Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study.

BACKGROUND: Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes. METHODS: In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914. FINDINGS: Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33.1 months (IQR 22.3-66.8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3.2-4.1) compared with 3.5 months (2.3-4.8) in the active supportive care group (hazard ratio 0.95, 95% CI 0.73-1.20, p=0.72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care. INTERPRETATION: No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma. FUNDING: Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.

Subphenotypes of mild-to-moderate COPD by factor and cluster analysis of pulmonary function, CT imaging and breathomics in a population-based survey.

INTRODUCTION: Classification of COPD is currently based on the presence and severity of airways obstruction. However, this may not fully reflect the phenotypic heterogeneity of COPD in the (ex-) smoking community. We hypothesized that factor analysis followed by cluster analysis of functional, clinical, radiological and exhaled breath metabolomic features identifies subphenotypes of COPD in a community-based population of heavy (ex-) smokers. METHODS: Adults between 50-75 years with a smoking history of at least 15 pack-years derived from a random population-based survey as part of the NELSON study underwent detailed assessment of pulmonary function, chest CT scanning, questionnaires and exhaled breath molecular profiling using an electronic nose. Factor and cluster analyses were performed on the subgroup of subjects fulfilling the GOLD criteria for COPD (post-BD FEV1/FVC < 0.70). RESULTS: Three hundred subjects were recruited, of which 157 fulfilled the criteria for COPD and were included in the factor and cluster analysis. Four clusters were identified: cluster 1 (n = 35; 22%): mild COPD, limited symptoms and good quality of life. Cluster 2 (n = 48; 31%): low lung function, combined emphysema and chronic bronchitis and a distinct breath molecular profile. Cluster 3 (n = 60; 38%): emphysema predominant COPD with preserved lung function. Cluster 4 (n = 14; 9%): highly symptomatic COPD with mildly impaired lung function. In a leave-one-out validation analysis an accuracy of 97.4% was reached. CONCLUSIONS: This unbiased taxonomy for mild to moderate COPD reinforces clusters found in previous studies and thereby allows better phenotyping of COPD in the general (ex-) smoking population.

Mass spectrometry analyses of κ and λ fractions result in increased number of complementarity-determining region identifications.

Sera from lung cancer patients contain antibodies against tumor-associated antigens. Specific amino acid sequences of the complementarity-determining regions (CDRs) in the antigen-binding fragment (Fab) of these antibodies have potential as lung cancer biomarkers. Detection and identification of CDRs by mass spectrometry can significantly be improved by reduction of the complexity of the immunoglobulin molecule. Our aim was to molecular dissect IgG into κ and λ fragments to reduce the complexity and thereby identify substantially more CDRs than by just total Fab isolation. We purified Fab, Fab-κ, Fab-λ, κ and λ light chains from serum from 10 stage I lung adenocarcinoma patients and 10 matched controls from the current and former smokers. After purification, the immunoglobulin fragments were enzymatically digested and measured by high-resolution mass spectrometry. Finally, we compared the number of CDRs identified in these immunoglobulin fragments with that in the Fab fragments. Twice as many CDRs were identified when Fab-κ, Fab-λ, κ and λ (3330) were combined than in the Fab fraction (1663) alone. The number of CDRs and κ:λ ratio was statistically similar in both cases and controls. Molecular dissection of IgG identifies significantly more CDRs, which increases the likelihood of finding lung cancer-related CDR sequences.

Management of lung nodules detected by volume CT scanning.

BACKGROUND: The use of multidetector computed tomography (CT) in lung-cancer screening trials involving subjects with an increased risk of lung cancer has highlighted the problem for the clinician of deciding on the best course of action when noncalcified pulmonary nodules are detected by CT. METHODS: A total of 7557 participants underwent CT screening in years 1, 2, and 4 of a randomized trial of lung-cancer screening. We used software to evaluate a noncalcified nodule according to its volume or volume-doubling time. Growth was defined as an increase in volume of at least 25% between two scans. The first-round screening test was considered to be negative if the volume of a nodule was less than 50 mm(3), if it was 50 to 500 mm(3) but had not grown by the time of the 3-month follow-up CT, or if, in the case of those that had grown, the volume-doubling time was 400 days or more. RESULTS: In the first and second rounds of screening, 2.6% and 1.8% of the participants, respectively, had a positive test result. In round one, the sensitivity of the screen was 94.6% (95% confidence interval [CI], 86.5 to 98.0) and the negative predictive value 99.9% (95% CI, 99.9 to 100.0). In the 7361 subjects with a negative screening result in round one, 20 lung cancers were detected after 2 years of follow-up. CONCLUSIONS: Among subjects at high risk for lung cancer who were screened in three rounds of CT scanning and in whom noncalcified pulmonary nodules were evaluated according to volume and volume-doubling time, the chances of finding lung cancer 1 and 2 years after a negative first-round test were 1 in 1000 and 3 in 1000, respectively. (Current Controlled Trials number, ISRCTN63545820.)

No benefit for consensus double reading at baseline screening for lung cancer with the use of semiautomated volumetry software.

PURPOSE: To retrospectively evaluate the performance of consensus double reading compared with single reading at baseline screening of a lung cancer computed tomography (CT) screening trial. MATERIALS AND METHODS: The study was approved by the Dutch Minister of Health and ethical committees. Written informed consent was obtained from all participants. The benefit of consensus double reading was expressed by the percentage change in cancer detection rate, recall rate, number of additional nodules detected, and change in sensitivity and specificity in 7557 participants. The reference standard was a retrospective analysis of the serial CT scans performed in participants diagnosed with lung cancer during a 2-year period after baseline. Semiautomated volumetric software was used for nodule evaluation. McNemar tests were performed to test statistical significance. In addition, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated and 95% confidence intervals (CIs) constructed. RESULTS: Seventy-four cases of lung cancer were qualified as detectable at baseline. Compared with single reading, consensus double reading did not increase the cancer detection rate (2.7%; 95% CI: -1.0%, 6.4%; P = .50) or change the recall rate (20.6% vs 20.8%, P = .28), but led to the detection of 19.0% (1635 of 8623; 95% CI: 18.0%, 19.9%, P < .01) more nodules. The sensitivity, specificity, PPV, and NPV were 95.9% (71 of 74), 80.2% (6001 of 7483), 4.6% (71 of 1553) and 99.9% (6001 of 6004) for single reading and 98.6% (73 of 74), 80.0% (1497 of 7483), 4.6% (73 of 1570), and 99.9% (5986 of 5987) for consensus double reading, respectively. CONCLUSION: There is no statistically significant benefit for consensus double reading at baseline screening for lung cancer with the use of a nodule management strategy based solely on semiautomated volumetry.

Performance of computer-aided detection of pulmonary nodules in low-dose CT: comparison with double reading by nodule volume.

OBJECTIVE: To evaluate performance of computer-aided detection (CAD) beyond double reading for pulmonary nodules on low-dose computed tomography (CT) by nodule volume. METHODS: A total of 400 low-dose chest CT examinations were randomly selected from the NELSON lung cancer screening trial. CTs were evaluated by two independent readers and processed by CAD. A total of 1,667 findings marked by readers and/or CAD were evaluated by a consensus panel of expert chest radiologists. Performance was evaluated by calculating sensitivity of pulmonary nodule detection and number of false positives, by nodule characteristics and volume. RESULTS: According to the screening protocol, 90.9 % of the findings could be excluded from further evaluation, 49.2 % being small nodules (less than 50 mm(3)). Excluding small nodules reduced false-positive detections by CAD from 3.7 to 1.9 per examination. Of 151 findings that needed further evaluation, 33 (21.9 %) were detected by CAD only, one of them being diagnosed as lung cancer the following year. The sensitivity of nodule detection was 78.1 % for double reading and 96.7 % for CAD. A total of 69.7 % of nodules undetected by readers were attached nodules of which 78.3 % were vessel-attached. CONCLUSIONS: CAD is valuable in lung cancer screening to improve sensitivity of pulmonary nodule detection beyond double reading, at a low false-positive rate when excluding small nodules. KEY POINTS: • Computer-aided detection (CAD) has known advantages for computed tomography (CT). • Combined CAD/nodule size cut-off parameters assist CT lung cancer screening. • This combination improves the sensitivity of pulmonary nodule detection by CT. • It increases the positive predictive value for cancer detection.

CT-quantified emphysema in male heavy smokers: association with lung function decline.

BACKGROUND: Emphysema and small airway disease both contribute to chronic obstructive pulmonary disease (COPD), a disease characterised by accelerated decline in lung function. The association between the extent of emphysema in male current and former smokers and lung function decline was investigated. METHODS: Current and former heavy smokers participating in a lung cancer screening trial were recruited to the study and all underwent CT. Spirometry was performed at baseline and at 3-year follow-up. The 15th percentile (Perc15) was used to assess the severity of emphysema. RESULTS: 2085 men of mean age 59.8 years participated in the study. Mean (SD) baseline Perc15 was -934.9 (19.5) HU. A lower Perc15 value correlated with a lower forced expiratory volume in 1 s (FEV(1)) at baseline (r=0.12, p<0.001). Linear mixed model analysis showed that a lower Perc15 was significantly related to a greater decline in FEV(1) after follow-up (p<0.001). Participants without baseline airway obstruction who developed it after follow-up had significantly lower mean (SD) Perc15 values at baseline than those who did not develop obstruction (-934.2 (17.1) HU vs -930.2 (19.7) HU, p<0.001). CONCLUSION: Greater baseline severity of CT-detected emphysema is related to lower baseline lung function and greater rates of lung function decline, even in those without airway obstruction. CT-detected emphysema aids in identifying non-obstructed male smokers who will develop airflow obstruction.

The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema.

RATIONALE: Genome-wide association studies have identified genetic variants in the nicotinic acetylcholine receptor (nAChR) on chromosome 15q24/25 as a risk for nicotine dependence, lung cancer, and chronic obstructive pulmonary disease (COPD). Assessment of bronchial obstruction by spirometry, typically used for diagnosing COPD, fails, however, to detect emphysema. OBJECTIVES: To determine the association of the 15q24/25 locus with emphysema. METHODS: The rs1051730 variant on 15q24/25 was genotyped in two independent white cohorts of 661 and 456 heavy smokers. Participants underwent pulmonary function tests and computed tomography (CT) of the chest, and took questionnaires assessing smoking behavior and health status. MEASUREMENTS AND MAIN RESULTS: The rs1051730 A-allele correlated with reduced FEV(1) and with increased susceptibility for bronchial obstruction with a pooled odds ratio (OR) of 1.33 (95% confidence interval [CI] = 1.11-1.61; P = 0.0026). In both studies a correlation between the rs1051730 A-allele and lung diffusing capacity (Dl(CO)) and diffusing capacity per unit alveolar volume (Kco) was observed. Consistently, the rs1051730 A-allele conferred increased risk for emphysema as assessed by CT (P = 0.0097 and P = 0.019), with a pooled OR of 1.39 (CI = 1.15-1.68; P = 0.00051). Visual emphysema scores and scores based on densities quantified on CT were more pronounced in A-allele carriers, indicating that rs1051730 correlates with the severity of emphysema. CONCLUSIONS: The 15q24/25 locus in nAChR is associated with the presence and severity of emphysema. This association was independent of pack-years smoking, suggesting that nAChR is causally involved in alveolar destruction as a potentially shared pathogenic mechanism in lung cancer and COPD.

Identification of chronic obstructive pulmonary disease in lung cancer screening computed tomographic scans.

CONTEXT: Smoking is a major risk factor for both cancer and chronic obstructive pulmonary disease (COPD). Computed tomography (CT)-based lung cancer screening may provide an opportunity to detect additional individuals with COPD at an early stage. OBJECTIVE: To determine whether low-dose lung cancer screening CT scans can be used to identify participants with COPD. DESIGN, SETTING, AND PATIENTS: Single-center prospective cross-sectional study within an ongoing lung cancer screening trial. Prebronchodilator pulmonary function testing with inspiratory and expiratory CT on the same day was obtained from 1140 male participants between July 2007 and September 2008. Computed tomographic emphysema was defined as percentage of voxels less than -950 Hounsfield units (HU), and CT air trapping was defined as the expiratory:inspiratory ratio of mean lung density. Chronic obstructive pulmonary disease was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV(1)/FVC) of less than 70%. Logistic regression was used to develop a diagnostic prediction model for airflow limitation. MAIN OUTCOME MEASURES: Diagnostic accuracy of COPD diagnosis using pulmonary function tests as the reference standard. RESULTS: Four hundred thirty-seven participants (38%) had COPD according to lung function testing. A diagnostic model with CT emphysema, CT air trapping, body mass index, pack-years, and smoking status corrected for overoptimism (internal validation) yielded an area under the receiver operating characteristic curve of 0.83 (95% CI, 0.81-0.86). Using the point of optimal accuracy, the model identified 274 participants with COPD with 85 false-positives, a sensitivity of 63% (95% CI, 58%-67%), specificity of 88% (95% CI, 85%-90%), positive predictive value of 76% (95% CI, 72%-81%); and negative predictive value of 79% (95% CI, 76%-82%). The diagnostic model showed an area under the receiver operating characteristic curve of 0.87 (95% CI, 0.86-0.88) for participants with symptoms and 0.78 (95% CI, 0.76-0.80) for those without symptoms. CONCLUSION: Among men who are current and former heavy smokers, low-dose inspiratory and expiratory CT scans obtained for lung cancer screening can identify participants with COPD, with a sensitivity of 63% and a specificity of 88%.

Sequencing and quantifying IgG fragments and antigen-binding regions by mass spectrometry.

In cancer and autoimmune diseases, immunoglobulins with a specific molecular signature that could potentially be used as diagnostic or prognostic markers are released into body fluids. An immunomics approach based on this phenomenon relies on the ability to identify the specific amino acid sequences of the complementarity-determining regions (CDR) of these immunoglobulins, which in turn depends on the level of accuracy, resolution, and sensitivity that can be achieved by advanced mass spectrometry. Reproducible isolation and sequencing of antibody fragments (e.g., Fab) by high-resolution mass spectrometry (MS) from seven healthy donors revealed 43 217 MS signals: 225 could be associated with CDR1 peptides, 513 with CDR2 peptides, and 19 with CDR3 peptides. Seventeen percent of the 43 217 MS signals did not overlap between the seven donors. The Fab isolation method used is reproducible and fast, with a high yield. It provides only one Fab sample fraction for subsequent characterization by high-resolution MS. In 17% and 4% of these seven healthy donors, qualitative (presence/absence) and quantitative (intensity) differences in Fab fragments could be demonstrated, respectively. From these results, we conclude that the identification of a CDR signature as biomarker for autoimmune diseases and cancer without prior knowledge of the antigen is feasible.

Pulmonary ground-glass nodules: increase in mass as an early indicator of growth.

PURPOSE: To compare manual measurements of diameter, volume, and mass of pulmonary ground-glass nodules (GGNs) to establish which method is best for identifying malignant GGNs by determining change across time. MATERIALS AND METHODS: In this ethics committee-approved retrospective study, baseline and follow-up CT examinations of 52 GGNs detected in a lung cancer screening trial were included, resulting in 127 GGN data sets for evaluation. Two observers measured GGN diameter with electronic calipers, manually outlined GGNs to obtain volume and mass, and scored whether a solid component was present. Observer 1 repeated all measurements after 2 months. Coefficients of variation and limits of agreement were calculated by using Bland-Altman methods. In a subgroup of GGNs containing all resected malignant lesions, the ratio between intraobserver variability and growth (growth-to-variability ratio) was calculated for each measurement technique. In this subgroup, the mean time for growth to exceed the upper limit of agreement of each measurement technique was determined. RESULTS: The kappa values for intra- and interobserver agreement for identifying a solid component were 0.55 and 0.38, respectively. Intra- and interobserver coefficients of variation were smallest for GGN mass (P < .001). Thirteen malignant GGNs were resected. Mean growth-to-variability ratios were 11, 28, and 35 for diameter, volume, and mass, respectively (P = .03); mean times required for growth to exceed the upper limit of agreement were 715, 673, and 425 days, respectively (P = .02). CONCLUSION: Mass measurements can enable detection of growth of GGNs earlier and are subject to less variability than are volume or diameter measurements.

Screening for lung cancer with digital chest radiography: sensitivity and number of secondary work-up CT examinations.

PURPOSE: To estimate the performance of digital chest radiography for detection of lung cancer. MATERIALS AND METHODS: The study had ethics committee approval, and a nested case-control design was used and included 55 patients with lung cancer detected at computed tomography (CT) and confirmed with histologic examination and a sample of 72 of 4873 control subjects without nodules at CT. All patients underwent direct-detector digital chest radiography in two projections within 2 months of the screening CT. Four radiologists with varying experience identified and localized potential cancers on chest radiographs by using a confidence scale of level 1 (no lesion) to 5 (definite lesion). Localization receiver operating characteristic (ROC) analysis was performed. On the basis of the assumption that suspicious lesions seen at chest radiography would lead to further work-up with CT, the number of work-up CT examinations per detected cancer (CT examinations per cancer) was calculated at various confidence levels for the screening population (cancer rate in study population, 1.3%). RESULTS: Tumor size ranged from 6.8 to 50.7 mm (median, 11.8 mm). Areas under the localization ROC curve ranged from 0.52 to 0.69. Detection rates substantially varied with the observers' experience and confidence level: At a confidence level of 5, detection rates ranged from 18% at one CT examination per cancer to 53% at 13 CT examinations per cancer. At a confidence level of 2 or higher, detection rates ranged from 94% at 62 CT examinations per cancer to 78% at 44 CT examinations per cancer. CONCLUSION: A detection rate of 94% for lung tumors with a diameter of 6.8-50.7 mm found at CT screening was achievable with chest radiography only at the expense of a high false-positive rate and an excessive number of work-up CT examinations. Detection performance is strongly observer dependent.

Volumetric measurement of pulmonary nodules at low-dose chest CT: effect of reconstruction setting on measurement variability.

OBJECTIVE: To assess volumetric measurement variability in pulmonary nodules detected at low-dose chest CT with three reconstruction settings. METHODS: The volume of 200 solid pulmonary nodules was measured three times using commercially available semi-automated software of low-dose chest CT data-sets reconstructed with 1 mm section thickness and a soft kernel (A), 2 mm and a soft kernel (B), and 2 mm and a sharp kernel (C), respectively. Repeatability coefficients of the three measurements within each setting were calculated by the Bland and Altman method. A three-level model was applied to test the impact of reconstruction setting on the measured volume. RESULTS: The repeatability coefficients were 8.9, 22.5 and 37.5% for settings A, B and C. Three-level analysis showed that settings A and C yielded a 1.29 times higher estimate of nodule volume compared with setting B (P = 0.03). The significant interaction among setting, nodule location and morphology demonstrated that the effect of the reconstruction setting was different for different types of nodules. Low-dose CT reconstructed with 1 mm section thickness and a soft kernel provided the most repeatable volume measurement. CONCLUSION: A wide, nodule-type-dependent range of agreement between volume measurements with different reconstruction settings suggests strict consistency is required for serial CT studies.

A new ultrafast and high-throughput mass spectrometric approach for the therapeutic drug monitoring of the multi-targeted anti-folate pemetrexed in plasma from lung cancer patients.

An analytical assay has been developed and validated for ultrafast and high-throughput mass spectrometric determination of pemetrexed concentrations in plasma using matrix assisted laser desorption/ionization-triple quadrupole-tandem mass spectrometry. Patient plasma samples spiked with the internal standard methotrexate were measured by multiple reaction monitoring. The detection limit was 0.4 fmol/µL, lower limit of quantification was 0.9 fmol/µL, and upper limit of quantification was 60 fmol/µL, respectively. Overall observed pemetrexed concentrations in patient samples ranged between 8.7 (1.4) and 142.7 (20.3) pmol/µL (SD). The newly developed mass spectrometric assay is applicable for (routine) therapeutic drug monitoring of pemetrexed concentrations in plasma from non-small cell lung cancer patients.

Stem cells and the natural history of lung cancer: implications for lung cancer screening.

Lung cancer is not simply a single disease, but a collection of several phenotypically very diverse and regionally distinct neoplasias. Its natural history is complex and not yet fully understood. Stem cells and the complex interaction with the microenvironment of the tumor and the immune system play an important role in tumor progression and metastasizing capacity. This finding explains why lung cancer does not always follow the multistep carcinogenetic and exponential growth model and why small lesions do not always equate to early-stage disease. Despite the fact that volume doubling times are increasingly used as surrogate markers for the natural history of lung cancer and as estimates for the proportion of overdiagnosed cases, it is only a momentary impression. At baseline screening especially, screen-detected lung cancer cases are preferably detected when they are in the indolent phase of their growth curve (length-biased sampling), from which it can by no means be concluded that they may not progress or metastasize at a later stage. Because the natural history of lung cancer is only partly elucidated, conclusions on the impact of overdiagnosis in lung cancer screening are premature.

Smooth or attached solid indeterminate nodules detected at baseline CT screening in the NELSON study: cancer risk during 1 year of follow-up.

PURPOSE: To retrospectively determine whether baseline nodule characteristics at 3-month and 1-year volume doubling time (VDT) are predictive for lung cancer in solid indeterminate noncalcified nodules (NCNs) detected at baseline computed tomographic (CT) screening. MATERIALS AND METHODS: The study, conducted between April 2004 and May 2006, was institutional review board approved. Patient consent was waived for this retrospective evaluation. NCNs between 5 and 10 mm in diameter (n = 891) were evaluated at 3 months and 1 year to assess growth (VDT < 400 days). Baseline assessments were related to growth at 3 months and 1 year by using chi(2) and Mann-Whitney U tests. Baseline assessments and growth were related to the presence of malignancy by using univariate and multivariate logistic regression analyses. RESULTS: At 3 months and at 1 year, 8% and 1% of NCNs had grown, of which 15% and 50% were malignant, respectively. One-year growth was related to morphology (P < .01), margin (P < .0001), location (P < .001), and size (P < .01). All cancers were nonspherical and purely intraparenchymal, without attachment to vessels, the pleura, or fissures. In nonsmooth unattached nodules, a volume of 130 mm(3) or larger was the only predictor for malignancy (odds ratio, 6.3; 95% confidence interval [CI]: 1.7, 23.0). After the addition of information on the 3-month VDT, large volume (odds ratio, 4.9; 95% CI: 1.2, 20.1) and 3-month VDT (odds ratio, 15.6; 95% CI: 4.5, 53.5) helped predict malignancy. At 1 year, only the 1-year growth remained (odds ratio, 213.3; 95% CI: 18.7, 2430.9) as predictor for malignancy. CONCLUSION: In smooth or attached solid indeterminate NCNs, no malignancies were found at 1-year follow-up. In nonsmooth purely intraparenchymal NCNs, size is the main baseline predictor for malignancy. When follow-up data are available, growth is a strong predictor for malignancy, especially at 1-year follow-up.

Effect of nodule characteristics on variability of semiautomated volume measurements in pulmonary nodules detected in a lung cancer screening program.

PURPOSE: To retrospectively assess volume measurement variability in solid pulmonary nodules (volume, 15-500 mm(3)) detected at lung cancer screening and to quantify the independent effects of nodule morphology, size, and location. MATERIALS AND METHODS: This retrospective study was a substudy of the screening program that was approved by the Dutch Ministry of Health, and all participants provided written informed consent. Two independent readers used semiautomated software to measure the volume of pulmonary nodules detected in 6774 participants aged 50-75 years (5917 men). Nodules were classified according to their location (purely intraparenchymal, pleural based, juxtavascular, or fissure attached), morphology (smooth, polylobulated, spiculated, or irregular), and size (50 mm(3)). The level of agreement was expressed by using the absolute values of the relative volume differences (RVDs). Multivariate logistic regression analysis was performed, and odds ratios (ORs) were computed to quantify the independent effects of morphology, location, and size on RVD categories. RESULTS: Altogether, 4225 nodules in 2239 participants were included. Complete agreement in volume was obtained for 3646 (86%) of the nodules. Disagreement was small (absolute value of RVD < 5%) for 173 (4%) nodules, moderate (absolute value of RVD >or= 5% but < 15%) for 232 (6%), and large (absolute value of RVD >or= 15%) for 174 (4%). Multivariate analysis showed that the ORs of volume disagreement were 15.7, 3.1, and 1.9 for irregular, spiculated, and polylobulated nodules, respectively; 3.5, 2.6, and 2.1 for juxtavascular, pleural-based, and fissure-attached nodules, respectively; and 1.3 for large nodules compared with smooth, purely intraparenchymal, and small reference nodules. CONCLUSION: Nodule morphology, location, and size influence volume measurement variability, particularly for juxtavascular and irregular nodules.

How to deal with incidentally detected pulmonary nodules less than 10mm in size on CT in a healthy person.

The high frequency of non-calcified pulmonary nodules (NCN) <10mm incidentally detected on a multi-detector CT (MDCT) of the chest raises the question of how clinicians and radiologists should deal with these nodules. Management algorithms for solitary pulmonary nodules >10mm do not carry across to sub-centimeter lesions. Purpose of this review is to provide a 10-step approach for routinely detected sub-centimeter NCN on a MDCT in healthy persons in order to be able to make an optimal discrimination between benign and malignant NCNs. Recommendations are primarily based on individual cancer risk, the presence or absence of calcifications and nodule size. In nodules >4-5mm nodule consistency, margin and shape should be taken into account. Next steps in the nodule evaluation are the assessment of localization, nodule number, presence or absence of growth and volume doubling time. Growth is defined as a volume doubling time of 400 days or less, based on volumetry. For nodules <4mm, a follow-up CT at 12 months is recommended in high risk persons, whilst for low-risk persons no follow-up is needed. If no growth is observed at 12 months, no further follow-up is required. For solid, smooth or attached indeterminate NCN between 5 and 10mm we recommend an annual repeat scan, whilst for purely intra-parenchymal nodules a 3-month repeat scan should be made to assess growth. Growing lesions with a volume doubling time <400 days require further work-up and diagnosis, otherwise an annual repeat scan to assess growth is recommended.

High affective risk perception is associated with more lung cancer-specific distress in CT screening for lung cancer.

Screening for cancer can cause distress. People who perceive their risk of cancer as high may be more vulnerable to distress. This study evaluated whether participants of a lung cancer Computed Tomography (CT) screening trial with a high affective risk perception of developing lung cancer had a higher level of lung cancer-specific distress during CT screening. Furthermore, we evaluated whether participants perceived their risk of developing lung cancer differently 6 months after screening compared with 1 day before screening. A total of 351 subsequent participants of the NELSON-trial (Dutch-Belgian randomized controlled trial for lung cancer screening in high-risk subjects), who were randomized to the screen arm, were asked to fill in questionnaires 1 day before and 6 months after screening. Lung cancer-specific distress (Impact of Event Scale (IES)), generic health-related quality of life (SF-12) and affective risk perception were assessed. One day before screening, the participants with a high affective risk perception (n=47/321, 14.6%) had significantly higher (i.e., worse) median IES scores than participants with a low affective risk perception (11.5 vs. 2.0, p<0.01). Although median IES scores were significantly lower 6 months after screening than 1 day before screening, participants with a high affective risk perception still showed significantly higher IES scores than participants with a low affective risk perception (6.5 vs. 1.0, p<0.01). Six months after screening, significantly less participants (10.5%) felt that their risk of developing lung cancer was high than 1 day before screening (14.5%) (p<0.01). Levels of distress were not severe, but were elevated compared to participants with a low affective risk perception, and therefore, attention for this group is recommended.

Limited value of shape, margin and CT density in the discrimination between benign and malignant screen detected solid pulmonary nodules of the NELSON trial.

PURPOSE: To evaluate prospectively the value of size, shape, margin and density in discriminating between benign and malignant CT screen detected solid non-calcified pulmonary nodules. MATERIAL AND METHODS: This study was institutional review board approved. For this study 405 participants of the NELSON lung cancer screening trial with 469 indeterminate or potentially malignant solid pulmonary nodules (>50mm3) were selected. The nodules were classified based on size, shape (round, polygonal, irregular) and margin (smooth, lobulated, spiculated). Mean nodule density and nodule volume were automatically generated by software. Analyses were performed by univariate and multivariate logistic regression. Results were presented as likelihood ratios (LR) with 95% confidence intervals (CI). Receiver operating characteristic analysis was performed for mean density as predictor for lung cancer. RESULTS: Of the 469 nodules, 387 (83%) were between 50 and 500mm3, 82 (17%) >500mm3, 59 (13%) malignant, 410 (87%) benign. The median size of the nodules was 103mm3 (range 50-5486mm3). In multivariate analysis lobulated nodules had LR of 11 compared to smooth; spiculated nodules a LR of 7 compared to smooth; irregular nodules a LR of 6 compared to round and polygonal; volume a LR of 3. The mean nodule CT density did not predict the presence of lung cancer (AUC 0.37, 95% CI 0.32-0.43). CONCLUSION: In solid non-calcified nodules larger than 50mm3, size and to a lesser extent a lobulated or spiculated margin and irregular shape increased the likelihood that a nodule was malignant. Nodule density had no discriminative power.