Mario Fabbri

Endothelin-1 in idiopathic pulmonary fibrosis.

AIMS--To evaluate whether endothelin-1 is involved in the pathology of idiopathic pulmonary fibrosis (IPF). METHODS--Plasma endothelin-1 concentrations were evaluated in 37 patients with IPF and 27 normal controls by radioimmunoassay. In addition, expression of endothelin-1 in lung tissue was evaluated in biopsy specimens obtained from four patients with IPF. Three biopsy specimens of normal lung were used as controls. Endothelin-1 immunoreactivity was detected using immunohistochemistry. RESULTS--Elevated endothelin-1 plasma concentrations were found in patients with IPF compared with controls and a positive correlation was found with duration of disease. No significant difference was observed between treated and untreated patients with IPF. Increased endothelin-1 immunoreactivity was found in lungs of three of four patients with IPF. Endothelin-1 positive consisted mainly of small vessel endothelial cells. Some scattered macrophages were also positive. CONCLUSIONS--Elevated plasma concentrations and expression of endothelin-1 in lung tissue are suggestive of increased production of endothelin-1 in at least a proportion of patients with IPF. Consequently, endothelin-1 activity could play a role in the fibrogenic process of the disease.

68Ga-DOTANOC PET/CT Allows Somatostatin Receptor Imaging in Idiopathic Pulmonary Fibrosis: Preliminary Results

Interstitial lung diseases include different clinical entities with variable prognoses. Idiopathic pulmonary fibrosis (IPF), the most common, presents the most severe outcome (death within 3–5 y), whereas nonspecific interstitial pneumonia (NSIP) shows a more indolent progression. Preclinical evidence of somatostatin receptor (SSTR) expression on fibroblasts in vitro and in lung fibrosis murine models, coupled with the longer survival of mice with fibrotic lungs treated with agents blocking SSTR, supports the hypothesis of imaging fibroblast activity in vivo by visualization of SSTR with 68Ga-DOTANOC PET/CT. The aim of this study was to evaluate 68Ga-DOTANOC PET/CT in patients with IPF and NSIP. Methods: Seven IPF patients and 7 NSIP patients were included in the study. 68Ga-DOTANOC PET/CT and high-resolution CT (HRCT) were performed in all cases by following a standard procedure. PET/CT results were compared with disease sites and extent on HRCT. Results: In IPF, 68Ga-DOTANOC uptake was peripheral, subpleural, and directly correlated with pathologic areas on HRCT (subpleural/reticular fibrosis, honeycombing). NSIP patients showed fainter tracer uptake, whereas corresponding HRCT showed areas of ground-glass opacity and rare fibrotic changes. Only IPF patients showed a linear correlation between maximal SUV and disease extent quantified both automatically (Q) (IPF: P = 0.002, R = 0.93) and using the visual score (Spearman ρ = 0.46, P = 0.0001). Q directly correlated with percentage carbon monoxide diffusing capacity in IPF (P = 0.03, R = 0.79) and NSIP (P = 0.05, R = 0.94), whereas maximal SUV did not present any correlation with percentage carbon monoxide diffusing capacity. Conclusion: Our preliminary data show that 68Ga-DOTANOC PET/CT demonstrates SSTR overexpression in IPF patients; this may prove interesting for the evaluation of novel treatments with somatostatin analogs.

Functional Predictors of Exertional Dyspnea, 6-min Walking Distance and HRCT Fibrosis Score in Idiopathic Pulmonary Fibrosis

Background: Exertional dyspnea and exercise incapacity are the most prominent and disabling symptoms and the main contributors to health-related quality of life in patients with idiopathic pulmonary fibrosis (IPF). Objectives: There are no comprehensive studies on pulmonary function tests (PFTs), dyspnea, exercise capacity and radiographic scores in IPF. We therefore sought to investigate the functional variables that can predict dyspnea, exercise capacity and disease extent in IPF. Methods: Thirty-four patients with IPF according to the ATS/ERS criteria underwent PFTs, Medical Research Council (MRC) dyspnea scoring, 6-min walking distance (6-MWD) and radiographic evaluation of fibrosis (HRCT score). Results: The 6-MWD (% pred.) was more impaired than PFTs. Residual volume (RV) showed the best correlation with the extent of fibrosis (r = –0.67, p = 0.0001) and, together with the alveolar-arterial gradient for O2 [ΔP(A – a)O2], was an independent predictor of disease extent (R2 = 0.44). PFTs showed significant though weak correlations with MRC score and 6-MWD. According to the regression analysis, DLCO and the HRCT fibrosis score were independent predictors of dyspnea, though they explained only 28% of the overall variance. FEV1 and ΔP(A – a)O2 were independent predictors of 6-MWD (R2 = 0.31). Conclusions: PFTs and lung volumes in particular are closely related to the HRCT score, a measure of the extent of IPF. The correlation of dyspnea score and 6-MWD to PFTs is limited, due to the complexity of mechanisms leading to exercise limitation in IPF. Therefore dyspnea and exercise performance are largely independent indices and should be followed together with PFTs and HRCT score in order to better assess the status and progress of IPF patients.

Mapping of topoisomerase II α epitopes recognized by autoantibodies in idiopathic pulmonary fibrosis

Autoantibodies against DNA topoisomerase II α have been identified in the sera of patients with idiopathic pulmonary fibrosis (IPF). To map topoisomerase II autoepitopes, we tested by ELISA and immunoblotting the IPF anti‐topoisomerase II‐positive sera against a series of recombinant proteins which covered the full length of topoisomerase II α. Specific patterns of reactivity were observed, indicating the existence of multiple epitopes on topoisomerase II, either highly complex or conformational/discontiguous or conformational/contiguous ones. The latter resided in amino acid residues 854–1147 and 1370–1447. A detailed analysis of these regions was undertaken, but we were not able to pinpoint a sequential peptide‐sized epitope, or any significant homology with foreign pathogens. Further, we observed a significant correlation between the progression from a contiguous to a quaternary/tertiary structure‐dependent autoepitope and the disease duration but not with the disease severity. Therefore, this result supports the hypothesis that anti‐topoisomerase II autoreactivity evolves following an antigen‐driven process.

Benign Metastasizing Leiomyoma of the Lung: Pet Findings

We report the case of pulmonary benign metastasizing leiomyoma in an asymptomatic 64-year-old woman who underwent hysterectomy for a uterine leiomyoma 26 years earlier. Routine chest radiograph revealed bilateral diffuse nodular opacities within the pulmonary lobes. Thoracic computed tomography (CT) scan showed peripheral lung nodules that do not display contrast enhancement. Positron emission tomography (PET)-CT with 18F-fluorodeoxyglucose (18F-FDG PET-CT) demonstrated no significant metabolic activity of the nodules. The lesions were diagnosed as benign metastasizing leiomyoma by histopathologic examination. To our best knowledge, this is the first case studied combining CT and FDG PET-CT technique.

Assessment of a chemically induced model of lung squamous cell carcinoma in mice by 18F-FDG small-animal PET.

BackgroundSmall-animal imaging has become a relevant research field in pre-clinical oncology. In particular, metabolic information provided by small-animal positron emission tomography (PET) is very useful to closely monitor tumour growth and assess therapy response in murine models of human disease. There are various murine models for human lung adenocarcinoma, but those for squamous cell lung carcinoma, the most common form of human cancer, are lacking. AimTo assess the feasibility of 18F-FDG small-animal PET to monitor tumour growth in a chemically induced model of squamous cell carcinoma of the lung. Materials and methodsNineteen NIH Swiss mice were skin painted by N-nitroso-tris-chloroethylurea (NTCU) twice a week, with a 3 day interval, for 8 months and 10 NIH Swiss mice skin painted with NTCU solvent (acetone) were used as controls. 18F-FDG PET was performed under sevofluorane anaesthesia and oxygen supplementation at 2, 4, 6 and 8 months from initial treatment. Images were assessed by visual analysis and semi-quantitatively. When a diffuse distribution of tumour was noted, the mean of the counts/pixel measured at three lung levels, corrected for the effective dose injected and for decay, was used for comparison between mutagen-painted and control mice. Pathological evaluation was carried out from the time of the first positive PET results in a subgroup of the whole population to assess correlation with PET findings. Small animal CT was performed at 8 months in another subgroup. ResultsIn both terms of visual analysis and measurement of total lung activity, 18F-FDG PET at 2 and 4 months from initial treatment were comparable in mutagen-painted and controls. At 6 months, PET images showed a faint and diffuse uptake over both lung fields in mutagen-painted mice with multiple focal areas of increased tracer uptake that merged into confluent masses at 8 months and seriously subverting lung architecture on computed tomography. Total lung activity was significantly higher in mutagen-painted versus control mice at 6 (P=0.00000668) and 8 months (P=0.00000043) from initial treatment and paralleled the progressive lung involvement and histological severity. Conclusions18F-FDG PET may be useful in the assessment of this chemically induced murine model of lung squamous cells carcinoma. The total lung activity may be used as a measure of tumour metabolic activity of the tumour-bearing animals and may be useful in new drug testing studies.

Inflammatory activity is still present in the advanced stages of idiopathic pulmonary fibrosis

Objective:  The role of active inflammation in idiopathic pulmonary fibrosis (IPF) is controversial. A gallium‐67 citrate (Ga67 scan) is a sensitive indicator of inflammatory activity. The aim of this study was to assess the Ga67 uptake and other markers of inflammation at different stages of IPF and to investigate its prognostic role.

Does technetium-99m diethylenetriaminepentaacetate clearance predict the clinical course of idiopathic pulmonary fibrosis?

Clearance of inhaled technetium-99m diethylenetriaminepentaacetate (99mTc-DTPA) is a potential indicator of disease activity and progression in idiopathic pulmonary fibrosis (IPF). The objective of the present study was to evaluate the prognostic value of 99mTc-DTPA scans in IPF. A total of 22 patients (18 males), aged 33 to 80 years with IPF were followed for six to 20 months (mean 13 months). At diagnosis, high resolution computed tomography (HRCT) scans showed a honeycomb pattern with bibasilar reticular opacities in all cases. At T0 (diagnosis) and T1 (follow-up), each patient had pulmonary function tests (forced vital capacity, diffusing capacity of the lung for carbon monoxide and partial arterial O2 pressure), extension of fibrosis evaluated by HRCT visual score and 99mTc-DTPA lung clearance. Results at T0 and T1 were compared, taking into account the whole population and patients with relatively fast and slow 99mTc-DTPA wash-out. 99mTc-DTPA clearance did not show any significant correlation with functional tests or HRCT score. These findings indicate that clearance of inhaled 99mTc-DTPA is not of value in following the progress of IPF.