils identifies two inflammatory phenotypes in stable COPD patients.

BACKGROUND: COPD is a heterogeneous chronic inflammatory disease of the airways and it is well accepted that the GOLD classification does not fully represent the complex clinical manifestations of COPD and this classification therefore is not well suited for phenotyping of individual patients with COPD. Besides the chronic inflammation in the lung compartment, there is also a systemic inflammation present in COPD patients. This systemic inflammation is associated with elevated levels of cytokines in the peripheral blood, but the precise composition is unknown. Therefore, differences in phenotype of peripheral blood neutrophils in vivo could be used as a read out for the overall systemic inflammation in COPD. METHOD: Our aim was to utilize an unsupervised method to assess the proteomic profile of peripheral neutrophils of stable COPD patients and healthy age matched controls to find potential differences in these profiles as read-out of inflammatory phenotypes. We performed fluorescence two-dimensional difference gel electrophoresis with the lysates of peripheral neutrophils of controls and stable COPD patients. RESULTS: We identified two groups of COPD patients based on the differentially regulated proteins and hierarchical clustering whereas there was no difference in lung function between these two COPD groups. The neutrophils from one of the COPD groups were less responsive to bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF). CONCLUSION: This illustrates that systemic inflammatory signals do not necessarily correlate with the GOLD classification and that inflammatory phenotyping can significantly add in an improved diagnosis of single COPD patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00807469 registered December 11th 2008.

Aortic Valve and Thoracic Aortic Calcification Measurements: How Low Can We Go in Radiation Dose?

OBJECTIVE: This study aimed to determine the lowest radiation dose and iterative reconstruction level(s) at which computed tomography (CT)-based quantification of aortic valve calcification (AVC) and thoracic aortic calcification (TAC) is still feasible. METHODS: Twenty-eight patients underwent a cardiac CT and 20 patients a chest CT at 4 different dose levels (routine dose and approximately 40%, 60%, and 80% reduced dose). Data were reconstructed with filtered back projection, 3 iDose levels, and 3 iterative model-based reconstruction levels. Two observers scored subjective image quality. The AVC and TAC were quantified using mass and compared to the reference scan (routine dose reconstructed with filtered back projection). RESULTS: In cardiac CT at 0.35 mSv (60% reduced), all scans reconstructed with iDose (all levels) were diagnostic, calcification detection errors occurred in only 1 patient, and there were no significant differences in mass scores compared to the reference scan. Similar results were found for chest CT at 0.48 mSv (75% reduced) with iDose levels 4 and 6 and iterative model reconstruction levels 1 and 2. CONCLUSIONS: Iterative reconstruction enables AVC and TAC quantification on CT at submillisievert dose.

Lung Cancer in the Oldest Old: A Nation-Wide Study in The Netherlands.

INTRODUCTION: An important step in improving research and care for the oldest patients with lung cancer is analyzing current data regarding diagnostic work-up, treatment choices, and survival. METHODS: We analyzed data on lung cancer from the Netherlands Cancer Registry (NCR-IKNL) regarding diagnostic work-up, treatment, and survival in different age categories; the oldest old (≥85 years of age) versus those aged 71-84 (elderly) and those aged ≤70 years (younger patients). RESULTS: 47,951 patients were included in the 2010-2014 NCR database. 2196 (5%) patients were aged ≥85 years. Histological diagnosis was obtained significantly less often in the oldest old (38%, p < 0.001), and less standard treatment regimen was given (8%, p < 0.001) compared to elderly and younger patients. 67% of the oldest old received best supportive care only versus 38% of the elderly and 20% of the younger patients (p < 0.001). For the oldest old receiving standard treatment, survival rates were similar in comparison with the elderly patients. In the oldest old, no survival differences were found when comparing standard or adjusted regimens for stage I and IV NSCLC; for stage III, oldest old receiving standard treatment had longer survival. No oldest old patients with stage II received standard treatment. CONCLUSION: Clinicians make limited use of diagnostics and invasive treatment in the oldest old; however, selected oldest old patients experienced similar survival rates as the elderly when receiving some form of anticancer therapy (standard or adjusted). More research is needed to further develop individualized treatment algorithms.

The Effect of A Geriatric Assessment on Treatment Decisions for Patients with Lung Cancer.

BACKGROUND: Decision-making for older patients with lung cancer can be complex and challenging. A geriatric assessment (GA) may be helpful and is increasingly being used since 2005 when SIOG advised to incorporate this in standard work-up for the elderly with cancer. Our aim was to evaluate the value of a geriatric assessment in decision-making for patients with lung cancer. METHODS: Between January 2014 and April 2016, data on patients with lung cancer from two teaching hospitals in the Netherlands were entered in a prospective database. Outcome of geriatric assessment, non-oncologic interventions, and suggested adaptations of oncologic treatment proposals were evaluated. RESULTS: 83 patients (median age 79 years) were analyzed with a geriatric assessment, of which 59% were treated with a curative intent. Half of the patients were classified as ECOG PS 0 or 1. The majority of the patients (78%) suffered from geriatric impairments and 43% (n = 35) of the patients suffered from three or more geriatric impairments (out of eight analyzed domains). Nutritional status was most frequently impaired (52%). Previously undiagnosed impairments were identified in 58% of the patients, and non-oncologic interventions were advised for 43%. For 33% of patients, adaptations of the oncologic treatment were proposed. Patients with higher number of geriatric impairments more often were advised a reduced or less intensive treatment (p < 0.001). CONCLUSION: A geriatric assessment uncovers previously unknown health impairments and provides important guidance for tailored treatment decisions in patients with lung cancer. More research on GA-stratified treatment decisions is needed.

Nurses' perspectives of a new individualized nursing care intervention for COPD patients in primary care settings: A mixed method study.

BACKGROUND: The major challenges in Chronic Obstructive Pulmonary Disease (COPD) care are guiding a patient in daily living with the consequences of the disease, reducing the impact of symptoms and improving Health Related Quality of Life (HRQoL). The new nurse-led COPD-Guidance, Research on an Illness Perception (COPD-GRIP) intervention translates the evidence concerning illness perceptions and Health Related Quality of Life (HRQoL) into a practice nurse intervention. The aim is to explore the nurses' experiences with applying the new COPD-GRIP intervention. METHOD: An explanatory mixed-method study nested in a cluster randomized trial in primary care was conducted. Pre-intervention questionnaires were sent to all participating nurses (N=24) to identify expectations. Post-intervention questionnaires identified experiences after applying the intervention followed by two focus groups to further extend exploration of findings. Questionnaires were analyzed by descriptive analyses. To identify themes the audio-taped and transcribed focus groups were independently coded by two researchers. RESULTS: The nurses described the intervention as a useful, structured and individualized tool to guide COPD patients in living with the consequences of COPD. Applying the intervention took less time than the nurses initially expected. The intervention enables to provide patient-centered care and to address patient needs. Barriers were encountered, especially in patients with a lower social economic status, in patients with a lower health literacy and in patients with other cultural backgrounds than the Dutch background. CONCLUSION: Nurses perceived the COPD-GRIP intervention as a feasible, individualized tool. According to the nurses, the intervention is a valuable improvement in the care for COPD patients.

Efficacy of an mHealth intervention to stimulate physical activity in COPD patients after pulmonary rehabilitation.

Physical inactivity in patients with chronic obstructive pulmonary disease (COPD) is associated with poor health status and increased disease burden. The present study aims to test the efficacy of a previously developed mobile (m)Health intervention to improve or maintain physical activity in patients with COPD after pulmonary rehabilitation.A randomised controlled trial was performed in 32 physiotherapy practices in the Netherlands. COPD patients were randomised into intervention or usual care groups. The intervention consisted of a smartphone application for the patients and a monitoring website for the physiotherapists. Measurements were performed at 0, 3, 6 and 12 months. Physical activity, functional exercise capacity, lung function, health-related quality of life and body mass index were assessed.157 patients started the study and 121 completed it. There were no significant positive effects of the intervention on physical activity (at 0 months: intervention 5824±3418 steps per weekday, usual care 5717±2870 steps per weekday; at 12 months: intervention 4819±2526 steps per weekday, usual care 4950±2634 steps per weekday; p=0.811) or on the secondary end-points. There was a significant decrease over time in physical activity (p<0.001), lung function (p<0.001) and mastery (p=0.017), but not in functional exercise capacity (p=0.585).Although functional exercise capacity did not deteriorate, our mHealth intervention did not improve or maintain physical activity in patients with COPD after a period of pulmonary rehabilitation.

Advanced glycation endproducts and their receptor in different body compartments in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by chronic airway inflammation and emphysema, and is caused by exposure to noxious particles or gases, e.g. cigarette smoke. Smoking and oxidative stress lead to accelerated formation and accumulation of advanced glycation end products (AGEs), causing local tissue damage either directly or by binding the receptor for AGEs (RAGE). This study assessed the association of AGEs or RAGE in plasma, sputum, bronchial biopsies and skin with COPD and lung function, and their variance between these body compartments. METHODS: Healthy smoking and never-smoking controls (n = 191) and COPD patients (n = 97, GOLD stage I-IV) were included. Autofluorescence (SAF) was measured in the skin, AGEs (pentosidine, CML and CEL) and sRAGE in blood and sputum by ELISA, and in bronchial biopsies by immunohistochemistry. eQTL analysis was performed in bronchial biopsies. RESULTS: COPD patients showed higher SAF values and lower plasma sRAGE levels compared to controls and these values associated with decreased lung function (p <0.001; adjusting for relevant covariates). Lower plasma sRAGE levels significantly and independently predicted higher SAF values (p < 0.001). One SNP (rs2071278) was identified within a region of 50 kB flanking the AGER gene, which was associated with the gene and protein expression levels of AGER and another SNP (rs2071278) which was associated with the accumulation of AGEs in the skin. CONCLUSION: In COPD, AGEs accumulate differentially in body compartments, i.e. they accumulate in the skin, but not in plasma, sputum and bronchial biopsies. The association between lower sRAGE and higher SAF levels supports the hypothesis that the protective mechanism of sRAGE as a decoy-receptor is impaired in COPD.

Fleischner recommendations for the management of subsolid pulmonary nodules: high awareness but limited conformance - a survey study.

OBJECTIVES: The aim of this study was to assess awareness and conformance to the Fleischner society recommendations for the management of subsolid pulmonary nodules (SSN) in clinical practice. METHODS: An online questionnaire with four imaging cases was sent to 1579 associates from the European Respiratory Society and 757 from the European Society of Thoracic Imaging. Each respondent was asked to choose from several options which one they thought was the indicated management for the nodule presented. Awareness and conformance to the Fleischner recommendations (FR) were assessed and correlated to respondents characteristics. RESULTS: In total, 119 radiologists (response rate 16.0 %) and 243 pulmonologists (response rate 16.5 %) were included. Awareness of the FR was higher in radiologists than in pulmonologists (93 % vs. 70 %, p < 0.001), as was implementation in daily practice (66 % vs. 47 %, p < 0.001). Radiologists conformed to FR in rates of 31, 69, 68, and 82 %, and pulmonologists in 12, 43, 70, and 75 % for cases 1 to 4, respectively. Overmanagement was common. Conformance in SSN management was associated with awareness, working in an academic practice, larger practice size, teaching residents, and higher SSN exposure. CONCLUSIONS: Although awareness of the Fleischner recommendations for SSN management is widespread, management choices in clinical practice show large heterogeneity. KEY POINTS: • Guideline awareness among clinicians is widespread, but conformance shows large heterogeneity. • Awareness and conformance is significantly higher among radiologists than pulmonologists. • Overmanagement is common, which may lead to avoidable financial and physical burden.

Inter-observer and inter-examination variability of manual vertebral bone attenuation measurements on computed tomography.

OBJECTIVE: To determine inter-observer and inter-examination variability of manual attenuation measurements of the vertebrae in low-dose unenhanced chest computed tomography (CT). METHODS: Three hundred and sixty-seven lung cancer screening trial participants who underwent baseline and repeat unenhanced low-dose CT after 3 months because of an indeterminate lung nodule were included. The CT attenuation value of the first lumbar vertebrae (L1) was measured in all CTs by one observer to obtain inter-examination reliability. Six observers performed measurements in 100 randomly selected CTs to determine agreement with limits of agreement and Bland-Altman plots and reliability with intraclass correlation coefficients (ICCs). Reclassification analyses were performed using a threshold of 110 HU to define osteoporosis. RESULTS: Inter-examination reliability was excellent with an ICC of 0.92 (p < 0.001). Inter-examination limits of agreement ranged from -26 to 28 HU with a mean difference of 1 ± 14 HU. Inter-observer reliability ICCs ranged from 0.70 to 0.91. Inter-examination variability led to 11.2 % reclassification of participants and inter-observer variability led to 22.1 % reclassification. CONCLUSIONS: Vertebral attenuation values can be manually quantified with good to excellent inter-examination and inter-observer reliability on unenhanced low-dose chest CT. This information is valuable for early detection of osteoporosis on low-dose chest CT. KEY POINTS: • Vertebral attenuation values can be manually quantified on low-dose unenhanced CT reliably. • Vertebral attenuation measurements may be helpful in detecting subclinical low bone density. • This could become of importance in the detection of osteoporosis.

Pulmonary Nodule Volumetry at Different Low Computed Tomography Radiation Dose Levels With Hybrid and Model-Based Iterative Reconstruction: A Within Patient Analysis.

OBJECTIVE: The aim of the study was to determine the effects of dose reduction and iterative reconstruction (IR) on pulmonary nodule volumetry. METHODS: In this prospective study, 25 patients scheduled for follow-up of pulmonary nodules were included. Computed tomography acquisitions were acquired at 4 dose levels with a median of 2.1, 1.2, 0.8, and 0.6 mSv. Data were reconstructed with filtered back projection (FBP), hybrid IR, and model-based IR. Volumetry was performed using semiautomatic software. RESULTS: At the highest dose level, more than 91% (34/37) of the nodules could be segmented, and at the lowest dose level, this was more than 83%. Thirty-three nodules were included for further analysis. Filtered back projection and hybrid IR did not lead to significant differences, whereas model-based IR resulted in lower volume measurements with a maximum difference of -11% compared with FBP at routine dose. CONCLUSIONS: Pulmonary nodule volumetry can be accurately performed at a submillisievert dose with both FBP and hybrid IR.

Incidental findings on chest CT imaging are associated with increased COPD exacerbations and mortality.

BACKGROUND: This study aimed to evaluate whether incidental CT findings of emphysema, airway thickening and bronchiectasis, as seen on CT scans performed for other non-pulmonary clinical indications, are associated with future acute exacerbations of COPD resulting in hospitalisation or death. METHODS: This multicentre prospective case-cohort study comprised 6406 subjects who underwent routine diagnostic chest CT for non-pulmonary indications. Using a case-cohort approach, we visually graded CT scans from cases and a random sample of ∼10% of the baseline cohort (n=704) for emphysema severity (range 0-20), airway thickening (range 0-5) and bronchiectasis (range 0-5). We used weighted Cox proportional hazards analysis to assess the independent association between CT findings and hospitalisation or death due to COPD exacerbation. RESULTS: During a median follow-up of 4.4 years (maximum 5.2 years), 338 COPD events were identified. The risk of experiencing a future acute exacerbation of COPD resulting in hospitalisation or death was significantly increased in subjects with severe emphysema (score ≥7) and severe airway thickening (score ≥3). The respective HRs were 4.6 (95% CI 3.0 to 7.1) and 5.9 (95% CI 3.4 to 10.5). Severe bronchiectasis (score ≥3) was not significantly associated with increased risk of adverse events (HR 1.5; 95% CI 0.9 to 2.5). CONCLUSIONS: Morphological correlates of COPD such as emphysema and airway thickening detected on CT scans obtained for other non-pulmonary indications are strong independent predictors of subsequent development of acute exacerbations of COPD resulting in hospitalisation or death.

Airway wall thickness associated with forced expiratory volume in 1 second decline and development of airflow limitation.

Airway wall thickness and emphysema contribute to airflow limitation. We examined their association with lung function decline and development of airflow limitation in 2021 male smokers with and without airflow limitation. Airway wall thickness and emphysema were quantified on chest computed tomography and expressed as the square root of wall area of a 10-mm lumen perimeter (Pi10) and the 15th percentile method (Perc15), respectively. Baseline and follow-up (median (interquartile range) 3 (2.9-3.1) years) spirometry was available. Pi10 and Perc15 correlated with baseline forced expiratory volume in 1 s (FEV1) (r= -0.49 and 0.11, respectively (p<0.001)). Multiple linear regression showed that Pi10 and Perc15 at baseline were associated with a lower FEV1 after follow-up (p<0.05). For each sd increase in Pi10 and decrease in Perc15 the FEV1 decreased by 20 mL and 30.2 mL, respectively. The odds ratio for developing airflow limitation after 3 years was 2.45 for a 1-mm higher Pi10 and 1.46 for a 10-HU lower Perc15 (p<0.001). A greater degree of airway wall thickness and emphysema was associated with a higher FEV1 decline and development of airflow limitation after 3 years of follow-up.

Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules?

Pulmonary subsolid nodules (SSNs) have a high likelihood of malignancy, but are often indolent. A conservative treatment approach may therefore be suitable. The aim of the current study was to evaluate whether close follow-up of SSNs with computed tomography may be a safe approach. The study population consisted of participants of the Dutch-Belgian lung cancer screening trial (Nederlands Leuvens Longkanker Screenings Onderzoek; NELSON). All SSNs detected during the trial were included in this analysis. Retrospectively, all persistent SSNs and SSNs that were resected after first detection were segmented using dedicated software, and maximum diameter, volume and mass were measured. Mass doubling time (MDT) was calculated. In total 7135 volunteers were included in the current analysis. 264 (3.3%) SSNs in 234 participants were detected during the trial. 147 (63%) of these SSNs in 126 participants disappeared at follow-up, leaving 117 persistent or directly resected SSNs in 108 (1.5%) participants available for analysis. The median follow-up time was 95 months (range 20-110 months). 33 (28%) SSNs were resected and 28 of those were (pre-) invasive. None of the non-resected SSNs progressed into a clinically relevant malignancy. Persistent SSNs rarely developed into clinically manifest malignancies unexpectedly. Close follow-up with computed tomography may be a safe option to monitor changes.

Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.

Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10(-5)) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value <10(-5) in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10(-6), OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10(-12)). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.

Pulmonary function and CT biomarkers as risk factors for cardiovascular events in male lung cancer screening participants: the NELSON study.

OBJECTIVE: The objective of this study was to investigate the association of spirometry and pulmonary CT biomarkers with cardiovascular events. METHODS: In this lung cancer screening trial 3,080 male participants without a prior cardiovascular event were analysed. Fatal and non-fatal cardiovascular events were included. Spirometry included forced expiratory volume measured in units of one-second percent predicted (FEV1%predicted) and FEV1 divided by forced vital capacity (FVC; FEV1/FVC). CT examinations were quantified for coronary artery calcium volume, pulmonary emphysema (perc15) and bronchial wall thickness (pi10). Data were analysed via a Cox proportional hazard analysis, net reclassification improvement (NRI) and C-indices. RESULTS: 184 participants experienced a cardiovascular event during a median follow-up of 2.9 years. Age, pack-years and smoking status adjusted hazard ratios were 0.992 (95% confidence interval (CI) 0.985-0.999) for FEV1%predicted, 1.000 (95%CI 0.986-1.015) for FEV1/FVC, 1.014 (95%CI 1.005-1.023) for perc15 per 10 HU, and 1.269 (95%CI 1.024-1.573) for pi10 per 1 mm. The incremental C-index (<0.015) and NRI (<2.8%) were minimal. Coronary artery calcium volume had a hazard ratio of 1.046 (95%CI 1.034-1.058) per 100 mm(3), an increase in C-index of 0.076 and an NRI of 16.9% (P < 0.0001). CONCLUSIONS: Pulmonary CT biomarkers and spirometry measurements were significantly associated with cardiovascular events, but did not contain clinically relevant independent prognostic information for cardiovascular events. KEY POINTS: • Pulmonary CT biomarkers and spirometry are associated with cardiovascular events • These pulmonary measurements do not contain clinically relevant independent prognostic information • Only coronary calcium score improved cardiovascular risk prediction above age and smoking.