Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.

BACKGROUND: The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD. METHODS: We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles. RESULTS: On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001). CONCLUSIONS: These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.).

Therapeutic Rigid Bronchoscopy Intervention for Malignant Central Airway Obstruction Improves Performance Status to Allow Systemic Treatment.

BACKGROUND: Malignant central airway obstruction may result in an Eastern Cooperative Oncology Group Performance Status (ECOG PS) that precludes treatment with systemic therapies. We sought to evaluate outcomes of patients undergoing rigid bronchoscopy for malignant central airways obstruction (MCAO) and its effect on access to systemic therapies including immunotherapy. PATIENTS AND METHODS: We conducted a retrospective observational single-center study evaluating 77 consecutive patients who underwent rigid bronchoscopy from March 2015 to November 2019. Procedural details, preprocedural and postprocedural ECOG PS, complications, and proportions of patients receiving systemic therapy postprocedure were recorded. RESULTS: The majority of patients were ECOG PS 2 to 3 at diagnosis (62%). The most common indication was MCAO due to squamous cell carcinoma (35.1%). MCAO was managed with a debulking/dilatation procedure alone (51.9%) or in combination with stenting (48.1%). The laser was unavailable, electrocautery was used for hemostasis only not tumor ablation. Significant improvement in ECOG PS postprocedure in the group with baseline ECOG PS 3 to 4 (P<0.0001) and in those with baseline ECOG PS 0 to 4 (P<0.00001) was observed. The main complication was bleeding, controlled bronchoscopically with mechanical compression with a rigid bronchoscope and/or electrocautery (68.8% of patients). No deaths occurred. Overall, 70% of those presenting with ECOG 3 to 4 went onto receive systemic therapies that would have been contraindicated due to poor baseline ECOG PS. CONCLUSION: Therapeutic rigid bronchoscopy is safe and efficacious in the management of MCAO, improving ECOG PS allowing for the administration of systemic therapies. This is especially important in the era of immunotherapy and directed therapies, which have been shown to provide significant survival benefit over conventional therapies alone.

Perifissural nodules seen at CT screening for lung cancer.

PURPOSE: To describe and characterize the potential for malignancy of noncalcified lung nodules adjacent to fissures that are often found in current or former heavy smokers who undergo computed tomography (CT) for lung cancer screening. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Baseline and follow-up thin-section multidetector CT scans obtained in 146 consecutive subjects at high risk for lung cancer (age range, 50-75 years; > 30 pack-year smoking history) were retrospectively reviewed. Noncalcified nodules (NCNs) were categorized according to location (parenchymal, perifissural), shape, septal connection, manually measured diameter, diameter change, and lung cancer outcome at 7(1/2) years. RESULTS: Retrospective review of images from 146 baseline and 311 follow-up CT examinations revealed 837 NCNs in 128 subjects. Of those 837 nodules, 234 (28%), in 98 subjects, were adjacent to a fissure and thus classified as perifissural nodules (PFNs). Multiple (range, 2-14) PFNs were seen in 47 subjects. Most PFNs were triangular (102/234, 44%) or oval (98/234, 42%), were located inferior to the carina (196/234, 84%), and had a septal connection (171/234, 73%). The mean maximal length was 3.2 mm (range, 1-13 mm). During 2-year follow-up in 71 subjects, seven of 159 PFNs increased in size on one scan but were then stable. The authors searched a lung cancer registry 7(1/2) years after study entry and found 10 lung cancers in 139 of 146 study subjects who underwent complete follow-up; none of these cancers had originated from a PFN. CONCLUSION: PFNs are frequently seen on screening CT scans obtained in high-risk subjects. Although PFNs may show increased size at follow-up CT, the authors in this study found none that had developed into lung cancer; this suggests that the malignancy potential of PFNs is low. (c) RSNA, 2010.

Development and evaluation of a consumer information resource, including Patient Decision Aid, for lung cancer screening: a quasi-experimental study.

Lung cancer screening of high-risk individuals with computed tomography is a promising intervention to reduce lung cancer mortality. Patient Decision Aids (PtDAs) may assist eligible individuals assess the risks and benefits associated with screening. Screening preference is high among lower-risk, screening-ineligible individuals and strategies are needed to reduce screening demand among this group. We developed and evaluated a resource comprising a recruitment pamphlet combined with either a PtDA for screening-eligible individuals or an education pamphlet for screening-ineligible individuals. Quasi-experimental pre-post pamphlet exposure design. Ever-smokers aged 55-80 years attending hospital outpatient clinics were invited. Among screening-eligible participants, the assessed outcome was change in score on the Decisional Conflict Scale (DCS). Among screening-ineligible participants, the assessed outcomes were change in screening preference. In the study 51% (55/107) of invited individuals participated, with mean ± standard deviation age 66.9 ± 6.4 years, 53% (29/55) male, and 65% (36/55) eligible for screening. Median (interquartile range) DCS among screening-eligible participants reduced from 28.9 (22.7-45.3) pre-PtDA to 25 (1.6-29.7) post-PtDA (p < .001), but there was no significant change in the proportion that reached the accepted threshold for decisional certainty (DCS < 25, 10/36 [28%] pre-exposure vs. 14/36 [39%] post-exposure, p = .1). Screening preference among screening-ineligible individuals reduced after viewing the screening-ineligible brochure (pre-exposure median of "Prefer" to post-exposure median of "Unsure," p = .001). Our consumer information pamphlets about lung cancer screening may reduce decisional conflict and improve alignment of screening preference with eligibility.

Lung nodules: CT-guided placement of microcoils to direct video-assisted thoracoscopic surgical resection.

PURPOSE: To prospectively assess the safety and effectiveness of computed tomography (CT)-guided placement of fiber-coated microcoils used to guide video-assisted thoracoscopic surgical (VATS) excision of small peripheral lung nodules, with successful excision as the primary outcome and successful CT-guided microcoil placement and procedural complications as secondary outcomes. MATERIALS AND METHODS: The institutional review board approved the study protocol. Informed consent was obtained from all 69 enrolled patients (30 men, 39 women; mean age, 60.7 years +/- 10.1 [standard deviation]) with 75 nodules. At CT, one end of an 80-mm long, 0.018-inch-diameter fiber-coated microcoil was placed deep to the small peripheral lung nodule, and the other end was coiled in the pleural space. VATS excision of lung tissue, nodules, and the microcoil was performed with fluoroscopic guidance. RESULTS: Seventy-three (97%) 4-24-mm nodules were successfully removed at fluoroscopically guided VATS excision; two nodules could not be removed. CT-guided microcoil placement was successful in all cases; however, two (3%) of 75 coils were displaced at VATS excision. Pneumothorax requiring chest tube placement occurred in two (3%) patients, and asymptomatic hemothorax occurred in one (1%) patient. The microcoil did not impede intraoperative frozen-section histopathologic analysis, which facilitated accurate clinical management in all patients. For 19 (28%) patients, the preoperative treatment plan based on bronchoscopy, needle biopsy, and positron emission tomography findings changed after VATS excision. CONCLUSION: Microcoil localization of small peripheral lung nodules enabled fluoroscopically guided VATS resection of 97% of the nodules, with a low rate of intervention (3%) for procedural complications.

Airway wall thickness assessed using computed tomography and optical coherence tomography.

RATIONALE: Computed tomography (CT) has been shown to reliably measure the airway wall dimensions of medium to large airways. Optical coherence tomography (OCT) is a promising new micron-scale resolution imaging technique that can image small airways 2 mm in diameter or less. OBJECTIVES: To correlate OCT measurements of airway dimensions with measurements assessed using CT scans and lung function. METHODS: Forty-four current and former smokers received spirometry, CT scans, and OCT imaging at the time of bronchoscopy. Specific bronchial segments were identified and measured using the OCT images and three-dimensional reconstructions of the bronchial tree using CT. MEASUREMENTS AND MAIN RESULTS: There was a strong correlation between CT and OCT measurements of lumen and wall area (r = 0.84, P < 0.001, and r = 0.89, P < 0.001, respectively). Compared with CT, OCT measurements were lower for both lumen and wall area by 31 and 66%, respectively. The correlation between FEV(1)% predicted and CT and OCT measured wall area (as percentage of the total area) of fifth-generation airways was very strong (r = -0.79, r = -0.75), but the slope of the relationship was much steeper using OCT than using CT (y = -0.33x + 82, y = -0.1x + 78), indicating greater sensitivity of OCT in detecting changes in wall measurements that relate to FEV(1). CONCLUSIONS: OCT can be used to measure airway wall dimensions. OCT may be more sensitive at detecting small airway wall changes that lead to FEV(1) changes in individuals with obstructive airway disease.

Health-related quality of life and anxiety in the PAN-CAN lung cancer screening cohort.

OBJECTIVES: The impact of lung cancer screening with low-dose chest CT (LDCT) on participants' anxiety levels and health-related quality of life (HRQoL) is an important consideration in the implementation of such programmes. We aimed to describe changes in anxiety and HRQoL in a high-risk Canadian cohort undergoing LDCT lung cancer screening. METHODS: 2537 subjects who had 2% or greater lung cancer risk over 6 years using a risk prediction tool were recruited from eight centres across Canada in the Pan-Canadian Early Detection of Lung Cancer Study (2008-2010). We compared HRQoL and anxiety levels before and after screening of 1237 participants with LDCT (excluding a subset of 1300 participants who also underwent autofluorescence bronchoscopy screening), as well as after investigations performed because of a positive screening examination. The 12-item short-form Physical and Mental Component Scales (SF-12), EQ-5D-3L scores and State Trait Anxiety Inventory-State anxiety were used at each assessment. RESULTS: Overall, there were no clinically significant differences in HRQoL outcomes between baseline and each of the survey time points following initial screening. No mean change in anxiety in the overall cohort was noted following baseline LDCT, but more participants had clinically significant increase in anxiety versus decrease after baseline screening (increase >minimal clinically important difference (MCID) (n=180) vs decrease >MCID (n=50), p<0.001). This finding persisted but to a lesser degree at the 12 month time point (increase >MCID (n=146) vs decrease >MCID (n=87), p<0.001). CONCLUSIONS: CT screening for lung cancer has no major overall impact on HRQoL among participants, although a minority of participants (number-needed-to-harm=7 after baseline screening and 18 at 1 year) demonstrated clinically significant increased anxiety levels. TRIALREGISTRATION NUMBER: NCT00751660; Results.

Predicting Malignancy Risk of Screen-Detected Lung Nodules-Mean Diameter or Volume.

OBJECTIVE: In lung cancer screening practice low-dose computed tomography, diameter, and volumetric measurement have been used in the management of screen-detected lung nodules. The aim of this study was to compare the performance of nodule malignancy risk prediction tools using diameter or volume and between computer-aided detection (CAD) and radiologist measurements. METHODS: Multivariable logistic regression models were prepared by using data from two multicenter lung cancer screening trials. For model development and validation, baseline low-dose computed tomography scans from the Pan-Canadian Early Detection of Lung Cancer Study and a subset of National Lung Screening Trial (NLST) scans with lung nodules 3 mm or more in mean diameter were analyzed by using the CIRRUS Lung Screening Workstation (Radboud University Medical Center, Nijmegen, the Netherlands). In the NLST sample, nodules with cancer had been matched on the basis of size to nodules without cancer. RESULTS: Both CAD-based mean diameter and volume models showed excellent discrimination and calibration, with similar areas under the receiver operating characteristic curves of 0.947. The two CAD models had predictive performance similar to that of the radiologist-based model. In the NLST validation data, the CAD mean diameter and volume models also demonstrated excellent discrimination: areas under the curve of 0.810 and 0.821, respectively. These performance statistics are similar to those of the Pan-Canadian Early Detection of Lung Cancer Study malignancy probability model with use of these data and radiologist-measured maximum diameter. CONCLUSION: Either CAD-based nodule diameter or volume can be used to assist in predicting a nodule's malignancy risk.

The effects of radiation dose and CT manufacturer on measurements of lung densitometry.

BACKGROUND: To evaluate the effect of radiation dose and scanner manufacturer on quantitative CT scan measurements of lung morphology in smokers. METHODS: Low-dose and high-dose, inspiratory, multislice CT scans were obtained in 50 subjects at intervals of approximately 6 months (mean [+/- SD] interval, 0.5 +/- 0.2 years). In another 30 subjects, multislice CT scans were acquired first using a GE LightSpeed Ultra (General Electric Healthcare; Milwaukee, WI), followed a mean time of 1.2 +/- 0.4 years later by using a Siemens Sensation 16 scanner (Siemens Medical Solutions; Erlangen, Germany). Custom software was used to measure lung volume, mass, mean density, and the extent of emphysema using threshold cutoffs of -950, -910, and -856 Hounsfield units (HU) and the lowest 15th and 5th percentile points. RESULTS: The change in radiograph dose significantly affected measurements of emphysema assessed using mean lung density, threshold, or percentile methods. There were also interactions between dose and total lung volume for all of the measurements except the -950-HU threshold and the lowest fifth percentile point. These two emphysema measurements suggest that there was more emphysema found in the CT scans obtained using a lower radiograph dose. Only the mean lung density and -856-HU threshold showed significant effects between CT scanner manufacturers and interactions between total lung volume and scanner. All other measures of lung structure were not different between the two CT scanners. CONCLUSION: CT scan measurements of very low density lung structures are significantly affected by radiation dose but are less sensitive to the lung volume. Image acquisition parameters including radiation dose, scanner type, and the subject's breath size should be standardized to estimate emphysema severity in longitudinal studies.

Low Prevalence of High-Grade Lesions Detected With Autofluorescence Bronchoscopy in the Setting of Lung Cancer Screening in the Pan-Canadian Lung Cancer Screening Study.

BACKGROUND: Lung cancer screening with low-dose CT (LDCT) scan has been demonstrated to reduce lung cancer mortality. Preliminary reports suggested that up to 20% of lung cancers may be CT scan occult but detectable by autofluorescence bronchoscopy (AFB). We evaluated the prevalence of CT scan occult, invasive, and high-grade preinvasive lesions in high-risk participants undergoing screening for lung cancer. METHODS: The first 1,300 participants from seven centers in the Pan-Canadian Early Detection of Lung Cancer Study who had ≥ 2% lung cancer risk over 5 years were invited to have an AFB in addition to a LDCT scan. We determined the prevalence of CT scan and AFB abnormalities and analyzed the association between selected predictor variables and preinvasive lesions plus invasive cancer. RESULTS: A total of 776 endobronchial biopsies were performed in 333 of 1,300 (25.6%) participants. Dysplastic or higher-grade lesions were detected in 5.3% of the participants (n = 68; mild dysplasia: n = 36, moderate dysplasia: n = 25, severe dysplasia: n = 3, carcinoma in situ [CIS]: n = 1, and carcinoma: n = 4). Only one typical carcinoid tumor and one CIS lesion were detected by AFB alone, for a rate of CT scan occult cancer of 0.15% (95% CI, 0.0%-0.6%). Fifty-six prevalence lung cancers were detected by LDCT scan (4.3%). The only independent risk factors for finding of dysplasia or CIS on AFB were smoking duration (OR, 1.05; 95% CI, 1.02-1.07) and FEV1 percent predicted (OR, 0.99; 95% CI, 0.98-0.99). CONCLUSIONS: The addition of AFB to LDCT scan in a high lung cancer risk cohort detected too few CT occult cancers (0.15%) to justify its incorporation into a lung cancer screening program. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00751660; URL: www.clinicaltrials.gov.

Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction.

Lung cancer is the leading cause of cancer death worldwide. Accurate prediction of lung cancer risk is of value for individuals, clinicians, and researchers. The aims of this study were to characterize the associations between pulmonary function and sputum DNA image cytometry (SDIC) and lung cancer, and their contributions to risk prediction. During 1990 to 2007, 2,596 high-risk individuals were enrolled and followed prospectively for development of lung cancer (n = 139; median follow-up 7.7 years) in trials at the British Columbia Cancer Agency. At baseline, an epidemiologic questionnaire was administered, sputum was collected for aneuploidy measurement and spirometry was obtained. Multivariable logistic models were prepared including known lung cancer predictors (model 1), that additionally included percent-expected-forced expiratory volume in 1 second [forced expiratory volume in 1 second (FEV(1)%), model 2], and that additionally included SDIC (model 3). Prediction was assessed by evaluating discrimination (receiver operator characteristic area under the curve (ROC AUC)) and calibration. Net reclassification indices (NRI) were calculated with cutoff points for 8-year risks identifying low, intermediate, and high risk at 1.5% and 3%. Lung cancer risk increased with decline in FEV(1)%, but did so more for men than for women (interaction P < 0.001). SDIC demonstrated a dose-response with lung cancer (P = 0.022). The ROC AUCs for models 1, 2, and 3 were 0.718 (95% CI: 0.671-0.765), 0.767 (95% CI: 0.725-0.809), and 0.773 (95% CI: 0.732-0.815), respectively. Model 2 versus 1 had a NRI of 12.6% (P < 0.0001) and model 3 versus 2 had a NRI of 3.1% (P = 0.059). Spirometry and SDIC data substantially and minimally improved lung cancer prediction, respectively.

Using laser Raman spectroscopy to reduce false positives of autofluorescence bronchoscopies: a pilot study.

INTRODUCTION: Preneoplastic lesions of the bronchial tree have a high probability of developing into malignant tumors. Currently, the best method for localizing them for further treatment is a combined white light bronchoscopy (WLB) and autofluorescence bronchoscopy (AFB) (WLB + AFB). The average specificity from large clinical trials for this combined detection method is approximately 60%, leading to many false positives. The object of this study is to determine whether adding point laser Raman spectroscopy (LRS) to a WLB + AFB has the potential to improve the specificity of preneoplastic lesion detection and what the implication is to the detection sensitivity. METHODS: An LRS system was developed to collect real-time, in vivo lung spectra with a fiber optic catheter passed down the instrument channel of a bronchoscope. WLB + AFB imaging modalities were used to identify lesions from 26 subjects, from which 129 Raman spectra were measured. Multivariate statistical analyses were performed on the spectra with a leave-one-out crossvalidation. RESULTS: Clear in vivo Raman spectra were obtained in 1 second. The location of individual Raman peaks in the spectra correlated well with the known positions of Raman peaks generated by lipids, proteins, and water molecules. Preneoplastic lesions were detected with a sensitivity of 96% and a specificity of 91%. CONCLUSION: Adding point LRS analysis to WLB + AFB imaging has the ability to detect preneoplastic lesions in real time with high sensitivity and specificity. The use of LRS has great potential for substantially reducing the number of false-positive biopsies associated with WLB + AFB with very little reduction in the detection sensitivity.

Evidence for dysanapsis using computed tomographic imaging of the airways in older ex-smokers.

We sought to determine the relationship between lung size and airway size in men and women of varying stature. We also asked if men and women matched for lung size would still have differences in airway size and if so where along the pulmonary airway tree would these differences exist. We used computed tomography to measure airway luminal areas of the large and central airways. We determined airway luminal areas in men (n = 25) and women (n = 25) who were matched for age, body mass index, smoking history, and pulmonary function and in a separate set of men (n = 10) and women (n = 11) who were matched for lung size. Men had greater values for the larger airways and many of the central airways. When male and female subjects were pooled there were significant associations between lung size and airway size. Within the male and female groups the magnitudes of these associations were decreased or nonsignificant. In males and females matched for lung size women had significantly smaller airway luminal areas. The larger conducting airways in females are significantly smaller than those of males even after controlling for lung size.

Lung cancer screening using multi-slice thin-section computed tomography and autofluorescence bronchoscopy.

BACKGROUND: Thoracic computed tomography (CT) for lung cancer screening is sensitive for the detection of early peripheral lung cancer but is not sensitive for detecting central preinvasive and microinvasive cancer. Our hypothesis is that the use of a two-step strategy, using a sputum biomarker, may increase the detection rate of lung cancer by identifying individuals at highest risk. METHODS: We completed a pilot study of 561 volunteer current or former smokers 50 years of age or older, with a smoking history of more than or equal to 30 pack years. All subjects received induced sputum examination and low-dose thoracic CT scan and were offered autofluorescence bronchoscopy. RESULTS: CT detected 2408 pulmonary nodules, 80% of which were less than or equal to 4 mm in diameter. During 2-year follow-up, 95% of these nodules were stable or resolved, with only 4% showing growth at any time. A total of 28 cancers were detected in 22 subjects: 21 by CT scan and seven by autofluorescence bronchoscopy. Overall, 0.9% nodules were malignant, but growth on more than or equal to two CT scans increased the malignancy rate to 75%. The mean diameter of malignant nodules on detection was 12.8 mm (range, 3 to 36.4 mm). However, 18% of malignant nodules were less than or equal to 4 mm in diameter when first seen. CONCLUSIONS: Multi-detector row CT scanners found multiple small nodules in most subjects screened, but most were stable over the 2-year follow-up. Persistent interval growth increases the probability of malignancy from less than 1% to 75%. One quarter of detected cancers were CT occult and only seen with autofluorescence bronchoscopy. Prescreening using a sputum biomarker improved the detection rate of lung cancer from 3 to 5%.