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Objectives: Several studies have identified airflow obstruction as a risk factor for lung cancer independent of smoking history, but the risk associated with the presence of radiographic evidence of emphysema has not been extensively studied. We proposed to assess this risk using a quantitative volumetric CT scan analysis.Methods: Sixty-four cases of lung cancer were identified from a prospective cohort of 1,520 participants enrolled in a spiral CT scan lung cancer screening trial. Each case was matched to six control subjects for age, sex, and smoking history. Quantitative CT scan analysis of emphysema was performed. Spirometric measures were also conducted. Data were analyzed using conditional logistic regression making use of the 1:6 set groups of 64 cases and 377 matched control subjects.Results: Decreased FEV(1) and FEV(1)/FVC were significantly associated with a diagnosis of lung cancer with ORs of 1.15 (95% CI, 1.00-1.32; P = .046) and 1.29 (95% CI, 1.02-1.62; P = .031), respectively. The quantity of radiographic evidence of emphysema was not found to be a significant risk for lung cancer with OR of 1.042 (95% CI, 0.816-1.329; P = .743). Additionally, there was no significant association between severe emphysema and lung cancer with OR of 1.57 (95% CI, 0.73-3.37).Conclusions: We confirm previous observations that airflow obstruction is an independent risk factor for lung cancer. The absence of a clear relationship between radiographic evidence of emphysema and lung cancer using an automated quantitative volumetric analysis may result from different population characteristics than those of prior studies, radiographic evidence of emphysema quantitation methodology, or absence of any relationship between emphysema and lung cancer risk. [ABSTRACT FROM AUTHOR]

Background: Although no study has prospectively documented the rate at which lung cancers grow, many have assumed exponential growth. The purpose of this study was to document the growth of lung cancers detected in high-risk participants receiving annual screening chest CT scans.Methods: Eighteen lung cancers were evaluated by at least four serial CT scans (4 men, 14 women; age range, 53 to 79 years; mean age, 66 years). CT scans were retrospectively reviewed for appearance, size, and volume (volume [v] = pi/6[ab(2)]). Growth curves (x = time [in days]; y = volume [cubic millimeters]) were plotted and subcategorized by histology, CT scan attenuation, stage, survival, and initial size.Results: Inclusion criteria favored smaller, less aggressive cancers. Growth curves varied, even when subcategorized by histology, CT scan attenuation, stage, survival, or initial size. Cancers associated with higher stages, mortality, or recurrence showed fairly steady growth or accelerated growth compared with earlier growth, although these growth patterns also were seen in lesser-stage lung cancers. Most lung cancers enlarged at fairly steady increments, but several demonstrated fairly flat growth curves, and others demonstrated periods of accelerated growth.Conclusions: This study is the first to plot individual lung cancer growth curves. Although parameters favored smaller, less aggressive cancers in women, it showed that lung cancers are not limited to exponential growth. Tumor size at one point or growth between two points did not appear to predict future growth. Studies and equations assuming exponential growth may potentially misrepresent an indeterminate nodule or the aggressiveness of a lung cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pulmonary nodules are spherical radiographic opacities that measure up to 30 mm in diameter. Nodules are extremely common in clinical practice and challenging to manage, especially small, 'subcentimeter' nodules. Identification of malignant nodules is important because they represent a potentially curable form of lung cancer. METHODS: We developed evidence-based clinical practice guidelines based on a systematic literature review and discussion with a large, multidisciplinary group of clinical experts and other stakeholders. RESULTS: We generated a list of 29 recommendations for managing the solitary pulmonary nodule (SPN) that measures at least 8 to 10 mm in diameter; small, subcentimeter nodules that measure < 8 mm to 10 mm in diameter; and multiple nodules when they are detected incidentally during evaluation of the SPN. Recommendations stress the value of risk factor assessment, the utility of imaging tests (especially old films), the need to weigh the risks and benefits of various management strategies (biopsy, surgery, and observation with serial imaging tests), and the importance of eliciting patient preferences. CONCLUSION: Patients with pulmonary nodules should be evaluated by estimation of the probability of malignancy, performance of imaging tests to characterize the lesion(s) better, evaluation of the risks associated with various management alternatives, and elicitation of patient preferences for treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe the clinical findings, treatment outcomes, disease recurrence rates, and survival of patients with pathologically confirmed mediastinal and cervicomediastinal lymphangioma. PATIENTS AND METHODS: There are 2 patient cohorts. Cohort A consisted of 12 Mayo Clinic patients with pathologically confirmed medilastinal or cervicomediastinal lymphangioma identified from 1986 to 1999. Cohort B consisted of 13 additional patients with mediastinal lymphangioma who had been previously reported from the Mayo Clinic (from 1976 to 1986). All patients were retrospectively identified, and follow-up was performed by either telephone or medical record review. RESULTS: The mean age at the time of diagnosis was 36.5 years, with a male-female ratio of 1:3. All but 3 patients were symptomatic at presentation, with dyspnea being the most common symptom. Computed tomographic scans commonly revealed a homogeneous, low-attenuation mass that often Involved vascular or airway structures. Although 3 patients were initially observed, all patients had surgical intervention because of symptoms or enlargement of the mass. Thoracotomy with resection was the most common surgical intervention. Five recurrences were noted. Recurrence was minimized by complete excision of the lymphangioma. On follow-up that spanned 23 years, 75% of patients were alive. These survival rates were not statistically different from the expected survival rates of the same age- and sex-matched controls. Only 1 death was attributed to complication from lymphangioma. CONCLUSION: Mediastinal and cervicomediastinal lymphangioma are rare lesions that can be treated successfully with surgical excision. Prognosis appears to be excellent because no difference in survival was found between patients and age- and sex-matched controls. [ABSTRACT FROM AUTHOR]

Objective: To better understand the microbial profile of complicated parapneumonic effusions and empyema, and to evaluate whether antimicrobial selection would differ if guided by targeted metagenomic sequencing (tMGS) vs conventional cultures (CCs) alone., Patients and Methods: We analyzed the pleural fluid of a cohort of 47 patients undergoing thoracentesis from January 1, 2017 to August 31, 2019, to characterize their microbial profile. All samples underwent 16S ribosomal ribonucleic acid gene polymerase chain reaction, followed by tMGS., Results: Pleural space infection was deemed clinically present in 20 of the 47 (43%) participants. Of those, n=7 (35%) had positive pleural fluid cultures and n=14 (70%) had positive tMGS results. The organisms identified by tMGS were concordant with CCs; however, tMGS detected additional bacterial species over CCs alone. Streptococcus and Staphylococcus species were the most common organisms identified, with Streptococcus intermedius/constellatus identified in 5 patients . Polymicrobial infections were found in 6 of the 20 patients, with anaerobes being the most common organisms identified in these cases., Conclusion: Streptococci and staphylococci were the most common organisms identified in infected pleural fluid. Anaerobes were common in polymicrobial infections. When compared with CCs, tMGS had higher sensitivity than CCs. Targeted metagenomic sequencing identified additional organisms, not identified by CCs, with associated potential management implications., Competing Interests: Dr Patel reports receiving grants from ContraFect, TenNor Therapeutics Limited, and BioFire. Dr Patel is a consultant for PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, and HealthTrackRx; monies are paid to Mayo Clinic. Mayo Clinic and Dr Patel have a relationship with Pathogenomix. Dr Patel has research supported by Adaptive Phage Therapeutics. Mayo Clinic has a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics. Dr Patel is also a consultant for Netflix, Abbott Laboratories, Oxford Nanopore Technologies, and CARB-X. In addition, Dr Patel has a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued. Dr Patel receives honoraria from the NBME, Up-to-Date and the Infectious Diseases Board Review Course. Dr Samhouri reports providing consultation (unpaid) to AI Therapeutics that is unrelated to the submitted work. Dr Carmona reports providing consultation to Boehringer Ingelheim for sarcoidosis that is unrelated to the submitted work., (© 2023 The Authors.)

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

Objective: The study sought to test the feasibility of conducting a phenome-wide association study to characterize phenotypic abnormalities associated with individuals at high risk for lung cancer using electronic health records., Materials and Methods: We used the beta release of the All of Us Researcher Workbench with clinical and survey data from a population of 225 000 subjects. We identified 3 cohorts of individuals at high risk to develop lung cancer based on (1) the 2013 U.S. Preventive Services Task Force criteria, (2) the long-term quitters of cigarette smoking criteria, and (3) the younger age of onset criteria. We applied the logistic regression analysis to identify the significant associations between individuals' phenotypes and their risk categories. We validated our findings against a lung cancer cohort from the same population and conducted an expert review to understand whether these associations are known or potentially novel., Results: We found a total of 214 statistically significant associations (P < .05 with a Bonferroni correction and odds ratio > 1.5) enriched in the high-risk individuals from 3 cohorts, and 15 enriched in the low-risk individuals. Forty significant associations enriched in the high-risk individuals and 13 enriched in the low-risk individuals were validated in the cancer cohort. Expert review identified 15 potentially new associations enriched in the high-risk individuals., Conclusions: It is feasible to conduct a phenome-wide association study to characterize phenotypic abnormalities associated in high-risk individuals developing lung cancer using electronic health records. The All of Us Research Workbench is a promising resource for the research studies to evaluate and optimize lung cancer screening criteria., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess how often transbronchial biopsy (TBBx) added unique positive findings apart from other synchronous bronchoscopic sampling techniques including the bronchoalveolar lavage-immunocompromised host (BAL-ICH) panel that justified changes in management in an array of immunocompromised patients with new pulmonary radiographic abnormalities., Methods: We retrospectively reviewed all bronchoscopies performed at Mayo Clinic Rochester between January 2012 and December 2017; on the basis of the physician's selection of a BAL-ICH panel, we identified 192 immunocompromised patients who underwent bronchoscopy with both a BAL-ICH panel and TBBx. The results of the BAL-ICH panel and TBBx were compared and subsequent management decisions analyzed from clinical notes. We identified changes in immunosuppressive agents, antibiotics, chemotherapy, goals of care, and decisions on further evaluation and procedures. We assessed whether the TBBx findings added information not identified on the BAL-ICH panel and other bronchoscopic sampling methods performed during the same procedure that justified subsequent management changes., Results: Of 192 bronchoscopic procedures performed on immunocompromised patients with acute and subacute pulmonary radiographic abnormalities, management changes justified by the unique positive results of the TBBx occurred 28% (51/192) of the time. Those immunocompromised by solid malignant neoplasms and receiving active immunosuppressive therapy had management changes justified 62.1% (18/29) of the time by the TBBx results. No additional fungal organisms were identified on TBBx that were accounted for on the BAL-ICH panel., Conclusion: Transbronchial biopsy may add information to other bronchoscopic findings in immunocompromised patients, especially those with solid malignant neoplasms receiving active immunosuppressive treatment. These potential benefits must be weighed against the risks inherent to the procedure., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the contribution and safety of bronchoscopic cryobiopsy vs traditional forceps biopsy used in clinical practice for diagnosing diffuse parenchymal lung disease (DPLD)., Patients and Methods: We identified 271 patients who underwent bronchoscopic biopsy for DPLD at Mayo Clinic, MN (June 1, 2013, through September 30, 2017). Medical records were reviewed including prebiopsy clinical and radiographic impressions. Diagnostic yield was assessed in terms of a specific histologic pattern resulting in a diagnosis when combined with the clinical-radiologic context. Clinical utility was defined as a biopsy result deemed useful in patient management., Results: The cohort included 120 cryobiopsy and 151 forceps biopsy cases with mean age 61±14 years and 143 (53%) men. Diagnostic yield (55% vs 41%; odds ratio [OR], 1.73; 95% CI, 1.07 to 2.83; P =.026) and clinical utility (60% vs 40%; OR, 2.21; 95% CI, 1.36 to 3.63; P =.001) were higher for the cryobiopsy group, and the association remained after control for prebiopsy clinical impressions (OR, 2.21; 95% CI, 1.22 to 4.08; P =.010 and OR, 3.23; 95% CI, 1.76 to 6.10; P <.001, respectively). However, pneumothorax (5.4% vs 0.7%; P =.022) and serious bleeding (7.1% vs 0%; P =.001) rates were higher for the cryobiopsy group. Thirty-day mortality was 1.6% in the cryobiopsy group vs 0% for the forceps biopsy group ( P =.20)., Conclusion: Bronchoscopic cryobiopsy revealed higher diagnostic yield and clinical utility than did forceps biopsy. However, procedure-related complications were higher in the cryobiopsy group. The choice of bronchoscopic biopsy procedure for patients with DPLD depends on the clinicalradiologic context., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Background: Bronchial carcinoid often appears hypervascular on bronchoscopic visualization and may be associated with hemoptysis. The diagnostic yield and bleeding complications associated with bronchoscopic biopsy of bronchial carcinoid tumors remain unclear., Materials and Methods: Patients with bronchial carcinoid tumors that were bronchoscopically visualized and biopsied at our tertiary referral medical center, over an 8-year period from 2010 to 2017, were retrospectively identified and reviewed to assess diagnostic yield and bleeding complications. Correlations with patient characteristics and carcinoid tumor features were analyzed., Results: Forty-nine patients were included (57% female). Tumors were predominantly (71%) located in proximal airways (mainstem and lobar bronchi). Bronchoscopic biopsy was diagnostic in 45 patients (92%). Thirteen patients (27%) experienced moderate (n=12, 25%) or severe (n=1, 2%) bleeding. Among these, 6 tumors (46%) had a vascular appearance and 4 patients (31%) had experienced recent hemoptysis. However, neither vascularity nor hemoptysis was associated with bleeding at biopsy (P=0.68 and 0.73, respectively). Carcinoid tumors were classified as typical in 79% and atypical in 21% with no difference in diagnostic yield or bleeding risk (P=0.28 and 0.92, respectively). Tumor size was also not associated with increased diagnostic yield or bleeding risk (P=0.54 and 0.39, respectively)., Conclusion: Bronchoscopic biopsy of endobronchial carcinoid is associated with a high diagnostic yield and severe bleeding is rarely encountered. Diagnostic yield and bleeding seemed independent of vascular tumor appearance or history of recent hemoptysis.

Background: The US Preventive Services Task Force (USPSTF) recommends lung cancer screening among individuals aged 55-80 years with a 30 pack-year cigarette smoking history and, if they are former smokers, those who quit within the past 15 years. Our previous report found that two-thirds of newly diagnosed patients with lung cancer do not meet these criteria; they are reported to be either long-term quitters (≥15 years since quitting) or from a younger age group (age 50-54 years). We aimed to assess survival outcomes in these two subgroups., Methods: For this prospective, observational cohort study we identified and followed up patients aged 50-80 years with lung cancer, with a smoking history of 30 pack-years or more, and included both current smokers and former smokers who quit within the past 30 years. We identified patients from two cohorts in the USA: a hospital cohort (Mayo Clinic, Rochester, MN) and a community cohort (Olmsted County, MN). Patients were divided into those meeting USPSTF criteria (USPSTF group) versus those not meeting USPSTF criteria (long-term quitters or the younger age group). The main outcome was overall survival at 5 years after diagnosis. 5-year overall survival was analysed with and without matching age and pack-years smoked for long-term quitters. The USPSTF group was subdivided into two age subgroups (55-69 years and 70-80 years) for multivariable regression analysis., Findings: Between Jan 1, 1997, and Dec 31, 2017, 8739 patients with lung cancer were identified and followed up. Median follow-up was 6·5 (IQR 3·8-10·0) years, and median overall survival was 16·9 months (95% CI 16·2-17·5). 5-year overall survival was 27% (95% CI 25-30) in long-term quitters, 22% (19-25) in the younger age group, and 23% (22-24) in the USPSTF group. In both cohorts, 5-year overall survival did not differ significantly between long-term quitters and the USPSTF group (hospital cohort: hazard ratio [HR] 1·02 [95% CI 0·94-1·10]; p=0·72; community cohort: 0·97 [0·75-1·26]; p=0·82); matched analysis showed similar results in both cohorts. 5-year overall survival also did not differ significantly between the younger age group and the USPSTF group in both cohorts (hospital cohort: HR 1·16 [95% CI 0·98-1·38], p=0·08; community cohort: 1·16 [0·74-1·82]; p=0·52); multivariable regression analyses stratified by age group yielded similar findings., Interpretation: Patients with lung cancer who quit 15 or more years before diagnosis and those who are up to 5 years younger than the age cutoff recommended for screening, but otherwise meet USPSTF criteria, have a similar risk of death to those individuals who meet all USPSTF criteria. Individuals in both subgroups could benefit from screening, as expansion of USPSTF screening criteria to include these subgroups could enable earlier detection of lung cancer and improved survival outcomes., Funding: National Institutes of Health and the Mayo Clinic Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In advanced non-small cell lung cancer (NSCLC), small biopsy specimens from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are often the only available material from cancer tissue for the analysis of programmed death ligand-1 (PD-L1) expression. We aim to assess the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression at ≥ 1% and ≥ 50% on EBUS-TBNA samples compared with their corresponding surgically resected tumor., Methods: We retrospectively reviewed all patients who underwent EBUS-TBNA followed by surgical resection of NSCLC between July 2006 and September 2016. Demographic information and periprocedural/surgical data were collected. The archived specimens were retrieved and assessed for PD-L1. A positive PD-L1 stain was defined using two separate cutoff points: ≥ 1% and ≥ 50% of tumor cell positivity. EBUS-TBNA aspirates were compared with the surgically resected specimen to calculate the sensitivity, specificity, PPV, and NPV., Results: Sixty-one patients were included. For PD-L1 ≥ 1%, the sensitivity, specificity, PPV, and NPV were 72%, 100%, 100%, and 80%, respectively. For PD-L1 ≥ 50%, the sensitivity, specificity, PPV, and NPV were 47%, 93%, 70%, and 84%, respectively. The concordance rates for PD-L1 ≥ 1% and ≥ 50% were 87% and 82%, respectively., Conclusions: A PD-L1 cutoff of ≥ 1% on EBUS-TBNA has a strong correlation with resected tumor specimen. For PD-L1 ≥ 50%, there is a significant decrease in the sensitivity and PPV of EBUS-TBNA specimen when compared with resected tumor. When analyzing for PD-L1 expression using a cutoff of ≥ 50%, EBUS-TBNA specimens may misclassify the status of PD-L1., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Background: There is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD., Methods: To test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0.7, FEV1% < 80%), and 30 non-COPD controls. Targeted next generation sequencing was used to measure total and allele-specific expression of 35 genes in genome maintenance (GM) genes pathways linked to COPD pathogenesis, including seven TP53 and CEBP transcription factor family members. Shrinkage linear discriminant analysis (SLDA) was used to identify COPD-classification models. COPD GWAS were queried for putative cis-regulatory SNPs in the targeted genes., Results: On a network basis, TP53 and CEBP transcription factor pathway gene pair network connections, including key DNA repair gene ERCC5, were significantly different in COPD subjects (e.g., Wilcoxon rank sum test for closeness, p-value = 5.0E-11). ERCC5 SNP rs4150275 association with chronic bronchitis was identified in a set of Lung Health Study (LHS) COPD GWAS SNPs restricted to those in putative regulatory regions within the targeted genes, and this association was validated in the COPDgene non-hispanic white (NHW) GWAS. ERCC5 SNP rs4150275 is linked (D' = 1) to ERCC5 SNP rs17655 which displayed differential allelic expression (DAE) in BEC and is an expression quantitative trait locus (eQTL) in lung tissue (p = 3.2E-7). SNPs in linkage (D' = 1) with rs17655 were predicted to alter miRNA binding (rs873601). A classifier model that comprised gene features CAT, CEBPG, GPX1, KEAP1, TP73, and XPA had pooled 10-fold cross-validation receiver operator characteristic area under the curve of 75.4% (95% CI: 66.3%-89.3%). The prevalence of DAE was higher than expected (p = 0.0023) in the classifier genes., Conclusions: GM genes comprised by COPD-associated BEC expression patterns were enriched for SNPs with cis-regulatory function, including a putative cis-rSNP in ERCC5 that was associated with COPD risk. These findings support additional total and allele-specific expression analysis of gene pathways with high prior likelihood for involvement in COPD pathogenesis.

Background: Delivering effective tobacco dependence treatment that is feasible within lung cancer screening (LCS) programs is crucial for realizing the health benefits and cost savings of screening. Large-scale trials and systematic reviews have demonstrated that digital cessation interventions (i.e. web-based and text message) are effective, sustainable over the long-term, scalable, and cost-efficient. Use of digital technologies is commonplace among older adults, making this a feasible approach within LCS programs. Use of cessation treatment has been improved with models that proactively connect smokers to treatment rather than passive referrals. Proactive referral to cessation treatment has been advanced through healthcare systems changes such as modifying the electronic health record to automatically link smokers to treatment., Methods: This study evaluates the impact of a proactive enrollment strategy that links LCS-eligible smokers with an evidence-based intervention comprised of a web-based (WEB) program and integrated text messaging (TXT) in a three-arm randomized trial with repeated measures at one, three, six, and 12 months post randomization. The primary outcome is biochemically confirmed abstinence at 12 months post randomization. We will randomize 1650 smokers who present for a clinical LCS to: (1) a usual care control condition (UC) which consists of Ask-Advise-Refer; (2) a digital (WEB + TXT) cessation intervention; or (3) a digital cessation intervention combined with tobacco treatment specialist (TTS) counseling (WEB + TXT + TTS)., Discussion: The scalability and sustainability of a digital intervention may represent the most cost-effective and feasible approach for LCS programs to proactively engage large numbers of smokers in effective cessation treatment. We will also evaluate the impact and cost-effectiveness of adding proven clinical intervention provided by a TTS. We expect that a combined digital/clinical intervention will yield higher quit rates than digital alone, but that it may not be as cost-effective or feasible for LCS programs to implement. This study is innovative in its use of interoperable, digital technologies to deliver a sustainable, scalable, high-impact cessation intervention and to facilitate its integration within clinical practice. It will add to the growing knowledge base about the overall effectiveness of digital interventions and their role in the healthcare delivery system., Trial Registration: ClinicalTrials.gov, NCT03084835 . Registered on 9 March 2017.

Benign granulomatous processes such as fungal infection may mimic metastatic lung cancer on FDG PET/CT. We found that these processes often have draining lymph node(s) with equal or greater FDG activity than associated lung nodule(s), a "flip-flop" of what is commonly seen in lung cancer. The aim of this study was to examine the utility of this "flip-flop fungus" (FFF) sign for diagnosing benign pulmonary disease. FDG PET/CT scans performed between 9/09-3/13 for the indications of pulmonary nodule or mass were reviewed. Scans with at least one hilar or mediastinal FDG avid draining node were included. Patients with a history of cancer, lack of pathologic confirmation, or without at least two years of imaging follow-up were excluded. A total of 209 FDG PET/CT exams were included and reviewed in a blinded fashion. A positive FFF sign had a sensitivity of 60.0% (95% CI: 47.6-71.5%) and specificity of 84.9% (95% CI: 77.8-90.4%) (P<0.0001) for benign disease. With additional strict imaging criteria applied, the FFF sign had a specificity of 98.6% (95% CI: 94.9-99.8%) (P<0.0001) and a positive predictive value of 90.0% (95% CI: 68.3-98.5%). A positive FFF sign was predominately due to granulomatous disease (91%), mostly histoplasmosis (73%). A positive FFF sign combined with positive fungal serology (n=16) had a specificity of 100% for benign disease. The FFF sign predicts benign disease in patients with a lung nodule(s) and an FDG avid draining lymph node(s) that would otherwise be considered worrisome for cancer., Competing Interests: None.

Introduction: Multifocal lung cancer is an increasingly common clinical scenario, but there is lack of high-level evidence for its optimal treatment. Thus, we surveyed members of the interdisciplinary International Association for the Study of Lung Cancer on their therapeutic approaches and analyzed the resultant practice patterns., Methods: We described the clinical scenario of an otherwise healthy 60-year-old man with bilateral pulmonary nodules and asked the 6373 members of the International Association for the Study of Lung Cancer whether they would recommend surgery, and if so, the extent of surgery. We also asked what other measures would be recommended to complete the staging and whether radiation therapy or chemotherapy would be suggested., Results: We received 221 responses (response rate 3.5%) from multiple specialists. Most respondents (140 [63%]) recommended surgery for this scenario. Surgeons were significantly more likely to recommend surgery than were those in other specialties. Of those who recommended surgery, most would obtain a PET/CT scan to rule out distant metastases and a magnetic resonance imaging scan to rule out brain metastases; but in the absence of radiographic lymph node involvement, most would not stage the mediastinum by bronchoscopy or mediastinoscopy before resection. When surgery was not recommended or declined, respondents commonly recommended radiation., Conclusions: This survey suggests that therapeutic recommendations for multifocal lung cancer are influenced to a large extent by physicians' specialty training, probably because of the lack of high-level evidence for its standard treatment. Ongoing systematic and multidisciplinary approaches with robust short-term and long-term patient outcomes may improve the quality of evidence for the optimal management of this clinical entity., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The management of bronchopleural fistulas can be challenging. The initial treatment is usually conservative, but operative intervention with transposition of vascularized pedicled flaps may be required in refractory cases. We present the case of a 67-year-old man with stage IIIa squamous cell carcinoma of the lung who underwent a lower and middle bilobectomy after receiving neoadjuvant chemoradiation. His postoperative course was complicated by empyema and a bronchopleural fistula. Because of difficulty accessing the fistula, endobronchial-guided vascularized tissue flaps were successfully used to close the fistula., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906-14. ©2016 AACR., Competing Interests: The authors have no conflict of interest, (©2016 American Association for Cancer Research.)

Most patients with lung cancer are diagnosed when they present with symptoms, they have advanced stage disease, and curative treatment is no longer an option. An effective screening test has long been desired for early detection with the goal of reducing mortality from lung cancer. Sputum cytology, chest radiography, and computed tomography (CT) scan have been studied as potential screening tests. The National Lung Screening Trial (NLST) demonstrated a 20% reduction in mortality with low-dose CT (LDCT) screening, and guidelines now endorse annual LDCT for those at high risk. Implementation of screening is underway with the desire that the benefits be seen in clinical practice outside of a research study format. Concerns include management of false positives, cost, incidental findings, radiation exposure, and overdiagnosis. Studies continue to evaluate LDCT screening and use of biomarkers in risk assessment and diagnosis in attempt to further improve outcomes for patients with lung cancer.

Introduction: Two-thirds of patients in the United States with newly diagnosed lung cancer would not meet the current U.S. Preventive Services Task Force (USPSTF) screening criteria, which suggests a need for amendment of the definition of high risk. To provide evidence of additional high-risk subpopulations and estimated gains and losses from using different criteria for screening eligibility, we conducted a two-step study using three cohorts., Methods: The two prospective cohorts comprised 5988 patients in whom primary lung cancer was diagnosed between 1997 and 2011 (the hospital cohort) and 850 defined-community residents (the community cohort); the retrospective cohort consisted of the population of Olmsted County, Minnesota, which was observed for 28 years (1984-2011). Subgroups of patients with lung cancer who might have been identified using additional determinates were estimated and compared between the community and hospital cohorts. The findings were supported by indirect comparative projections of two ratios: benefit to harm and cost to effectiveness., Results: Former cigarette smokers who had a smoking history of 30 or more pack-years and 15 to 30 quit-years and were 55 to 80 years old formed the largest subgroup not meeting the current screening criteria; they constituted 12% of the hospital cohort and 17% of community cohort. Using the expanded criteria suggested by our study may add 19% more CT examinations for detecting 16% more cases when compared with the USPSTF criteria. Meanwhile, the increases in false-positive results, overdiagnosis, and radiation-related lung cancer deaths are 0.6%, 0.1%, and 4.0%, respectively., Conclusions: Current USPSTF screening criteria exclude many patients who are at high risk for development of lung cancer. Including individuals who are younger than 81 years, have a smoking history of 30 or more pack-years, and have quit for 15 to 30 years may significantly increase the number of cases of non-overdiagnosed screen-detected lung cancer, does not significantly add to the number of false-positive cases, and saves more lives with an acceptable amount of elevated exposure to radiation and cost., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We present the case of a 49-year-old man who developed pulmonary abscess as a complication of transbronchial lung cryobiopsy. He had been receiving prednisone therapy, but otherwise had no specific risk factors for lung abscess. Cryobiopsy is a novel technique for obtaining peripheral lung parenchymal tissue for the evaluation of diffuse parenchymal lung diseases. Cryobiopsy is being increasingly proposed as an alternative to surgical lung biopsy or conventional bronchoscopic transbronchial forceps biopsy, but the safety profile of the procedure has not been fully appreciated. Pulmonary abscess has been rarely reported as a complication of other bronchoscopic procedures such as endobronchial ultrasound-guided needle biopsy, however, to our knowledge this is the first reported case of pulmonary abscess complicating peripheral lung cryobiopsy.

Rationale: Annual low-radiation-dose computed tomography (LDCT) screening for lung cancer has been shown to reduce lung cancer mortality among high-risk individuals and is now recommended by multiple organizations. However, LDCT screening is complex, and implementation requires careful planning to ensure benefits outweigh harms. Little guidance has been provided for sites wishing to develop and implement lung cancer screening programs., Objectives: To promote successful implementation of comprehensive LDCT screening programs that are safe, effective, and sustainable., Methods: The American Thoracic Society (ATS) and American College of Chest Physicians (ACCP) convened a committee with expertise in lung cancer screening, pulmonary nodule evaluation, and implementation science. The committee reviewed the evidence from systematic reviews, clinical practice guidelines, surveys, and the experience of early-adopting LDCT screening programs and summarized potential strategies to implement LDCT screening programs successfully., Measurements and Main Results: We address steps that sites should consider during the main three phases of developing an LDCT screening program: planning, implementation, and maintenance. We present multiple strategies to implement the nine core elements of comprehensive lung cancer screening programs enumerated in a recent ACCP/ATS statement, which will allow sites to select the strategy that best fits with their local context and workflow patterns. Although we do not comment on cost-effectiveness of LDCT screening, we outline the necessary costs associated with starting and sustaining a high-quality LDCT screening program., Conclusions: Following the strategies delineated in this policy statement may help sites to develop comprehensive LDCT screening programs that are safe and effective.

Background: Pulmonary nodules are frequently detected during diagnostic chest imaging and as a result of lung cancer screening. Current guidelines for their evaluation are largely based on low-quality evidence, and patients and clinicians could benefit from more research in this area., Methods: In this research statement from the American Thoracic Society, a multidisciplinary group of clinicians, researchers, and patient advocates reviewed available evidence for pulmonary nodule evaluation, characterized six focus areas to direct future research efforts, and identified fundamental gaps in knowledge and strategies to address them. We did not use formal mechanisms to prioritize one research area over another or to achieve consensus., Results: There was widespread agreement that novel tests (including novel imaging tests and biopsy techniques, biomarkers, and prognostic models) may improve diagnostic accuracy for identifying cancerous nodules. Before they are used in clinical practice, however, better evidence is needed to show that they improve more distal outcomes of importance to patients. In addition, the pace of research and the quality of clinical care would be improved by the development of registries that link demographic and nodule characteristics with patient-level outcomes. Methods to share data from registries are also necessary., Conclusions: This statement may help researchers to develop impactful and innovative research projects and enable funders to better judge research proposals. We hope that it will accelerate the pace and increase the efficiency of discovery to improve the quality of care for patients with pulmonary nodules.

Introduction: Indeterminate pulmonary nodules (IPNs) lack clinical or radiographic features of benign etiologies and often undergo invasive procedures unnecessarily, suggesting potential roles for diagnostic adjuncts using molecular biomarkers. The primary objective was to validate a multivariate classifier that identifies likely benign lung nodules by assaying plasma protein expression levels, yielding a range of probability estimates based on high negative predictive values (NPVs) for patients with 8 to 30 mm IPNs., Methods: A retrospective, multicenter, case-control study was performed using multiple reaction monitoring mass spectrometry, a classifier comprising five diagnostic and six normalization proteins, and blinded analysis of an independent validation set of plasma samples., Results: The classifier achieved validation on 141 lung nodule-associated plasma samples based on predefined statistical goals to optimize sensitivity. Using a population based nonsmall-cell lung cancer prevalence estimate of 23% for 8 to 30 mm IPNs, the classifier identified likely benign lung nodules with 90% negative predictive value and 26% positive predictive value, as shown in our prior work, at 92% sensitivity and 20% specificity, with the lower bound of the classifier's performance at 70% sensitivity and 48% specificity. Classifier scores for the overall cohort were statistically independent of patient age, tobacco use, nodule size, and chronic obstructive pulmonary disease diagnosis. The classifier also demonstrated incremental diagnostic performance in combination with a four-parameter clinical model., Conclusions: This proteomic classifier provides a range of probability estimates for the likelihood of a benign etiology that may serve as a noninvasive, diagnostic adjunct for clinical assessments of patients with IPNs.

Distal airway foreign bodies can be challenging to remove with a flexible bronchoscope because of angulation or deep impaction. Thoracic surgery may be required if bronchoscopy is not successful. The use of electromagnetic navigation for pulmonary nodule localization and characterization is well established; however, its use to localize and remove distal foreign bodies has not been described. We report the initial case of electromagnetic navigation-assisted foreign body removal.

Efforts in lung cancer screening with chest X-ray (CXR) and sputum cytology in the 1970s and 1980s were negative. In the ensuing decade, the early lung cancer action project (ELCAP), and the Mayo screening study showed the promise of low-dose CT. These and other studies led to the National lung screening study (NLST), which showed definitively that low-dose spiral computed tomography had a measurable impact on mortality and could be justified as a tool for lung cancer screening. This review examines the results of past and recent studies of lung cancer screening., (© 2013 Wiley Periodicals, Inc.)

Objectives: The objective of this article is to update previous evidence-based recommendations for evaluation and management of individuals with solid pulmonary nodules and to generate new recommendations for those with nonsolid nodules., Methods: We updated prior literature reviews, synthesized evidence, and formulated recommendations by using the methods described in the "Methodology for Development of Guidelines for Lung Cancer" in the American College of Chest Physicians Lung Cancer Guidelines, 3rd ed., Results: We formulated recommendations for evaluating solid pulmonary nodules that measure &gt; 8 mm in diameter, solid nodules that measure ≤ 8 mm in diameter, and subsolid nodules. The recommendations stress the value of assessing the probability of malignancy, the utility of imaging tests, the need to weigh the benefits and harms of different management strategies (nonsurgical biopsy, surgical resection, and surveillance with chest CT imaging), and the importance of eliciting patient preferences., Conclusions: Individuals with pulmonary nodules should be evaluated and managed by estimating the probability of malignancy, performing imaging tests to better characterize the lesions, evaluating the risks associated with various management alternatives, and eliciting their preferences for management.