Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma.

OBJECTIVES: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as 'soluble mesothelin-related proteins' (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage. MATERIALS AND METHODS: A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the '3-biomarker classifier' was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated. RESULTS AND CONCLUSION: The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone.

Computer-aided quantification of interstitial lung disease from high resolution computed tomography images in systemic sclerosis: correlation with visual reader-based score and physiologic tests.

OBJECTIVE: To evaluate the performance of a computerized-aided method (CaM) for quantification of interstitial lung disease (ILD) in patients with systemic sclerosis and to determine its correlation with the conventional visual reader-based score (CoVR) and the pulmonary function tests (PFTs). METHODS: Seventy-nine patients were enrolled. All patients underwent chest high resolution computed tomography (HRCT) scored by two radiologists adopting the CoVR. All HRCT images were then analysed by a CaM using a DICOM software. The relationships among the lung segmentation analysis, the readers, and the PFTs results were calculated using linear regression analysis and Pearson's correlation. Receiver operating curve analysis was performed for determination of CaM extent threshold. RESULTS: A strong correlation between CaM and CoVR was observed (P < 0.0001). The CaM showed a significant negative correlation with forced vital capacity (FVC) (P < 0.0001) and the single breath carbon monoxide diffusing capacity of the lung (DLco) (P < 0.0001). A CaM optimal extent threshold of 20% represented the best compromise between sensitivity (75.6%) and specificity (97.4%). CONCLUSIONS: CaM quantification of SSc-ILD can be useful in the assessment of extent of lung disease and may provide reliable tool in daily clinical practice and clinical trials.

Utility of an open-source DICOM viewer software (OsiriX) to assess pulmonary fibrosis in systemic sclerosis: preliminary results.

To investigate the utility of an open-source Digital Imaging and Communication in Medicine viewer software-OsiriX-to assess pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc). Chest high-resolution computed tomography (HRCT) examinations obtained from 10 patients with diagnosis of SSc were analysed by two radiologists adopting a standard semiquantitative scoring for PF. Pulmonary involvement was evaluated in three sections (superior, middle and inferior). For the assessment of the extension of PF, the adopted semiquantitative HRCT score ranged from 0 to 3 (0 = absence of PF; 1 = 1-20 % of lung section involvement; 2 = 21-40 % of lung section involvement; 3 = 41-100 % of lung section involvement). Further, a quantitative assessment (i.e. parameters of distribution of lung attenuation such as kurtosis and mean lung attenuation) of PF was independently performed on the same sections by a rheumatologist, independently and blinded to radiologists' scoring, using OsiriX. The results obtained were compared with those of HRCT semiquantitative analysis. Intra-reader reliability of HRCT findings and feasibility of OsiriX quantitative segmentation was recorded. A significant association between the median values of kurtosis by both the quantitative OsiriX assessment and the HRCT semiquantitative analysis was found (p < 0.0001). Moreover, kurtosis correlated significantly with the mean lung attenuation (Spearman's rho = 0.885; p = 0.0001). An excellent intra-reader reliability of HRCT findings among both readers was obtained. A significant difference between the mean time spent on the OsiriX quantitative analysis (mean 1.85 ± SD 1.3 min) and the mean time spent by the radiologist for the HRCT semiquantitative assessment (mean 8.5 ± SD 4.5 min, p < 0.00001) was noted. The study provides the new working hypothesis that OsiriX may be a useful and feasible tool to achieve a quantitative evaluation of PF in SSc patients.

Utility of a simplified ultrasound assessment to assess interstitial pulmonary fibrosis in connective tissue disorders--preliminary results.

INTRODUCTION: Interstitial pulmonary fibrosis (IPF) is a frequent manifestation in patients with connective tissue disorders (CTD). Recently the ultrasound (US) criterion validity for its assessment has been proposed; however, the US scoring systems adopted include the study of several lung intercostal spaces (LIS), which could be time-consuming in daily clinical practice. The aim of this study was to investigate the utility of a simplified US B-lines scoring system compared with both the US comprehensive assessment and the high-resolution computed tomography (HRCT) findings of IPF in CTD patients. METHODS: Thirty-six patients with a diagnosis of CTD were enrolled. Each patient underwent chest HRCT and lung US by an experienced radiologist and rheumatologist, respectively. Both comprehensive and simplified US B-lines assessments were scanned. The comprehensive US assessment was performed at 50 LIS level, whereas the simplified US assessment included bilaterally 14 LIS; for the anterior chest: the second LIS along the para-sternal lines, the fourth LIS along the mid-clavear, anterior axillary and mid-axillary lines; for the posterior chest: the eighth LIS along the paravertebral, sub-scapular and posterior axillary lines. For criterion validity, HRCT was considered the gold standard. Feasibility, inter and intra-observer reliability was also investigated. RESULTS: A highly significant correlation between comprehensive and simplified US assessment was found (P = 0.0001). A significant correlation was also found between the simplified US assessment and HRCT findings (P = 0.0006). Kappa values for the inter-observer simplified US assessment were in a range from 0.769 to 0.885, whereas the concordance correlation coefficient values for the intra-observer were from 0.856 to 0.955. There was a relevant difference in time spent on comprehensive (mean 23.3 ± SD 4.5 minutes) with respect to the simplified US assessment (mean 8.6 ± SD 1.4) (P < 0.00001). CONCLUSIONS: Our results provide a new working hypothesis in favor of the utility of a simplified US B-lines assessment as an adjunct method to assess IPF in patients with CTD.

Diagnosis of asbestos-related pleuropolmonary diseases.

A revision of criteria for diagnosis of asbestos-related pathological conditions was performed studying specially asbestosis, pleural plaques and malignant mesothelioma, also taking into account the problems connected with histopathology. As regards the histological diagnosis of asbestosis, it requires the presence of diffuse interstitialfibrosis in a well inflated tissue remote from the site of a tumour or other large lesion, plus the presence of two or more asbestos bodies in a 1 cm2 section. As regards the imaging diagnosis, the HRTC 4-point scale proposed by Paris et al. (2004) has been adopted:--0 images not suggestive of interstitial pneumonia;--1 modest unilateral or bilateral interstitial abnormalities, involving restricted areas if bilateral;--2 interstitial abnormalities of limited extent, but consistent with a diagnosis of asbestosis, i.e. honeycombing, even without other parenchymal changes and even though unilateral, or else any two abnormal findings among thickened interlobular septa, intralobular lines or subpleural curved lines;--3 numerous bilateral changes on several slices involving more than 2/3 of the posterior third of each hemi thorax. Only points 2 and 3 were considered consistent with the diagnosis of lung fibrosis. Such HRCT findings are not specific for asbestosis, changes in the pleural wall such as diffuse plaques and thickenings contribute to the diagnosis of asbestosis. As regards the pleural plaques and asbestos bodies we remark that they are merely exposition markers. We also discussed the problems the pathologist may encounter in diagnosing mesothelioma; in this field the prospects are encouraging as microarray analysis are beginning to identify new molecular markers for mesothelioma.

Risk assessment of patients with hematologic malignancies who develop fever accompanied by pulmonary infiltrates: a historical cohort study.

BACKGROUND: The mortality rate associated with fever accompanied by pulmonary infiltrates after chemotherapy for hematologic malignancies remains higher than the corresponding rate associated with febrile neutropenia without pulmonary infiltrates. Nonetheless, few studies have focused on the factors that predict outcome for patients with lung infiltrates. The purpose of the current study was to construct a risk model for clinical use by assessing the factors that affect outcome for patients with fever and pulmonary infiltrates. METHODS: A historical cohort of 110 patients with hematologic malignancies who developed fever and pulmonary infiltrates was examined. Using parameters for which data were available at the onset of lung infiltrates, univariate and multivariate analyses were performed to assess factors affecting outcome. After a value of one point was assigned to each significant variable, a prediction score was calculated for each patient; scores were used to generate a system for identifying patients with a low risk of death due to fever accompanied by pulmonary infiltrates. RESULTS: The crude mortality rate associated with pulmonary infiltrates was 23%; factors associated with cure included a favorable change in white blood cell counts (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.7-18.9; P = 0.001), C-reactive protein levels < 10 mg/dL (OR, 4.6; 95% CI, 1.6-13.8; P = 0.001), and serum albumin levels > or = 3 g/dL (OR, 3.2; 95% CI, 1.4-7.3; P = 0.004). Low-risk patients (risk score, 2-3) and high-risk patients (risk score, 0-1) had survival rates of 95% and 46%, respectively (P < 0.0001). The risk model had a specificity of 88% and a positive predictive value of 95%. CONCLUSIONS: The risk model tested in the current study accurately predicted the survival of patients with hematologic malignancies who developed fever with pulmonary infiltrates. Once prospectively validated, the model could be used to select patients for trials involving novel diagnostic and therapeutic strategies.