Fabio Falaschi

Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT

BACKGROUND Results of randomized clinical trials (RCTs) are needed to assess the efficacy of lung cancer screening with low-dose chest computed tomography (CT) in reducing lung cancer mortality. We report design and results of enrolment and baseline screening test in the ITALUNG trial, a RCT. METHODS Invitation letters were sent to subjects of 55-69 years of age clients of 269 general practitioners. Smokers or former smokers of at least 20 pack/years were eligible and after written consent were randomized in an active arm undergoing a low-dose CT annually for 4 years and in a control arm receiving no screening. Management of positive screening test was carried out using follow-up low-dose CT, fluorodeoxyglucose positron emission tomography, fine needle aspiration cytology and fiber optic bronchoscopy. RESULTS A sample of 3206 eligible subjects was achieved by sending 71,232 letters (enrolment efficacy = 4.5%). Subjects in control (n = 1593) and active (n = 1613) arm were balanced for age, gender and smoking history. Two-hundred and seven (12.8%) subjects did not undergo CT after randomization. The baseline screening test was positive in 426 (30.3%) of 1406 subjects. Twenty-one lung cancers (prevalence = 1.5%) were found in 20 subjects: 18 non-small cell lung cancer (NSCLC), 2 small cell lung cancer (SCLC) and a case of typical carcinoid. Ten NSCLC (47.6%) were in Stage I. Sixteen fine needle aspirations were performed in 15 lung cancers, with a positive result in 12 (75%) cases. One biopsy only (6.3%) was performed on a benign lesion. Seventeen lung cancers (81%) were treated with surgical resection in 16 subjects. One subject underwent surgery for a benign lesion (5.5% of all surgical resections). CONCLUSIONS Recruitment by mail of high risk subjects for a lung cancer screening RCT is feasible but not efficient. Results of the baseline screening test in the active arm of the ITALUNG trial are substantially in line with those of RCT and observational studies.

A novel multithreshold method for nodule detection in lung CT

Multislice computed tomography (MSCT) is a valuable tool for lung cancer detection, thanks to its ability to identify noncalcified nodules of small size (from about 3 mm). Due to the large number of images generated by MSCT, there is much interest in developing computer-aided detection (CAD) systems that could assist radiologists in the lung nodule detection task. A complete multistage CAD system, including lung boundary segmentation, regions of interest (ROIs) selection, feature extraction, and false positive reduction is presented. The selection of ROIs is based on a multithreshold surface-triangulation approach. Surface triangulation is performed at different threshold values, varying from a minimum to a maximum value in a wide range. At a given threshold value, a ROI is defined as the volume inside a connected component of the triangulated isosurface. The evolution of a ROI as a function of the threshold can be represented by a treelike structure. A multithreshold ROI is defined as a path on this tree, which starts from a terminal ROI and ends on the root ROI. For each ROI, the volume, surface area, roundness, density, and moments of inertia are computed as functions of the threshold and used as input to a classification system based on artificial neural networks. The method is suitable to detect different types of nodules, including juxta-pleural nodules and nodules connected to blood vessels. A training set of 109 low-dose MSCT scans made available by the Pisa center of the Italung-CT trial and annotated by expert radiologists was used for the algorithm design and optimization. The system performance was tested on an independent set of 23 low-dose MSCT scans coming from the Pisa Italung-CT center and on 83 scans made available by the Lung Image Database Consortium (LIDC) annotated by four expert radiologists. On the Italung-CT test set, for nodules having a diameter greater than or equal to 3 mm, the system achieved 84% and 71% sensitivity at false positive/scan rates of 10 and 4, respectively. For nodules having a diameter greater than or equal to 4 mm, the sensitivities were 97% and 80% at false positive/scan rates of 10 and 4, respectively. On the LIDC data set, the system achieved a 79% sensitivity at a false positive/scan rate of 4 in the detection of nodules with a diameter greater than or equal to 3 mm that have been annotated by all four radiologists.

Four-year results of low-dose CT screening and nodule management in the ITALUNG trial.

Introduction: Recruitment and nodule management are critical issues of lung cancer screening with low-dose computed tomography (LDCT). We report subjects’ compliance and results of LDCT screening and management protocol in the active arm of the ITALUNG trial. Methods: Three thousand two hundred six smokers or former smokers invited by mail were randomized to receive four annual LDCT (n = 1613) or usual care (n = 1593). Management protocol included follow-up LDCT, 2-[18F]fluoro-2-deoxy-D glucose positron emission tomography (FDG-PET), and CT-guided fine-needle aspiration biopsy (FNAB). Results: One thousand four hundred six subjects (87%) underwent baseline LDCT, and 1263 (79%) completed four screening rounds. LDCT was positive in 30.3% of the subjects at baseline and 15.8% subsequently. Twenty-one lung tumors in 20 subjects (1.5% detection) were found at baseline, and 20 lung tumors in 18 subjects (0.5% detection) in subsequent screening rounds. Ten of 18 prevalent (55%) and 13 of 17 incident (76%) non–small-cell cancers were in stage I. Interval growth enabled diagnosis of lung cancer in 16 subjects (42%), but at least one follow-up LDCT was obtained in 741 subjects (52.7%) over the screening period. FDG-PET obtained in 6.5% of subjects had 84% sensitivity and 90% specificity for malignant lesions. FNAB obtained in 2.4% of subjects showed 90% sensitivity and 88% specificity. Positivity of both FDG-PET and FNAB invariably predicted malignancy. Surgery for benign lesions was performed on four subjects (10% of procedures) but followed protocol violations on three subjects. Conclusions: High-risk subjects recruited by mail who entered LDCT screening showed a high and stable compliance. Efficacy of screening is, however, weakened by low detection rate and specificity. Adhesion to management protocol might lessen surgery for benign lesions.

Automatic Lung Segmentation in CT Images with Accurate Handling of the Hilar Region

A fully automated and three-dimensional (3D) segmentation method for the identification of the pulmonary parenchyma in thorax X-ray computed tomography (CT) datasets is proposed. It is meant to be used as pre-processing step in the computer-assisted detection (CAD) system for malignant lung nodule detection that is being developed by the Medical Applications in a Grid Infrastructure Connection (MAGIC-5) Project. In this new approach the segmentation of the external airways (trachea and bronchi), is obtained by 3D region growing with wavefront simulation and suitable stop conditions, thus allowing an accurate handling of the hilar region, notoriously difficult to be segmented. Particular attention was also devoted to checking and solving the problem of the apparent ‘fusion’ between the lungs, caused by partial-volume effects, while 3D morphology operations ensure the accurate inclusion of all the nodules (internal, pleural, and vascular) in the segmented volume. The new algorithm was initially developed and tested on a dataset of 130 CT scans from the Italung-CT trial, and was then applied to the ANODE09-competition images (55 scans) and to the LIDC database (84 scans), giving very satisfactory results. In particular, the lung contour was adequately located in 96% of the CT scans, with incorrect segmentation of the external airways in the remaining cases. Segmentation metrics were calculated that quantitatively express the consistency between automatic and manual segmentations: the mean overlap degree of the segmentation masks is 0.96 ± 0.02, and the mean and the maximum distance between the mask borders (averaged on the whole dataset) are 0.74 ± 0.05 and 4.5 ± 1.5, respectively, which confirms that the automatic segmentations quite correctly reproduce the borders traced by the radiologist. Moreover, no tissue containing internal and pleural nodules was removed in the segmentation process, so that this method proved to be fit for the use in the framework of a CAD system. Finally, in the comparison with a two-dimensional segmentation procedure, inter-slice smoothness was calculated, showing that the masks created by the 3D algorithm are significantly smoother than those calculated by the 2D-only procedure.

Value of chest radiography in phenotyping chronic obstructive pulmonary disease

The objectives of the present study were to reappraise chest radiography for the diagnosis of emphysema, using computed tomography (CT) as the reference standard, and to establish whether or not chest radiography is useful for phenotyping chronic obstructive pulmonary disease (COPD). Patients (n = 154) who had undergone posteroanterior and lateral chest radiography and CT for diagnostic purposes were studied. CT data were scored for emphysema using the picture-grading method. Chest radiographs were examined independently by five raters using four criteria for emphysema that had been validated against lung pathology. These criteria were then used to assess the prevalence of emphysema in 458 COPD patients. Patients with and without evidence of emphysema were compared with regard to age, sex, smoking history, body mass index (BMI), forced expiratory volume in one second (FEV1), diffusing capacity of the lung for carbon monoxide (DL,CO) and health status. Chest radiography yielded a sensitivity of 90% and a specificity of 98% for emphysema. Of the 458 COPD patients, 245 showed radiological evidence of emphysema. Emphysemic patients had a significantly lower BMI, FEV1 and DL,CO, greater restriction of physical activity and worse quality of life than nonemphysemic patients. There was no difference across the two groups with regard to age, sex or smoking history. Chest radiography is a simple means of diagnosing moderate-to-severe emphysema. It is useful in phenotyping chronic obstructive pulmonary disease and may aid physicians in their choice of treatment.

MRI of spinal epidural lymphoma

We reviewed the MRI features in eight patients with spinal epidural lymphoma (clinically primary in 4 patients); one patient had multiple lesions. The cervical spine was involved in one patient, the thoracolumbar spine in 5 and the sacrum in two. Mean longitudinal extension of the epidural lesion was 2.6 vertebral segments. The tumours were homogeneously isointense with the spinal cord on T1-weighted images and isointense or hyperintense on proton-density and T2-weighted images. The spinal cord was compressed in four patients but showed signal changes in only one. In five patients the lesions communicated through the intervertebral formaina with paravertebral soft tissue masses. In all but one of the patients diffuse signal changes in the vertebral body marrow consistent with osteolytic or osteobalstic changes were identified adjacent to or at distance from the epidural lesion. Vertebral collapse was observed in two patients.

Chest radiography and high resolution computed tomography in the evaluation of workers exposed to silica dust: relation with functional findings.

OBJECTIVES--To compare the usefulness of high resolution computed tomography (HRCT) with chest radiography (CR) in the diagnosis and assessment of severity of silicosis. METHODS--27 workers exposed to silica underwent CR, HRCT, and pulmonary function tests. Two experienced readers independently evaluated CR by International Labour Office classification, and grouped the results into four categories. HRCT categories of nodule profusion and the extent of emphysema were graded on a four point scale; in 20 subjects the percentage distribution of lung densities were measured by HRCT. RESULTS--Concordance between readers was higher for HRCT than for CR (K statistic = 0.49 and 0.29 respectively). There was poor concordance between CR and HRCT in the early stage of silicosis. No significant difference in pulmonary function tests was found among different CR categories, but forced expiratory volume in one second (FEV1), maximal expiratory flow at 50% and 75% of FVC (MEF50, MEF75), and diffusion capacity significantly decreased with increasing HRCT categories. Subjects with simple silicosis detected by HRCT had a lower FEV1 than subjects without silicosis, whereas subjects with conglomerated silicosis showed higher residual volume and functional residual capacity than subjects with simple silicosis. These relations were not affected by smoking or symptoms of chronic bronchitis. Different grades of emphysema detected by HRCT were significantly different in diffusion capacity. Only the HRCTs of the lowest and the highest categories of profusion of parenchymal opacities were significantly different in their distribution of density classes. CONCLUSION--HRCT is more reproducible and accurate than CR, as suggested by the higher agreement between readers and the better correlation with pulmonary function tests, irrespective of smoking and chronic bronchitis; however, these data do not support the hypothesis that HRCT is more sensitive than CR in the early detection of silicosis.

Comparison of spirometric-gated and -ungated HRCT in COPD.

Purpose: The purpose of this work was to evaluate feasibility of spirometric‐gated high‐resolution computed tomography (HRCT) in patients with chronic obstructive pulmonary disease (COPD) and to compare the lung density CT measurements obtained with and without spirometric control of lung volume. Method: Twenty‐nine patients with COPD underwent pulmonary function tests and spirometric‐gated (3 slices at 10% and 90% of vital capacity) and ‐ungated (12 slices at maximum expiration and inspiration) HRCT in the same day. Four lung density measurements (inspiratory pixel index, expiratory pixel index, inspiratory and expiratory mean lung density) derived from gated and ungated acquisitions were compared using the nonparametric Wilcoxon test, the line of equality, and the Bland and Altman test. Results: The vital capacity measured at pulmonary function tests and on the CT table showed a substantial agreement. All but one patient completed the gated and ungated examination, but only 8 (28%) of 28 patients reached the expiratory and inspiratory gating level for CT acquisitions at the first attempt. Only the inspiratory mean lung density derived from the 3 gated and 12 ungated slices showed borderline agreement. Other CT measurements, and notably all those from the 3 gated and ungated scans, acquired at the same anatomic level, did not agree. Conclusions: Although the procedure can be difficult for individual patients, spirometric gating significantly influences the lung density CT measurements and might improve standardization of CT evaluation of COPD. Index Terms: high‐resolution computed tomography, chronic obstructive pulmonary disease, spirometric gating

Dose exposure in the ITALUNG trial of lung cancer screening with low-dose CT

Few data are available on the effective dose received by participants in lung cancer screening programmes with low-dose CT (LDCT). We report the collective effective dose delivered to 1406 current or former smokers enrolled in the ITALUNG trial who completed 4 annual LDCT examinations and related further investigations including follow-up LDCT, 2-[(18)F]flu-2-deoxy-d-glucose positron emission tomography (FDG-PET) or CT-guided fine needle aspiration biopsy (FNAB). Using the air CT dose index and Monte Carlo simulations on an anthropomorphic phantom, the whole-body effective dose associated with LDCT was determined for the eight CT scanners used in the trial. A value of 7 mSv was assigned to FDG-PET while the measured mean effective dose of CT-guided FNAB was 1.5 mSv. The mean collective effective dose in the 1406 subjects ranged between 8.75 and 9.36 Sv and the mean effective dose to the single subject over 4 years was between 6.2 and 6.8 mSv (range 1.7-21.5 mSv) according to the cranial-caudal length of the LDCT volume. 77.4% of the dose was owing to annual LDCT and 22.6% to further investigations. Considering the nominal risk coefficients for stochastic effects after exposure to low-dose radiation according to the National Radiological Protection Board, International Commission on Radiological Protection (ICRP) 60, ICRP103 and Biological Effects of Ionizing Radiation VII, the mean number of radiation-induced cancers ranged between 0.12 and 0.33 per 1000 subjects. The individual effective dose to participants in a 4-year lung cancer screening programme with annual LDCT is very low and about one-third of the effective dose that is associated with natural background radiation and diagnostic radiology in the same time period.

Is Incidentally Detected Pulmonary Embolism in Cancer Patients Less Severe? A Case-Control Study

Incidental pulmonary embolism (PE) in cancer patients is usually thought to be of mild degree. We investigated the severity of PE and evaluated the potential of raising the suspicion of PE in such patients. The computed tomography (CT) extent of PE was evaluated in 19 consecutive unsuspected and 19 randomly selected symptomatic patients. A clinical pattern useful for suspecting PE was also searched. On CT, number of embolized vessels, location of emboli, and simple instrumental findings were not different in the two groups. PE is not less severe in unsuspected cancer patients; moreover, PE may be clinically suspected in such patients.