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Rationale: Individuals eligible for lung cancer screening (LCS) by low-dose computed tomography (LDCT) are also at risk of chronic obstructive pulmonary disease (COPD) due to age and smoking exposure. Whether the LCS episode is useful for early detection of COPD is not well established. Objectives: To explore associations between symptoms, comorbidities, spirometry, and emphysema in participants enrolled in the Lung Screen Uptake Trial. Methods: This cross-sectional study was a prespecified analysis nested within Lung Screen Uptake Trial, which was a randomized study testing the impact of differing invitation materials on attendance of 60- to 75-year-old smokers and ex-smokers to a “lung health check” between November 2015 and July 2017. Participants with a smoking history ≥30 pack-years and who quit ≤15 years ago, or meeting a lung cancer risk of ≥1.51% via the Prostate Lung Colorectal Ovarian model or ≥2.5% via the Liverpool Lung Project model, were offered LDCT. COPD was defined and classified according to the GOLD (Global Initiative for Obstructive Lung Disease) criteria using prebronchodilator spirometry. Analyses included the use of descriptive statistics, chi-square tests to examine group differences, and univariable and multivariable logistic regression to explore associations between symptom prevalence, airflow limitation, and visually graded emphysema. Results: A total of 560 of 986 individuals included in the analysis (57%) had prebronchodilator spirometry consistent with COPD; 67% did not have a prior history of COPD and were termed “undiagnosed.” Emphysema prevalence in those with known and “undiagnosed” COPD was 73% and 68%, respectively. A total of 32% of those with “undiagnosed COPD” had no emphysema on LDCT. Inhaler use and symptoms were more common in the “known” than the “undiagnosed” COPD group (63% vs. 33% with persistent cough [P

Summary Tobacco smoking causes lung cancer1–3, driven by the 60+ carcinogens in cigarette smoke that directly damage and mutate DNA4,5. The profound effects of tobacco on the lung cancer genome have been well documented6–10, but we lack equivalent data for normal bronchial cells. We sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutation burden, adding 1000-10,000+ mutations/cell, massively increasing both within-subject and between-subject variance, and generating several distinct signatures of substitutions and indels. A population of cells in subjects with smoking history had mutation burdens equivalent to that expected for never-smokers: these cells had less damage from tobacco-specific mutational processes, were four-fold more frequent in ex-smokers than current smokers, and had significantly longer telomeres than their more mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged never-smokers. In current smokers, ≥25% of cells carried driver mutations and 0-6% cells had 2 or even 3 drivers. Thus, tobacco smoking increases mutation burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.

Patients with isolated mediastinal lymphadenopathy (IML) are a common presentation to physicians, and mediastinoscopy is traditionally considered the "gold standard" investigation when a pathological diagnosis is required. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as an alternative to mediastinoscopy in patients with lung cancer.To determine the efficacy and health care costs of EBUS-TBNA as an alternative initial investigation to mediastinoscopy in patients with isolated IML.Prospective multicenter single-arm clinical trial of 77 consecutive patients with IML from 5 centers between April 2009 and March 2011. All patients underwent EBUS-TBNA. If EBUS-TBNA did not provide a diagnosis, then participants underwent mediastinoscopy.EBUS-TBNA prevented 87% of mediastinoscopies (95% confidence interval [CI], 77-94%; P0.001) but failed to provide a diagnosis in 10 patients (13%), all of whom underwent mediastinoscopy. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML were 92% (95% CI, 83-95%) and 40% (95% CI, 12-74%), respectively. One patient developed a lower respiratory tract infection after EBUS-TBNA, requiring inpatient admission. The cost of the EBUS-TBNA procedure per patient was £1,382 ($2,190). The mean cost of the EBUS-TBNA strategy was £1,892 ($2,998) per patient, whereas a strategy of mediastinoscopy alone was significantly more costly at £3,228 ($5,115) per patient (P0.001). The EBUS-TBNA strategy is less costly than mediastinoscopy if the cost per EBUS-TBNA procedure is less than £2,718 ($4,307) per patient.EBUS-TBNA is a safe, highly sensitive, and cost-saving initial investigation in patients with IML. Clinical trial registered with ClinicalTrials.gov (NCT00932854).

In 2002, endobronchial ultrasound (EBUS) was developed by integrating a convex transducer with a frequency of 7.5 MHz into the tip of a flexible fiber-optic bronchoscope (XBF-UC40P, Olympus, Tokyo, Japan). For the first time, the linear curved array transducer allowed real-time sampling of lymph nodes adjacent to the airway by scanning in parallel to the insertion direction of the bronchoscope. The immediate application for the new technology in lung cancer staging was clear, and EBUS-guided transbronchial needle aspiration (EBUS-TBNA) is now performed by trained interventional pulmonologists and thoracic surgeons in selected centers around the world for a range of indications. However, the technique has faced many hurdles along the way, and uptake of the procedure was surprisingly slow initially. This was due not just to capital costs but also to problems with appropriate reimbursement and the fact that many pulmonologists preferred conventional TBNA. However, we believe that most pulmonologists across the world now agree that EBUS-TBNA is superior to blind or conventional TBNA. In 2008, Wallace and colleagues showed in a prospective study where patients underwent conventional TBNA and EBUS-TBNA (as well as endoscopic ultrasound–guided fine needle aspiration) that EBUS-TBNA had a significantly better sensitivity than conventional TBNA for diagnosing lymph node metastases in patients with lung cancer (1). EBUS-TBNA allows sampling of smaller lymph nodes and in lymph node locations that are challenging for conventional TBNA. It has long been the argument that EBUS-TBNA is not required when lymph nodes are bulky. However, in patients with sarcoidosis, a condition often characterized by bulky intrathoracic lymphadenopathy, a randomized controlled trial of EBUS-guided versus conventional TBNA demonstrated a statistically higher diagnostic yield for the EBUS group (83% vs. 54%, P < 0.05) (2). Thoracic surgeons were understandably anxious and skeptical about the rise of EBUS-TBNA and the potential fall of mediastinoscopy. In a crossover trial in patients with lung cancer, mediastinoscopy had a sensitivity of 78% for detecting lymph node metastases, whereas EBUS-TBNA had a sensitivity of 90%, primarily due to the ability of EBUS-TBNA to sample posterior subcarinal lymph nodes (3). However, many thoracic surgeons have embraced the new technology, taken it into the operating theater, and also helped to advance the field. A recent trial led by pioneering thoracic surgeons demonstrated a similar sensitivity for mediastinoscopy and EBUS-TBNA and led them to conclude that EBUS-TBNA could replace mediastinoscopy in patients with lung cancer (4). Although EBUS-TBNA may be a barrier to training in mediastinoscopy, many thoracic surgeons value the presence of EBUS-TBNA as it frees operating room time for more therapeutic rather than diagnostic surgical procedures. While pulmonologists and surgeons were being persuaded that EBUS-TBNA was superior to conventional TBNA and a suitable alternative to mediastinoscopy in patients with lung cancer, the landscape of lung cancer management was changing. Oncologists became increasingly interested in tissue acquisition to allow suitable samples for the personalized management of patients with advanced lung cancer. EBUS-TBNA has risen to this challenge as well. In a study of 774 patients undergoing EBUS-TBNA, 90% of samples submitted were suitable for epidermal growth factor receptor mutation status testing (5). Samples obtained in routine practice were also suitable for immunohistochemistry to aid subtyping of lung cancer. Many oncologists understand the merits of EBUS-TBNA, as it offers a technique that allows sampling of multiple tumor metastatic sites, which may be important as we increasingly recognize tumor heterogeneity (6). Because EBUS-TBNA is easily repeated, it can also be performed after disease progression to recharacterize tumor phenotype and genotype. This may be of particular significance if the patient is on a first-line TKI, given the occasional transformation of epidermal growth factor receptor–positive adenocarcinomas to small cell carcinoma (7). EBUS-TBNA has a role in the restaging of the mediastinum after chemotherapy (8) and can also biopsy parenchymal lesions adjacent to the airway (9). Radiation oncologists may use EBUS-TBNA for mapping disease in the mediastinum to guide radiotherapy fields in conjunction with integrated positron emission tomography–computed tomography and also for minimally invasive mediastinal staging prior to stereotactic radiotherapy. In patients with extrathoracic malignancy and enlarged mediastinal lymphadenopathy, oncologists often turn to EBUS-TBNA to confirm metastases and exclude other processes in the mediastinum (10). EBUS-TBNA has further been found to be of importance in patients with isolated mediastinal lymphadenopathy (IML), where the differential diagnosis often lies between sarcoidosis, tuberculosis, and lymphoma (11). In patients with sarcoidosis, EBUS-TBNA has recently been confirmed to be superior to conventional bronchoscopic techniques when lymph nodes are present (12). In populations with high tuberculosis incidence, EBUS-TBNA is also a useful investigation for the diagnosis of mycobacterial disease and welcomed by microbiologists and infectious disease clinicians, as it improves the culture-positive rate (13). Although EBUS-TBNA has been embraced by most pulmonologists, thoracic surgeons, and oncologists, its role in diagnosing lymphoma has always been controversial, and many hematooncologists remain unconvinced that the smaller samples from EBUS-TBNA are sufficient for diagnosis. This is a view shared in recent British Thoracic Society guidelines, which suggested that EBUS-TBNA was not the preferred diagnostic procedure when lymphoma was suspected (14). In this issue of the Journal, Moonim and colleagues (pp. 1216–1223) demonstrate the utility of EBUS-TBNA in patients with lymphoma and continue the work toward reaching this final frontier (15). The treatment of lymphoma relies on knowing the specific subtype and histological grade, and although this may be apparently achievable with EBUS-TBNA samples, concern exists that there is a high rate of discordance between cytologic and histologic specimens. The authors conducted an analysis of EBUS-TBNA procedures performed at their tertiary institution and identified 100 patients with a diagnosis of lymphoma. Cell blocks obtained at EBUS-TBNA were subjected to immunocytochemistry, flow cytometry, and fluorescent in situ hybridization. Using this protocol, they demonstrated that EBUS-TBNA provided adequate information for clinical management in 84 (84%) cases. All cases of relapsed lymphoma were correctly diagnosed, as were 88% of de novo cases, with one false-positive result. The study highlights several important points. The pathologist’s handling, processing, and interpretation of the specimen has a critical role in the EBUS-TBNA procedure. For centers wishing to replicate the high-quality results demonstrated by Moonim and colleagues, it is important to appreciate the learning curve for our pathology colleagues as well as the operators (16). EBUS-TBNA allows sampling from all bilateral mediastinal and hilar lymph node stations other than the aortopulmonary and paraaortic areas, which is a larger area than any single surgical procedure. A further key advantage of EBUS-TBNA over mediastinoscopy is that EBUS-TBNA can be performed easily after mediastinal radiotherapy—an important scenario when considering diagnosis of lymphoma relapse. Some nettlesome questions remain. Is the role of the on-site pathologist (routinely available in this study) relevant to obtaining sufficient tissue to allow multimodality analysis? Although favored by Moonim and colleagues, it could be argued that staining specimens on slides in the endoscopy suite may reduce the total volume of analyzable material in the cell block for the laboratory. The diagnosis of granulomatous lymphadenopathy by EBUS-TBNA in patients with lymphoma is described, but its significance and negative predictive value is unclear and requires further study in the context of lymphomas and other malignancies. Unfortunately, the small numbers of patients in each category of lymphoma preclude definitive conclusions about the utility of EBUS-TBNA in lymphoma subtypes. When data from this study is combined with information from other studies of EBUS-TBNA in lymphoma (17–21), we can begin to conclude that EBUS-TBNA now has a key role in the diagnosis of relapsed lymphoma. The results demonstrated in this study show that it is also possible to diagnose the majority of de novo lymphoma. When we also consider that the incidence of lymphoma is low in patients with IML (11), the study adds great weight to the utility of EBUS-TBNA as an initial procedure in patients with IML, even when lymphoma is the most likely diagnosis on clinical and radiological grounds. More data on EBUS-TBNA in patients with known and suspected lymphoma will continue to emerge and may help to persuade our hematooncology colleagues of its clinical utility. The challenge for interventional pulmonologists is to replicate the high standards of diagnostic yield achieved by Moonim and colleagues. In the meantime, EBUS-TBNA can be proud of its progress over the last 10 years from conception to a central diagnostic tool for a wide range of disorders in pulmonology.

From the Authors: We thank Drs. Maturu, Agarwal, and Rossi for their interest in our article (1). Drs. Maturu and Agarwal question the cost effectiveness of endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) compared with standard bronchoscopy in the diagnosis of lung cancer. None of the patients included in our study had endobronchial disease, and we cannot agree with their statement that the vast majority of patients with lung cancer have abnormal endobronchial findings. Drs. Maturu and Agarwal also miss an important point regarding the utility of EBUS-TBNA in patients with lung cancer. Not only can EBUS-TBNA provide a lung cancer phenotype and genotype, but it also provides a highly accurate nodal stage, critical to determining the treatment options. EBUS-TBNA, therefore, provides considerable information in addition to that provided by bronchoscopy and may prevent the need for further investigations such as integrated positron emission tomography–computed tomography, endoscopic ultrasound–guided fine needle aspiration, and mediastinoscopy. We are currently investigating the clinical efficacy and cost effectiveness of EBUS-TBNA as an initial investigation after staging computed tomography scan in patients with suspected lung cancer (2). We agree with Dr. Rossi that the personalization of advanced non–small cell lung cancer (NSCLC) management has adjusted the spotlight onto tissue acquisition techniques and their interpretation. A paradox currently exists whereby patients with metastatic disease (in whom cancer phenotyping and genotyping is mandatory for best outcomes) have the smallest biopsies, whereas patients with considerably larger surgically resected specimens currently do not have systemic treatment tailored to their tumor. Dr. Rossi highlights the key role that the pathologist plays in deciding treatment options for patients with advanced NSCLC as well as the demands now placed on small biopsy samples. As well as the pathologist requiring more dedicated lung cancer expertise, the same may apply to pulmonologists. Evidence already exists that the presence of dedicated thoracic surgeons may result in better lung cancer outcomes (3). The number of centers using EBUS-TBNA as a diagnostic and staging tool continues to increase internationally. Although the learning curve to reach competency in the procedure may be short (4), the focus has been on procedure sensitivity, whereas the assessment of quality of samples generated has not yet been built into competency assessment. The centers included in our study are recognized for their expertise in lung cancer management, and it is unclear whether the results seen in our study may be generalizable to centers without specific expertise in lung cancer. Dr. Rossi calls for pathologists dedicated to lung cancer in each laboratory that receives lung cancer samples. However, given current progress and the prospect of further genetic targets in NSCLC reaching clinical utility in the very near future, perhaps the time has come to consider centers dedicated to lung cancer imaging and tissue acquisition as well as pathological diagnostics. This model may optimize the patient experience for lung cancer diagnosis and staging, raise standards of diagnostics to a more uniform level, be cost effective, and facilitate recruitment to clinical trials.

Rationale: The current management of advanced non–small cell lung cancer (NSCLC) requires differentiation between squamous and nonsquamous subtypes as well as epidermal growth factor receptor (EGFR) mutation status. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for the diagnosis and staging of lung cancer. However, it is unclear whethercytologyspecimensobtainedwithEBUS-TBNAaresuitable for the subclassification and genotyping of NSCLC. Objectives: To determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC. Methods: Cytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across five centers in the United Kingdom between 2009 and 2011. Measurements and Main Results: The proportion of patients with a final diagnosis by EBUS-TBNA in whom subtype was classified was 77% (95% confidence interval [CI], 73–80). The rate of NSCLC not otherwisespecified(NSCLC-NOS)wassignificantlyreducedinpatientswho underwent immunohistochemistry (adjusted odds ratio, 0.50; 95% CI, 0.28–0.82;P¼0.016).EGFRmutationanalysiswaspossiblein107(90%) of the 119 patients in whom mutation analysis was requested. The sensitivity, negative predictive value, and diagnostic accuracy of EBUSTBNA in patients with NSCLC were 88% (95% CI, 86–91), 72% (95% CI, 66–77), and 91% (95% CI, 89–93), respectively. Conclusions: This large, multicenter, pragmatic study demonstrates