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1.
Am J Respir Crit Care Med ; 209(1): 83-90, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37523681

ABSTRACT

Rationale: Global Lung Function Initiative (GLI) Global spirometry reference equations were recently derived to offer a "race-neutral" interpretation option. The impact of transitioning from the race-specific GLI-2012 to the GLI Global reference equations is unknown. Objectives: Describe the direction and magnitude of changes in predicted lung function measurements in a population of diverse race and ethnicity using GLI Global in place of GLI-2012 reference equations. Methods: In this multicenter cross-sectional study using a large pulmonary function laboratory database, 109,447 spirometry tests were reanalyzed using GLI Global reference equations and compared with the existing GLI-2012 standard, stratified by self-reported race and ethnicity. Measurements and Main Results: Mean FEV1 and FVC percent predicted increased in the White and Northeast Asian groups and decreased in the Black, Southeast Asian, and mixed/other race groups. The prevalence of obstruction increased by 9.7% in the White group, and prevalences of possible restriction increased by 51.1% and 37.1% in the Black and Southeast Asian groups, respectively. Using GLI Global in a population with equal representation of all five race and ethnicity groups altered the interpretation category for 10.2% of spirometry tests. Subjects who self-identified as Black were the only group with a relative increase in the frequency of abnormal spirometry test results (32.9%). Conclusions: The use of GLI Global reference equations will significantly impact spirometry interpretation. Although GLI Global offers an innovative approach to transition from race-specific reference equations, it is important to recognize the continued need to place these data within an appropriate clinical context.


Subject(s)
Lung , Humans , Cross-Sectional Studies , Forced Expiratory Volume , Reference Values , Spirometry/methods , Vital Capacity
2.
Diagn Cytopathol ; 51(9): 554-562, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37288984

ABSTRACT

BACKGROUND: Obtaining a diagnosis and treating pulmonary malignancies during the same anesthesia requires either an on-site pathologist or a system for remotely evaluating microscopic images. Cytology specimens are challenging to remotely assess given the need to navigate through dispersed and three-dimensional cell clusters. Remote navigation is possible using robotic telepathology, but data are limited on the ease of use of current systems, particularly for pulmonary cytology. METHODS: Air dried modified Wright-Giemsa stained slides from 26 touch preparations of transbronchial biopsies and 27 smears of endobronchial ultrasound guided fine needle aspirations were scored for ease of adequacy assessment and ease of diagnosis on robotic (rmtConnect Microscope) and non-robotic telecytology platforms. Diagnostic classifications were compared between glass slides and the robotic and non-robotic telecytology assessments. RESULTS: Compared to non-robotic telecytology, robotic telecytology had a greater ease of adequacy assessment and non-inferior ease of diagnosis. The median time to diagnosis using robotic telecytology was 85 s (range 28-190 s). Diagnostic categories were concordant for 76% of cases in robotic versus non-robotic telecytology and 78% of cases in robotic telecytology versus glass slide diagnosis. Weighted Cohen's kappa scores for agreement in these comparisons were 0.84 and 0.72, respectively. CONCLUSIONS: Use of a remote-controlled robotic microscope improved the ease of adequacy assessment compared to non-robotic telecytology and enabled strongly concordant diagnoses to be expediently rendered. This study provides evidence that modern robotic telecytology is a feasible and user-friendly method of remotely and potentially intraoperatively rendering adequacy assessments and diagnoses on bronchoscopic cytology specimens.


Subject(s)
Microscopy , Telepathology , Humans , Cytodiagnosis/methods , Cytological Techniques/methods , Biopsy, Fine-Needle/methods , Telepathology/methods
3.
Nat Commun ; 13(1): 6572, 2022 11 02.
Article in English | MEDLINE | ID: mdl-36323656

ABSTRACT

A model's ability to express its own predictive uncertainty is an essential attribute for maintaining clinical user confidence as computational biomarkers are deployed into real-world medical settings. In the domain of cancer digital histopathology, we describe a clinically-oriented approach to uncertainty quantification for whole-slide images, estimating uncertainty using dropout and calculating thresholds on training data to establish cutoffs for low- and high-confidence predictions. We train models to identify lung adenocarcinoma vs. squamous cell carcinoma and show that high-confidence predictions outperform predictions without uncertainty, in both cross-validation and testing on two large external datasets spanning multiple institutions. Our testing strategy closely approximates real-world application, with predictions generated on unsupervised, unannotated slides using predetermined thresholds. Furthermore, we show that uncertainty thresholding remains reliable in the setting of domain shift, with accurate high-confidence predictions of adenocarcinoma vs. squamous cell carcinoma for out-of-distribution, non-lung cancer cohorts.


Subject(s)
Adenocarcinoma , Carcinoma, Squamous Cell , Deep Learning , Humans , Uncertainty , Adenocarcinoma/pathology
4.
Genomics ; 112(6): 5313-5323, 2020 11.
Article in English | MEDLINE | ID: mdl-33144219

ABSTRACT

Intraoperative diagnosis is routinely performed on cytology touch preparations (TPs) from core needle biopsies (CNBs). Current interest promotes their utility as an important source of patient tissue for clinical genomic testing. Herein we present whole genome structural variant analysis (SVA) from mate-pair sequencing (MPseq) and whole exome sequencing (WES) mutation calling in DNA directly whole genome amplified (WGA) from TPs. Chromosomal copy changes and somatic DNA junction detection from MPseq of TPs were highly consistent with associated CNBs and bulk resected tissues in all cases. While increased frequency coverage noise from limitations of amplification of limited sample input was significant, this was effectively compensated by natural tumor enrichment during the TP process, which also enhanced variant detection and loss of heterozygosity evaluations from WES. This novel TP methodology enables expanded utility of frequently limited CNB for both clinical and research genomic testing.


Subject(s)
High-Throughput Nucleotide Sequencing , Neoplasms/genetics , Sequence Analysis, DNA , Alleles , Biopsy, Large-Core Needle , Cytological Techniques , Genomics/methods , Humans , Loss of Heterozygosity , Neoplasms/pathology , Exome Sequencing
5.
J Thorac Oncol ; 14(2): 276-287, 2019 02.
Article in English | MEDLINE | ID: mdl-30316012

ABSTRACT

INTRODUCTION: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy. METHODS: We used mate-pair (n = 22), RNA (n = 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. RESULTS: We observed that inter- or intrachromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific major histocompatibility complex molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient's circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival. CONCLUSIONS: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.


Subject(s)
Antigens/genetics , Chromothripsis , Mesothelioma/genetics , Pleural Neoplasms/genetics , Transcriptome/genetics , Clonal Selection, Antigen-Mediated , Computer Simulation , DNA, Neoplasm/analysis , Gene Dosage , Gene Rearrangement , Genomics , HLA-A Antigens/genetics , HLA-B Antigens/genetics , Humans , Lymphocytes, Tumor-Infiltrating , Mesothelioma/pathology , Peptides/genetics , Peptides/immunology , Pleural Neoplasms/pathology , Receptors, Antigen, T-Cell/genetics , Sequence Analysis, DNA/methods , Sequence Analysis, RNA , Survival Rate , T-Lymphocytes/immunology
6.
Cancer Lett ; 410: 191-200, 2017 12 01.
Article in English | MEDLINE | ID: mdl-28965852

ABSTRACT

The intragenic tumor-suppressor microRNA miR-486-5p is often down-regulated in non-small cell lung cancer (NSCLC) but the mechanism is unclear. This study investigated epigenetic co-regulation of miR-486-5p and its host gene ANK1. MiR-486-5p expression in lung tumors and cell lines was significantly reduced compared to normal lung (p < 0.001) and is strongly correlated with ANK1 expression. In vitro, siRNA-mediated ANK1 knockdown in NSCLC cells also reduced miR-486-5p while the DNA methylation inhibitor 5-aza-2'-deoxycytidine induced expression of both. ANK1 promoter CpG island was unmethylated in normal lung but methylated in 45% (118/262) lung tumors and 55% (17/31) NSCLC cell lines. After adjustment for tumor histology and smoking, methylation was significantly more prevalent in adenocarcinoma (101/200, 51%) compared to squamous cell carcinoma (17/62, 27%), p < 0.001; HR = 3.513 (CI: 1.818-6.788); and in smokers (73/128, 57%) than never-smokers (28/72, 39%), p = 0.014; HR = 2.086 (CI: 1.157-3.759). These results were independently validated using quantitative methylation data for 809 NSCLC cases from The Cancer Genome Atlas project. Together, our data indicate that aberrant ANK1 methylation is highly prevalent in lung cancer, discriminate tumors by histology and patients' smoking history, and contributes to miR-486-5p repression.


Subject(s)
Adenocarcinoma/genetics , Ankyrins/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , DNA Methylation , Epigenesis, Genetic , Lung Neoplasms/genetics , MicroRNAs/genetics , Smoking/adverse effects , Adenocarcinoma/etiology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Ankyrins/metabolism , Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/etiology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , CpG Islands , Databases, Genetic , Down-Regulation , Gene Expression Regulation, Neoplastic , Humans , Introns , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , MicroRNAs/metabolism , Promoter Regions, Genetic , Risk Factors
7.
Clin Proteomics ; 12(1): 18, 2015.
Article in English | MEDLINE | ID: mdl-26279647

ABSTRACT

BACKGROUND: Support for early detection of lung cancer has emerged from the National Lung Screening Trial (NLST), in which low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20 % relative to chest x-ray. The US Preventive Services Task Force (USPSTF) recently recommended annual screening for the high-risk population, concluding that the benefits (life years gained) outweighed harms (false positive findings, abortive biopsy/surgery, radiation exposure). In making their recommendation, the USPSTF noted that the moderate net benefit of screening was dependent on the resolution of most false-positive results without invasive procedures. Circulating biomarkers may serve as a valuable adjunctive tool to imaging. RESULTS: We developed a broad-based proteomics discovery program, integrating liquid chromatography/mass spectrometry (LC/MS) analyses of freshly resected lung tumor specimens (n = 13), lung cancer cell lines (n = 17), and conditioned media collected from tumor cell lines (n = 7). To enrich for biomarkers likely to be found at elevated levels in the peripheral circulation of lung cancer patients, proteins were prioritized based on predicted subcellular localization (secreted, cell-membrane associated) and differential expression in disease samples. 179 candidate biomarkers were identified. Several markers selected for further validation showed elevated levels in serum collected from subjects with stage I NSCLC (n = 94), relative to healthy smoker controls (n = 189). An 8-marker model was developed (TFPI, MDK, OPN, MMP2, TIMP1, CEA, CYFRA 21-1, SCC) which accurately distinguished subjects with lung cancer (n = 50) from high risk smokers (n = 50) in an independent validation study (AUC = 0.775). CONCLUSIONS: Integrating biomarker discovery from multiple sample types (fresh tissue, cell lines and conditioned medium) has resulted in a diverse repertoire of candidate biomarkers. This unique collection of biomarkers may have clinical utility in lung cancer detection and diagnoses.

8.
Sci Rep ; 5: 9755, 2015 May 18.
Article in English | MEDLINE | ID: mdl-25985019

ABSTRACT

Lung adenocarcinomas from never smokers account for approximately 15 to 20% of all lung cancers and these tumors often carry genetic alterations that are responsive to targeted therapy. Here we examined mutation status in 10 oncogenes among 89 lung adenocarcinomas from never smokers. We also screened for oncogene fusion transcripts in 20 of the 89 tumors by RNA-Seq. In total, 62 tumors had mutations in at least one of the 10 oncogenes, including EGFR (49 cases, 55%), K-ras (5 cases, 6%), BRAF (4 cases, 5%), PIK3CA (3 cases, 3%), and ERBB2 (4 cases, 5%). In addition to ALK fusions identified by IHC/FISH in four cases, two previously known fusions involving EZR- ROS1 and KIF5B-RET were identified by RNA-Seq as well as a third novel fusion transcript that was formed between exons 1-9 of SND1 and exons 2 to 3' end of BRAF. This in-frame fusion was observed in 3/89 tested tumors and 2/64 additional never smoker lung adenocarcinoma samples. Ectopic expression of SND1-BRAF in H1299 cells increased phosphorylation levels of MEK/ERK, cell proliferation, and spheroid formation compared to parental mock-transfected control. Jointly, our results suggest a potential role of the novel BRAF fusion in lung cancer development and therapy.


Subject(s)
Adenocarcinoma/genetics , Lung Neoplasms/genetics , Mutation , Nuclear Proteins/genetics , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Proteins B-raf/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Aged , Aged, 80 and over , Biomarkers, Tumor , Endonucleases , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Gene Order , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Middle Aged , Mitogen-Activated Protein Kinases/metabolism , Neoplasm Staging , Nuclear Proteins/metabolism , Oncogene Proteins, Fusion/metabolism , Oncogenes , Phosphorylation , Proto-Oncogene Proteins B-raf/metabolism , Reproducibility of Results , Transcription, Genetic
9.
Lung Cancer ; 80(1): 91-8, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23357462

ABSTRACT

Lung adenocarcinoma is the most common type of primary lung cancer. The purpose of this study was to delineate gene expression patterns for survival prediction in lung adenocarcinoma. Gene expression profiles of 82 (discovery set) and 442 (validation set 1) lung adenocarcinoma tumor tissues were analyzed using a systems biology-based network approach. We also examined the expression profiles of 78 adjacent normal lung tissues from 82 patients. We found a significant correlation of an expression module with overall survival (adjusted hazard ratio or HR=1.71; 95% CI=1.06-2.74 in discovery set; adjusted HR=1.26; 95% CI=1.08-1.49 in validation set 1). This expression module contained genes enriched in the biological process of the cell cycle. Interestingly, the cell cycle gene module and overall survival association were also significant in normal lung tissues (adjusted HR=1.91; 95% CI, 1.32-2.75). From these survival-related modules, we further defined three hub genes (UBE2C, TPX2, and MELK) whose expression-based risk indices were more strongly associated with poor 5-year survival (HR=3.85, 95% CI=1.34-11.05 in discovery set; HR=1.72, 95% CI=1.21-2.46 in validation set 1; and HR=3.35, 95% CI=1.08-10.04 in normal lung set). The 3-gene prognostic result was further validated using 92 adenocarcinoma tumor samples (validation set 2); patients with a high-risk gene signature have a 1.52-fold increased risk (95% CI, 1.02-2.24) of death than patients with a low-risk gene signature. These results suggest that a network-based approach may facilitate discovery of key genes that are closely linked to survival in patients with lung adenocarcinoma.


Subject(s)
Adenocarcinoma/genetics , Cell Cycle Proteins/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Lung Neoplasms/genetics , Adenocarcinoma/pathology , Aged , Aged, 80 and over , Female , Humans , Lung Neoplasms/pathology , Male , Microtubule-Associated Proteins/genetics , Middle Aged , Models, Genetic , Nuclear Proteins/genetics , Oligonucleotide Array Sequence Analysis , Predictive Value of Tests , Prognosis , Protein Serine-Threonine Kinases/genetics , Survival Analysis , Time Factors , Ubiquitin-Conjugating Enzymes/genetics
10.
J Thorac Oncol ; 8(1): 31-6, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23201823

ABSTRACT

INTRODUCTION: The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography-based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography-based screening and promote its rapid implementation. METHODS: We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules. RESULTS: Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2Rα, stromal cell-derived factor-1α+ß, tumor necrosis factor α, and macrophage inflammatory protein 1 α. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%. CONCLUSION: We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.


Subject(s)
Biomarkers, Tumor/blood , Cytokines/blood , Interleukin-2 Receptor alpha Subunit/blood , Lung Neoplasms/blood , Multiple Pulmonary Nodules/blood , Solitary Pulmonary Nodule/blood , Adult , Aged , Aged, 80 and over , Area Under Curve , Chemokine CCL3/blood , Chemokine CXCL12/blood , Female , Granuloma/blood , Humans , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-10/blood , Interleukin-6/blood , Lung Neoplasms/diagnosis , Male , Middle Aged , Multiple Pulmonary Nodules/diagnostic imaging , Multiple Pulmonary Nodules/pathology , Pneumonia/blood , Predictive Value of Tests , ROC Curve , Radiography , Respiratory Tract Infections/blood , Solitary Pulmonary Nodule/diagnostic imaging , Solitary Pulmonary Nodule/pathology , Tumor Necrosis Factor-alpha/blood , Young Adult
11.
J Bronchology Interv Pulmonol ; 19(3): 176-81, 2012 Jul.
Article in English | MEDLINE | ID: mdl-23207457

ABSTRACT

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for evaluating mediastinal and/or hilar lymphadenopathy in patients with malignancy. Granulomatous inflammation is occasionally identified in this setting and has unclear clinical implications. Therefore, we set out to describe a cohort of patients found to have evidence of granulomatous inflammation during EBUS-TBNA done for diagnosis and/or staging of concurrent cancer. METHODS: A retrospective analysis of all EBUS-TBNA cases performed over 32 months at our institution was completed. Patients with evidence of granulomatous inflammation during EBUS-TBNA that was not attributable to an infectious etiology or prior sarcoidosis and a concurrent diagnosis of cancer were included. RESULTS: Granulomatous inflammation was identified in 154/1275 patients (12.1%), of whom 12/154 (7.8%) had a concurrent diagnosis of cancer. Primary cancer diagnoses varied, but the primary site of malignancy was in or near the thorax in 10/12 cases (83.3%). When available, 7/8 cases (87.5%) of granulomatous lymphadenopathy were detectable by positron emission tomography. The most common histologic pattern consisted of well-formed non-necrotizing granulomas without fibrosis in 6/12 patients (50%). CONCLUSIONS: Granulomatous inflammation is occasionally identified in mediastinal and/or hilar lymphadenopathy in patients with concurrent malignancy. Although the clinical implications of this phenomenon remain to be clarified, these findings emphasize the importance of histologic confirmation of suspected lymph node involvement and suggest that the presence of granulomatous inflammation on EBUS-TBNA may occasionally be consistent with active malignancy and prompt further investigations.


Subject(s)
Bronchoscopy/methods , Endosonography/methods , Granuloma/pathology , Lymphatic Diseases/pathology , Mediastinum/pathology , Neoplasms/pathology , Aged , Aged, 80 and over , Biopsy, Fine-Needle/methods , Diagnosis, Differential , Female , Granuloma/complications , Granuloma/diagnostic imaging , Humans , Inflammation/complications , Inflammation/diagnosis , Lymphatic Diseases/complications , Lymphatic Diseases/diagnostic imaging , Male , Mediastinum/diagnostic imaging , Middle Aged , Neoplasms/complications , Neoplasms/diagnostic imaging , Retrospective Studies
12.
J Bronchology Interv Pulmonol ; 19(4): 271-6, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23207525

ABSTRACT

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used to sample mediastinal and hilar lymph nodes and has excellent diagnostic test characteristics. The determinants of sampling adequacy, however, have not been extensively examined. We set out to determine which procedural variables were associated with acquisition of tissue sufficient for pathologic analysis during EBUS-TBNA. METHODS: A retrospective analysis of all EBUS-TBNA cases performed over 32 months by 10 proceduralists at our institution was completed. Variables potentially associated with sampling adequacy were analyzed. RESULTS: A total of 1304 procedures performed by 10 proceduralists while the patient received conscious sedation were included for analysis. Sampling adequacy was 94.2% overall and varied with the primary proceduralist (87% to 99.2%; P<0.001). Diagnostic yield per procedure for malignancy or a specific benign diagnosis was 43.2% overall. Proceduralists with a higher average number of lymph node stations sampled per procedure had improved sampling adequacy (parameter estimate=1.32; P=0.007). Sampling adequacy was lower with lymph nodes smaller than 10 mm (parameter estimate=-0.7; P=0.002) but was not associated with procedural environment (hospital procedural suite vs. clinic-based procedural suite) (P=0.08), lymph node station (P=0.69), propofol use (P=0.90), or average annual proceduralist cases performed (P=0.21). Only 6/216 (2.8%) patients had subsequent procedures (EBUS-TBNA or surgery) that indicated the initial EBUS-TBNA had inadequate sampling potentially leading to a missed cancer diagnosis. CONCLUSIONS: Excellent EBUS-TBNA sampling adequacy can be achieved by pulmonologists in a large group setting, who are not exclusively dedicated to interventional pulmonary medicine, using only moderate conscious sedation.


Subject(s)
Clinical Competence/standards , Endoscopic Ultrasound-Guided Fine Needle Aspiration/standards , Lung Neoplasms/pathology , Pulmonary Medicine/standards , Specimen Handling/standards , Bronchoscopy/standards , Conscious Sedation , Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods , Humans , Lymphatic Metastasis , Retrospective Studies
13.
Cancer Epidemiol Biomarkers Prev ; 21(6): 988-92, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22523180

ABSTRACT

BACKGROUND: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke. METHODS: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. RESULTS: Overall, the frequency of EGFR mutation was 41% [95% confidence interval (CI), 32%-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. CONCLUSIONS: The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking.


Subject(s)
ErbB Receptors/genetics , Lung Neoplasms/genetics , Mutation , Radon/analysis , Smoking/genetics , Tobacco Smoke Pollution/adverse effects , Aged , Case-Control Studies , Female , Humans , Lung Neoplasms/epidemiology , Lung Neoplasms/etiology , Middle Aged , Missouri/epidemiology , Prognosis , Smoking/adverse effects
14.
Cancer Epidemiol Biomarkers Prev ; 21(5): 786-92, 2012 May.
Article in English | MEDLINE | ID: mdl-22374995

ABSTRACT

BACKGROUND: Current management of lung nodules is complicated by nontherapeutic resections and missed chances for cure. We hypothesized that a serum proteomic signature may add diagnostic information beyond that provided by combined clinical and radiographic data. METHODS: Cohort A included 265 and cohort B 114 patients. Using multivariable logistic regression analysis we calculated the area under the receiver operating characteristic curve (AUC) and quantified the added value of a previously described serum proteomic signature beyond clinical and radiographic risk factors for predicting lung cancer using the integration discrimination improvement (IDI) index. RESULTS: The average computed tomography (CT) measured nodule size in cohorts A and B was 37.83 versus 23.15 mm among patients with lung cancer and 15.82 versus 17.18 mm among those without, respectively. In cohort A, the AUC increased from 0.68 to 0.86 after adding chest CT imaging variables to the clinical results, but the proteomic signature did not provide meaningful added value. In contrast, in cohort B, the AUC improved from 0.46 with clinical data alone to 0.61 when combined with chest CT imaging data and to 0.69 after adding the proteomic signature (IDI of 20% P = 0.0003). In addition, in a subgroup of 100 nodules between 5 and 20 mm in diameter, the proteomic signature added value with an IDI of 15% (P ≤ 0.0001). CONCLUSIONS: The results show that this serum proteomic biomarker signature may add value to the clinical and chest CT evaluation of indeterminate lung nodules. IMPACT: This study suggests a possible role of a blood biomarker in the evaluation of indeterminate lung nodules.


Subject(s)
Lung Neoplasms/blood , Neoplasm Proteins/blood , Proteomics/methods , Solitary Pulmonary Nodule/blood , Aged , Biomarkers, Tumor/blood , Cohort Studies , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Prospective Studies , Risk Factors , Solitary Pulmonary Nodule/pathology
15.
Radiology ; 235(1): 259-65, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15695622

ABSTRACT

PURPOSE: To report results of a 5-year prospective low-dose helical chest computed tomographic (CT) study of a cohort at high risk for lung cancer. MATERIALS AND METHODS: After informed written consent was obtained, 1520 individuals were enrolled. Protocol was approved by institutional review board and National Cancer Institute and was compliant with Health Insurance Portability and Accountability Act, or HIPAA. Participants were aged 50 years and older and had smoked for more than 20 pack-years. Participants underwent five annual (one initial and four subsequent) CT examinations. A significant downward shift was evaluated in non-small cell lung cancers detected initially from advanced stage down to stage I by using a one-sided binomial test of proportions. Poisson regression and Fisher exact tests were used for comparisons with Mayo Lung Project. RESULTS: In 788 (52%) men and 732 (48%) women, 61% (927 of 1520) were current smokers, and 39% were former smokers. After five annual CT examinations, 3356 uncalcified lung nodules were identified in 1118 (74%) participants. Sixty-eight lung cancers were diagnosed (31 initial, 34 subsequent, three interval cancers) in 66 participants. Twenty-eight subsequent cases of non-small cell cancers were detected, of which 17 (61%; 95% confidence interval: 41%, 79%) were stage I tumors. Diameter of cancers detected subsequently was 5-50 mm (mean, 14.4 mm; median, 10.0 mm). Analysis for a more than 50% shift in proportion of stage I non-small cell cancer detection did not show statistical significance. Forty-eight participants died of various causes since enrollment. Lung cancer mortality rate for incidence portion of trial was 1.6 per 1000 person-years. There was no significant difference in lung cancer mortality rates of cancers detected in subsequent examinations between this trial and Mayo Lung Project after separation of participants into subsets (2.8 vs 2.0 per 1000 person-years, P = .43). CONCLUSION: CT allows detection of early-stage lung cancers. Benign nodule detection rate is high. Results suggest no stage shift.


Subject(s)
Lung Neoplasms/diagnostic imaging , Tomography, X-Ray Computed , Aged , Aged, 80 and over , Female , Humans , Incidence , Lung Neoplasms/epidemiology , Male , Mass Screening , Middle Aged , Prevalence , Prospective Studies , Time Factors
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