Short-Term Benefits of Smoking Cessation Improve Respiratory Function and Metabolism in Smokers.

Background: Cigarette smoke exposure is the main preventable cause of chronic obstructive pulmonary disease (COPD). Airflow limitation is closely associated with smoking exposure. Smoking could also interfere with lipid metabolism. Aim: To determine the respiratory functional and metabolic changes after smoking cessation in smokers in the short term. Methods: All patients were current smokers. They were assessed by spirometry and questionnaires such as COPD assessment test(CAT), modified Medical Research Council (mMRC) test for dyspnea, Fagestrom's test for nicotine dependence. Exhaled CO was detected in order to evaluate smoking exposure and smoking cessation (normal value<7 ppm). A blood sampling was eventually taken for vitamin D and cholesterol assay. All patients underwent therapy with counselling and varenicline as first-line treatment according to its schedule. Detection time: at baseline and one month after smoking cessation. Results: All patients quit smoking during treatment. The mean age was 62 with a prevalence of males. The analysis revealed the following mean values at baseline: CAT mean score was 15, pack-years 35.5, Fagestrom's Test mean score 5.0. The West's value was 8.5, whereas Body mass index (BMI) was 25.5.Cigarette daily consumption mean value was 22.5. The comparison before and at follow up one month after smoking cessation about functional and metabolic parameters, show us the following results: FEV 1 was increased by 200 mL (p<0.02), FEF 25/75 was improved as well as mMRC test. The eCO was dropped to as low as 8 ppM. Interestingly the vitamin D level was increased from 25 to 28 ng/mL without any support therapy. The cholesterol total level was reduced and CAT value and DLCO were also significantly improved. Conclusion: Quit smoking is useful to improve symptoms, respiratory function and metabolic parameters in the short term.

Histologic Analysis of Idiopathic Pulmonary Fibrosis by Morphometric and Fractal Analysis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disorder, ultimately leading to respiratory failure and death. Despite great research advances in understanding the mechanisms underlying the disease, its diagnosis, and its treatment, IPF still remains idiopathic without known biological or histological markers able to predict disease progression or response to treatment. The histologic hallmark of IPF is usual interstitial pneumonia (UIP), with its intricate architectural distortion and temporal inhomogeneity. We hypothesize that normal lung alveolar architecture can be compared to fractals, such as the Pythagoras tree with its fractal dimension (Df), and every pathological insult, distorting the normal lung structure, could result in Df variations. In this study, we aimed to assess the UIP histologic fractal dimension in relationship to other morphometric parameters in newly diagnosed IPF patients and its possible role in the prognostic stratification of the disease. Clinical data and lung tissue specimens were obtained from twelve patients with IPF, twelve patients with non-specific interstitial pneumonia (NSIP), and age-matched "healthy" control lung tissue from patients undergoing lung surgery for other causes. Histology and histomorphometry were performed to evaluate Df and lacunarity measures, using the box counting method on the FracLac ImageJ plugin. The results showed that Df was significantly higher in IPF patients compared to controls and fibrotic NSIP patients, indicating greater architectural distortion in IPF. Additionally, high Df values were associated with higher fibroblastic foci density and worse prognostic outcomes in IPF, suggesting that Df may serve as a potential novel prognostic marker for IPF. The scalability of Df measurements was demonstrated through repeated measurements on smaller portions from the same surgical biopsies, which were selected to mimic a cryobiopsy. Our study provides further evidence to support the use of fractal morphometry as a tool for quantifying and determining lung tissue remodeling in IPF, and we demonstrated a significant correlation between histological and radiological Df in UIP pattern, as well as a significant association between Df and FF density. Furthermore, our study demonstrates the scalability and self-similarity of Df measurements across different biopsy types, including surgical and smaller specimens.

Surfactant Protein B Plasma Levels: Reliability as a Biomarker in COPD Patients.

Background: The diagnosis of COPD is based on both clinical signs and functional tests. Although there are different functional tests used to assess COPD, no reliable biomarkers able to provide information on pathogenesis and severity are available. The aim of the present study is to explore the relationship between surfactant protein B (Sp-B) serum levels and clinical, radiological, and functional pulmonary parameters in COPD patients. Methods: Forty COPD patients and twenty smokers without airflow limitations or respiratory symptoms were enrolled. Each patient was given questionnaires (CAT and mMRC) and 6MWT, spirometry, DLCO, and computer tomography (CT) were performed. All participants underwent a venous blood sample drawing, and quantitative detection of their Sp-B plasma levels was performed by an enzyme-linked immunosorbent assay. The spirometry and Sp-B plasma levels were assessed after 12 months. Results: A statistically significant difference was found in the plasma Sp-B levels between COPD patients compared to the other group (4.72 + 3.2 ng/mL vs. 1.78 + 1.5 ng/mL; p < 0.001). The change in FEV1 after 12 months (Delta FEV1) showed a significantly negative correlation with respect to the change in Sp-B levels (Delta SpB) (r = −0.4; p < 0.05). This correlation indicates that increasing the plasma dosage of SpB is a foretoken of functional decline. Conclusions: SpB may be considered as a useful marker in COPD assessment and provides prognostic information on lung functional decline. Despite its usefulness, further studies are needed to define its reliability as a biomarker.

B4GALT1 as a New Biomarker of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by progressive scarring of the lung that involves the pulmonary interstitium. The disease may rapidly progress, leading to respiratory failure, and the long-term survival is poor. There are no accurate biomarkers available so far. Our aim was to evaluate the expression of the B4GALT1 in patients with IPF. Analysis of B4GALT1 gene expression was performed in silico on two gene sets, retrieved from the Gene Expression Omnibus database. Expression of B4GALT1 was then evaluated, both at the mRNA and protein levels, on lung specimens obtained from lung biopsies of 4 IPF patients, on one IPF-derived human primary cell and on 11 cases of IPF associated with cancer. In silico re-analysis demonstrated that the B4GALT1 gene was overexpressed in patients and human cell cultures with IPF (p = 0.03). Network analysis demonstrated that B4GALT1 upregulation was correlated with genes belonging to the EMT pathway (p = 0.01). The overexpression of B4GALT1 was observed, both at mRNA and protein levels, in lung biopsies of our four IPF patients and in the IPF-derived human primary cell, in other fibrotic non-lung tissues, and in IPF associated with cancer. In conclusion, our results indicate that B4GALT1 is overexpressed in IPF and could represent a novel marker of this disease.

Adenocarcinomas of the Lung and Neurotrophin System: A Review.

Neurotrophins (NTs) represent a group of growth factors with pleiotropic activities at the central nervous system level. The prototype of these molecules is represented by the nerve growth factor (NGF), but other factors with similar functions have been identified, including the brain derived-growth factor (BDNF), the neurotrophin 3 (NT-3), and NT-4/5. These growth factors act by binding specific low (p75) and high-affinity tyrosine kinase (TrkA, TrkB, and TrkC) receptors. More recently, these growth factors have shown effects outside the nervous system in different organs, particularly in the lungs. These molecules are involved in the natural development of the lungs, and their homeostasis. However, they are also important in different pathological conditions, including lung cancer. The involvement of neurotrophins in lung cancer has been detailed most for non-small cell lung cancer (NSCLC), in particular adenocarcinoma. This review aimed to extensively analyze the current knowledge of NTs and lung cancer and clarify novel molecular mechanisms for diagnostic and therapeutic purposes. Several clinical trials on humans are ongoing using NT receptor antagonists in different cancer cell types for further therapeutic applications. The pharmacological intervention against NT signaling may be essential to directly counteract cancer cell biology, and also indirectly modulate it in an inhibitory way by affecting neurogenesis and/or angiogenesis with potential impacts on tumor growth and progression.

Road Toward a New Model of Care for Idiopathic Pulmonary Fibrosis in the Lazio Region.

A timely, confirmed diagnosis of Idiopathic Pulmonary Fibrosis (IPF) has a significant impact on the evolution of the disease. The current model of care in the Lazio region (in Italy) was assessed on the basis of real-world data provided by the four reference centers responsible for diagnosing and treating IPF. The 5-year, population-based, retrospective longitudinal study provided the data that is at the basis of the current proposal for a new clinical and therapeutic pathway (DTCP) and has been shared with regional decision makers. A DTCP must be defined and based on four pillars: GPs, pulmonologists, IPF centers, and telemedicine. Each must play a role within a sort of hub-and-spoke model. IPF centers remain the hubs, while spokes are identified in trained GPs and pulmonologists.

Predictors of respiratory failure after thoracic surgery: a retrospective cohort study with comparison between lobar and sub-lobar resection.

OBJECTIVE: Only approximately 15% of patients with lung cancer are suitable for surgery and clinical postoperative outcomes vary. The aim of this study was to investigate variables associated with post-surgery respiratory failure in this patient cohort. METHODS: Patients who underwent surgery for lung cancer were retrospectively studied for respiratory function. All patients had undergone lung resection by a mini-thoracotomy approach. The study population was divided into two subgroups for comparison: lobectomy group, who underwent lobar resection; and sub-lobar resection group. RESULTS: A total of 85 patients were included, with a prevalence of lung cancer stage IA and adenocarcinoma histotype. Lobectomy (versus sub-lobar resection), the presence of chronic obstructive pulmonary disease (COPD), and a COPD assessment test (CAT) score >10, were all associated with an increased risk of respiratory failure. The partial pressure of arterial oxygen decreased more in the lobectomy group than in the sub-lobar resection group following surgery, with a significant postoperative between-group difference in values. Postoperative CAT scores were also better in the sub-lobar resection group. CONCLUSIONS: Post-surgical variations in functional parameters were greater in the group treated by lobectomy. COPD, high CAT score and surgery type were associated with postoperative development of respiratory failure.

Deconvolution of malignant pleural effusions immune landscape unravels a novel macrophage signature associated with worse clinical outcome in lung adenocarcinoma patients.

BACKGROUND: Immune checkpoint inhibitors are still unable to provide clinical benefit to the large majority of non-small cell lung cancer (NSCLC) patients. A deeper characterization of the tumor immune microenvironment (TIME) is expected to shed light on the mechanisms of cancer immune evasion and resistance to immunotherapy. Here, we exploited malignant pleural effusions (MPEs) from lung adenocarcinoma (LUAD) patients as a model system to decipher TIME in metastatic NSCLC. METHODS: Mononuclear cells from MPEs (PEMC) and peripheral blood (PBMC), cell free pleural fluid and/or plasma were collected from a total of 24 LUAD patients and 12 healthy donors. Bulk-RNA sequencing was performed on total RNA extracted from PEMC and matched PBMC. The DEseq2 Bioconductor package was used to perform differential expression analysis and CIBERSORTx for the regression-based immune deconvolution of bulk gene expression data. Cytokinome analysis of cell-free pleural fluid and plasma samples was performed using a 48-Plex Assay panel. THP-1 monocytic cells were used to assess macrophage polarization. Survival analyses on NSCLC patients were performed using KM Plotter (LUAD, N=672; lung squamous cell carcinoma, N=271). RESULTS: Transcriptomic analysis of immune cells and cytokinome analysis of soluble factors in the pleural fluid depicted MPEs as a metastatic niche in which all the components required for an effective antitumor response are present, but conscripted in a wound-healing, proinflammatory and tumor-supportive mode. The bioinformatic deconvolution analysis revealed an immune landscape dominated by myeloid subsets with the prevalence of monocytes, protumoral macrophages and activated mast cells. Focusing on macrophages we identified an MPEs-distinctive signature associated with worse clinical outcome in LUAD patients. CONCLUSIONS: Our study reports for the first time a wide characterization of MPEs LUAD microenvironment, highlighting the importance of specific components of the myeloid compartment and opens new perspectives for the rational design of new therapies for metastatic NSCLC.

Functional Benefit of Smoking Cessation and Triple Inhaler in Combustible Cigarette Smokers with Severe COPD: A Retrospective Study.

Introduction: Chronic obstructive pulmonary disease (COPD) is the third cause of mortality and it is smoking-related. It is characterized by a non-reversible airflow limitation and a progressive worsening of the respiratory function. Objective: The aim of this study is to point out the benefit of smoking cessation combined with a single inhaler triple therapy in terms of clinical and functional outcome in this setting. Methods: A retrospective analysis was performed in patients affected by severe COPD and at least one exacerbation a year, who underwent a smoking cessation program. All patients underwent a 6 min walking test, body plethysmography, and an exhaled test for carbon monoxide. The modified medical research council test (mMRC) test, the Fagestrom nicotine dependency test (FTND) and the COPD assessment test (CAT) questionnaire were also administered. All patients were checked at the baseline and in the six-month follow-up after the start of the treatment. Results: Smoking cessation was achieved by 51% of patients within a month and it was confirmed by eCO measure (<7 ppm). Patients who quit smoking reported better results after six months compared with patients who did not. The increase in FEV1 within the group of quitters was 90 mL (p < 0.05) and the walking test improved by 90 m (p < 0.01); eCO decreased by 15 ppm (p < 0.01) while FVC increased by 70 mL (p < 0.05). No significant changes were recorded within the group of sustainers. The difference in functional changes between groups was significant with regard to FEV1, cCO, and WT. Conclusions: Smoking cessation enhances the efficacy of single inhaler triple therapy, improving clinical and functional variables after six months from the start.

Multi-omic approach identifies a transcriptional network coupling innate immune response to proliferation in the blood of COVID-19 cancer patients.

Clinical outcomes of COVID-19 patients are worsened by the presence of co-morbidities, especially cancer leading to elevated mortality rates. SARS-CoV-2 infection is known to alter immune system homeostasis. Whether cancer patients developing COVID-19 present alterations of immune functions which might contribute to worse outcomes have so far been poorly investigated. We conducted a multi-omic analysis of immunological parameters in peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with and without cancer. Healthy donors and SARS-CoV-2-negative cancer patients were also included as controls. At the infection peak, cytokine multiplex analysis of blood samples, cytometry by time of flight (CyTOF) cell population analyses, and Nanostring gene expression using Pancancer array on PBMCs were performed. We found that eight pro-inflammatory factors (IL-6, IL-8, IL-13, IL-1ra, MIP-1a, IP-10) out of 27 analyzed serum cytokines were modulated in COVID-19 patients irrespective of cancer status. Diverse subpopulations of T lymphocytes such as CD8+T, CD4+T central memory, Mucosal-associated invariant T (MAIT), natural killer (NK), and γδ T cells were reduced, while B plasmablasts were expanded in COVID-19 cancer patients. Our findings illustrate a repertoire of aberrant alterations of gene expression in circulating immune cells of COVID-19 cancer patients. A 19-gene expression signature of PBMCs is able to discriminate COVID-19 patients with and without solid cancers. Gene set enrichment analysis highlights an increased gene expression linked to Interferon α, γ, α/ß response and signaling which paired with aberrant cell cycle regulation in cancer patients. Ten out of the 19 genes, validated in a real-world consecutive cohort, were specific of COVID-19 cancer patients independently from different cancer types and stages of the diseases, and useful to stratify patients in a COVID-19 disease severity-manner. We also unveil a transcriptional network involving gene regulators of both inflammation response and proliferation in PBMCs of COVID-19 cancer patients.

The Role of Lung Colonization in Connective Tissue Disease-Associated Interstitial Lung Disease.

Connective tissue diseases (CTDs) may frequently manifest with interstitial lung disease (ILD), which may severely impair quality and expectation of life. CTD-ILD generally has a chronic clinical course, with possible acute exacerbations. Although several lines of evidence indicate a relevant role of infections in the acute exacerbations of CTD-ILD, little information is available regarding the prevalence of infections in chronic CTD-ILD and their possible role in the clinical course. The aim of the present retrospective study was the identification of lung microbial colonization in broncho-alveolar lavage from patients affected by stable CTD-ILD with radiologically defined lung involvement. We demonstrated that 22.7% of patients with CTD-ILD display microbial colonization by Pseudomonas aeruginosa, Haemophilus influenzae, and non-tuberculous mycobacteria. Moreover, these patients display a major radiologic lung involvement, with higher impairment in lung function tests confirmed in a multivariate logistic regression analysis. Overall, the present study provides new information on lung colonization during CTD-ILD and its possible relationship with lung disease progression and severity.

Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies.

BACKGROUND: Low T3 syndrome is frequent in patients admitted to intensive care units for critical illness and pneumonia. It has been reported also in patients with COVID-19, Hodgkin disease and chronic lymphocytic leukemia. We analyzed the clinical relevance of Low T3 syndrome in COVID-19 patients and, in particular, in those with associated hematological malignancies. METHODS: Sixty-two consecutive patients, hospitalized during the first wave of SARS-CoV-2 outbreak in Sant'Andrea University Hospital in Rome, were subdivided in 38 patients (Group A), showing low levels of FT3, and in 24 patients (Group B), with normal FT3 serum values. During the acute phase of the disease, we measured serum, radiologic and clinical disease severity markers and scores, in search of possible correlations with FT3 serum values. In addition, in 6 COVID-19 patients, 4 with Low T3 syndrome, including 2 with a hematological malignancy, and 2 with normal FT3 values, we performed, high-dimensional single-cell analysis by mass cytometry, multiplex cytokine assay and gene expression profiling in peripheral blood mononuclear cells (PBMC). RESULTS: Low FT3 serum values were correlated with increased Absolute Neutrophil Count, NLR and dNLR ratios and with reduced total count of CD3+, CD4+ and CD8+ T cells. Low FT3 values correlated also with increased levels of inflammation, tissue damage and coagulation serum markers as well as with SOFA, LIPI and TSS scores. The CyTOF analysis demonstrated reduction of the effector memory and terminal effector subtypes of the CD4+ T lymphocytes. Multiplex cytokine assay indicates that mainly IL-6, IP-10 and MCAF changes are associated with FT3 serum levels, particularly in patients with coexistent hematological malignancies. Gene expression analysis using Nanostring identified four genes differently expressed involved in host immune response, namely CD38, CD79B, IFIT3 and NLRP3. CONCLUSIONS: Our study demonstrates that low FT3 serum levels are associated with severe COVID-19. Our multi-omics approach suggests that T3 is involved in the immune response in COVID-19 and coexistent hematological malignancy and new possible T3 target genes in these patients have been identified.

Circulating Vitamin D levels status and clinical prognostic indices in COVID-19 patients.

BACKGROUND: Several immune mechanisms activate in COVID-19 pathogenesis. Usually, coronavirus infection is characterized by dysregulated host immune responses, interleukine-6 increase, hyper-activation of cytotoxic CD8 T lymphocytes. Interestingly, Vitamin D deficiency has been often associated with altered immune responses and infections. In the present study, we evaluated Vitamin D plasma levels in patients affected with different lung involvement during COVID-19 infection. METHODS: Lymphocyte phenotypes were assessed by flow cytometry. Thoracic CT scan involvement was obtained by an image analysis program. RESULTS: Vitamin D levels were deficient in (80%) of patients, insufficient in (6.5%) and normal in (13.5%). Patients with very low Vitamin D plasma levels had more elevated D-Dimer values, a more elevated B lymphocyte cell count, a reduction of CD8 + T lymphocytes with a low CD4/CD8 ratio, more compromised clinical findings (measured by LIPI and SOFA scores) and thoracic CT scan involvement. CONCLUSIONS: Vitamin D deficiency is associated with compromised inflammatory responses and higher pulmonary involvement in COVID-19 affected patients. Vitamin D assessment, during COVID-19 infection, could be a useful analysis for possible therapeutic interventions. TRIAL REGISTRATION: 'retrospectively registered'.

Full-Length TrkB Variant in NSCLC Is Associated with Brain Metastasis.

Despite remarkable therapeutic advances have been made in the last few decades, non-small cell lung cancer (NSCLC) is still one of the leading causes of death worldwide. Brain metastases are a common complication of a wide range of human malignancies and in particular NSCLC. Brain-derived neurotrophic factor (BDNF), binding its high-affinity tyrosine kinase B receptor, has been shown to promote cancer progression and metastasis. We hereby investigated the expression of the BDNF and its TrkB receptor in its full-length and truncated isoform T1, in samples from primary adenocarcinomas (ADKs) of the lung and in their metastasis to evaluate if their expression was related to preferential tumor entry into the central nervous system (CNS). By immunohistochemistry, 80% of the ADKs that metastasize to central nervous system expressed TrkB receptor compared to 33% expressing of ADKs without CNS metastasis. Moreover, ADKs with CNS metastasis showed an elevated expression of the full-length TrkB receptor. The TrkB receptor FL/T1 ratio was statistically higher in primary ADKs with brain metastasis compared to ADKs without brain metastasis. Our data indicate that TrkB full-length isoform expression in primary ADK cells may be associated with higher risk to develop brain metastasis. Therefore, TrkB receptor may possess prognostic and therapeutic implications in lung ADK.

Assessing Static Lung Hyperinflation by Whole-Body Plethysmography, Helium Dilution, and Impulse Oscillometry System (IOS) in Patients with COPD.

Purpose: Lung hyperinflation is a feature of chronic obstructive pulmonary disease (COPD) and can determine pivotal consequence on symptoms, exercise tolerance and quality of life. Despite the relevance of assessing lung hyperinflation, there is still no single consensus as to what volume should be taken into account. We investigate which spirometric measurement is more reliable in assessing static lung hyperinflation and which is more related with impulse oscillometry system (IOS) measurements in COPD. Patients and Methods: Fifty-five COPD patients were enrolled. TLC, RV and RV:TLC ratio were obtained both with helium and plethysmography techniques. IOS measurements (X5, Fres and R5-R20) were performed. Pearson and Spearman correlation determined the relationships between the functional parameters that evaluate static hyperinflation (RV: TLC, TLC, RV) and IOS measurements. Results: As expected, we reported a statistically significant difference between these two techniques in terms of mean percentage values of TLC (7.57 ± 3.26 L; p= 0.02) and RV (15.24 ± 7.51 L; p=0.04), while RV:TLC measured with the two methods was similar (5.21 ± 4.69%; p=0.27). The correlation analysis showed that IOS parameters, such as difference in resistance between 5 Hz and 20 Hz (R(5-20)) and resonant frequency (Fres), were positively correlated with RV:TLC ratio, while reactance at 5 Hz (X(5)) was negatively correlated with it. In particular, we pointed out a weak correlation between RV:TLC (%) (Pleth) and R(5-20) (r=0.3, p=0.04), Fres (r=0.3; p=0.03), while X5 had a mild correlation with RV:TLC (%) (r=-0.5;p<0.0001). Moreover, we noticed a strong relationship between RV:TLC (%)(He) and X5 (r=-0.7; p=0.0001) and a mild correlation between RV:TLC (%) (He) and Fres (r=0.4; p=0.003). Between R5-R20 and RV:TLC, there was a weak correlation (r=0.3; p=0.001). No correlation between TLC, RV (L,%) (both helium and Pleth derived) and IOS parameters (R(5-20), X5, Fres) was found. Conclusion: RV:TLC can represent the most reliable parameter in the assessment of hyperinflation, considering the absence of significant difference in its measurement between the two techniques. IOS provides supplementary information in the assessment of static hyperinflation.

Expression and role of p16 and GLUT1 in malignant diseases and lung cancer: A review.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death and in most cases it is often diagnosed at an advanced stage. Many genetic and microenvironmental factors are able to modify the cell cycle inducing carcinogenesis and tumor growth. Among the metabolic and genetic factors that come into play in carcinogenesis and tumor cell differentiation and growth there are two different proteins that should be considered which are glucose transporters (GLUTs) and p16INK4 The first are glucose transporters which are strongly involved in tumor metabolism, notably accelerating cancer cell metabolism both in aerobic and anaerobic conditions. There are different subtypes of GLUT family factors of which GLUT 1 is the most important and widely expressed. By contrast, p16 is mainly a tumor-suppressor protein that acts on cyclin-dependent kinase favoring cell cycle arrest in the G1 phase. Our search focused on the action of the aforementioned factors.

Prognostic Value of p16 Protein in Patients With Surgically Treated Non-small Cell Lung Cancer; Relationship With Ki-67 and PD-L1.

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. Patients eligible for surgery have better overall survival rate than patients who are not eligible. We investigated the prognostic value of p16 in patients who underwent surgery for lung cancer, in association with other factors such as PD-L1 and Ki-67. MATERIALS AND METHODS: Expression of p16 was evaluated along with the presence of Ki-67 and PD-L1 in 256 NSCLC patients treated only surgically. RESULTS: Adenocarcinoma was the prevalent histotype (56%) followed by squamous cell (29%) and differentiation grade of 3 was the most common (60%). p16 was detected in 83 patients (30%): low positivity (<10% cells) was observed in 30 samples (11%) and high positivity (>10 % cells) in 53 patients (20%). Ki-67 was detected in 89 patients (34%) with mild positivity in 46 patients (10-25% cells), moderate positivity (26-75% cells) in 30 patients (11%), and high positivity (>75% cells) in 13 patients (5%). An influence of p16 expression (p<0.05) along with grading and staging on overall survival (OS) was found. The average OS was 36 months, but the OS increased up to 54 months when patients were stratified according to p16 expression levels. The stratification by staging showed a significant prognostic value for p16 at an early stage (p<0.014). CONCLUSION: p16 significantly influences prognosis, notably at an early stage, along with other variables such as grading and staging.

Amiodarone-induced pulmonary toxicity with an excellent response to treatment: A case report.

Amiodarone is an anti-arrhythmic drug widely used, but its administration can be associated with several adverse side-effects. Among these, amiodarone-induced pulmonary toxicity (APT) occurs in 4-17% of cases and, if not early diagnosed and treated, may evolve towards pulmonary fibrosis and respiratory failure. A 76 years-old-man went to the hospital for accidental trauma. The patient did not report respiratory symptoms but was suffering from atrial fibrillation treated with amiodarone 200 mg/day from three years (cumulative dose >150 gr). HRCT showed ground-glass opacities and nodules in both lungs. The patient underwent fibreoptic bronchoscopy with BAL. Cytologic examination of BALF sediment put in evidence foamy macrophages. The electronic microscopy revealed into the alveolar macrophages "… the presence of multilamellar intracytoplasmic bodies and lysosomes, loads of lipid material". LFTs showed a restrictive syndrome and an impairment of DLCO. Amiodarone discontinuation and steroid administration led to the regression of radiological lesions and the recovery of lung function. Patients taking amiodarone can experience APT. They should perform a basal chest x-ray with LFTs before starting therapy. Monitoring could reveal early the pulmonary toxicity, and patients can respond favourably to the treatment.

Functional benefit of smoking cessation in severe COPD patients undergoing bronchial valve implantation.

INTRODUCTION: Tobacco smoke is the leading cause of chronic obstructive pulmonary disease. The aim of this study is to highlight the effectiveness of smoking cessation along with bronchial valve implantation in subjects with severe COPD. METHODS: A sample of 25 patients, current smokers, affected by severe COPD and heterogeneous emphysema who quit smoking were compared with a group of 15 patients who did not quit smoking. MEASUREMENTS AND MAIN RESULTS: Patients performed plethysmography, 6 minute walking test (WT), haemogasanalysis, exhaled CO test (eCO), COPD assessment test (CAT) together with the mMRC test. A clearer improvement of examined parameters was registered in the group of patients who quit smoking by varenicline and counselling. In particular, we observed a significant increase of FEV1 by 350 ml in the abstainers group compared with 100 ml increase in the non-abstainers(p < .05) group. We noticed that the RV% decreased by 30% compared with the 10% in the non-abstainers(p < .001). The CAT value decreased by 20 compared with 10 in current smokers(p < .001) as well as the mMRC score (p < .001) was more improved in abstainers. The total resistances were reduced by 30% versus 10% (p < .01)and notably there was a higher improvement of walking test (30 m versus 5) (p < .001). The eCO was clearly reduced in abstainers, 14 versus 8 (p < .002),. PaO2 increased by 4 mmHg versus 1(p < .0001). CONCLUSIONS: Smoking cessation treatment by varenicline strengthens the effects of bronchial valve implantation and shows up its crucial therapeutic role in severe COPD.

Effect of OSAS on cerebral vasoreactivity and cIMT before and after CPAP treatment.

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) has been shown to be an important risk factor for ischaemic cerebral disease. Specific Doppler parameters may be used to measure cerebral vascular dynamics opening the door to new markers/predictors of risk. The objective of our study was to shed light on how the treatment of OSA with continuous positive airway pressure (CPAP) may have an impact on these parameters and, consequently, lower the risk of cerebral ischemic events in these patients. METHODS: A total of 40 untreated patients diagnosed with moderate to severe obstructive sleep apnoea were submitted to a comprehensive ultrasonographic transcranial Doppler evaluation. The parameters measured were: Breath holding index (BHI), mean blood flow velocity (MBFV) and pulsatility index in middle cerebral artery. Colour Doppler ultrasound was also used to measure carotid intima-media thickness (cIMT). These parameters were compared before and after CPAP treatment. RESULTS: After CPAP treatment, MBFV and BHI were shown to be increased (without statistical significance), while cIMT and polysomnographic parameters were significantly decreased. CONCLUSION: The improvement of cerebral vasoreactivity parameters and cIMT after long-term CPAP treatment suggest that treatment of OSA may influence the cerebral vascular regulation and consequently reduce the risk of stroke.