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Background: Despite the potential of exhaled breath analysis of volatile organic compounds to diagnose lung cancer, clinical implementation has not been realized, partly due to the lack of validation studies., Research Question: This study addressed two questions. First, can we simultaneously train and validate a prediction model to distinguish patients with non-small cell lung cancer from non-lung cancer subjects based on exhaled breath patterns? Second, does addition of clinical variables to exhaled breath data improve the diagnosis of lung cancer?, Study Design and Methods: In this multicenter study, subjects with non-small cell lung cancer and control subjects performed 5 min of tidal breathing through the aeoNose, a handheld electronic nose device. A training cohort was used for developing a prediction model based on breath data, and a blinded cohort was used for validation. Multivariable logistic regression analysis was performed, including breath data and clinical variables, in which the formula and cutoff value for the probability of lung cancer were applied to the validation data., Results: A total of 376 subjects formed the training set, and 199 subjects formed the validation set. The full training model (including exhaled breath data and clinical parameters from the training set) were combined in a multivariable logistic regression analysis, maintaining a cut off of 16% probability of lung cancer, resulting in a sensitivity of 95%, a specificity of 51%, and a negative predictive value of 94%; the area under the receiver-operating characteristic curve was 0.87. Performance of the prediction model on the validation cohort showed corresponding results with a sensitivity of 95%, a specificity of 49%, a negative predictive value of 94%, and an area under the receiver-operating characteristic curve of 0.86., Interpretation: Combining exhaled breath data and clinical variables in a multicenter, multi-device validation study can adequately distinguish patients with lung cancer from subjects without lung cancer in a noninvasive manner. This study paves the way to implement exhaled breath analysis in the daily practice of diagnosing lung cancer., Clinical Trial Registration: The Netherlands Trial Register; No.: NL7025; URL: https://trialregister.nl/trial/7025., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Lung cancer is the largest cause of cancer-related deaths worldwide. Eighty-five percent of patients is diagnosed with non-small cell lung cancer (NSCLC). Almost a third of patients is aged over 75, but this group is poorly represented in clinical trials. This study compares the effects of therapy in non-operable stage III NSCLC in elderly patients compared to their younger counterparts., Patients and Methods: This is a retrospective cohort study. Patients are divided into three groups; patients younger than 65, patients aged between 65 and 75 and patients of 75 years or older. Concurrent chemoradiotherapy is compared to sequential chemoradiotherapy using Cox regression analysis. The primary outcome is survival. A sub analysis is performed for the presence of toxicity using logistic regression., Results: Seven hundred and fifty patients were diagnosed with stage III NSCLC and treated with concurrent (442) or sequential (308) chemoradiotherapy. Concurrent chemoradiotherapy provides a decreased HR of death of 0.72 (0.560-0.85) compared to sequential chemoradiotherapy, even when corrected for age. Elderly patients receiving concurrent chemoradiotherapy do not have a significantly larger risk of toxicity., Conclusions: Patients of all ages with stage III NSCLC benefit from concurrent chemoradiotherapy compared to sequential chemoradiotherapy. Age is not a deciding factor in this prospect, nor do the patients experience more severe toxicity than their younger counterparts., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: As there is increasing evidence for comparable survival after either stereotactic body radiotherapy (SBRT) or surgery for patients with stage I non-small-cell lung cancer (NSCLC), treatment impact on the quality of life (QoL) is essential for well-informed decision-making. Our previous work evaluated health utility between surgery and SBRT in stage I NSCLC. The aim of this secondary analysis is to directly compare QoL in the first year after SBRT and surgery., Materials and Methods: QoL was assessed at baseline and 3, 6, and 12 months after treatment. Two prospectively collected databases of patients with clinically proven stage I NSCLC, from 2 large hospitals in the Netherlands, were pooled (n = 306; 265 patients were treated with SBRT and 41 patients with surgery). To correct for confounding, propensity scores were calculated, to be selected for surgical treatment. A mixed model analysis was used to study differences in QoL between the 2 treatments., Results: The 41 surgical patients were matched to 41 SBRT patients on propensity score with a 1:1 ratio. At baseline, patients in the surgery group report a lower QoL compared with patients in the SBRT group. However, during the first year after treatment, no clinical meaningful differences were observed, except for role functioning, between patients treated using either modality., Conclusion: This study comparing a matched cohort revealed no clinically significant differences in QoL following either SBRT or surgery for early stage NSCLC. These results support the hypothesis that surgery and SBRT are comparable treatments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: There is an ongoing debate on the optimal treatment for stage I NSCLC, with increasing evidence for comparable health outcomes after surgery and stereotactic body radiation therapy (SBRT). For clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choosing between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus after SBRT before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility., Methods: Prospectively collected databases containing data on patients with stage I NSCLC treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data were measured by the Quality of Life Questionnaire-Core 30 questionnaire at baseline and 3, 6, and 12 months after treatment. Health utility (measured using the European Quality of Life Five-Dimension questionnaire) was calculated from the Quality of Life Questionnaire-Core 30 questionnaire by using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients by using a longitudinal mixed model approach., Results: After correction for Eastern Cooperative Oncology Group score, sex, and age, the difference in 1-year averaged health utility between the SBRT and surgery groups was 0.026 (95% confidence interval: 0.028-0.080). Differences in health utility decreased over time., Conclusions: A small but not statistically significant difference in health utility was found between patients with stage I NSCLC treated with surgery and those treated with SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early-stage NSCLC. Comparative cost-effectiveness remains to be determined., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The mechanisms that lead to the fibrotic obliteration in bronchiolitis obliterans syndrome (BOS) may involve the interactions between T-helper (Th)1 and Th2 cytokines. The aim of this study is to determine the Th1 and Th2 cytokine and chemokine profiles in serum and exhaled breath condensate (EBC) in lung transplant recipients and to assess their usefulness as biomarkers to predict the development of BOS., Methods: Serum and EBC from 10 patients with BOS (BOS(pos)) and 10 patients without BOS (BOS(neg)), matched for clinical and demographic variables, were analyzed with a multiplex immunoassay to measure a panel of 27 cytokines and chemokines., Results: The pro-inflammatory cytokines in serum were elevated in lung transplant recipients compared with controls. BOS(pos) patients had significantly lower concentrations of interleukin (IL)-4, IL-13, and vascular endothelial growth factor (VEGF) compared with BOS(neg) patients. The concentration of IL-5, however, was significantly higher in BOS(pos) patients. Levels of IL-4 and IL-5 were hardly detectable in EBC. IL-13 and VEGF, both decreased in serum in BOS(pos) patients, were also decreased in EBC in BOS(pos) patients compared with BOS(neg) patients. Longitudinal analysis of cytokines and chemokines in serum and EBC from the time of lung transplantation onwards did not reveal significant trends in cytokines and chemokines that preceded the diagnosis of BOS., Conclusions: Levels of pro-inflammatory cytokines were increased in lung transplant recipients compared with controls. From the moment of transplantation onwards, there is a different pattern of Th2 cytokines in serum in BOS(pos) patients than in BOS(neg) patients., (Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary epithelium is the primary target of injury in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. Matrix metalloproteinases (MMP)-8 and -9 already have been implicated in the pathogenesis of BOS. MMP-7, which is involved in the repair of the lung epithelium, has not been studied in this respect. We hypothesized that genetic polymorphisms in MMP7 influence its expression and correlate with serum MMP-7 levels and the development of BOS., Methods: DNA was collected from 110 lung transplant recipients, including 21 patients with BOS. We genotyped 7 single nucleotide polymorphisms in MMP7 and measured serum MMP-7 levels. The control group comprised 422 healthy individuals., Results: BOS(pos) patients had lower levels of MMP-7 than BOS(neg) patients (7.87 vs 10.18 ng/ml). Significant differences in genotype and haplotype distribution between the BOS(pos) and BOS(neg) patients and controls were found. An increased risk for BOS development was found in patients homozygous for the major alleles of rs17098318, rs11568818, and rs12285347, and for the minor allele rs10502001 (odds ratio, 3.88-5.30). Haplotypes constructed with 3 or 4 risk alleles correlated with lower MMP-7 levels., Conclusions: Genetic polymorphisms of MMP7 predispose to the development of BOS. Patients carrying these risk alleles express lower levels of MMP-7, which may contribute to aberrant tissue repair and culminate in the development of BOS., (Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Activation of the immune system is suggested to prevent transplant tolerance and to promote the development of bronchiolitis obliterans syndrome (BOS). The innate immune system is activated by the interaction of pathogen-associated molecular patterns of microorganisms with Toll-like receptors (TLRs). Activation of innate immunity via TLRs was shown to be a barrier to the induction of transplantation tolerance after lung transplantation. We hypothesized that polymorphisms in 10 genes coding for TLR1 to TLR10 might contribute to an altered immune response and the subsequent development of BOS., Methods: DNA was collected from 110 lung transplant recipients. Twenty patients developed BOS. The control group comprised 422 individuals. Sixty-four single-nucleotide polymorphisms (SNPs) in 10 genes coding for TLR1 to TLR10 were genotyped., Results: The genotype distribution of TLR2 (rs1898830 and rs7656411), TLR4 (rs1927911) and TLR9 (rs352162 and rs187084) was significantly different between BOS(pos) patients and BOS(neg) patients and controls. The BOS(pos) group had significantly more patients with 3 or 4 of these risk alleles compared with the BOS(neg) and control groups., Conclusions: Polymorphisms in TLR2, TLR4 and TLR9 that recognize bacterial and viral pathogens are associated with BOS after lung transplantation., (Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)