Wilson DO, Weissfeld JL, Fuhrman CR, et al. The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15232, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 11/2008; 178(9):956-61. DOI: 10.1164/rccm.200802-336OC
Source: PubMed


The role of computed tomography (CT) screening for lung cancer is controversial, currently under study, and not yet fully elucidated.
To report findings from initial and 1-year repeat screening low-radiation-dose CT of the chest and 3-year outcomes for 50- to 79-year-old current and ex-smokers in the Pittsburgh Lung Screening Study (PLuSS).
Notified of findings on screening CT, subjects received diagnostic advice from both study and personal physicians. Tracking subjects for up to three years since initial screening, we obtained medical records to document diagnostic procedures, lung cancer diagnoses, and deaths.
3,642 and 3,423 subjects had initial and repeat screening. A total of 1,477 (40.6% of 3,624) were told about noncalcified lung nodules on the initial screening and, before repeat screening, 821 (55.6% of 1,477, 22.5% of 3,642) obtained one or more subsequent diagnostic imaging studies (CT, positron emission tomography [PET], or PET-CT). Tracking identified 80 subjects with lung cancer, including 53 subjects with tumor seen at initial screening. In all, 36 subjects (1.0% of the 3,642 screened), referred for abnormalities on either the initial or repeat screening, had a major thoracic surgical procedure (thoracotomy, video-assisted thoracoscopic surgery [VATS], median sternotomy, or mediastinoscopy) leading to a noncancer final diagnosis. Out of 82 subjects with thoracotomy or VATS to exclude malignancy in a lung nodule, 28 (34.1%) received a noncancer final diagnosis. Forty of 69 (58%) subjects with non-small cell lung cancer had stage I disease at diagnosis.
Though leading to the discovery of early stage lung cancer, CT screening also led to many diagnostic follow-up procedures, including major thoracic surgical procedures with noncancer outcomes.

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    • "The National Lung Screening Trial (NLST) demonstrated that screening smokers and ex-smokers for lung cancer can lead to early diagnosis and reduced lung cancer mortality [6]. However, the low (4%) positive predictive value (PPV) of CT screening in the NLST cohort leads to a large number of unnecessary follow-up procedures, including surgery for benign nodules, as was first reported in the Pittsburgh Lung Screening Study (PLuSS) and later in the NLST [6,7]. The European NELSON CT screening study includes tumor volume and doubling time in the assessment of pulmonary nodules and improves the PPV to 41% by only referring small nodules (50-500 mm3) for clinical follow-up if they show evidence of growth and a doubling time of less than 400 days [8,9]. "
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    ABSTRACT: Background CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. Results Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. Conclusions Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.
    Clinical Proteomics 08/2014; 11(1):32. DOI:10.1186/1559-0275-11-32
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    • "Study participants for the replication cohort were from the Pittsburgh Lung Screening Study (PLuSS), a volunteer cohort established to investigate lung cancer biomarkers in an at-risk population of smokers which has previously been described [21,22]. From the total cohort (n = 3638), 490 NHW individuals (183 men and 307 women) had information allowing classification with respect to chronic mucous hypersecretion and had provided sputum for DNA isolation. "
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    ABSTRACT: Chronic mucous hypersecretion (CMH) contributes to COPD exacerbations and increased risk for lung cancer. Because methylation of gene promoters in sputum has been shown to be associated with lung cancer risk, we tested whether such methylation was more common in persons with CMH. Eleven genes commonly silenced by promoter methylation in lung cancer and associated with cancer risk were selected. Methylation specific PCR (MSP) was used to profile the sputum of 900 individuals in the Lovelace Smokers Cohort (LSC). Replication was performed in 490 individuals from the Pittsburgh Lung Screening Study (PLuSS). CMH was significantly associated with an overall increased number of methylated genes, with SULF2 methylation demonstrating the most consistent association. The association between SULF2 methylation and CMH was significantly increased in males but not in females both in the LSC and PLuSS (OR = 2.72, 95 % CI = 1.51-4.91, p = 0.001 and OR = 2.97, 95 % CI = 1.48-5.95, p = 0.002, respectively). Further, the association between methylation and CMH was more pronounced among 139 male former smokers with persistent CMH compared to current smokers (SULF2; OR = 3.65, 95 % CI = 1.59-8.37, p = 0.002). These findings demonstrate that especially male former smokers with persistent CMH have markedly increased promoter methylation of lung cancer risk genes and potentially could be at increased risk for lung cancer.
    Respiratory research 01/2014; 15(1):2. DOI:10.1186/1465-9921-15-2 · 3.09 Impact Factor
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    • "A recent survey of individuals with a high risk for developing lung cancer by the National Institutes of Health demonstrated that the patients screened through low-dose helical computed tomography (CT) had a 20% lower mortality rate than those screened by a traditional chest x-ray, presumably due to the improved image quality associated with the CT (Aberle et al. 2011). However, the relatively high cost of the helical CT, a limited access to this technology in some geographical areas, and problems of differentiating benign pulmonary nodules from lung cancer (Welch et al. 2007; Wilson et al. 2008), leading to higher-than-desired false-positive rates, have limited its widespread use. Molecular tests based on glycoconjugate measurements have also been developed to identify potential markers of lung cancer (Heo et al. 2007; Ueda et al. 2009; Zeng et al. 2010; Arnold et al. 2011). "
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    ABSTRACT: Glycosylation is a key post-translational protein modification which appears important in malignant transformation and tumor metastasis. Abnormal glycosylation of different proteins can often be measured in blood serum. In this study, we extend our serum-based structural investigations to samples provided by patients diagnosed with lung cancer, paying particular attention to the effects of smoking on the serum glycomic traces. Following a battery of glycomic tests, we find that several fucosylated tetra-antennary structures with varying degrees of sialylation are increased in their abundances in control samples provided by the former smokers, with further elevations in the lung cancer patients who were former smokers. Further detailed investigations demonstrated that the level of outer-arm fucosylation was elevated in the control samples of the former smokers and again in the lung cancer samples provided by the former smokers. This trend was particularly noticeable for the tri- and tetra-antennary structures. Different ratios of sialylation linkages were also observed that could be correlated with the different states-of-health and smoking status. Decreases in the abundance levels of isomers with two and three α2,3-linked sialic acids and an increased abundance of an isomer with two α2,6-linked sialic acids were noted for a fucosylated tri-sialylated tri-antennary glycan. These results demonstrate the long-term effects of smoking on glycomic profiles and that this factor needs to be considered in these and other serum-based analyses.
    Glycobiology 07/2012; 22(12). DOI:10.1093/glycob/cws108 · 3.15 Impact Factor
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