Johan Coolen

Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene

Introduction Vitamin D deficiency has been associated with many chronic illnesses, but little is known about its relationship with chronic obstructive pulmonary disease (COPD). Objectives Serum 25-hydroxyvitamin D (25-OHD) levels were measured in 414 (ex)-smokers older than 50 years and the link between vitamin D status and presence of COPD was assessed. The rs7041 and rs4588 variants in the vitamin D-binding gene (GC) were genotyped and their effects on 25-OHD levels were tested. Results In patients with COPD, 25-OHD levels correlated significantly with forced expiratory volume in 1 s (FEV1) (r=0.28, p<0.0001). Compared with 31% of the smokers with normal lung function, as many as 60% and 77% of patients with GOLD (Global Initiative for Obstructive Lung Disease) stage 3 and 4 exhibited deficient 25-OHD levels <20 ng/ml (p<0.0001). Additionally, 25-OHD levels were reduced by 25% in homozygous carriers of the rs7041 at-risk T allele (p<0.0001). This correlation was found to be independent of COPD severity, smoking history, age, gender, body mass index, corticosteroid intake, seasonal variation and rs4588 (p<0.0001). Notably, 76% and 100% of patients with GOLD stage 3 and 4 homozygous for the rs7041 T allele exhibited 25-OHD levels <20 ng/ml. Logistic regression corrected for age, gender and smoking history further revealed that homozygous carriers of the rs7041 T allele exhibited an increased risk for COPD (OR 2.11; 95% CI 1.20 to 3.71; p=0.009). Conclusion Vitamin D deficiency occurs frequently in COPD and correlates with severity of COPD. The data warrant vitamin D supplementation in patients with severe COPD, especially in those carrying at-risk rs7041 variants.

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.

Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality.

Rationale In COPD patients, mortality risk is influenced by age, severity of respiratory disease, and comorbidities. With an unbiased statistical approach we sought to identify clusters of COPD patients and to examine their mortality risk. Methods Stable COPD subjects (n = 527) were classified using hierarchical cluster analysis of clinical, functional and imaging data. The relevance of this classification was validated using prospective follow-up of mortality. Results The most relevant patient classification was that based on three clusters (phenotypes). Phenotype 1 included subjects at very low risk of mortality, who had mild respiratory disease and low rates of comorbidities. Phenotype 2 and 3 were at high risk of mortality. Phenotype 2 included younger subjects with severe airflow limitation, emphysema and hyperinflation, low body mass index, and low rates of cardiovascular comorbidities. Phenotype 3 included older subjects with less severe respiratory disease, but higher rates of obesity and cardiovascular comorbidities. Mortality was associated with the severity of airflow limitation in Phenotype 2 but not in Phenotype 3 subjects, and subjects in Phenotype 2 died at younger age. Conclusions We identified three COPD phenotypes, including two phenotypes with high risk of mortality. Subjects within these phenotypes may require different therapeutic interventions to improve their outcome.

Integrated PET/CT in the staging of nonsmall cell lung cancer: technical aspects and clinical integration

Lung cancer is a common disease and is a leading cause of death in many countries. The management of lung cancer is directed by an optimal staging of the tumour. Integrated positron emission tomography (PET)/computed tomography (CT) is an anatomo-metabolic imaging modality that has recently been introduced to clinical practice and combines two different techniques: CT, which provides very detailed anatomic information; and PET, which provides metabolic information. One of the advantages of PET/CT is the improved image interpretation. This improvement can result in the detection of lesions initially not seen on CT or PET, a more precise location of lesions, a better characterisation of the lesion as benign or malignant and a better differentiation between tumour and surrounding structures. Initial studies demonstrate better results for PET/CT in the staging of lung cancer in comparison with PET alone, CT alone or visual correlation of PET and CT. The purpose of the present article is to discuss technical aspects of integrated PET/CT and to attempt to outline how to introduce integrated PET/CT in clinical and daily practice.

Malignant Pleural Disease: Diagnosis by Using Diffusion-weighted and Dynamic Contrast-enhanced MR Imaging—Initial Experience

PURPOSE To investigate the use of diffusion-weighted (DW) imaging for differentiating benign lesions from malignant pleural disease (MPD) and to retrospectively assess dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging acquisitions to find out whether combining these measurements with DW imaging could improve the diagnostic value of DW imaging. MATERIALS AND METHODS This study was approved by the local ethics committee, and all patients provided written informed consent. Thirty-one consecutive patients with pleural abnormalities suspicious for MPD underwent whole-body positron emission tomography (PET)/computed tomography (CT) and thorax MR examinations. Diagnostic thoracoscopy with histopathologic analysis of pleural biopsies served as the reference standard. First-line evaluation of each suspicious lesion was performed by using the apparent diffusion coefficient (ADC) calculated from the DW image, and the optimal cutoff value was found by using receiver operating characteristic curve analysis. Afterward, DCE MR imaging data were used to improve the diagnosis in the range of ADCs where DW imaging results were equivocal. RESULTS Sensitivity, specificity, and accuracy of PET/CT for diagnosis of MPD were 100%, 35.3%, and 64.5%. The optimal ADC threshold to differentiate benign lesions from MPD with DW MR imaging was 1.52 × 10(-3) mm(2)/sec, with sensitivity, specificity, and accuracy of 71.4%, 100%, and 87.1%, respectively. This result could be improved to 92.8%, 94.1%, and 93.5%, respectively, when DCE MR imaging data were included in those cases where ADC was between 1.52 and 2.00 × 10(-3) mm(2)/sec. A total of 20 patients had disease diagnosed correctly, nine had disease diagnosed incorrectly, and two cases were undetermined with PET/CT. DW imaging helped stage disease correctly in 27 patients and incorrectly in four. The undetermined cases at PET/CT were correctly diagnosed at MR imaging. CONCLUSION DW imaging is a promising tool for differentiating MPD from benign lesions, with high accuracy, and supplementation with DCE MR imaging seems to further improve sensitivity.

Imaging in pleural mesothelioma: a review of the 13th International Conference of the International Mesothelioma Interest Group

Imaging plays an important role in the detection, diagnosis, staging, response assessment, and surveillance of malignant pleural mesothelioma. The etiology, biology, and growth pattern of mesothelioma present unique challenges for each modality used to capture various aspects of this disease. Clinical implementation of imaging techniques and information derived from images continue to evolve based on active research in this field worldwide. This paper summarizes the imaging-based research presented orally at the 2016 International Conference of the International Mesothelioma Interest Group (iMig) in Birmingham, United Kingdom, held May 1-4, 2016. Presented topics included intraoperative near-infrared imaging of mesothelioma to aid the assessment of resection completeness, an evaluation of tumor enhancement improvement with increased time delay between contrast injection and image acquisition in standard clinical magnetic resonance imaging (MRI) scans, the potential of early contrast enhancement analysis to provide MRI with a role in mesothelioma detection, the differentiation of short- and long-term survivors based on MRI tumor volume and histogram analysis, the response-assessment potential of hemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans, the correlation of CT-based tumor volume with post-surgical tumor specimen weight, and consideration of the need to update the mesothelioma tumor response assessment paradigm.

Malignant Pleural Mesothelioma: Visual Assessment by Using Pleural Pointillism at Diffusion-weighted MR Imaging

PURPOSE To evaluate the diagnostic accuracy of the visual assessment of malignant pleural mesothelioma (MPM) on magnetic resonance (MR) images by using two known visual markers (mediastinal pleural thickness and shrinking of the lung) and a newly introduced one (pleural pointillism). MATERIALS AND METHODS With the approval of the local ethics committee, 100 consecutive patients (mean age, 61.4 years; age range, 18-87 years; 75 men, 25 women) suspected of having MPM pleural abnormalities underwent positron emission tomography/computed tomography and MR imaging, including diffusion-weighted (DW) MR imaging, followed by explorative thoracoscopy or guided biopsy with histopathologic confirmation. Because visual assessment is still the preferred method of image interpretation, the diagnostic accuracy of mediastinal pleural thickening, shrinking lung (hemithorax volume decrease due to fibrosis), and pleural pointillism were examined. Pleural pointillism was denoted by the presence of multiple, hyperintense pleural spots on high-b-value DW images. Histopathologic findings in the surgical specimen served as the reference standard. McNemar tests with Bonferroni correction were used to assess differences in accuracy among the three examined markers. RESULTS Of 100 patients, 33 had benign pleural alterations, and 67 had malignant pleural diseases (MPDs); 57 of 67 had MPM. A total of 78 patients received a correct diagnosis (benign vs malignant) on the basis of mediastinal pleural thickening (sensitivity, 81%; specificity, 73%; accuracy, 78%); and 66 patients, on the basis of shrinking lung (sensitivity, 60%; specificity, 79%; accuracy, 66%). The correct diagnosis was indicated on the basis of pleural pointillism in 88 patients (sensitivity, 93%; specificity, 79%; accuracy, 88%). CONCLUSION Visual assessment of pleural pointillism on high-b-value DW images is useful to differentiate MPD from benign alterations, performing substantially better than mediastinal pleural thickness and shrinking lung, and might obviate unnecessary invasive procedures for MPM.

The crazy-paving pattern: a radiological-pathological correlation.

The crazy-paving pattern is a linear pattern superimposed on a background of ground-glass opacity, resembling irregularly shaped paving stones. The crazy-paving pattern is initially described as the pathognomonic sign of alveolar proteinosis. Nowadays this pattern is a common finding on high-resolution CT imaging, and can be seen in a number of acute and chronic diseases. The purpose of this paper is to illustrate different diseases that cause this crazy-paving pattern and to correlate the radiological findings from computed tomography with the histopathological findings.

Imaging in pleural mesothelioma

Imaging of malignant pleural mesothelioma (MPM) is essential to the diagnosis, assessment, and monitoring of this disease. The complex morphology and growth pattern of MPM, however, create unique challenges for image acquisition and interpretation. These challenges have captured the attention of investigators around the world, some of whom presented their work at the 2012 International Conference of the International Mesothelioma Interest Group (iMig 2012) in Boston, Massachusetts, USA, September 2012. The measurement of tumor thickness on computed tomography (CT) scans is the current standard of care in the assessment of MPM tumor response to therapy; in this context, variability among observers in the measurement task and in the tumor response classification categories derived from such measurements was reported. Alternate CT-based tumor response criteria, specifically direct measurement of tumor volume change and change in lung volume as a surrogate for tumor response, were presented. Dynamic contrast-enhanced CT has a role in other settings, but investigation into its potential use for imaging mesothelioma tumor perfusion only recently has been initiated. Magnetic resonance imaging (MRI) and positron-emission tomography (PET) are important imaging modalities in MPM and complement the information provided by CT. The pointillism sign in diffusion-weighted MRI was reported as a potential parameter for the classification of pleural lesions as benign or malignant, and PET parameters that measure tumor activity and functional tumor volume were presented as indicators of patient prognosis. Also reported was the use of PET/CT in the management of patients who undergo high-dose radiation therapy. Imaging for MPM impacts everything from initial patient diagnosis to the outcomes of clinical trials; iMig 2012 captured this broad range of imaging applications as investigators exploit technology and implement multidisciplinary approaches toward the benefit of MPM patients.

Thin-Section CT Features of Idiopathic Pulmonary Fibrosis Correlated with Micro-CT and Histologic Analysis.

Purpose To elucidate the underlying lung changes responsible for the computed tomographic (CT) features of idiopathic pulmonary fibrosis (IPF) and to gain insight into the way IPF proceeds through the lungs and progresses over time. Materials and Methods Micro-CT studies of tissue cores obtained from explant lungs were examined and were correlated 1:1 with a CT study obtained immediately before transplantation. Samples for histologic analysis were obtained from selected cores. Results In areas with no or minimal abnormalities on CT images, small areas of increased attenuation located in or near the interlobular septa can be seen on micro-CT studies. In more involved lung areas, the number of opacities increases and opacities enlarge and approach each other along the interlobular septa, causing a fine reticular pattern on CT images. Simultaneously, air-containing structures in and around these opacities arise, corresponding with small cysts on CT images. Honeycombing is caused by a progressive increase in the number and size of these cystic structures and tissue opacities that gradually extend toward the centrilobular region and finally replace the entire lobule. At histologic analysis, the small islands of increased attenuation very likely correspond with fibroblastic foci. Near these fibroblastic foci, an abnormal adjacency of alveolar walls was seen, suggesting alveolar collapse. In later stages, normal lung tissue is replaced by a large amount of young collagen, as seen in patients with advanced fibrosis. Conclusion Fibrosis and cyst formation in patients with IPF seem to start at the periphery of the pulmonary lobule and progressively extend toward the core of this anatomic lung unit. Evidence was found that alveolar collapse might already be present in an early stage when there is only little pulmonary fibrosis.