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Screening with low-dose computed tomography of high-risk individuals with a smoking history reduces lung cancer mortality. Current screening guidelines and eligibility criteria can miss more than 50% of lung cancers, and in some geographic areas, such as East Asia, a large proportion of the missed lung cancers are in never-smokers. Although randomized trials revealed the benefits of screening for people who smoke, these trials generally excluded never-smokers. Thus, the feasibility and effectiveness of lung cancer screening of individuals who never smoked are uncertain. Several known and suspected risk factors for lung cancers in never-smokers such as exposure to secondhand smoke, occupational carcinogens, radon, air pollution, and pulmonary diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases, and intrinsic factors, such as age, are well noted. In this regard, knowledge of risk factors may make possible quantification and prediction of lung cancer risk in never smokers. It is worth considering if and how never smokers could be included in population-based screening programs. As the implementation of these programs is challenging in many countries owing to multiple factors and the epidemiologic differences by global regions, these issues will need to be evaluated in each country taking into account various factors, including accuracy of risk assessment and cost-effectiveness of screening in never smokers. This report aims to outline current knowledge on risk factors for lung cancer in never smokers to propose research strategies for this topic and initiate a broader discussion on lung cancer screening of never smokers. Similar considerations can be made in current and ex-smokers, which do not fulfill the current screening inclusion criteria, but otherwise are at increased risk. Although screening of never smokers may in the future be effectively conducted, current evidence to support widespread implementation of this practice is lacking.

Study design participants, supplementary figure legends and List of cancer-related differentially methylated CpGs

Purpose: Lung cancer remains as the leading cause of cancer-related death worldwide, mainly due to late diagnosis. Cytology is the gold-standard method for lung cancer diagnosis in minimally invasive respiratory samples, despite its low sensitivity. We aimed to identify epigenetic biomarkers with clinical utility for cancer diagnosis in minimally/noninvasive specimens to improve accuracy of current technologies.Experimental Design: The identification of novel epigenetic biomarkers in stage I lung tumors was accomplished using an integrative genome-wide restrictive analysis of two different large public databases. DNA methylation levels for the selected biomarkers were validated by pyrosequencing in paraffin-embedded tissues and minimally invasive and noninvasive respiratory samples in independent cohorts.Results: We identified nine cancer-specific hypermethylated genes in early-stage lung primary tumors. Four of these genes presented consistent CpG island hypermethylation compared with nonmalignant lung and were associated with transcriptional silencing. A diagnostic signature was built using multivariate logistic regression model based on the combination of four genes: BCAT1, CDO1, TRIM58, and ZNF177. Clinical diagnostic value was also validated in multiple independent cohorts and yielded a remarkable diagnostic accuracy in all cohorts tested. Calibrated and cross-validated epigenetic model predicts with high accuracy the probability to detect cancer in minimally and noninvasive samples. We demonstrated that this epigenetic signature achieved higher diagnostic efficacy in bronchial fluids as compared with conventional cytology for lung cancer diagnosis.Conclusions: Minimally invasive epigenetic biomarkers have emerged as promising tools for cancer diagnosis. The herein obtained epigenetic model in combination with current diagnostic protocols may improve early diagnosis and outcome of lung cancer patients. Clin Cancer Res; 22(13); 3361–71. ©2016 AACR.

Epigenetic signature in lung cancer and non-tumoral paraffins classified based on histological subtypes.

Flow chart indicating study design and biological and bioinformatic filters

Predictions of cancer using the epigenetic model for the 24 false negatives cytologies.

Heatmap representing the patients' methylation profile for the four genes involved in the prediction model and Nomogram for prediction of cancer risk, constructed using the coefficients of our combined logistic regression model as weights.

Epigenetic and expression analysis based on histological subtypes from primary tissues of the TCGA database.

Primers for pyrosequencing and priority list.

The authors make the argument that the so-calledtraditional risk factors for lung cancer (older age,male sex, heavy smoking status), apart from geneticand environmental factors, are no longer the only riskfactors one should consider when defifining high riskand organizing early detection programs with low-dosecomputed tomography (LDCT). In general, a worldwideapproach to perform early detection LDCTs in individuals without additional risk factors who neversmoked cannot be mandated. Despite the fact thatLDCT can detect early lung cancer in individuals whonever smoked, the risk-to-benefifit ratio without additional risk factors is currently not favorable either onthe individual or the population level.

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.

The study objective was to determine the relationship between lung resection and the development of postoperative hiatal hernia.Preoperative and postoperative computed tomography imaging from 373 patients from the International Early Lung Cancer Action Program and the Initiative for Early Lung Cancer Research on Treatment were compared at a median of 31.1 months of follow-up after resection of clinical early-stage non-small cell lung cancer. Incidence of new hiatal hernia or changes to preexisting hernias were recorded and evaluated by patient demographics, surgical approach, extent of resection, and resection site.New hiatal hernias were seen in 9.6% of patients after lung resection (5.6% after wedge or segmentectomy and 12.4% after lobectomy;Both open and minimally invasive lung resection for clinical early-stage lung cancer are associated with new or enlarging postoperative hiatal hernia, especially after resections involving the left lower lobe.

Purpose Chronic Obstructive Pulmonary Disease (COPD) includes chronic bronchitis, small airways disease, and emphysema. Diagnosis of COPD requires spirometric evidence and may be normal even when small airways disease or emphysema is present. Emphysema increases the risk of exacerbations, and is associated with all-cause mortality and increased risk of lung cancer. We evaluated the prevalence of emphysema in participants with and without a prior history of COPD. Methods We reviewed a prospective cohort of 52,726 subjects who underwent baseline low dose CT screening for lung cancer from 2003 to 2016 in the International Early Lung Cancer Action Program. Results Of 52,726 participants, 23.8%(12,542) had CT evidence of emphysema. Of these 12,542 participants with emphysema, 76.5%(9595/12,542) had no prior COPD diagnosis even though 23.6% (2258/9595) had moderate or severe emphysema. Among 12,542 participants, significant predictors of no prior COPD diagnosis were: male (OR = 1.47, p Conclusion Emphysema was identified in 23.8% participants undergoing LDCT and was unsuspected in 76.5%. LDCT provides an opportunity to identify emphysema, and recommend smoking cessation.

Alveolar epithelial cells have been shown to be involved in the initiation and perpetuation of the fibrotic process. It is now becoming clear the importance of complex crosstalk between the neighboring mesenchyme and the alveolar type 2 (AT2) cells identified as the stem cell population in the adult lung. Now we demonstrate that, although the development of fibrosis remains also unknown, a Notch signal derived from AT2 cells is necessary for myofibroblast differentiation. First, we observed an increase in Notch3 activity in a subset of fibroblasts following bleomycin administration. Next, we analyzed the lungs of Notch3 KO mice and we found a significant reduction in bleomycin-induced fibrosis. Masson’s trichromic staining revealed less damage and quantification of collagen content showed a decrease in the absence of Notch3. Consistently, bleomycin-treated Notch3 KO lungs exhibited less aSMA+ cells and the expression of profibrotic genes as well as their protein levels were reduced compared to control lungs. Consequently, the function of these lungs was better. In addition, the elimination of the Notch ligand from AT2 cells using conditional mice phenocopied the elimination of fibroblast Notch3. Finally, we demonstrated the direct interaction between AT2 cells and fibroblasts using an in vitro co-culture system, which confirmed that a Notch signal derived from lung stem cells is necessary to activate Notch3 in fibroblast and induce their differentiation into myofibroblasts. Targetting the AT2 Notch ligand or the activation of Notch in fibroblasts may be a therapeutic strategy to block the initiation and/or progression of lung fibrosis.

To determine long-term survival of visceral pleural invasion (VPI) and parenchymal invasion (PAI) (angiolymphatic and/or vascular) on survival of NSCLCs less than 30 mm in maximum diameter.Kaplan-Meier survivals for NSCLCs, with and without VPI and/or PAI, were determined for a prospective cohort of screening participants stratified by pathologic tumor size (≤10 mm, 11-20 mm, and 21-30 mm) and nodule consistency. Log-rank test statistics were calculated.The frequency of PAI versus VPI was significantly lower in patients with subsolid nodules than in those with solid nodules (4.9% versus 27.7% [p0.0001]), and correspondingly, Kaplan-Meier lung cancer survival was significantly higher among patients with subsolid nodules (99.1% versus 91.3% [p = 0.0009]). Multivariable Cox regression found that only tumor diameter (adjusted hazard ratio [HR] =1.07, 95% confidence interval [CI]: 1.01-1.14, p = 0.02) and PAI (adjusted HR = 3.15, 95% CI: 1.25-7.90, p = 0.01) remained significant, whereas VPI was not significant (p = 0.15). When clinical and computed tomography findings were included with the pathologic findings, Cox regression showed that the risk of dying of lung cancer increased 10-fold (HR = 10.06, 95% CI: 1.35-75.30) for NSCLCs in patients with solid nodules and more than twofold (by a factor of 2.27) in patients with moderate to severe emphysema (HR = 2.27, 95% CI: 1.01-5.11), as well as with increasing tumor diameter (HR = 1.06, 95% CI: 1.01-1.13), whereas PAI was no longer significant (p = 0.19).Nodule consistency on computed tomography was a more significant prognostic indicator than either PAI or VPI. We propose that patients with NSCLC with VPI and a maximum tumor diameter of 30 mm or less not be upstaged to T2 without further large, multicenter studies of NSCLCs, stratified by the new T status and that classification be considered separately for patients with subsolid or solid nodules.

Rationale: Smoking has been associated with osteoporosis. Little is known about the combined role of clinical, spirometric, radiological and biochemical markers in the identification of osteoporosis in this high-risk population. Methods: 135 smokers were consecutively recruited. Clinical and demographic data was registered, presence and degree of airway limitation identified, presence of emphysema detected in a low-dose chest computed tomography, blood bone turnover markers (BTM) measured and their fracture risk assessment tool (FRAX) score calculated. Bone densitometry was performed on all patients, classifying their bone as healthy, with osteopenia or osteoporosis. Results: One hundred and six (78.5%) patients had an abnormal densitometry and 37 (27%) had osteoporosis. A multivariable analysis showed that emphysema presence (odds ratio [OR]: 3.90; 95% confidence interval [CI]: 1.43-10.64), a FRAX for a hip fracture 10-year risk>3% (OR: 5.29; 95% CI: 1.59-17.63) and a beta-crosslaps (β–CTX) level>0.20 ng/mL (OR: 3.16; 95% CI: 1.10-9.08) were independently associated with osteoporosis. Using their OR, the Score for Identification of Osteoporosis in Smokers (SIOS) was constructed that goes from 0 to 3.7. A SIOS> 2 points was associated a high risk of osteoporosis (OR: 5.6; 95% CI: 2.4-12.9). Conclusions: The present study demonstrated that radiological emphysema, a FRAX score for hip fracture >3%, and a β–CTX level>0.20 ng/mL were the best predictors of the presence of osteoporosis. A SIOS>2 could be use as a screening tool to help clinicians identify smokers at high risk of osteoporosis.

Objetivo: Demostrar la utilidad del tratamiento genico (TG) in vivo en los tumores subcutaneos de cancer de pulmon murino. Material y metodos: Se inyectaron a ratones C57BL/6 por via subcutanea 5 x 105 celulas de la linea de cancer de pulmon murino de Lewis. A los 10 dias se formaron tumores subcutaneos de unos 5 mm de diametro. En ese momento se trataron mediante inyeccion intratumoral con un adenovirus recombinante defectivo portador del gen de la timidincinasa (AdCMV-Tk), o del gen de la interleucina 12 (AdCMV-IL12), o con celulas dendriticas (CD) singenicas transducidas con el gen de la interleucina 12 (CD-IL12). Como grupos control se incluyeron tumores tratados con suero salino o con un adenovirus con el gen de la s-galactosidasa (AdCMV-LacZ), que es un gen indicador sin efecto terapeutico. El numero de animales por grupo oscilo entre 14 y 25 con adenovirus y entre 10 y 12 con CD. A continuacion se realizo un seguimiento del tamano tumoral desde el primer dia de tratamiento hasta la tercera (adenovirus) o cuarta (CD) semanas para comparar su evolucion. Resultados: Se objetivo una disminucion significativa del crecimiento de los tumores subcutaneos en los grupos tratados con AdCMV-Tk, AdCMV-IL12 y CD-IL12 comparados con los grupos control tratados con suelo salino y AdCMV-LacZ. En el grupo AdCMV-Tk esta diferencia fue estadisticamente significativa desde el dia 7, en AdCMV-IL12 desde el dia 9 y en CD-IL12 desde el dia 10 y se mantuvo hasta el final del seguimiento. Conclusiones: El TG con AdCMV-Tk, AdCMV-IL12 o CD-IL12 es efectivo en nuestro modelo de tumores subcutaneos de celulas de carcinoma pulmonar de Lewis, ya que es capaz de disminuir su tasa de crecimiento de forma significativa respecto a los grupos de control.

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 [(18)F]FDG PET might help predict KRAS and EFGR mutation status in NSCLC.Between January 2005 and October 2011, 340 NSCLC patients were tested for KRAS and EGFR mutation status. We identified patients with stage III and IV disease who had undergone [(18)F]FDG PET/CT scanning for initial staging. SUVpeak, SUVmax and SUVmean of the single hottest tumour lesions were calculated, and their association with KRAS and EGFR mutation status was assessed. A receiver operator characteristic (ROC) curve analysis and a multivariate analysis (including SUVmean, gender, age and AJCC stage) were performed to identify the potential value of [(18)F]FDG PET/CT for predicting KRAS mutation.From 102 patients staged using [(18)F]FDG PET/CT, 28 (27%) had KRAS mutation (KRAS+), 22 (22%) had EGFR mutation (EGFR+) and 52 (51%) had wild-type KRAS and EGFR profiles (WT). KRAS+ patients showed significantly higher [(18)F]FDG uptake than EGFR+ and WT patients (SUVmean 9.5, 5.7 and 6.6, respectively; p 0.001). No significant differences were observed in [(18)F]FDG uptake between EGFR+ patients and WT patients. ROC curve analysis for KRAS mutation status discrimination yielded an area under the curve of 0.740 for SUVmean (p 0.001). The multivariate analysis showed a sensitivity and specificity of 78.6% and 62.2%, respectively, and the AUC was 0.773.NSCLC patients with tumours harbouring KRAS mutations showed significantly higher [(18)F]FDG uptake than WT patients, as assessed in terms of SUVpeak, SUVmax and SUVmean. A multivariate model based on age, gender, AJCC stage and SUVmean might be used as a predictive marker of KRAS mutation status in patients with stage III or IV NSCLC.

Patients with chronic obstructive pulmonary disease (COPD) are afflicted by comorbidities. Few studies have prospectively evaluated COPD comorbidities and mortality risk.To prospectively evaluate COPD comorbidities and mortality risk.We followed 1,664 patients with COPD in five centers for a median of 51 months. Systematically, 79 comorbidities were recorded. We calculated mortality risk using Cox proportional hazard, and developed a graphic representation of the prevalence and strength of association to mortality in the form of a "comorbidome". A COPD comorbidity index (COPD specific comorbidity test [COTE]) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis. We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the validated BODE index.Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors. Of those, 12 predicted mortality and were integrated into the COTE index. Increases in the COTE index were associated with an increased risk of death from COPD-related (hazard ratio [HR], 1.13; 95% confidence interval, 1.08-1.18; P0.001) and non-COPD-related causes (HR, 1.18; 95% confidence interval, 1.15-1.21; P0.001). Further, increases in the BODE and COTE were independently associated with increased risk of death. A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death (HR, 2.26-2.68; P0.001) in all BODE quartile.Comorbidities are frequent in COPD and 12 of them negatively influence survival. A simple disease-specific comorbidities index (COTE) helps assess mortality risk in patients with COPD.

OBJECTIVE: To assess the effectiveness of in vivo gene therapy to treat subcutaneous tumors generated from murine lung cancer cells. MATERIAL AND METHODS: C57BL/6 mice received subcutaneus injections of 5×105 cells from the murine Lewis lung cancer cell line. By 10 days, subcutaneous tumors of approximately 5 mm diameter were formed. At that point, treatment was provided by intratumor injection of a replication-defective recombinant adenovirus carrying the gene for thymidine kinase (AdCMV-Tk) or interleukin (IL) 12 (AdCMV-IL12), or by injection of syngeneic dendritic cells previously transduced with adenovirus containing the IL-12 gene (DC-IL12). Control groups were treated with saline or adenovirus containing the gene for β-galactosidase (AdCMV-LacZ), which functions as a reporter gene and does not have a therapeutic effect. The number of animals in each group ranged from 14 to 25 in experiments using adenovirus and from 10 to 12 in experiments using dendritic cells. Tumor size was followed for 3 weeks in the case of treatment with adenovirus and 4 weeks for treatment with dendritic cells. RESULTS: A significant reduction in subcutaneous tumor growth was observed in the groups treated with AdCMVTk, AdCMV-IL12, and DC-IL12 compared with control groups treated with saline or AdCMV-LacZ. The difference was statistically significant from day 7 of treatment in the AdCMV-Tk group, from day 9 in the AdCMV-IL12 group, and from day 10 in the DC-IL12 group, and in all cases it was maintained until the end of the follow-up period. CONCLUSIONS: Gene therapy with AdCMV-Tk, AdCMVIL12, or DC-IL12 is effective in our model of subcutaneous tumors arising from cells of the Lewis lung cancer cell line. The treatment leads to a significant reduction in tumor growth compared with control groups.