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Rationale Poor muscle quality in COPD patients relates to exercise intolerance and mortality. Muscle quality can be estimated on computed tomography (CT) by estimating psoas density (PsD). We tested the hypothesis that PsD is lower in COPD patients than in controls and relates to all-cause mortality. Methods At baseline, PsD was measured using axial low-dose chest CT images in 220 COPD patients, 80% men, who were 65 ± 8 years old with mild to severe airflow limitation and in a control group of 58 subjects matched by age, sex, body mass index (BMI) and body surface area (BSA). COPD patients were prospectively followed for 76.5 (48–119) months. Anthropometrics, smoking history, BMI, dyspnoea, lung function, exercise capacity, BODE index and exacerbations history were recorded. Cox proportional risk analysis determined the factors more strongly associated with long-term mortality. Results PsD was lower in COPD patients than in controls (40.5 vs 42.5, p = 0.045). During the follow-up, 54 (24.5%) deaths occurred in the COPD group. PsD as well as age, sex, pack-year history, FEV1%, 6MWD, mMRC, BODE index, were independently associated with mortality. Multivariate analysis showed that age (HR 1.06; 95% CI 1.02–1.12, p = 0.006) and CT-assessed PsD (HR 0.97; 95%CI 0.94–0.99, p = 0.023) were the variables independently associated with all-cause mortality. Conclusions In COPD patients with mild to severe airflow limitation, chest CT-assessed psoas muscle density was lower than in matched controls and independently associated with long-term mortality. Muscle quality using the easy to evaluate psoas muscle density from chest CT may provide clinicians with important prognostic information in COPD.

Lung cancer screening detects early-stage cancers, but also a large number of benign nodules. Molecular markers can help in the lung cancer screening process by refining inclusion criteria or guiding the management of indeterminate pulmonary nodules. In this study, we developed a diagnostic model based on the quantification in plasma of complement-derived fragment C4c, cytokeratin fragment 21-1 (CYFRA 21-1) and C-reactive protein (CRP). The model was first validated in two independent cohorts, and showed a good diagnostic performance across a range of lung tumor types, emphasizing its high specificity and positive predictive value. We next tested its utility in two clinically relevant contexts: assessment of lung cancer risk and nodule malignancy. The scores derived from the model were associated with a significantly higher risk of having lung cancer in asymptomatic individuals enrolled in a computed tomography (CT)-screening program (OR = 1.89; 95% CI = 1.20–2.97). Our model also served to discriminate between benign and malignant pulmonary nodules (AUC: 0.86; 95% CI = 0.80–0.92) with very good specificity (92%). Moreover, the model performed better in combination with clinical factors, and may be used to reclassify patients with intermediate-risk indeterminate pulmonary nodules into patients who require a more aggressive work-up. In conclusion, we propose a new diagnostic biomarker panel that may dictate which incidental or screening-detected pulmonary nodules require a more active work-up.

Objective To determine the accuracy of visual analysis and the retention index (RI) with dual-time point 18F-FDG PET/CT for the characterization of indeterminate pulmonary nodules (IPN) with low FDG uptake. Materials and methods A retrospective analysis was performed on 43 patients (28 men, 64 ± 11 years old, range 36–83 years) referred for IPN characterization with 18F-FDG-PET/CT and maximum standard uptake value ≤2.5 at 60 min post-injection (SUVmax1). Nodules were analyzed by size, visual score for FDG uptake on standard (OSEM 2,8) and high definition (HD) reconstructions, SUVmax1, SUVmax at 180 min post-injection (SUVmax2), and RI was calculated. The definitive diagnosis was based on histopathological confirmation (n = 28) or ≥2 years of follow-up. Results Twenty-four nodules (56%) were malignant. RI ≥ 10% on standard reconstruction detected 18 nodules that would have been considered negative using the standard SUVmax ≥ 2.5 criterion for malignancy. RI ≥ 10% had a sensitivity, specificity, PPV, NPV and accuracy of 75%, 73.7%, 78.3%, 70%, and 74.4%, respectively, while for FDG uptake > liver on HD these were 79.1%, 63.2%, 73.1%, 70.6%, and 72.1%, respectively. SUVmax1 ≥ 2, SUVmax2 > 2.5 and FDG uptake > liver on standard reconstruction had a PPV of 100%. FDG uptake > mediastinum on HD had a NPV of 100%. Conclusions RI ≥ % was the most accurate criterion for malignancy, followed by FDG uptake > liver on HD reconstruction. On standard reconstruction, SUVmax1 ≥ 2 was highly predictive of malignancy, as well as SUVmax2 > 2.5 and FDG uptake > liver. FDG uptake

Fibroblast activation includes differentiation to myofibroblasts and is a key feature of organ fibrosis. The Notch pathway has been involved in myofibroblast differentiation in several tissues, inc...

Objective Lung cancer (LC) is the leading cause of death from cancer worldwide. More than 27,000 LCs are diagnosed annually in Spain, and most are unresectable. Early detection and treatment reduce LC mortality. This study describes surgical outcomes in a longstanding LC screening cohort in Spain. Methods We conducted a retrospective study of surgical outcomes in a LC screening (LCS) program using low dose computed tomography (LDCT) since the year 2000. A descriptive analysis of clinical and radiological parameters, presence or absence of a preoperative diagnosis, pathological staging, morbidity, mortality, and survival was performed. Results Ninety-seven (2.5%) LC were diagnosed in 3825 screened. Twenty individuals with LC had no surgery due to advanced stage or small cell histology. Eighty-seven surgical procedures were carried out for suspected or biopsy proven LC, detected by LDCT. Most operated patients were male (57[85%]) aged 64 ± 9.1 years. Nine patients underwent a second operation for a metachronous primary lung cancer. Mean tumor size was 15.2 ± 7.6 mm. Eight nodules were benign (9.2%). Lobectomy was performed in 56 cases (83.6%). Adenocarcinoma (n = 39; 58.2%) was the most frequent histological type followed by squamous cell carcinoma (n = 17; 25.4%). Fifty-nine (88%) tumors were in Stage I. Thirteen patients (15.4%) had 16 complications. The estimated survival rates at 5 and 10 years for stage I were 93% (95% CI: 79%–98%) and 83% (95% CI: 65%–92%), respectively. Conclusion Lung cancer screening was associated with excellent surgical outcomes with 5 and 10-year survival rates exceeding 90 and 80%, respectively.

Rationale Emphysema and osteoporosis are tobacco-related diseases. Many studies have shown that emphysema is a strong and independent predictor of low bone mineral density (BMD) in smokers; however, none of them explored its association with different emphysema subtypes. Objective To explore the association between the different emphysema subtypes and the presence of low bone mineral density in a population of active or former smokers with and without chronic obstructive pulmonary disease (COPD). Methods One hundred and fifty-three active and former smokers from a pulmonary clinic completed clinical questionnaires, pulmonary function tests, a low-dose chest computed tomography (LDCT) and a dual-energy absorptiometry (DXA) scans. Subjects were classified as having normal BMD or low BMD (osteopenia or osteoporosis). Emphysema was classified visually for its subtype and severity. Logistic regression analysis explored the relationship between the different emphysema subtypes and the presence of low BMD adjusting for other important factors. Results Seventy-five percent of the patients had low BMD (78 had osteopenia and 37 had osteoporosis). Emphysema was more frequent (66.1 vs 26.3%, p=

We learned many unanticipated and valuable lessons since we started planning our study of low-dose computed tomography (CT) screening for lung cancer in 1991. The publication of the baseline results of the Early Lung Cancer Action Project (ELCAP) in Lancet 1999 showed that CT screening could identify a high proportion of early, curable lung cancers. This stimulated large national screening studies to be quickly started. The ELCAP design, which provided evidence about screening in the context of a clinical program, was able to rapidly expand to a 12-institution study in New York State (NY-ELCAP) and to many international institutions (International-ELCAP), ultimately working with 82 institutions, all using the common I-ELCAP protocol. This expansion was possible because the investigators had developed the ELCAP Management System for screening, capturing data and CT images, and providing for quality assurance. This advanced registry and its rapid accumulation of data and images allowed continual assessment and updating of the regimen of screening as advances in knowledge and new technology emerged. For example, in the initial ELCAP study, introduction of helical CT scanners had allowed imaging of the entire lungs in a single breath, but the images were obtained in 10 mm increments resulting in about 30 images per person. Today, images are obtained in submillimeter slice thickness, resulting in around 700 images per person, which are viewed on high-resolution monitors. The regimen provides the imaging acquisition parameters, imaging interpretation, definition of positive result, and the recommendations for further workup, which now include identification of emphysema and coronary artery calcifications. Continual updating is critical to maximize the benefit of screening and to minimize potential harms. Insights were gained about the natural history of lung cancers, identification and management of nodule subtypes, increased understanding of nodule imaging and pathologic features, and measurement variability inherent in CT scanners. The registry also provides the foundation for assessment of new statistical techniques, including artificial intelligence, and integration of effective genomic and blood-based biomarkers, as they are developed.

Rationale Idiopathic pulmonary fibrosis (IPF) has a dismal prognosis. Mesenchymal stromal cells (MSCs) have shown benefit in other inflammatory diseases. Objectives To evaluate the safety and feasibility of endobronchial administration of bone marrow autologous MSCs (BM-MSC) in patients with mild-to-moderate IPF. Methods A phase I multicentre clinical trial (ClinicalTrials.gov NCT01919827) with a single endobronchial administration of autologous adult BM-MSCs in patients diagnosed with mild-to-moderate IPF. In a first escalating-dose phase, three patients were included sequentially in three dose cohorts (10×106, 50×106 and 100×106 cells). In a second phase, nine patients received the highest tolerated dose. Follow-up with pulmonary function testing, 6-min walk test and St George's Respiratory Questionnaire was done at 1, 2, 3, 6 and 12 months, and with computed tomography at 3, 6 and 12 months. Results 21 bone marrow samples were obtained from 17 patients. Three patients were excluded from treatment due to chromosome aberrations detected in MSCs after culture, and one patient died before treatment. Finally, 13 patients received the BM-MSC infusion. No treatment-related severe adverse events were observed during follow-up. Compared to baseline, the mean forced vital capacity showed an initial decline of 8.1% at 3 months. The number of patients without functional progression was six (46%) at 3 months and three (23%) at 12 months. Conclusions The endobronchial infusion of BM-MSCs did not cause immediate serious adverse events in IPF patients, but a relevant proportion of patients suffered clinical and/or functional progression. Genomic instability of BM-MSCs during culture found in three patients may be troublesome for the use of autologous MSCs in IPF patients., Endobronchial autologous mesenchymal stromal cells (MSCs) did not cause direct serious adverse events in IPF patients. However, significant progression was seen in seven out of 13 patients. Genomic instability of autologous MSCs may limit use in IPF. https://bit.ly/39akv7z

Rationale: Chronic obstructive pulmonary disease (COPD) is a well-established independent risk factor for lung cancer; however, the literature on the association between asthma and lung cancer is m...

In December 2019, an outbreak of severe acute respiratory syndrome associated to SARS-CoV2 was reported in Wuhan, China. To date, little is known on histopathological findings in patients infected with the new SARS-CoV2. Lung histopathology shows features of acute and organising diffuse alveolar damage. Subtle cellular inflammatory infiltrate has been found in line with the cytokine storm theory. Medium-size vessel thrombi were frequent, but capillary thrombi were not present. Despite the elevation of biochemical markers of cardiac injury, little histopathological damage could be confirmed. Viral RNA from paraffin sections was detected at least in one organ in 90% patients.

Background: A recent study estimated that more than 1.5 million Americans have an indeterminate pulmonary nodule (IPN) identified on a chest computed tomography (CT) scan each year outside of lung cancer screening programs. However, the cost and pattern of subsequent IPN workup have not been described for real-world settings. Objectives: To examine the pattern and cost of IPN workup in real-world practice using insurer administrative claims data for commercially-insured individuals. Methods: The primary source for this retrospective observational study was the MarketScan® 2013-2016 databases, which include information on 28 to 47 million insured lives. The newly diagnosed IPN study population consisted of members with an IPN diagnosis code on a claim in 2014 who did not have prior diagnosis of an IPN or lung cancer in 2013 and who had coverage from 2014 to 2016. Subsequent claims were examined for workups included in the American College of Chest Physicians (ACCP) guideline recommendations and the costs of workup were tabulated. Results: Of the 15 064 patients in the study population, only 5471 (36%) received any subsequent workup. The average and median costs of workup for these patients were $3270 and $2068, respectively. Spread across the commercially-insured population, the workup is estimated to cost between $1 and $2 per member per year. Conclusions: The majority of commercially-insured members with newly identified IPNs do not appear to have any guideline-recommended workup, despite a low incremental cost of such workup services on a population basis.

Background: tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES). Methods: we performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age ( extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). Results: the mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48x10(-5)) was located in the tumor-suppressor gene ALPK2. Conclusions: we describe genetic variants associated with extreme phenotypes of high and low risk for the development of tobacco-induced lung adenocarcinoma. Our results and our strategy may help to identify high-risk subjects and to develop new therapeutic strategies. This work was supported by the Spanish Society of Medical Oncology; Fundación SEOM and Fundación Salud 2000; and Government of Navarra. LMM research work is supported by Foundation for Applied Medical Research (FIMA), Fundación Científica de la Asociación Espanola Contra el Cáncer, Fundación Ramón Areces, and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional 'Una manera de hacer Europa' (PI19/00098).

SARS-CoV-2, the COVID-19 causative agent, has infected millions of people and killed over 1.6 million worldwide. A small percentage of cases persist with prolonged positive RT-PCR on nasopharyngeal swabs. The aim of this study was to determine risk factors for prolonged viral shedding amongst patient's basal clinical conditions.We have evaluated all 513 patients attended in our hospital between 1 March and 1 July. We have selected all 18 patients with prolonged viral shedding and compared them with 36 sex-matched randomly selected controls. Demographic, treatment and clinical data were systematically collected.Global median duration of viral clearance was 25.5 days (n = 54; IQR, 22-39.3 days), 48.5 days in cases (IQR 38.7-54.9 days) and 23 days in controls (IQR 20.2-25.7), respectively. There were not observed differences in demographic, symptoms or treatment data between groups. Chronic rhinosinusitis and atopy were more common in patients with prolonged viral shedding (67%) compared with controls (11% and 25% respectively) (P 0.001 and P = 0.003). The use of inhaled corticosteroids was also more frequent in case group (P = 0.007). Multivariate analysis indicated that CRS (odds ratio [OR], 18.78; 95% confidence interval [95%CI], 3.89-90.59; P 0.001) was independently associated with prolonged SARS-CoV-2 RNA shedding in URT samples, after adjusting for initial PCR Ct values.We found that chronic rhinosinusitis and atopy might be associated with increased risk of prolonged viral shedding. If confirmed in prospective trials, this finding might have clinical implications for quarantine duration due to increased risk of pandemic spread.

Background: Pulmonary artery enlargement (PAE) detected using chest computed tomography (CT) is associated with poor outcomes in chronic obstructive pulmonary disease (COPD). It is unknown whether nocturnal hypoxemia occurring in smokers, with or without COPD, obstructive sleep apnoea (OSA) or their overlap, may be associated with PAE assessed by chest CT. Methods: We analysed data from two prospective cohort studies that enrolled 284 smokers in lung cancer screening programs and completing baseline home sleep studies and chest CT scans. Main pulmonary artery diameter (PAD) and the ratio of the PAD to that of the aorta (PA:Ao ratio) were measured. PAE was defined as a PAD ≥ 29 mm in men and ≥27 mm in women or as a PA:Ao ratio &gt, 0.9. We evaluated the association of PAE with baseline characteristics using multivariate logistic models. Results: PAE prevalence was 27% as defined by PAD measurements and 11.6% by the PA:Ao ratio. A body mass index ≥ 30 kg/m2 (OR 2.01, 95%CI 1.06–3.78), lower % predicted of forced expiratory volume in one second (FEV1) (OR 1.03, 95%CI 1.02–1.05) and higher % of sleep time with O2 saturation &lt, 90% (T90) (OR 1.02, 95%CI 1.00–1.03), were associated with PAE as determined by PAD. However, only T90 remained significantly associated with PAE as defined by the PA:Ao ratio (OR 1.02, 95%CI 1.01–1.03). In the subset group without OSA, only T90 remains associated with PAE, whether defined by PAD measurement (OR 1.02, 95%CI 1.01–1.03) or PA:Ao ratio (OR 1.04, 95%CI 1.01–1.07). Conclusions: In smokers with or without COPD, nocturnal hypoxemia was associated with PAE independently of OSA coexistence.

Lung Cancer (LC) screening with low dose chest computed tomography (LDCT) in smokers reduces LC mortality. Patients with Obstructive Lung Disease (OLD) are at high risk for LC. The potential effect of LC screening in this population is unknown.To determine if screening with LDCT reduces LC mortality in smokers with spirometrically defined OLD.The National Lung Screening Trial-American College of Radiology Imaging Network (NLST-ACRIN) study included 13,831 subjects (55-74 years of age with ≥30 pack-year history of smoking) that had a baseline spirometry. Randomly assigned to LDCT or Chest X-ray, all had 3 annual rounds of screening. LC mortality was compared between the LDCT and chest X-ray arms during the 1st year and at 6 years of follow up. Landmark analysis explored LC mortality differences between arms after the first year.From the 4584 subjects with OLD (FEV1/FVC0.7), 152 (3.3%) died from LC. Multivariable analysis showed that screening trended to decrease LC mortality at 6 years (HR, 95%CI: 0.75, 0.55-1.04, p=0.09). During the 1st year no differences were found between arms (p=0.65). However, after this year, LDCT significantly decreased LC mortality (HR, 95%CI: 0.63, 0.44-0.91, p=0.01). The number needed to screen to avoid one LC death in these subjects was 108 while in those without OLD was 218.LC screening with LDCT in smokers with spirometrically diagnosed OLD, showed a trend to reduce lung cancer mortality but a study with a larger number of patients and with a more robust design would be needed to confirm these findings.

Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was demonstrated in the National Lung Screening Trial (NLST) to reduce mortality from the disease. European mortality data has recently become available from the Nelson randomised controlled trial, which confirmed lung cancer mortality reductions by 26% in men and 39–61% in women. Recent studies in Europe and the USA also showed positive results in screening workers exposed to asbestos. All European experts attending the “Initiative for European Lung Screening (IELS)”—a large international group of physicians and other experts concerned with lung cancer—agreed that LDCT-LCS should be implemented in Europe. However, the economic impact of LDCT-LCS and guidelines for its effective and safe implementation still need to be formulated. To this purpose, the IELS was asked to prepare recommendations to implement LCS and examine outstanding issues. A subgroup carried out a comprehensive literature review on LDCT-LCS and presented findings at a meeting held in Milan in November 2018. The present recommendations reflect that consensus was reached.

Lung cancer screening (LCS) has the potential to reduce the risk of lung cancer death in healthy individuals, but the impact of coexisting chronic illnesses on LCS outcomes has not been well defined. Consideration of the complex relationship between baseline risk of lung cancer, treatment-related harms, and risk of death from competing causes is crucial in determining the balance of benefits and harms of LCS.To summarize evidence, identify knowledge and research gaps, prioritize topics, and propose methods for future research on how best to incorporate comorbidities in making decisions regarding LCS.A multidisciplinary group of international clinicians and researchers reviewed available data on the effects of comorbidities on LCS outcomes, focusing on the juxtaposition of lung cancer risk and competing risks of death, consideration of benefits and risks in patients with chronic obstructive pulmonary disease, communication of risk, and treatment of screen-detected lung cancer.This statement identifies gaps in knowledge regarding how comorbidities and competing causes of death impact outcomes in LCS, and we have developed questions to help guide future research efforts to better inform patient selection, education, and implementation of LCS.There is an urgent need for further research that can help guide clinical decision-making with patients who may not benefit from LCS owing to coexisting chronic illness. This statement establishes a research framework to address essential questions regarding how to incorporate and communicate risks of comorbidities into patient selection and decisions regarding LCS.

Each of the pathological stages (I-IIIa) of surgically resected non-small-cell lung cancer has hidden biological heterogeneity, manifested as heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers with which to assess individual patient risk is an unmet medical need. Here, we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI, and SLC2A1) to stratify early-stage lung adenocarcinoma patients according to their risk of recurrence or death. Patients were staged according to the new International Association for the Study of Lung Cancer (IASLC) staging criteria (8th edition, 2018). A test cohort (n = 239) was used to assess the value of this new prognostic index (PI) based on the three proteins. The prognostic signature was developed by Cox regression with the use of stringent statistical criteria (TRIPOD: Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The model resulted in a highly significant predictor of 5-year outcome for disease-free survival (p < 0.001) and overall survival (p < 0.001). The prognostic ability of the model was externally validated in an independent multi-institutional cohort of patients (n = 114, p = 0.021). We also demonstrated that this molecular classifier adds relevant information to the gold standard TNM-based pathological staging, with a highly significant improvement of the likelihood ratio. We subsequently developed a combined PI including both the molecular and the pathological data that improved the risk stratification in both cohorts (p ≤ 0.001). Moreover, the signature may help to select stage I-IIA patients who might benefit from adjuvant chemotherapy. In summary, this protein-based signature accurately identifies those patients with a high risk of recurrence and death, and adds further prognostic information to the TNM-based clinical staging, even when the new IASLC 8th edition staging criteria are applied. More importantly, it may be a valuable tool for selecting patients for adjuvant therapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document has modified the grading system directing pharmacotherapy, but how this relates to the previous one from 2015 and to comorbidities, hospitalizations, and mortality risk is unknown.The aim of this study was to evaluate the changes in the GOLD groups from 2015 to 2017 and to assess the impact on severity, comorbidities, and mortality within each group.We prospectively enrolled and followed, for a mean of 5 years, 819 patients with chronic obstructive pulmonary disease (84% male) in clinics in Spain and the United States. We determined anthropometrics, lung function (FEVCompared with 2015, the 2017 grading decreased by half the proportion of patients in groups C and D (20.5% vs. 11.2% and 24.6% vs. 12.9%; P 0.001). The distribution of Charlson also changed, whereas group D was higher than B in 2015, they become similar in the 2017 system. In 2017, the BODE index and risk of death were higher in B and D than in A and C. The mortality risk was better predicted by the 2015 than the 2017 system.Compared with 2015, the GOLD ABCD 2017 classification significantly shifts patients from grades C and D to categories A and B. The new grading system equalizes the Charlson comorbidity score in all groups and minimizes the differences in BODE between groups B and D, making the risk of death similar between them.

Sorafenib is a multi-kinase inhibitor and a vascular endothelial growth factor (VEGF) inhibitor approved to treat patients with advanced hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid carcinoma. Its most common side effects are asthenia/fatigue, skin toxicity, diarrhea and arterial hypertension. Reported respiratory adverse reactions include dyspnea, cough, pleural effusion and hoarseness. The aim of this report is to describe for the first time the occurrence of pneumatocele in two patients treated with Sorafenib. Patients had no respiratory symptoms and alternative diagnoses were ruled out. Primary tumors were different (liver metastases from a pancreatic neuroendocrine tumor and hepatocellular carcinoma) but both patients had been treated with yttrium 90 radioembolization 9 and 17 months before starting on Sorafenib, respectively. No complications occurred and Sorafenib withdrawal was followed by radiologic improvement.

Introduction The prevalence of bronchiectasis in the general population and in individuals undergoing lung cancer screening with low dose computed tomography (LDCT) is unknown. The aim of this study is to estimate the prevalence and impact of bronchiectasis in a screening lung cancer program. Methods 3028 individuals participating in an international multicenter lung cancer screening consortium (I-ELCAP) were selected from 2000 to 2012. Patients with bronchiectasis on baseline CT were identified and compared to selected controls. Detection of nodules, need for additional studies and incidence of cancer were analyzed over the follow-up period. Results The prevalence of bronchiectasis was 11.6%(354/3028). On the baseline LDCT, the number of subjects with nodules identified was 189(53.4%) in patients with bronchiectasis compared to 63(17.8%) in controls (p

The present review is an update of the research and development efforts regarding the use of molecular biomarkers in the lung cancer screening setting. The two main unmet clinical needs, namely, the refinement of risk to improve the selection of individuals undergoing screening and the characterization of undetermined nodules found during the computed tomography-based screening process are the object of the biomarkers described in the present review. We first propose some principles to optimize lung cancer biomarker discovery projects. Then, we summarize the discovery and developmental status of currently promising molecular candidates, such as autoantibodies, complement fragments, microRNAs, circulating tumor DNA, DNA methylation, blood protein profiling, or RNA airway or nasal signatures. We also mention other emerging biomarkers or new technologies to follow, such as exhaled breath biomarkers, metabolomics, sputum cell imaging, genetic predisposition studies, and the integration of next-generation sequencing into study of circulating DNA. We also underline the importance of integrating different molecular technologies together with imaging, radiomics, and artificial intelligence. We list a number of completed, ongoing, or planned trials to show the clinical utility of molecular biomarkers. Finally, we comment on future research challenges in the field of biomarkers in the context of lung cancer screening and propose a design of a trial to test the clinical utility of one or several candidate biomarkers.

BackgroundTo assess the relationship between lung cancer and emphysema subtypes.ObjectiveAirflow obstruction and emphysema predispose to lung cancer. Little is known, however, about the lung cancer risk associated with different emphysema phenotypes. We assessed the risk of lung cancer based on the presence, type and severity of emphysema, using visual assessment.MethodsSeventy-two consecutive lung cancer cases were selected from a prospective cohort of 3,477 participants enrolled in the Clínica Universidad de Navarra's lung cancer screening program. Each case was matched to three control subjects using age, sex, smoking history and body mass index as key variables. Visual assessment of emphysema and spirometry were performed. Logistic regression and interaction model analysis were used in order to investigate associations between lung cancer and emphysema subtypes.ResultsAirflow obstruction and visual emphysema were significantly associated with lung cancer (OR = 2.8, 95%CI: 1.6 to 5.2; OR = 5.9, 95%CI: 2.9 to 12.2; respectively). Emphysema severity and centrilobular subtype were associated with greater risk when adjusted for confounders (OR = 12.6, 95%CI: 1.6 to 99.9; OR = 34.3, 95%CI: 25.5 to 99.3, respectively). The risk of lung cancer decreases with the added presence of paraseptal emphysema (OR = 4.0, 95%CI: 3.6 to 34.9), losing this increased risk of lung cancer when it occurs alone (OR = 0.7, 95%CI: 0.5 to 2.6).ConclusionsVisual scoring of emphysema predicts lung cancer risk. The centrilobular phenotype is associated with the greatest risk.

Background A major drawback of lung cancer screening programs is the high frequency of false-positive findings on computed tomography (CT). We investigated the accuracy of selective 2-[fluorine-18]-fluoro-2-deoxy- d -glucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) scan in assessing radiologically indeterminate lung nodules detected in lung cancer screening. Methods FDG PET/CT was performed to characterize 64 baseline lung nodules >10 mm and 36 incidence nodules detected on low-dose CT screening in asymptomatic current or former smokers (83 men, age range 40–83 years) at high risk for lung cancer. CT images were acquired without intravenous contrast. Nodules were analyzed by size, density, and metabolic activity and visual scored on a 5-point scale for FDG uptake. Nodules were classified as negative for malignancy when no FDG uptake was observed, or positive when focal uptake was observed in the visual analysis, and the maximum standardized uptake value (SUVmax) was measured. Final diagnosis was based on histopathological evaluation or at least 24 months of follow-up. Results A total of 100 nodules were included. The prevalence of lung cancer was 1%. The sensitivity, specificity, NPV and PPV of visual analysis to detect malignancy were 84%, 95%, 91%, and 91%, respectively, with an accuracy of 91% (AUC 0.893). FDG PET/CT accurately detected 31 malignant tumors (diameters 9–42 mm, SUVmax range 0.6–14.2) and was falsely negative in 6 patients. With SUVmax thresholds for malignancy of 1.5, 2, and 2.5, specificity was 97% but sensitivity decreased to 65%, 49%, and 46% respectively, and accuracy decreased to 85%, 79%, and 78% respectively (AUC 0.872). Conclusions The visual analysis of FDG PET/CT scan is highly accurate in characterizing indeterminate pulmonary nodules detected in lung cancer screening with low-dose CT. Semi-quantitative analysis does not improve the accuracy of FDG PET/CT over that obtained with a qualitative method for lung nodule characterization.

Introduction The Spanish COPD guidelines (GesEPOC) have been recently modified. The aim of this study is to assess this revision and evaluate the prognosis of patients according to the new classification of severity. Methods A total of 700 COPD patients (83.9% men) were prospectively followed up for a mean period of 5 years in tertiary hospitals in Spain and the USA. Anthropometric data, lung function tests, dyspnea (according to the mMRC scale), BODE and Charlson index were collected. We calculated mortality at 5 years following the risk criteria proposed by the new GesEPOC. Results Mean age was 66±9.6 years and mean FEV1% was 59.7±20.2. The proportion of patients in the low-risk group was 40.43%. Patients in the high-risk group had a significantly higher BODE index than those in the low-risk group (2.92±0.66 vs 0.52±1.91, P Conclusions The new severity index proposed by GesEPOC accurately predicts 5-year mortality. However, dyspnea and FEV1% have the same strength in predicting mortality.

Clinical management decisions arising from the baseline round for lung cancer screening are the most challenging, as findings have accumulated over a lifetime and may be of no clinical concern. To minimize unnecessary harms and costs of workup prior to the first, annual repeat screening, workup should be limited to participants with the highest suspicion of lung cancer while still aiming to identify small, early lung cancers. We compared recommendations for immediate, delayed (by 3 or 6 months) workup to assess growth at a malignant rate, and the resulting overall and potential biopsies of three baseline screening protocols: I-ELCAP, the two scenarios of ACR-LungRADS, and the European Consortium. For each protocol, the efficiency ratio (ER) of each recommendation was calculated by dividing the number of participants recommended for that workup by the number of resulting lung cancer diagnoses. The ER for potential biopsies was calculated, assuming that biopsies were performed on all participants recommended for immediate workup as well as those diagnosed with lung cancer after delayed workup. For I-ELCAP, ACR-LungRADS Scenario 1, ACR-LungRADS Scenario 2, and the European consortium, the overall ER was 13.9, 18.3, 18.3, and 31.9, respectively, and for potential biopsies, it was 2.2, 8.1, 3.2, and 4.4, respectively. ER for immediate workup was 2.9, 8.6, 3.9, and 5.6, respectively, and for delayed workup was 36.1, 160.3, 57.8, and 111.9, respectively. I-ELCAP recommendations had the lowest ER values for overall, immediate, and delayed workup, and for potential biopsies. • Small differences in protocol thresholds can lead to many unnecessary diagnostic workups. • I-ELCAP recommendations were the most efficient for immediate and overall workup, and potential biopsies. • Definition of a “positive result” and recommendations for further workup in the baseline round needs to be continually reevaluated and updated.

A fully automated system is presented for bone mineral density (BMD) assessment from low-dose chest CT (LDCT). BMD assessment is central in the diagnosis and follow-up therapy monitoring of osteoporosis, which is characterized by low bone density and is estimated to affect 12.3 million US population aged 50 years or older, creating tremendous social and economic burdens. BMD assessment from DXA scans (BMDDXA) is currently the most widely used and gold standard technique for the diagnosis of osteoporosis and bone fracture risk estimation. With the recent large-scale implementation of annual lung cancer screening using LDCT, great potential emerges for the concurrent opportunistic osteoporosis screening. In the presented BMDCT assessment system, each vertebral body is first segmented and labeled with its anatomical name. Various 3D region of interest (ROI) inside the vertebral body are then explored for BMDCT measurements at different vertebral levels. The system was validated using 76 pairs of DXA and LDCT scans of the same subject. Average BMDDXA of L1-L4 was used as the reference standard. Statistically significant (p-value < 0.001) strong correlation is obtained between BMDDXA and BMDCT at all vertebral levels (T1 – L2). A Pearson correlation of 0.857 was achieved between BMDDXA and average BMDCT of T9-T11 by using a 3D ROI taking into account of both trabecular and cortical bone tissue. These encouraging results demonstrate the feasibility of fully automated quantitative BMD assessment and the potential of opportunistic osteoporosis screening with concurrent lung cancer screening using LDCT.

Rationale Pulmonary artery enlargement (PAE) is associated with exacerbations in Chronic Obstructive Pulmonary Disease (COPD) and with survival in moderate to severe patients. The potential role of PAE in survival prediction has not been compared with other clinical and physiological prognostic markers. Methods In 188 patients with COPD, PA diameter was measured on a chest CT and the following clinical and physiological parameters registered: age, gender, smoking status, pack-years history, dyspnea, lung function, exercise capacity, Body Mass Index, BODE index and history of exacerbations in year prior to enrolment. Proportional Cox regression analysis determined the best predictor of all cause survival. Results During 83 months (±42), 43 patients died. Age, pack-years history, smoking status, BMI, FEV1%, six minute walking distance, Modified Medical Research Council dyspnea scale, BODE index, exacerbation rate prior to enrollment, PA diameter and PAE (diameter≥30mm) were associated with survival. In the multivariable analysis, age (HR: 1.08; 95%CI: 1.03–1.12, p

Purpose To extract radiologic features from small pulmonary nodules (SPNs) that did not meet the original criteria for a positive screening test and identify features associated with lung cancer risk by using data and images from the National Lung Screening Trial (NLST). Materials and Methods Radiologic features in SPNs in baseline low-dose computed tomography (CT) screening studies that did not meet NLST criteria to be considered a positive screening examination were extracted. SPNs were identified for 73 incident case patients who were given a diagnosis of lung cancer at either the first or second follow-up screening study and for 157 control subjects who had undergone three consecutive negative screening studies. Multivariable logistic regression was used to assess the association between radiologic features and lung cancer risk. All statistical tests were two sided. Results Nine features were significantly different between case patients and control subjects. Backward elimination followed by bootstrap resampling identified a reduced model of highly informative radiologic features with an area under the receiver operating characteristic curve of 0.932 (95% confidence interval [CI]: 0.88, 0.96), a specificity of 92.38% (95% CI: 52.22%, 84.91%), and a sensitivity of 76.55% (95% CI: 87.50%, 95.35%) that included total emphysema score (odds ratio [OR] = 1.71; 95% CI: 1.39, 2.01), attachment to vessel (OR = 2.41; 95% CI: 0.99, 5.81), nodule location (OR = 3.25; 95% CI: 1.09, 8.55), border definition (OR = 7.56; 95% CI: 1.89, 30.8), and concavity (OR = 2.58; 95% CI: 0.89, 5.64). Conclusion A set of clinically relevant radiologic features were identified that that can be easily scored in the clinical setting and may be of use to determine lung cancer risk among participants with SPNs.

http://hdl.handle.net/20.500.11768/96517

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n = 3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (pcombined = 5.66 × 10-5 ; ORcombined = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (pcombined = 1.02 × 10-4 ; ORcombined = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10DmRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p = 0.01 and p

The original version of this article, published on 03 December 2018, unfortunately contained a mistake.

Development of molecular markers that help to identify high-risk individuals or diagnose indeterminate pulmonary nodules could have a major impact on lung cancer clinical management. In this study, we evaluated the diagnostic potential of a newly-developed ELISA that specifically detects complement C4d. We measured this marker in five independent cohorts of plasma and bronchoalveolar lavage samples from lung cancer patients and controls. In case-control studies, the area under the ROC curve for the diagnosis of lung cancer was 0.82 (95%CI = 0.72-0.92) in plasma samples, and 0.80 (95%CI = 0.69 to 0.90) in bronchoalveolar lavage fluids. In a set of plasma samples from the MILD CT-screening trial, the assay was unable to discriminate between asymptomatic high-risk individuals with or without early stage lung cancer. On the contrary, in two independent cohorts of individuals with indeterminate pulmonary nodules, plasma samples from patients with lung cancer nodules presented higher levels of C4d than those from patients with benign nodules. Using a target population of patients with 8 to 30 mm nodules, the test identified likely benign lung nodules with 84% negative predictive value and 54% positive predictive value, at 89% specificity and 44% sensitivity. In conclusion, the specific determination of C4d may serve as an adjunct to current clinical practice in the diagnosis of indeterminate pulmonary nodules.

Lung cancer (LC) screening using low-dose chest computed tomography is now recommended in several guidelines using the National Lung Screening Trial (NLST) entry criteria (age, 55-74; ≥30 pack-years; tobacco cessation within the previous 15 yr for former smokers). Concerns exist about their lack of sensitivity.To evaluate the performance of NLST criteria in two different LC screening studies from Europe and the United States, and to explore the effect of using emphysema as a complementary criterion.Participants from the Pamplona International Early Lung Action Detection Program (P-IELCAP; n = 3,061) and the Pittsburgh Lung Screening Study (PLuSS; n = 3,638) were considered. LC cumulative frequencies, incidence densities, and annual detection rates were calculated in three hypothetical cohorts, including subjects who met NLST criteria alone, those with computed tomography-detected emphysema, and those who met NLST criteria and/or had emphysema.Thirty-six percent and 59% of P-IELCAP and PLuSS participants, respectively, met NLST criteria. Among these, higher LC incidence densities and detection rates were observed. However, applying NLST criteria to our original cohorts would miss as many as 39% of all LC. Annual screening of subjects meeting either NLST criteria or having emphysema detected most cancers (88% and 95% of incident LC of P-IELCAP and PLuSS, respectively) despite reducing the number of screened participants by as much as 52%.LC screening based solely on NLST criteria could miss a significant number of LC cases. Combining NLST criteria and emphysema to select screening candidates results in higher LC detection rates and a lower number of cancers missed.

Introduction and objectives European experience regarding lung cancer screening using low-dose chest CT (LDCT) is available. However, there is limited data on the Spanish experience in this matter. Our aim is to present the results from the longest ongoing screening program in Spain. Methodology The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) is actively screening participants for lung cancer using LDCT since the year 2000 following the IELCAP protocol, including spirometric assessments. Men and women, ≥40 years of age, current or former smokers with a tobacco history of ≥10 pack-years are included. Results are compared to those from other European trials. Results A total of 2989 participants were screened until March 2014 (73% male). A median of 2 (IQR 1–3) annual screening rounds were performed. Sixty lung cancers were detected in 53 participants (73% in Stage I). Adenocarcinoma was the most frequent. The lung cancer prevalence and incidence proportion was 1.0% and 1.4%, respectively, with an annual detection rate of 0.41. The estimated 10-year survival rate among individuals with lung cancer was 70%. Chronic obstructive pulmonary disease and emphysema are important lung cancer predictors. Conclusions The experience in Spain's longest lung cancer screening program is comparable to what has been described in the rest of Europe, and confirms the feasibility and efficacy of lung cancer screening using LDCT.

Patients with chronic obstructive pulmonary disease (COPD) are at high risk for lung cancer (LC) and represent a potential target to improve the diagnostic yield of screening programs.To develop a predictive score for LC risk for patients with COPD.The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) and the Pittsburgh Lung Screening Study (PLuSS) databases were analyzed. Only patients with COPD on spirometry were included. By logistic regression we determined which factors were independently associated with LC in PLuSS and developed a COPD LC screening score (COPD-LUCSS) to be validated in P-IELCAP.By regression analysis, age greater than 60, body mass index less than 25 kg/m(2), pack-years history greater than 60, and emphysema presence were independently associated with LC diagnosis and integrated into the COPD-LUCSS, which ranges from 0 to 10 points. Two COPD-LUCSS risk categories were proposed: low risk (scores 0-6) and high risk (scores 7-10). In comparison with low-risk patients, in both cohorts LC risk increased 3.5-fold in the high-risk category.The COPD-LUCSS is a good predictor of LC risk in patients with COPD participating in LC screening programs. Validation in two different populations adds strength to the findings.

Background Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for cardiovascular (CV) disease, one of the most frequent causes of death in COPD patients. The goal of the present study was to evaluate the prognostic value of non-invasive CV risk markers in COPD patients. Methods CV risk was prospectively evaluated in 287 COPD patients using non-invasive markers including the Framingham score, the Systematic Coronary Risk Evaluation (SCORE) charts, coronary arterial calcium (CAC), epicardial adipose tissue (EAT), as well as clinical, biochemical and physiological variables. The predictive power of each parameter was explored using CV events as the main outcome. Results During a median follow up of 65 months (ICR: 36–100), 44 CV events were recorded, 12 acute myocardial infarctions (27.3%), 10 ischemic heart disease/angina (22.7%), 12 peripheral artery disease events requiring surgery (27.3%) and 10 strokes (22.7%). A total of 35 CV deaths occurred during that period. Univariable analysis determined that age, hypertension, CRP, total Cholesterol, LDL-Cholesterol, Framingham score and CAC were independently associated with CV events. Multivariable analysis identified CAC as the best predictor of CV events (HR; 95%CI: 1.32; 1.19–1.46, p

Background Aging is an important risk factor for most chronic diseases. Patients with COPD develop more comorbidities than non-COPD subjects. We hypothesized that the development of comorbidities characteristically affecting the elderly occur at an earlier age in subjects with the diagnosis of COPD. Methods and findings We included all subjects carrying the diagnosis of COPD (n = 27,617), and a similar number of age and sex matched individuals without the diagnosis, extracted from the 727,241 records of individuals 40 years and older included in the EpiChron Cohort (Aragon, Spain). We compared the cumulative number of comorbidities, their prevalence and the mortality risk between both groups. Using network analysis, we explored the connectivity between comorbidities and the most influential comorbidities in both groups. We divided the groups into 5 incremental age categories and compared their comorbidity networks. We then selected those comorbidities known to affect primarily the elderly and compared their prevalence across the 5 age groups. In addition, we replicated the analysis in the smokers’ subgroup to correct for the confounding effect of cigarette smoking. Subjects with COPD had more comorbidities and died at a younger age compared to controls. Comparison of both cohorts across 5 incremental age groups showed that the number of comorbidities, the prevalence of diseases characteristic of aging and network’s density for the COPD group aged 56–65 were similar to those of non-COPD 15 to 20 years older. The findings persisted after adjusting for smoking. Conclusion Multimorbidity increases with age but in patients carrying the diagnosis of COPD, these comorbidities are seen at an earlier age.

Background The Global Initiative for Obstructive Lung Diseases (GOLD) defines COPD as a disease that is usually progressive. GOLD also provides a spirometric classification of airflow limitation. However, little is known about the long-term changes of patients in different GOLD grades. Objective Explore the proportion and characteristics of COPD patients that change their spirometric GOLD grade over long-term follow-up. Methods Patients alive for at least 8 years since recruitment and those who died with at least 4 years of repeated spirometric measurements were selected from the BODE cohort database. We purposely included the group of non survivors to avoid a “survival selection” bias. The proportion of patients that had a change (improvement or worsening) in their spirometric GOLD grading was calculated and their characteristics compared with those that remained in the same grade. Results A total of 318 patients were included in the survivor and 217 in the non-survivor groups. Nine percent of survivors and 11% of non survivors had an improvement of at least one GOLD grade. Seventy one percent of survivors and non-survivors remained in the same GOLD grade. Those that improved had a greater degree of airway obstruction at baseline. Conclusions In this selected population of COPD patients, a high proportion of patients remained in the same spirometric GOLD grade or improved in a long-term follow-up. These findings suggest that once diagnosed, COPD is usually a non-progressive disease.

Purpose The tumour molecular profile predicts the activity of epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). However, tissue availability and tumour heterogeneity limit its assessment. We evaluated whether [18F]FDG PET might help predict KRAS and EFGR mutation status in NSCLC.

As a result of therapeutic advances, a revolution is taking place in the lung cancer field with major implications for pathologic diagnosis and tissue management. We report a case of a non–small cell lung carcinoma patient with coexistence of EGFR mutations and ALK-EML4 rearrangements that responded to EGFR inhibitors and in which the development of a new resistance mutation in exon 20 of EGFR-determined treatment resistance. All the molecular determinations were performed in cytological samples. To our knowledge, this is the first case reported with these characteristics, and the 11th case described with coexistence of EGFR mutations and ALK-EML4 rearrangements. The EGFR L858R mutation in exon 21 was found at diagnosis, and the patient presented a 4-year response to erlotinib. On progression, the T790M resistance mutation in the EGFR exon 20 was also confirmed in cytological samples. At this point, fluorescence in situ hybridization also detected ALK-EML4 translocation. This case emphasizes the usefulness of cytological samples for molecular analysis in lung adenocarcinoma, as well as the relevance of repeating biopsies/fine-needle aspirations in tumor recurrences to assess the mutation profile of the disease.

1540 Background: Individual susceptibility to carcinogens may depend on the genetic background. We characterized the constitutional exome of individuals presenting extreme phenotypes of high sensitivity and resistance to develop tobacco induced LUAD, correlating the results to KRAS status. Methods: From an identification cohort (n=3,631) we selected 100 caucasian heavy smokers that either developed LUAD at early age (cancer cohort, n=50) or did not develop LUAD or other tumors at advanced age (cancer free cohort, n=50). We sequenced their germline DNA with the Agilent Human Exome Capture v5 (21,522 genes, 357,999 exons). Using logistic regression we selected the most significant variants between both cohorts and correlated them with KRAS mutation status of LUAD patients. Results: mean ages for the cancer and cancer free cohorts were 50 (range 34-55) and 78 years (72-90). Mean tobacco consumptions were 44 (range 6-72) and 55 pack-years (20-124). Median coverage was 96% at >10X; median depth was 97X. Table shows the most significant variants. rs7240666 ( ALPK2) achieved top significance (p=8.14x10-5, OR 0.18). rs78898229 ( ANKRD36C) and rs74866537 ( PTPN4) were predominantly represented in patients with KRAS+ tumors, OR: 16 (3.3-78) and 11.9 (3.3-43); and rs12426243 (CCDC41) in KRAS- tumors (OR: 13 (3-53). Conclusions: Our study characterizes for the first time the genotype of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced LUAD according to KRAS status. Our results warrants further study to assess their value to screen these clinically relevant phenotypes; and to identify mechanisms of high susceptibility and resistance to carcinogens. [Table: see text]