Elisa Calabrò

Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment

The identification of lung tumor-initiating cells and associated markers may be useful for optimization of therapeutic approaches and for predictive and prognostic information in lung cancer patients. CD133, a surface glycoprotein linked to organ-specific stem cells, was described as a marker of cancer-initiating cells in different tumor types. Here, we report that a CD133+, epithelial-specific antigen-positive (CD133+ESA+) population is increased in primary nonsmall cell lung cancer (NSCLC) compared with normal lung tissue and has higher tumorigenic potential in SCID mice and expression of genes involved in stemness, adhesion, motility, and drug efflux than the CD133− counterpart. Cisplatin treatment of lung cancer cells in vitro resulted in enrichment of CD133+ fraction both after acute cytotoxic exposure and in cells with stable cisplatin-resistant phenotype. Subpopulations of CD133+ABCG2+ and CD133+CXCR4+ cells were spared by in vivo cisplatin treatment of lung tumor xenografts established from primary tumors. A tendency toward shorter progression-free survival was observed in CD133+ NSCLC patients treated with platinum-containing regimens. Our results indicate that chemoresistant populations with highly tumorigenic and stem-like features are present in lung tumors. The molecular features of these cells may provide the rationale for more specific therapeutic targeting and the definition of predictive factors in clinical management of this lethal disease.

MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer

The efficacy of computed tomography (CT) screening for early lung cancer detection in heavy smokers is currently being tested by a number of randomized trials. Critical issues remain the frequency of unnecessary treatments and impact on mortality, indicating the need for biomarkers of aggressive disease. We explored microRNA (miRNA) expression profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up. miRNA expression patterns significantly distinguished: (i) tumors from normal lung tissues, (ii) tumor histology and growth rate, (iii) clinical outcome, and (iv) year of lung cancer CT detection. Interestingly, miRNA profiles in normal lung tissues also displayed remarkable associations with clinical features, suggesting the influence of a permissive microenvironment for tumor development. miRNA expression analyses in plasma samples collected 1–2 y before the onset of disease, at the time of CT detection and in disease-free smokers enrolled in the screening trial, resulted in the generation of miRNA signatures with strong predictive, diagnostic, and prognostic potential (area under the ROC curve ≥ 0.85). These signatures were validated in an independent cohort from a second randomized spiral-CT trial. These results indicate a role for miRNAs in lung tissues and plasma as molecular predictors of lung cancer development and aggressiveness and have theoretical and clinical implication for lung cancer management.

Transcription Deregulation at the 15q25 Locus in Association with Lung Adenocarcinoma Risk

Purpose: We characterized the candidacy of the six candidate genes mapping in the chromosome 15q25 locus, which was previously reported as associated with lung cancer risk, and confirmed the locus association with lung cancer risk in an Italian population of lung adenocarcinoma patients and controls. Experimental Design: We did a quantitative analysis of mRNA levels of IREB2 (iron-responsive element-binding protein 2), LOC123688, PMSA4 [proteasome (prosome, macropain) subunit α type 4], CHRNB4 (cholinergic receptor nicotinic β 4), CHRNA3 (cholinergic receptor nicotinic α 3), and CHRNA5 (cholinergic receptor nicotinic α 5) genes in paired normal lung and lung adenocarcinoma tissue, and an immunohistochemical localization of CHRNA3- and CHRNA5-encoded proteins. We also examined the association of CHRNA5 D398N polymorphism with lung cancer risk and with CHRNA5 mRNA levels in the normal lung. Results: Expression analysis of the six candidate genes mapping in the lung cancer risk–associated chromosome 15q25 locus revealed a 30-fold up-regulation of the gene encoding the CHRNA5 subunit and a 2-fold down-regulation of the CHRNA3 subunit in lung adenocarcinoma as compared with the normal lung. The expression of the four other candidate genes resulted either unchanged or absent. The carrier status of the 398N allele at the D398N polymorphism of the CHRNA5 gene was associated with lung adenocarcinoma risk (odds ratio, 1.5; 95% confidence interval, 1.2-2.0) in a population-based series of lung adenocarcinoma patients (n = 467) and healthy controls (n = 739). Analysis of a family-based series of nonsmoker lung cancer cases (n = 80) and healthy sib controls (n = 80) indicated a similar trend. In addition, the same D398N variation correlated with CHRNA5 mRNA levels in normal lung of adenocarcinoma patients. Conclusions: Our results point to the candidacy of the CHRNA5 gene for the 15q25 locus.

Pulmonary Nodules: Volume Repeatability at Multidetector CT Lung Cancer Screening

PURPOSE To assess in vivo volumetric repeatability of an automated software algorithm in pulmonary nodules detected during a lung cancer screening trial. MATERIALS AND METHODS This study was approved by an institutional review board. Written informed consent was obtained from all participants. Data were collected from the Multicentric Italian Lung Detection project, a randomized controlled lung cancer screening trial. The first 1236 consecutive baseline computed tomographic (CT) studies performed at the Istituto Nazionale Tumori of Milan were evaluated. Among the enrolled participants, those who underwent repeat low-dose CT after 3 months and had at least one indeterminate nodule with a volume of more than 60 mm(3) (diameter of 4.8 mm or greater) were considered. Nonsolid, part-solid, and pleural-based nodules were excluded from this study. A descriptive analysis was performed by calculating means and standard deviations of nodule volumes at three assessment times (at baseline and 3 and 12 months later). The volume measurement repeatability was determined by using the approach described by Bland and Altman. RESULTS One hundred one subjects (70 men, 31 women; mean age, 58 years) with 233 eligible nodules (mean volume, 98.3 mm(3); range, 5-869 mm(3)) were identified. The 95% confidence interval for difference in measured volumes was in the range of +/-27%. About 70% of measurements had a relative difference in nodule volume of less than 10%. No malignant lesions were registered during the follow-up of these subjects. CONCLUSION Semiautomatic volumetry is sufficiently accurate and repeatable and may be useful in assisting with lung nodule management in a lung cancer screening program.

Diagnostic Imaging of Diffuse Infiltrative Disease of the Lung

Plain chest radiography remains the first diagnostic approach to diffuse infiltrative lung disease but has limited diagnostic sensitivity and specificity. Many diseases remain occult or are not correctly assessed using chest X-ray, appearing as a nonspecific ‘reticulonodular pattern’. High-resolution CT (HRCT) is actually the recommended imaging technique in the diagnosis, assessment, and follow-up of these diseases, allowing also the evaluation of the effectiveness of the medical therapy and the selection of the type and the location of the biopsy when required. Appropriate techniques must be used to acquire high-quality HRCT scans, with the thin collimation and high spatial reconstruction algorithm being the most important factors. A nodular pattern, linear and reticular opacities, cystic lesions, ground-glass opacities and consolidations are the most common HRCT patterns of diffuse infiltrative lung disease. This article reviews the role of chest radiography and HRCT in the diagnosis and assessment of these diseases, the technical aspects of HRCT, its clinical indications and the radiological pattern of the most common types of chronic diffuse infiltrative lung disease.

FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung

The association of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism with clinical stage and overall survival in a series of 541 Italian lung adenocarcinoma (ADCA) patients indicated a significantly decreased survival in patients carrying the rare Arg388 allele as compared to that in Gly/Gly homozygous patients [hazard ratio (HR) = 1.5; 95% confidence interval (CI) 1.1–1.9], with the decrease related to the association of the same polymorphism with clinical stage (HR = 1.8, 95% CI 1.3–2.6). By contrast, no significant association was detected in small series of either Norwegian lung ADCA patients or Italian lung squamous cell carcinoma (SQCC) patients. Single nucleotide polymorphisms of known FGFR4 ligands expressed in lung (FGF9, FGF18 and FGF19) were not associated with clinical stage or survival and showed no interaction with FGFR4. Analysis of gene expression profile in normal lungs according to FGFR4 genotype indicated a specific transcript pattern associated with the allele carrier status, suggesting a functional role for the FGFR4 polymorphism already detectable in normal lung. These findings confirm the significant association of the FGFR4 Gly388Arg polymorphism with clinical stage and overall survival in an Italian lung ADCA population and demonstrate a FGFR4 genotype‐dependent transcriptional profile present in normal lung tissue.

Reliability of quantitative computed tomography to predict postoperative lung function in patients with chronic obstructive pulmonary disease having a lobectomy.

Objective: To verify the reliability of quantitative computed tomography (CT) to estimate the postoperative lung function in patients with mild to severe chronic obstructive pulmonary disease (COPD) who underwent a lobectomy. Methods: Nine COPD patients with lung cancer having a lung lobectomy with preoperative CT were enrolled. By applying a density mask technique and a specific equation, predicted postoperative forced expiratory volume in 1 second (FEV1) and vital capacity (VC) were calculated. Predicted values were correlated with postoperative measured values. Results: Estimated FEV1 and VC were always significantly lower than the corresponding postoperative values; however, CT-estimated postresection FEV1 values were better than the postresection VC values (biases between estimated and measured values were −0.14 and −0.536 L, respectively, according to the Bland-Altman method). Quantitative CT predicted postoperative FEV1 (r = 0.97, P < 0.001) and VC (r = 0.93, P < 0.001) well in all patients, however. Conclusions: Quantitative CT may be an alternative tool to perfusion scan to predict postresection lung function, even in patients with borderline pulmonary function undergoing a lobectomy.

Elevated levels of the acute-phase serum amyloid are associated with heightened lung cancer risk

The authors investigated whether early stage lung cancer could be identified by proteomic analyses of plasma.

Visual score and quantitative CT indices in pulmonary fibrosis: Relationship with physiologic impairment

PurposeThe aim of this study was to assess the accuracy of some computed tomography (CT) quantitative indices (histogram features, ranges of density and one novel volumetric index) in the discrimination between normals and patients affected by lung fibrosis, and to compare their morphologic-functional relationship with the visual score one.Materials and methodsWe analysed thin-section CTs and pulmonary function tests (PFTs) of six healthy subjects and 31 patients affected by lung fibrosis, including 17 with a usual interstitial pneumonia pattern (UIP group), and 14 with a predominant pattern of ground-glass opacities without honeycombing (non-UIP group). Presence and extent of various CT findings were assessed by the visual score as well as by CT computer indices.ResultsTogether with the histogram features, fibrosis ratio (defined as the ratio of nonfibrotic CT lung volume divided by total CT lung volume) contributed to objectively differentiate fibrotic lungs from normal lungs. The range of density 700 to 400 HU showed the greatest degree of correlation with physiologic abnormality in the non-UIP group. In the UIP group, the lone visual score provided prediction of functional impairment.ConclusionsThe visual score is still the main radiological method of quantifying the extent of abnormalities in patients with UIP, whilst the range of density 700 to 400 HU can be helpfully applied in a predominant pattern of ground-glass and reticular opacities without honeycombing.RiassuntoObiettivoValutare l’accuratezza di alcuni indici quantitativi utilizzati in tomografia computerizzata (TC) (istogrammi, intervalli di densità ed indici volumetrici) nel discriminare pazienti normali da pazienti affetti da fibrosi polmonare e confrontare la loro relazione morfologica-funzionale con lo score visivo.Materiali e methodiAbbiamo analizzato scansioni TC a strato sottile di sei soggetti sani e di 31 pazienti con fibrosi polmonare, compresi 17 con un pattern di polmonite interstiziale usuale (gruppo di UIP) e 14 con un pattern predominante di ground-glass senza honey-combing (gruppo non-UIP). La presenza e l’estensione dei vari reperti TC sono stati valutati sia con score visivo che con indici TC quantitativi.RisultatiInsieme agli istogrammi, l’indice fibrotico volumetrico (definito come il rapporto tra il volume di polmone non fibrotico e il volume polmonare totale) ha contributio nel differenziare in modo obiettivo i polmoni fibrotici dai polmoni normali. Il range di densità −700–400 HU ha mostrato la maggiore correlazione con i parametri funzionali nel gruppo dei pazienti non-UIP. Nel gruppo UIP, solo lo score visivo ha fornito una corretta previsione del danno funzionale.ConclusioniLo score visivo è ancora il metodo radiologico principale per quantificare l’estensione della patologia in pazienti con UIP, mentre l’intervallo di densità −700–400 HU può essere vantaggiosamente applicato in un pattern predominante a ground-glass e reticolare senza honey-combing.

Prolonged Remission of Disseminated Atypical Adenomatous Hyperplasia Under Gefitinib

Atypical adenomatous hyperplasia (AAH) is a putative precursor of bronchioloalveolar carcinoma (BAC) and adenocarcinoma of the lung, developing from terminal respiratory unit cells. AAH and BAC lesions typically present as ground-glass opacities at spiral chest computed tomography. Epidermal growth factor receptor polysomy/mutations, conferring higher sensitivity to Gefitinib, are frequent in BAC but less common in AAH. We describe an interesting case of disseminated AAH showing a sustained remission under Gefitinib therapy.