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Interstitial lung disease (ILD) remains a major cause of morbidity and mortality in systemic sclerosis (SSc). Study aim is to characterize and quantify SSc-ILD by using Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER). Secondly, our objective is to evaluate which radiological pattern is predictive of lung function decline at 12 months follow-up. In the prospective study (IRB 5435), 66 SSc patients underwent high-resolution computerized tomography (HRCT) at baseline. HRCT was performed according to standard protocol using a CT 64GE light speed VCT power scanner. CALIPER classified lung parenchyma on volume units. Every volume unit was classified into radiological parenchymal patterns (honeycombing, reticular and ground glass). Pulmonary function tests (PFTs) were performed at baseline and after 12 months of follow-up. Cigarette smoking and other lung diseases unrelated to SSc are exclusion criteria. CALIPER analysis showed normal lung parenchyma 87.4 ± 9.8%, ground glass 2.8 ± 5.3%, reticular 4 ± 5.7%, and honeycombing 1 ± 1%. In multiple regression analysis, FEV1 (p 0.0001), FVC (p = 0.001), and DLCO (p 0.0001) measurements at baseline showed a negative correlation with the reticular pattern percentage. At follow-up, DLCO reduction showed a positive correlation (p 0.001) with the percentage of ground glass pattern (r = 0.33, beta coefficient = 0.51). In the ROC curve analysis, ground glass score is a good predictor (0.75, p = 0.009; 95% CI 0.59-0.91) of DLCO worsening, defined as a decrease of more than 10% of DLCO. Using a cutoff ≥ 4.5 for ground glass score, the RR for DLCO worsening is 6.8 (p 0.01; 95% CI 1.6-29.2). The results of this study show that CALIPER is useful not only for quantifying lung damage but also for assessing worsening PFTs, but larger studies are needed to confirm these preliminary data.Key Points• At baseline reticular pattern showed negative correlation with PFTs• At follow-up ground glass pattern predicts worsening of DLCO• CALIPER is a useful to quantify lung damage.

Sarcoidosis is a systemic granulomatous disorder of unknown etiology characterized by non-caseating granulomas at the site of disease. A confident diagnosis should be established by the evidence of typical granulomas on biopsy and after exclusion of other conditions. Clinically recognizable Gastrointestinal involvement (GI) occurs in less than 1.6% of patients with sarcoidosis, with data revealing small intestine participation in 0.03% of the cases and few anecdotal reports describe a peritoneal presentation. Clinical manifestations of peritoneal sarcoidosis are abdominal discomfort, bloating, weight loss, epigastric and peri-umbilical pain with or without ascites, bowel obstruction. Treatment depends on symptoms and disease activity. Herein we describe the case of a 42-years-old male patient who developed an acute, life–threatening small bowel obstruction as first manifestation of sarcoidosis. To the best of our knowledge, this is the only report showing such extensive and acute onset of intra-abdominal sarcoidosis in the absence of a previous disease manifestation and without pulmonary involvement., Highlights • Abdominal sarcoidosis is a sporadic event and localization without pulmonary involvement is rarer mimicking GI diseases. • Reaching abdominal sarcoidosis diagnosis is not a straightforward process. • It is pivotal to confirm sarcoidosis diagnosis before subjecting patients to an appropriate treatment. • Corticosteroids are considered the cornerstone treatment. • Asymptomatic patients may undergo a watch and wait follow-up with no need for a pharmacological therapy. • Surgery is not often required but individualized patient evaluation is recommended.

Background: ILDs are heterogeneous disorders with similar radiologic and clinical features but different pathogenesis, prognosis and therapeutic options. New markers are needed to optimize their treatment and management. Aim of the Study: To evaluate the role of different biomarkers: Myeloperoxidase (MPO), Human Neutrophil Peptides (HNP) and Eosinophil Cationic Protein (ECP) in ILD discrimination and course prediction. Methods: the prospective study enrolled 12 healthy individuals (HS), 55 patients with sarcoidosis, 22 with CTD-ILD and 24 IPF, measuring MPO, HNP and ECP in BAL. Patients were evaluated for 52 weeks to estimate pulmonary worsening and identify a biomarker predictive for disease behavior. Results: MPO was significantly higher in patients with sarcoidosis (29.2 pg/ml) and CTD-ILD (28.9 pg/ml) as compared to HS (17.3 pg/ml) and IPF (2.4 pg/ml), p Conclusions: MPO and HNP may have a role in discriminating ILD and in predicting IPF behavior, while ECP may be effective in predicting sarcoidosis pulmonary function worsening.

Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by the overproduction of collagen leading to fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is one of the major causes of death in patients with SSc. Exercise tolerance can be investigated by cardio-pulmonary exercise testing (CPET). First-line therapies in patients with SSc associated with ILD (SSc-ILD) include cyclophosphamide and mycophenolate mofetil (MMF). The aim of this study was to evaluate the response of patients with SSc-ILD to MMF by means of CPET. Methods Ten consecutive SSc patients were enrolled in this study. All SSc patients underwent clinical evaluation, echocardiography, pulmonary function tests, high-resolution computed tomography (HRCT) and CPET at baseline and after 2 years of therapy with MMF. Results After 24 months of treatment with MMF (target dose 1500 mg twice daily), forced vitality capacity, diffusing capacity of the lungs for carbon monoxide and systolic pulmonary arterial pressure had not improved significantly and there were no significant differences in HRCT findigns. In addition, peak oxygen uptake (V′O2 peak) and ventilatory equivalents for carbon dioxide production (V′E/V′CO2 slope) had not improved significantly. In contrast, there was a significant improvement from baseline to 24 months of treatment in the respiratory exchange ratio [median (interquartile range): 1.07 (0.92–1.22) vs. 1.26 (1.22–1.28), respectively; p

Major vascular complication, such as digital ulcers (DUs), pulmonary arterial hypertension (PAH) and scleroderma renal crisis (SRC) are hallmarks of systemic sclerosis (SSc). Interstitial lung disease (ILD) is the major cause of mortality in SSc. The aim of study is to identify cardiopulmonary exercise testing (CPET) variables that predict MVC and mortality for ILD in SSc patients.In this cohort study, 45 SSc patients underwent clinical evaluation, echocardiography, pulmonary function tests (PFTs), high resolution computerised tomography (HRCT) and CPET. PFTs and echocardiography were performed annually for a 5-year follow-up.16 (35.6%) SSc patients had MVC: 14 new DUs (31.1%), 1 PAH (2.2%) and 1 SRC (2.2%). At univariate regression analysis, mRss [HR 1.099 (1.008-1.199), p0.05], NVC patterns (active and late) [HR 0.032 (0.004-0.250), p0.001], V'E/V'CO2 slope [HR 1.123 (1.052-1.198), p0.001] were predictive of new onset of MVC. In multivariate analysis, NVC patterns (active and late) (HR 0.044 (0.004-0.486), p0.05), V'E/V'CO2 (HR 1.094 (1.020-1.198), p0.05) were predictive of new onset of MVC. The 5-year mortality for ILD is 8.9%. In univariate analysis, DLco [(HR 0.927(CI 0.874- 0.983), p0.05], V'E/V'CO2 slope and lung parenchymal with radiological patterns of ILD [(1.2.02 (CI 1.018-1.419), p0.05], represent risk factors for 5-year mortality for ILD [HR 1.142 (1.030-1.267), p0.05]. In multivariate analysis, only V'E/V'CO2 slope [1.268 (CI 1.003-1.602), p0.05] represents a risk factor for 5-year mortality for ILD.V' E/V' CO2 slope is a prognostic marker of MVC and five-year mortality for ILD.

Background: Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder. Most of case of severe AAT are caused by Z and S mutations in the SERPINA1 gene, that reduces serum AAT concentrations till to 15% of normal levels. Mutations causing total absence of serum AAT (Null mutations) are very rare. Individuals homozygouse for Null mutations should be considered a subgroup at particularly high risk of emphysema, but their clinical phenotype is poorly described. Objectives: We would like to evaluate the differences between clinical history of AATD in subject with the most prevalent deficient genotype (PI*ZZ) and those with rare PI*Null/Null genotypes, and the different impact that the only available specific therapy for AATD (augmentation therapy with purified AAT) could have on them. Methods: We analyzed clinical and demographic characteristics of 8 PI*Null/Null patients in comparison to 338 PI*ZZ subjects from the Italian Registry of Severe AATD. Results: In comparison to PI*ZZ, PI*Null/Null patients have early respiratory symptoms (31.7 vs 45.2 years, p=0,006), and worse lung function at diagnosis (FEV1 41.5 vs 70.7, p=0.01; FVC 77.4 vs 87.57 %pred.) and obstruction (FEV1/FVC 0.6 vs 0.7). They are most frequently treated with augmentation therapy (100% vs 31.4%, p Conclusions: Early detection of PI*Null/Null subject is desirable for preventive and therapeutic interventions. PI*Null/Null subjects have great benefit from early augmentation therapy.

The incidence and prevalence of pulmonary nontuberculous mycobacterial (NTM) infection is increasing worldwide arousing concerns that NTM infection may become a serious health challenge. We recently observed a significant increase of NTM-positive sputa samples from patients referred to respiratory disease wards of a large tertiary hospital in Rome. A survey to identify possible NTM contamination revealed a massive presence of NTM in the hospital water supply network. After decontamination procedures, NTM presence dropped both in water pipelines and sputa samples. We believe that this observation should encourage water network surveys for NTM contamination and prompt decontamination procedures should be considered to reduce this potential source of infection.

Tuberculosis is the deadliest infectious disease in the world. The variable efficacy of the current treatments highlights the need for more effective agents against this disease. In the past few years, we focused on the investigation of antigenic glycoconjugates starting from recombinant Ag85B (rAg85B), a potent protein antigen from

Tuberculosis is the deadliest infectious disease in the world. The variable efficacy of the current treatments highlights the need for more effective agents against this disease. In the past few years, we focused on the investigation of antigenic glycoconjugates starting from recombinant Ag85B (rAg85B), a potent protein antigen from Mycobacterium tuberculosis. In this paper, structural modifications were rationally designed in order to obtain a rAg85B variant protein able to maintain its immunogenicity after glycosylation. Lysine residues involved in the main T-epitope sequences (namely, K30 and K282) have been substituted with arginine to prevent their glycosylation by a lysine-specific reactive linker. The effectiveness of the mutation strategy and the detailed structure of resulting neo-glycoconjugates have been studied by intact mass spectrometry, followed by peptide and glycopeptide mapping. The effect of K30R and K282R mutations on the T-cell activity of rAg85B has also been investigated with a preliminary immunological evaluation performed by enzyme-linked immunospotting on the different variant proteins and their glycosylation products. After glycosylation, the two variant proteins with an arginine in position 30 completely retain the original T-cell activity, thus representing adequate antigenic carriers for the development of efficient glycoconjugate vaccines against tuberculosis.

Introduction: Decree Law (DL) No. 6 January 2016 transposes European Directive 2014/40 / EU and is aimed at ensuring a high level of protection from tobacco smoke, particularly with respect to young people. Methods: In 2016 in compliance with the limits set out by the smoke DL, S Camillo Hospital has placed at a distance of 10 meters from the hospital wards named in the legislation (main entrance, departments of pediatric emergency room, obstetrics and gynecology) indications on the ground with the warnings: SMOKING AREA LIMIT with the aim to reduce the fine particles, and compare the data recorded in the same locations in 2011 *. The measurements analyzed the levels of particulate matter (pM 2.5 and 10) in those areas. For monitoring we used the same devices: Aerocent GT 331 and GT 531 Metone Instruments. Results: In measurements obtained prior the warnings, the PM 2.5 concentrations were above 18 mg / m3 in 24 hours and exceeded the 10 mg / m3 established by WHO for good air quality. With the application of the warnings PM2.5 concentrations observed in 24 h were reduced to 0.7 mg / m3 (average data of all the monitors) Conclusion With the application of D.L.N ° January 6, 2016, our data show that the warnings should be considered is useful tool with a low cost / benefit ratio. * R.Principe, G. Paone, S. Damante, Implementation of smoking ban: a survey in a public hospital setting The European Journal of Public Health Advance Access published December 15, 2013

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial pneumonia of unknown etiology, which is associated with the histopathologic pattern of usual interstitial pneumonia (UIP) and leads to a progressive decrease of respiratory function. The present article describes a case of a 62-year-old ex-smoker referred to our hospital because of IPF. After 2 years of follow-up, the subject experienced a significant worsening of pulmonary function and was enrolled in a lung transplantation program. Afterward, a pharmacological treatment with pirfenidone was started, achieving a stabilization of respiratory function. The patient underwent a single lung transplantation by means of a normothermic ex vivo lung perfusion (EVLP) approach according to the Toronto model. At 20-month evaluation the subject's respiratory function was significantly improved, and quality of life was considerably ameliorated. We believe that an integrated multidisciplinary approach should be considered a key option for the treatment of individuals with IPF.

SummaryIntroductionAmbulatory oxygen (O2) is prescribed to interstitial lung disease (ILD) patients with mild hypoxemia, breathlessness and dyspnea on exertion. Oxygen titration is generally done with the 6 minute walk test (6MWT) to determine the O2 flow preventing oxygen saturation by pulse oximetry (SpO2) from falling below 88%. His study was designed to generate a 6MWT index predicting the O2 flow allowing completion of the 6MWT without oxygen desaturation.MethodsOxygen titration data from a group of 66 ILD patients and 30 controls, were used to generate the algorithm determining an index (O2-GAP) predicting oxygen flow required to complete a 6MWT without desaturation below 88%. This index was validated in a group of 93 ILD patients.ResultsThe O2-GAP index, as obtained from the derivation population, (r2 = 0.97, p

COPD is characterised by airway inflammation and oxidative stress contributing to corticosteroid resistance.Carbocysteine lysine salt (CLS) is a mucoactive drug with antinflammatory and antioxidant activities and in vitro evidence suggests that CLS may improve corticosteroid response in COPD.The PEACE study demonstrated in a RCT setting a 25% reduction of exacerbations for carbocysteine in GOLD II-IV.However, only 17% of PEACE study patients received background inhaled steroids(IS) therapy. This is a prospective clinical trial. Main eligibility criteria include GOLD stage II-IV, FEV1 31%-79% predicted.Primary objective is to compare the frequency of >2 exacerbations over a 1-year treatment period with CLS added to background therapy either with or without IS in COPD patients with>1 exacerbation in the previous year.202 patients were included in the study and 108 patients completed the 1 year period.Of these,67 patients had≥2 exacerbations at baseline:CLS was added to background therapy including IS in 68.6% and without IS in 58.9%. After 1 year, only 64.2% of these 67 patients experienced≥2 exacerbations,respectively 58.3% and 67.4% in the group receiving IS vs. non receiving IS.Also the mean number of exacerbations declined significantly, overall from 2.6 to 1.2:significant improvement was seen both in IS and non-IS patients. These results show that addition of CLS allows a reduction of COPD exacerbations in patients with>2 exacerbations at baseline.At 12 months,the effect of CLS on exacerbations is similar for background therapy with or without IS.

Alpha-1 antitrypsin (A1AT) is a 52-kDa, acute phase glycoprotein encoded by the protease inhibitor (PI) locus, located on the long arm of chromosome 14 (14q31-32.3). Its structure is composed of a total of 7 exons, 4 coding (II, III, IV, and V) and 3 non-coding (IA, IB, and IC). A1AT is produced primarily by hepatocytes and acts as a serine protease inhibitor with antiprotease and immunoregulatory activities. The main target of A1AT is neutrophil elastase (NE), an enzyme released during a neutrophil-mediated inflammatory process. When the enzyme is not adequately balanced by A1AT activity, it can cause tissue injury and destruction. A1AT deficiency (A1ATD) is a genetic autosomal recessive disease, characterized by low serum levels of A1AT. The condition may lead to liver disease, early-onset pulmonary emphysema and, rare multi-organ vasculitis, necrotizing panniculitis and fibromyalgia. At least 100 allelic variants of the polymorphic PI locus have been described with groups including associations with different A1AT plasma levels and functions. Treatments with purified A1AT preparations, obtained through pooled human plasma (augmentation therapy), have been proven to improve survival and disease-related quality of life, as well as, slow down the progression of organ damage. Furthermore, ongoing research is now focusing on the development of specifically targeted, new medications. The aim of this review is to summarize our knowledge of the genetic A1AT variants, focusing on their variable clinical manifestation, report routine and recently updated laboratory diagnostic techniques, and to highlight the relevance of early diagnosis of A1ATD. Moreover, we will review the role of augmentation therapy recommendations and future perspectives focusing on a personalized treatment of A1ATD.

The pivotal role of neutrophils and macrophages in smoking-related lung inflammation and COPD development is well-established.We aimed to assess whether sputum concentrations of Human Neutrophil Peptides (HNP), Neutrophil Elastase (NE), Interleukin-8 (IL-8), and Metalloproteinase-9 (MMP-9), major products of neutrophils and macrophages, could be used to trace airway inflammation and progression towards pulmonary functional impairment characteristic of COPD.Forty-two symptomatic smokers and 42 COPD patients underwent pulmonary function tests; sputum samples were collected at enrolment, and 6 months after smoking cessation.HNP, NE, IL-8, MMP-9 levels were increased in individuals with COPD (p< 0.0001). HNP and NE concentrations were higher in patients with severe airways obstruction, as compared to patients with mild-to-moderate COPD (p= 0.002). A negative correlation was observed between FEV1and HNP, NE and IL-8 levels (p< 0.01), between FVC1/FVC and HNP, NE and IL-8 levels (p< 0.01), and between NE enrolment levels and FEV1decline after 2 years (p= 0.04).ROC analysis, to discriminate symptomatic smokers and COPD patients, showed the following AUCs: for HNP 0.92; for NE 0.81; for IL-8 0.89; for MMP-9 0.81; for HNP, IL-8 and MMP-9 considered together 0.981.The data suggest that the measurement of sputum markers may have an important role in clinical practice for monitoring COPD.

Background. Long-term home noninvasive mechanical ventilation (NIV) is beneficial in COPD but its impact on inflammation is unknown. We assessed the hypothesis that NIV modulates systemic and pulmonary inflammatory biomarkers in stable COPD.Methods. Among 610 patients referred for NIV, we shortlisted those undergoing NIV versus oxygen therapy alone, excluding subjects with comorbidities or non-COPD conditions. Sputum and blood samples were collected after 3 months of clinical stability and analyzed for levels of human neutrophil peptides (HNP), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha). Patients underwent a two-year follow-up. Unadjusted, propensity-matched, and pH-stratified analyses were performed.Results. Ninety-three patients were included (48 NIV, 45 oxygen), with analogous baseline features. Sputum analysis showed similar HNP, IL-6, IL-10, and TNF-alpha levels (P>0.5). Conversely, NIV group exhibited higher HNP and IL-6 systemic levels (P<0.001) and lower IL-10 concentrations (P<0.001). Subjects undergoing NIV had a significant reduction of rehospitalizations during follow-up compared to oxygen group (P=0.005). These findings were confirmed after propensity matching and pH stratification.Conclusions. These findings challenge prior paradigms based on the assumption that pulmonary inflammation isper sedetrimental. NIV beneficial impact on lung mechanics may overcome the potential unfavorable effects of an increased inflammatory state.

Tuberculosis (TB) still remains one of the most relevant public health problems worldwide with high prevalence, morbidity and un-necessary mortality (1), with the need of appropriate and efficient diagnostic tools (1, 2). In this context, one of the most significant development during the past 100 years has been the introduction in the diagnostic armamentarium for TB of the the whole-blood based Interferon Gamma Release Assays (IGRAs) for the diagnosis of TB infection (2, 3). IGRAs, that in the commercial version have been developed in two different technology readout systems such as QuantiFERON®-TB Gold In-Tube test (QFT-G-IT, QIAGEN, Gaithersburg, US) and T-SPOT®.TB (Oxford Immunotec Ltd, Abingdon,UK), are based on the detection of a T-cell immune response towards RD1 antigens (ESAT-6, CFP-10, with the addition of the TB7.7 for QFT-G-IT only) (2, 3). IGRAs present typically a great specificity, as the antigens used in IGRAs are almost exclusively expressed by the Mycobacterium tuberculosis (MTB)-complex and are less likely to be confounded by prior BCG vaccination and/or exposure to non-tuberculous mycobacteria (NTM), with the exception of few NTM) (2, 3). However, the diagnostic sensitivity of IGRAs to diagnose TB infections in still suboptimal and varies greatly worldwide from 75% to 85% in HIV-negative active TB patients (4), especially under the background of high TB-burden (5).

Background: A worldwide increase in prevalence of Non tuberculous Mycobacteria (NTM) infection has been observed over the past decades. There is no evidence of human-to-human transmission and human disease may be acquired from environmental exposures. Aim: We started a survey to identify NTM in sputa from patients from the Respiratory wards of S. Camillo-Forlanini Hospital in Rome and to test NTM presence in the hospital water supply network . Methods: From January 2011 to December 2014 sputa were collected from each individual referred to the respiratory wards and tested for Mycobacterium presence . Positive samples were examined by INNO-Lipa Mycobacteria v2 assay for subtypes identification.Samples from respiratory wards tap water and showers were also collected . Results: Sputa analysis confirmed an increase in NTM infection: in 2011 27.5% of 190 acid fast bacilli (AFB) positive patients were NTM positive NTM, while in 2013 we observed 240 AFB positive patients 60% positive for NTM (p Survey on the water supply network of the Respiratory Department pointed out a significant NTM presence.In 2014, following water decontamination a significant decrease of NTM presence in respiratory wards pipeline was observed and only 3.5 % of 209 positive sputa were positive for NTM (p Conclusions: We showed a NTM increase in sputa from respiratory wards patients associated with NTM hospital water pipeline contamination.These findings are important because NTM infection of patients with lung diseases may be life-threatening. We believe that prompt water network surveys and decontamination should be taken to reduce this source of infection.

Background: In a multidimensional approach the association of Pulmonary Rehabilitation (PR) with a drug-induced bronchodilation and reduction of lung hyperinflation, should maximize the improvement in exercise tolerance and pulmonary function achievable in COPD patients. Aims: This observational study evaluated the response to PR in COPD treated with different therapy. Methods: A population of COPD patients treated with fluticasone 500mcg+formoterol 20mcg bid (group A) or beclomethasone 400mcg+salbutamol 1250mcg bid (group B) underwent a 3-week PR protocol following guidelines. Lung function, gas exchange, 6-minute walk distance, BORG and St. George's Respiratory Questionnaire (SGRQ) scores were collected at admission (T0), at discharge (T1=21 days) and at a 1-month follow up (T2=51 days). Repeated-measures ANOVA models for testing groups differences over time were fitted using Stata/SE 12.1. Results: 30 COPD patients aged 72.63(8.34) years, and including 56.67% females were enrolled. FEV1 significantly improved at T1 and T2 both in group A (1.37(0.77) lt, 1.14(0.46) lt, 1.01(0.41) lt at T2, T1 and T0 evaluation), and in group B (1.30(0.41) lt vs 1.23(0.62) lt vs 1.12(0.48) lt). A 2-fold increase in FEV1 was observed in group A (+0.36) vs group B (+0.18) (p

// Alessandra Ulivieri 1, 2 , Giuseppe Cardillo 3 , Liborio Manente 1 , Gregorino Paone 4 , Andrea Petricca Mancuso 5 , Leonardo Vigna 5 , Enrico Di Stasio 6 , Rita Gasbarra 1 , Salvatore Girlando 7 , Alvaro Leone 1 1 Anatomic Pathology Unit, San Camillo-Forlanini Hospitals, Rome, Italy 2 Laboratory of Biomedical research “Fondazione Niccolo Cusano per la Ricerca Medico-Scientifica” Niccolo Cusano University of Rome, Rome, Italy 3 Thoracic Surgery Unit, San Camillo-Forlanini Hospitals, Rome, Italy 4 Department of Respiratory Diseases, San Camillo-Forlanini Hospitals, Rome, Italy 5 Department of Medical Oncology, San Camillo-Forlanini Hospitals, Rome, Italy 6 Institute of Biochemistry and Clinical Biochemistry, Universita Cattolica del Sacro Cuore, Rome, Italy 7 Anatomic Pathology Unit, S. Chiara Hospital, Trento, Italy Correspondence to: Alvaro Leone, e-mail: aleone@scamilloforlanini.rm.it Keywords: Pathology, melanoma, pulmonary metastases, BRAF, NRAS, EGFR Received: May 15, 2015 Accepted: June 20, 2015 Published: July 04, 2015 ABSTRACT Background: Melanoma is highly curable in early stages but holds devastating consequences in advanced phases with a median survival of 6–10 months. Lungs are a common metastasis target, but despite this, limited data are available on the molecular status of pulmonary lesions. Materials and Methods: 25 patients with surgically resected melanoma lung metastases were screened for BRAF, NRAS, CKIT and EGFR alterations. The results were correlated with time to lung metastasis (TLM), relapse-free survival after metastasectomy (RFS) and overall survival (OS). Results: BRAF or NRAS were mutated in 52% and 20% of cases while CKIT was unaffected. Chromosome 7 polysomy was detected in 47% of cases with 17.5% showing EGFR amplification and concomitant BRAF mutation. NRAS mutated patients developed LM within 5 yrs from primary melanoma with larger lesions compared with BRAF (mean diameter 3.3 ± 2.2cm vs 1.9 ± 1.1cm, p = 0.2). NRAS was also associated with a shorter median RFS and OS after metastasectomy. Moreover, Cox regression analysis revealed that NRAS mutation was the only predictive factor of shorter survival from primary melanoma ( p = 0.039, OR = 5.5 (1.1–27.6)). Conclusions: Molecular characterization identifies advanced melanoma subgroups with distinct prognosis and therapeutic options. The presence of NRAS mutation was associated to a worse disease evolution.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity in Western countries. The increased oxidative stress, caused by the release of reactive oxygen and nitrogen species (ROS/RNS) from inflammatory airways cells, contributes to the pathogenesis of the disease. The aim of the present study was to evaluate (a) whether the oxidative imbalance can lead to specific alterations of red blood cells (RBCs) from stable COPD patients; (b) whether treatment with N-acetyl-cysteine (NAC), in widespread use as mucolytic agent in clinical practice, can counteract these effects; and (c) whether an in vitro model represented by the exposure of RBC to ROS/RNS could mimic the in vivo situation. The results obtained clearly indicated that the RBC integrity and function are similarly altered in COPD patients and in ROS/RNS in vitro-treated samples and that NAC administration was capable of counteracting RBC oxidative modifications both in vivo, as detected by clinical and laboratory evaluations, and in vitro. Altogether these results point to RBC oxidative modifications as valuable bioindicators in the clinical management of COPD and indicate that in vitro RBC exposure to ROS/RNS as a useful tool in experimental studies aimed at the comprehension of the pathogenic mechanisms of the redox-associated diseases.

Epithelial cells lining human airways and cells recruited to airways participate in the innate immune response in part by releasing human neutrophil peptides (HNP). Arginine-specific ADP-ribosyltransferases (ART) on the surface of these cells can catalyze the transfer of ADP-ribose from NAD to proteins. We reported that ART1, a mammalian ADP-ribosyltransferase, present in epithelial cells lining the human airway, modified HNP-1, altering its function. ADP-ribosylated HNP-1 was identified in bronchoalveolar lavage fluid (BALF) from patients with asthma, idiopathic pulmonary fibrosis, or a history of smoking (and having two common polymorphic forms of ART1 that differ in activity), but not in normal volunteers or patients with lymphangioleiomyomatosis. Modified HNP-1 was not found in the sputum of cystic fibrosis patients or in leukocyte granules of normal volunteers. The finding of ADP-ribosyl-HNP-1 in BALF but not in leukocyte granules suggests that the modification occurred in the airway. Most of the HNP-1 in the BALF from individuals with a history of smoking was, in fact, mono- or di-ADP-ribosylated. ART1 synthesized in Escherichia coli, glycosylphosphatidylinositol-anchored ART1 released with phosphatidylinositol-specific phospholipase C from transfected NMU cells, or ART1 expressed endogenously on C2C12 myotubes modified arginine 14 on HNP-1 with a secondary site on arginine 24. ADP-ribosylation of HNP-1 by ART1 was substantially greater than that by ART3, ART4, ART5, Pseudomonas aeruginosa exoenzyme S, or cholera toxin A subunit. Mouse ART2, which is an NAD:arginine ADP-ribosyltransferase, was able to modify HNP-1, but to a lesser extent than ART1. Although HNP-1 was not modified to a significant degree by ART5, it inhibited ART5 as well as ART1 activities. Human beta-defensin-1 (HBD1) was a poor transferase substrate. Reduction of the cysteine-rich defensins enhanced their ability to serve as ADP-ribose acceptors. We conclude that ADP-ribosylation of HNP-1 appears to be primarily an activity of ART1 and occurs in inflammatory conditions and disease.

The aim of our study was to compare the diagnostic yield of two bronchoscopic procedures: endobronchial ultrasound-driven transbronchial biopsy (EBUS-TBB) and transbronchial biopsy (TBB) in peripheral pulmonary lesions.Prospective, randomized, blinded study.University Hospital of Rome, Italy.We examined 799 patients with peripheral lung lesions using bronchoscopy. Patients who could undergo a complete clinical diagnostic follow-up (n = 293) were enrolled in the study and randomly assigned to EBUS-TBB or TBB. We performed these two procedures on 221 patients (97 EBUS-TBB and 124 TBB). Patients in whom biopsies were not diagnostic underwent more invasive procedures to obtain a final diagnosis, and a complete follow-up was possible in 206 patients (87 EBUS-TBB and 119 TBB).Lung cancer was diagnosed in 61 patients in the EBUS-TBB group and in 83 patients in the TBB group. Pulmonary diseases other than cancer were diagnosed in 26 patients and 36 patients, respectively. For patients with lung cancer, sensitivity was 0.79 in the EBUS group and 0.55 in the TBB group (p = 0.004), and accuracy was 0.85 and 0.69, respectively (p = 0.007). The analysis of a subset of patients with lesions3 cm showed no significant difference in diagnostic ability between the two procedures. In lesions3 cm, we found a considerable decline in TBB sensitivity and accuracy (0.31 and 0.50) while EBUS-TBB maintained their diagnostic yield (0.75 and 0.83) [p = 0.0002 and p = 0.001, respectively]. A similar difference was observed when we compared the sensitivity of the two procedures in lesions2 cm (0.23 vs 0.71, p0.001).EBUS-TBB can be an important option in the early diagnosis of peripheral lung cancer, especially in small-sized lesions and in patients who are not eligible for surgery.

Individuals with α1-antitrypsin (α1-AT) deficiency are at risk for early-onset destructive lung disease as a result of insufficient lower respiratory tract α1-AT and an increased burden of neutrophil products such as elastase. Human neutrophil peptides (HNP), the most abundant protein component of neutrophil azurophilic granules, represent another potential inflammatory component in lung disease characterized by increased numbers of activated or deteriorating neutrophils. The purpose of this study was to determine the role of HNP in lower respiratory tract inflammation and destruction occuring in α1-AT deficiency. α1-AT-deficient individuals ( n = 33) and healthy control subjects ( n = 21) were evaluated by bronchoalveolar lavage. HNP concentrations were significantly higher in α1-AT-deficient individuals (1,976 ± 692 vs. 29 ± 12 nM, P < 0.0001), and levels correlated with markers of neutrophil-mediated lung inflammation. In vitro, HNP produced a dose-dependent cytotoxic effect on alveolar macrophages and stimulated production of the potent neutrophil chemoattractants leukotriene B4and interleukin-8 by alveolar macrophages, with a 6- to 10-fold increase in chemoattractant production over negative control cultures ( P < 0.05). A synergistic effect was noted between HNP and neutrophil elastase with regard to leukotriene B4production. Importantly, the proinflammatory effects of HNP were blocked by α1-AT. HNP likely play an important role in amplifying and maintaining neutrophil-mediated inflammation in the lungs.

"Rare" diseases are a family of different disorders or conditions affecting fewer than 1/2000 in the general population. Among them, 150 involve respiratory system. To date, most reviews in literature focuses on the more important pulmonary lung diseases without taking in account the overall framework and diagnostic and therapeutic algorithms that allow a correct comprehensive approach to these disorders. The aim of our review is to describe a possible global approach to the management of these diseases trying to take a picture of the overall complexity of the field. We also want to highlight the role played by research on rare diseases pathogenesis in revealing, at least in part, mechanisms underlying many of "more common" disorders with the purpose to update the current state of knowledge.

Introduction. This paper presents the final results of a cross-sectional study started in 2010. It compares the perceived efficacy of different types of tobacco health warning (texts versus shocking pictures) to quit or reduce tobacco use.Methods. The study conducted between 2010 and 2012 in Italy enrolled adults smokers. Administering a questionnaire demographic data, smokers behaviors were collected. Showing text and graphic warnings (the corpse of a smoker, diseased lungs, etc.) the most perceived efficacy to reduce tobacco consumption or to encourage was quit.Results. 666 subjects were interviewed; 6% of responders referred that they stopped smoking at least one month due to the textual warnings. The 81% of the smokers perceived that the warnings with shocking pictures are more effective in reducing/quitting tobacco consumption than text-only warnings. The younger group (P<0.05.Conclusions. This study suggests that pictorial warnings on cigarette packages are more likely to be noticed and rated as effective by Italian smokers. Female and younger smokers appear to be more involved by shock images. The jarring warnings also appear to be supporting those who want to quit smoking. This type of supportive information in Italy may become increasingly important for helping smokers to change their behavior.

Pulmonary tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. This microorganism is capable of inducing a delayed hypersensitivity reaction in the lung, with subsequent expression of the disease. This reaction depends on the presence of different cytokines that exert specific functions. The aim of this study was to evaluate the presence and the concentrations of nine different modulators in bronchoalveolar lavage fluid (BALF). For this purpose, 15 patients with active pulmonary tuberculosis were enrolled at the time of diagnosis, prior to institution of antituberculous therapy. All the patients demonstrated M. tuberculosis in the sputum, and their disease extention was defined by high-resolution computed tomography (HRCT) using a score which included the presence of six findings: miliary nodules, nodules10 mm, consolidation, ground glass, cavity and bronchial wall thickening. This score was more sensitive than an equivalent score calculated on the basis of chest radiology. HRCT score was calculated for each area of the two lungs in order to define the more and the less affected lung for each patient. The bronchoalveolar lavage (BAL) was performed in the more affected area for each lung. The HRCT total score for each washed area ranged between 1 and 15, and showed more significant differences between the more and less affected lungs (p = 0.0004) than those obtained with the individual radiologic findings (p ranged between 0.60 and 0. 004). The BAL concentrations of the nine cytokines evaluated for the more and less affected lungs were compared: interleukin-6 (IL-6), IL-8, IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) showed significant differences (p ranged between 0. 016 and 0.0007). In addition, each cytokine concentration was correlated with the HRCT score. Significant correlations were found with IL-12, IL-6, IL-8, IL-2, and TNF-alpha. The correlations between cytokines and HRCT total score were better than those observed with the individual radiologic findings. A correlation matrix for the different cytokines evaluated one against each other, has also been added to show common behavior of these modulators. A similar analysis was also performed for the radiologic abnormalities.

Smoking in hospitals is banned in most of European countries; nevertheless, implementing a total smoking ban is particularly difficult and policy breaches are frequent. Aim of our study was to monitor the compliance with the smoke-free policy within a hospital district by measuring particulate matters (PM2.5). We designed an observational study and identified six sensitive locations within the hospitals: surgical units, administrative offices, hall, outdoor main entrances and as controls an outdoor and an indoor area. To rule out potential confounders we included in the evaluation the roadways surrounding the hospital district. PM2.5 median concentrations observed in outdoor main entrances and in hall were significantly higher (16.4 and 13.4 µg m(-3)), as compared with the other settings (P < 0.0001). This data warrant an implementation of current policies to protect patients, visitors and employees from passive second-hand smoke leading to a smoking prohibition in any hospital surroundings.

Chronic obstructive pulmonary (COPD) is one of the major causes of morbidity and mortality in the world. COPD is characterized by chronic inflammation in the pulmonary compartment and in the systemic circulation. This disorder is associated with clinically significant alterations in biochemistry and organ function; thyroid dysfunctions are common in chronic diseases, such as COPD. Several characteristics of COPD patients could increase their likelihood of developing hypothyroidism or hyperthyroidism. The purpose of our study was to assess the impact of thyroid dysfunction in patients with COPD.We evaluated the pulmonary function tests, arterial blood gases, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and thyroid functions in patients with COPD, recruited between admissions in Respiratory Diseases Unit, Policlinico Umberto I, Rome, Italy, from June 2012 to May 2013. We selected patients with subclinical hypothyroidism (ScH), overt hypothyroidism, and hyperthyroidism, and a control group without thyroid disturbance.Our results indicate that patients with overt hypothyroidism have lower levels of pO2, MIP, and MEP compared with subjects with ScH, hyperthyroidism, and the control group. We also found a substantial tendency towards pCO2 levels increase in patients with hypothyroidism (p = 0.06).Patients with thyroid dysfunctions have a greater impairment of MIP and MEP and a negative correlation was observed between hypoxemia and TSH. Further studies are needed to investigate whether the treatment of thyroid disfunction could have a beneficial effect on COPD patients' lung function and prognosis.

The classification of lung cancer into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) is essential for disease prognosis and treatment. For this purpose, we have tried to optimize the use of three tumour markers determined on pleural effusions, to differentiate SCLC from NSCLC by means of a canonic variable, generated by discriminant analysis, including subjects with histologically proven lung cancer. Discriminant analysis was performed by using carcinoembryonic antigen, neuron-specific enolase and tissue polypeptide antigen pleural levels, determined in 65 consecutive and unselected patients, histologically classified as 49 NSCLC and 16 SCLC. To validate the formula generated, a control group of 37 lung cancer patients (10 SCLC and 27 NSCLC), enrolled subsequently, was employed. Applying the discriminant analysis to SCLC and NSCLC patients a good classification was obtained (92% rate of correct classification). The aforementioned formula, applied to the validation group, showed a 92% rate of correct classification. This method, which is rapid, inexpensive and routinely applicable to malignant pleural effusions, may be reliably used to classify lung cancer patients.

Heat shock proteins (HSP) are the most conserved molecules known to date that may also function as immune targets during infection. Hence, theoretically there is a high chance of cross-reactive responses to epitopes shared by host and microbe HSP. If not properly regulated, these responses may contribute to the pathogenesis of autoimmune disease. To determine if immune responses to HSP could contribute to the pathogenesis of multiple sclerosis, we raised T lymphocyte lines specific for the purified protein derivative of Mycobacterium tuberculosis (PPD) from patients with multiple sclerosis, patients with tuberculosis and from healthy individuals. These lines were then screened for their proliferative response to a M. tuberculosis 70-kDa heat shock protein (M.tb.HSP70). The relative frequency of the recognition of highly conserved sequences of M.tb.HSP70 compared to variable ones was also assessed by mapping experiments on those PPD specific T lymphocyte lines which also recognized the mycobacterial 70-kDa heat shock protein. In patients with multiple sclerosis, we observed a significantly higher estimated frequency of PPD-specific T lines responding to M.tb.HSP70 compared to healthy individuals and patients with tuberculosis. Furthermore, mapping experiments using recombinant proteins representing mycobacterial and human HSP70 sequences and a panel of synthetic peptides encompassing the whole sequence of Mycobacterium leprae HSP70, showed that the response to conserved epitopes of HSP70 is a frequent event in each of the three conditions studied, often leading to the cross-recognition of microbial and human sequences. These findings implicate the 70-kDa heat shock proteins as potential autoantigens in multiple sclerosis.

To date, no sufficiently sensitive and specific single marker has been found to predict the clinical course of sarcoidosis. We designed a cohort study to investigate whether a panel of biomarkers measured in bronchoalveolar lavage (BAL) and peripheral blood could help predict pulmonary function worsening during the clinical course of sarcoidosis. We analyzed 30 individuals with histologically proven sarcoidosis. At baseline, participants underwent pulmonary function tests (PFTs), fiberoptic bronchoscopy and radiological investigations. BAL and blood cellular profiles were obtained from all individuals and six pro-inflammatory molecules were quantified in BAL and serum. PFTs were performed at follow-up visits over a 2-year period. Using discriminant function analysis, a canonical variable was generated to optimize the accuracy of selected variables in predicting pulmonary function worsening and was validated on a subset of nine consecutive individuals with sarcoidosis. A combination of 6 markers from BAL was able to predict pulmonary function worsening in 96 % of patients [95 % confidence interval (CI) 84.4–99.81]. We validated the generated formula on a group of nine patients with sarcoidosis, obtaining 77.8 % correct classification (95 % CI 45.3–93.7). Our results show that a combinational approach could contribute to identifying individuals likely to experience pulmonary function worsening, thus helping to decide the correct therapeutic strategies.

To the Editor We read with interest the article that appeared in the Journal by De Smet and colleagues,1 who applied likelihood ratios (rather than a dichotomous interpretation) for different results intervals for 3 laboratory tests (the percentage of bronchoalveolar lavage fluid [BALF] lymphocytes, the BALF CD4/CD8 ratio, and the serum angiotensin-converting enzyme activity) to improve clinical interpretation for the diagnosis of pulmonary sarcoidosis. They also examined the allocation power of the 3 diagnostic tests combined together by means of logistic regression analysis. The authors retrospectively evaluated the data for 153 subjects (36 with diagnosed sarcoidosis and 117 control subjects with clinical suspicion of sarcoidosis, but with diagnosis of other pulmonary diseases). The combination of the 3 laboratory tests allowed exclusion of sarcoidosis in 57 (48.7%) of 117 control subjects and confirmation of the diagnosis in 12 (33%) of 36 cases of pulmonary sarcoidosis.1 We strongly agree with the authors that the common practice of applying diagnostic tests by using strict cutoff values may result in a loss of …

BACKGROUND: Hypercapnic Chronic Obstructive Pulmonary Disease (COPD) exacerbation in patients with comorbidities and multidrug therapy is complicated by mixed acid-base, hydro-electrolyte and lactate disorders. Aim of this study was to determine the relationships of these disorders with the requirement for and duration of noninvasive ventilation (NIV) when treating hypercapnic respiratory failure. METHODS: Sixty-seven consecutive patients who were hospitalized for hypercapnic COPD exacerbation had their clinical condition, respiratory function, blood chemistry, arterial blood gases, blood lactate and volemic state assessed. Heart and respiratory rates, pH, PaO(2) and PaCO(2) and blood lactate were checked at the 1st, 2nd, 6th and 24th hours after starting NIV. RESULTS: Nine patients were transferred to the intensive care unit. NIV was performed in 11/17 (64.7%) mixed respiratory acidosis-metabolic alkalosis, 10/36 (27.8%) respiratory acidosis and 3/5 (60%) mixed respiratory-metabolic acidosis patients (p = 0.026), with durations of 45.1 ± 9.8, 36.2 ± 8.9 and 53.3 ± 4.1 hours, respectively (p = 0.016). The duration of ventilation was associated with higher blood lactate (p

1 Anatomic Pathology Unit, San Camillo-Forlanini Hospital, Rome, Italy 2 Department of Cardiovascular and Respiratory Sciences, San Camillo-Forlanini Hospital, Rome, Italy 3 Thoracic Surgery Unit, San Camillo-Forlanini Hospital, Rome, Italy Medical Oncology Unit, San Camillo-Forlanini Hospital, Rome, Italy 5 1st Oncological Pulmonary Unit, San Camillo-Forlanini Hospital, Rome, Italy 6 2nd Oncological Pulmonary Unit, San Camillo-Forlanini Hospital, Rome, Italy

The correlation between low insulin levels and a decreased sensitivity of the muscarinic receptor has been shown on induced-diabetes animal models. We designed a cohort study with the aim of evaluating the effects of insulin therapy on airway responsiveness (AR) in human patients with type 2 diabetes mellitus.We enrolled 92 patients with type 2 diabetes who had switched from oral anti-diabetic therapy to treatment by insulin subcutaneous injection. Patients were administered the methacholine challenge test (MCT) at time 0 (pre-insulin therapy) and at intervals of 15, 30, 90, 180, and 360 days after insulin treatment. The decline of forced expiratory volume in 1 second (FEV(1))% from baseline (Delta FEV(1)) in response to inhaled methacholine (MCH) was determined to assess airway hyper-responsiveness (AHR).A total of 81 patients (18 women and 63 men) completed the study. Their mean age was 58 +/- 7 years and the mean duration of disease was 13.5 +/- 7.7 years. The mean decrease of FEV(1) at pre-insulin assessment was 2.96 +/- 2.6%. Compared with the pre-insulin value, a significant increase of Delta FEV(1) was observed at 15, 30, and 90 days after treatment (6.25%, CI 95% 5.4 to 7.2, p = 0.0005; 7.64%, CI 95% 6.6 to 8.1, p0.001; 6.45%, CI 95% 5.5 to 7.3, p = 0.0004, respectively), while after 180 and 360 days AR was similar to pre-insulin values (Delta FEV(1), 3.62%, CI 95% 2.7 to 3.5 and 3.11%, CI 95% 7.9 to 9.3, respectively).The finding of an increased AR in patients with type 2 diabetes during the first 3 months of insulin therapy may underline the importance of monitoring pulmonary function and respiratory symptoms in patients switching from oral anti-diabetic drugs to insulin therapy, especially in the subset of individuals with respiratory disorders.

Objective: Interventional bronchoscopy is one of the modalities for palliation and definitive treatment of benign tracheal stenosis. There is however no general agreement on the management of this disease. Aim of this work is to define, in the largest group of patients presented in the literature, what types of tracheal stenosis are amenable to definitive treatment by interventional endoscopy. Methods: From January 1996 to June 2006 209 consecutive patients (105 men, 104 women) with benign tracheal stenosis were referred to our center. Etiology included 167 post-intubation and 34 cases of post-tracheostomy stenoses, 8 cases of other diseases. The lesions were classified into two groups: simple and complex. All but nine patients underwent interventional procedures (mechanical dilatation, laser photoresection and placement of a silicone stent). Two years follow-up was complete for all patients. Results: Simple stenoses (n = 167) were treated by 346 endoscopic procedures (mean of 2.07 per patient), 16 stents and 1 end-to-end anastomosis. Thirty-eight granulomas were treated by 59 procedures (1.56 per patient), 97 concentrical stenoses by 228 procedures (2.35 per patient) and 32 web-like lesions with 59 operative endoscopies (1.84 per patient). Overall success rate was 96%. Among the 42 complex stenoses, 9 were immediately treated by surgical resection and the remaining 33 lesions underwent 123 endoscopic procedures (3.27 per patient), with 34 stents and 1 end-to-end anastomosis subsequent to recurrence after stent removal. In this group the success rate was 69%. Conclusions: Our study shows that, after a correct classification and stratification, interventional endoscopy may have a crucial role in the treatment of tracheal stenoses. In particular, endoscopy should be considered the first choice for simple stenoses, whereas complex stenoses need a multidisciplinary approach and often require surgery.