Introduction: Lung cancer is the second most frequent malignancy worldwide, but its aetiology is still unclear. Inflammatory cytokines and Th cells, including Th17, are now emerging as being involved in NSCLC pathways, thus postulating a role of IL-17 in tumour angiogenesis by stimulating the vascular endothelial growth factor and the release of nitric oxide. Despite the fact that many biomarkers are used for chest malignancy diagnosis, data on FeNO levels and inflammatory cytokines in NSCLC are still few. Our study aimed to evaluate the relationship between pulmonary nitric oxide production and VEGF and Th17-related cytokines in the EBC of patients affected by early-stage NSCLC. Methods: FeNO measurement and lung function tests were performed in both patients affected by NCSLC and controls; EBC samples were also taken, and Th1 (IL-1, IL-6, IL-12, IFN-g, TNF-a), Th17 (IL-17, IL-23) and Th2 (IL-4, IL-5, IL-13) related cytokines were measured. Results: Th1 and Th17-related cytokines in EBC, except for IFN-gamma and TNF-alpha, were significantly higher in patients than in healthy controls, whereas no differences were seen for Th2-related cytokines. FeNO at the flow rate of 50 mL/s, JawNO and CalvNO levels were significantly higher in patients affected by NSCLC compared to controls. Significant correlations were found between FeNO 50 mL/s and IL-17, IL-1 and VEGF. JawNO levels positively correlated with IL-6, IL-17 and VEGF. No correlations were found between FeNO and Th2-related cytokines. Conclusion: This is the first report assessing a relationship between FeNO levels and Th17-related cytokines in the EBC of patients affected by early-stage NSCLC. IL-17, which could promote angiogenesis through the VEGF pathway, might be indirectly responsible for the increased lung production of NO in patients with NSCLC.

Inflammation mediated by the immune system is known to be important in carcinogenesis and, specifically, T helper 17 cells have been reported to play a role in tumor progression by promoting neo-angiogenesis. The aim of this study was to investigate whether inflammatory cytokines and vascular endothelial growth factor (VEGF) levels in exhaled breath condensate (EBC) and in serum were related to tumor size in patients with non-small cell lung cancer (NSCLC). Il-6, IL-17, TNF-α and VEGF levels were measured in EBC and serum of 15 patients with stage I-IIA NSCLC and in 30 healthy controls by immunoassay. The tumor size was measured by a CT scan. The concentrations of IL-6, IL-17 and VEGF were significantly higher in EBC of patients with lung cancer, compared with controls, while only serum IL-6 concentration was higher in patients compared to controls. A significant correlation (r = 0.78, p = 0.001) was observed between EBC levels of IL-6 and IL-17; IL-17 was also correlated to EBC levels of the VEGF (r = 0.83, p < 0.001) and TNF-α (r = 0.62, p = 0.014). The tumor diameter was significantly correlated with EBC concentrations of VEGF (r = 0.58, p = 0.039), IL-6 (r = 0.67, p = 0.013) and IL-17 (r = 0.66, p = 0.017). Our results show a significant relationship between inflammatory and angiogenic markers, measured in EBC by a non-invasive method, and tumor mass.

Background Exercise-induced (EI) symptoms may be associated with bronchospasm (EI-B), or laryngospasm, that is a paradoxical VC adduction (VCD) mimicking asthma. We previously found that vitamin D deficiency (Ddef) favours the occurrence of VCD during hyperventilation test (HV), particularly in hypocapnic conditions. We evaluated the occurrence of EI-B and EI-VCD during HV in relationship with Ddef, in 37 non smoking young athletes (24 males, 13 females, age: 13–25 years).

Background : Systemic and local inflammatory microenvironment may be an important contributor to morbidity and mortality associated with NSCLC. Exhaled breath condensate(EBC) is a non-invasive method to collect airway lining fluid for assessing lung inflammation. Interleukin-6 (IL-6) is associated with poor prognosis and correlates with neoplastic cachexia and with stage of disease. PET scan has been included in standard staging workup and the standardized uptake value(SUV) of PET-scan has been shown to correlate with poor prognosis in lung cancer. Aim and Objective : to assess the correlations between serum and EBC IL-6 levels and SUV in patients with NSCLC. Methods : Fifteen consecutive patients (12 males, mean age 64 years, range 39-82) receiving a curative resection for NSCLC were enrolled. All the patients underwent PET scan and IL-6 values measurement both in serum and EBC. Results : PET scan was positive in all the patients with a mean SUV value 10.64 ± 4.28(range: 6-18.8). Mean IL-6 value was 1.05 pg/ml ± 1.27 in serum and 0.29 pg/ml ± 0.09 in EBC. Significant correlation between SUV and IL-6 levels both in serum and in EBC was found (r= p Conclusions : the observed relationship suggest that lung and systemic inflammation is proportional to tumor metabolic activity.

Background : both local and systemic inflammation play a key role in the genesis and progression of lung cancer; vascular endothelial growth factor (VEGF) has been related to progression and local extension of many tumors. Involvement of T helper 17 lymphocytes (Th17) and their cytokines (IL17, IL6) in cancer has been recently postulated. Lung inflammation may be non-invasively assessed by cytokine assay in exhaled breath condensate (EBC). Aim and objectives : to assess the possible correlations between systemic and local Th17 related cytokines, VEGF and tumor size evaluated by CT-scan in patients with NSCLS. Methods : Fifteen consecutive patients (12 males; mean age 64 years) with NSCLC classified in stage IA-IB-IIA, were enrolled. Lung CT-scan, EBC and serum samples were obtained in each patient. IL-6, IL-17 and VEGF were measured by ELISA. Results: Tumor mean diameter was 3.28 cm (SD 2.33). Mean cytokines values in serum and EBC are shown in table 1. View this table: Table 1 EBC level of VEGF was significantly correlated with EBC IL-6 (r=0.314, p=0.030) and IL-17 (r=0.697, p<0.001). A significant correlation between tumor diameter and IL-6, IL-17 and VEGF in EBC was observed (r=0.440 p=0.013, r=0.444 p=0.013, r=0.332 p=0.039 respectively). No correlation was found between serum cytokine and tumor size. Conclusion: This is the first observation reporting Th17 cytokines in EBC in NSCLC. The correlation between Th17 cytokines and tumor size suggests the involvement of Th17 cells in the progression of neoplasia.

BACKGROUND Chronic cough is characterized by sensory neuropathy. Vitamin B-12 (cobalamin) deficiency (Cbl-D) causes central and peripheral nervous system damage and has been implicated in sensory neuropathy and autonomic nervous system dysfunction. OBJECTIVE We evaluated whether Cbl-D has a role in chronic, unexplained cough. DESIGN Laryngeal threshold (histamine concentration that provokes a 25% decrease in the midinspiratory flow), bronchial threshold (histamine concentration that provokes a 20% decrease in the forced expiratory volume in 1 s), and cough threshold (histamine concentration that causes ≥5 coughs) in response to an inhaled histamine were assessed in 42 patients with chronic, unexplained cough [27 Cbl-D patients and 15 patients without Cbl-D (Cbl-N)] before and after intramuscular injections of cobalamin for 2 mo. Laryngeal, bronchial, and cough hyperresponsiveness was diagnosed when histamine concentration thresholds were ≤8 mg/mL. Seven Clb-D and 3 Cbl-N patients underwent an oropharyngeal biopsy before treatment. RESULTS Cbl-D patients had a higher prevalence of laryngeal hyperresponsiveness than did Cbl-N patients (92.6% compared with 66.7%; P = 0.03), a thinner oropharyngeal epithelium [133.7 μm (95% CI: 95, 172 μm) compared with 230.8 μm (95% CI: 224, 237 μm); P = 0.002], a lower number of myelinated nerve fibers [2.25/mm(2) (95% CI: 1.8, 2.7/mm(2)) compared with 3.44/mm(2) (95% CI: 3, 3.8/mm(2)); P = 0.05], and a higher immunoreactive score for nerve growth factor (NGF) [6.7 (95% CI: 6, 7.3) compared with 2.8 (95% CI: 2.5, 3.1); P = 0.02]. After cobalamin supplementation, symptoms and laryngeal, bronchial, and cough thresholds were significantly improved in Cbl-D but not in Cbl-N patients. CONCLUSIONS This study suggests that Cbl-D may contribute to chronic cough by favoring sensory neuropathy as indicated by laryngeal hyperresponsiveness and increased NGF expression in pharyngeal biopsies of Cbl-D patients. Cbl-D should be considered among factors that sustain chronic cough, particularly when cough triggers cannot be identified.

Background: Perennial rhinitis (PR), chronic rhinosinusitis (CRS), or both, asthma, and gastroesophageal reflux disease (GERD) are the most frequent triggers of chronic cough (CC). Extrathoracic airway receptors might be involved in all 3 conditions because asthma is often associated with PR/CRS and gastroesophageal refluxate might reach the upper airway. We previously found that most patients with rhinosinusitis, postnasal drip, and pharyngolaryngitis show laryngeal hyperresponsiveness (LHR; ie, vocal cord adduction on histamine challenge) that is consistent with an irritable larynx.Objective: We sought to evaluate the role of LHR in patients with CC.Methods: LHR and bronchial hyperresponsiveness (BHR) to histamine were assessed in 372 patients with CC and in 52 asthmatic control subjects without cough (asthma/CC-). In 172 patients the challenge was repeated after treatment for the underlying cause of cough.Results: The primary trigger of CC was PR/CRS in 208 (56%) patients, asthma in 41 (11%) patients (asthma/CC+), GERD in 62 (17%) patients, and unexplained chronic cough (UNEX) in 61 (16%) patients. LHR prevalence was 76% in patients with PR/CRS, 77% in patients with GERD, 66% in patients with UNEX, 93% in asthma/CC+ patients, and 11% in asthma/CC- patients. Upper airway disease was found in most (95%) asthma/CC+ patients and in 6% of asthma/CC- patients. BHR discriminated asthmatic patients and atopy discriminated patients with PR/CRS from patients with GERD and UNEX. Absence of LHR discriminated asthmatic patients without cough. After treatment, LHR resolved in 63% of the patients and improved in 11%, and BHR resolved in 57% and improved in 18%.Conclusions: An irritable larynx is common in patients with CC and indicates upper airway involvement, whether from rhinitis/sinusitis, gastric reflux, or idiopathic sensory neuropathy. (J Allergy Clin Immunol 2011;127:412-9.)

INTRODUCTION:Upper airway inflammation and narrowing are characteristics of obstructive sleep apnoea (OSA). Inflammatory markers have been found to be increased in exhaled breath and induced sputum of patients with OSA.OBJECTIVES:The aim of this study was to investigate if the measurement of exhaled nitric oxide (F(ENO) ), as marker of airway inflammation, together with the forced mid-expiratory/mid-inspiratory airflow ratio (FEF(50) /FIF(50) ), as marker of upper airway narrowing, may help to predict OSA.METHODS:Two hundred one consecutive outpatients with suspected OSA were prospectively studied between January 2004 and December 2005. All patients underwent clinical examination, spirometry with measurement of FEF(50) /FIF(50) , maximum inspiratory pressure, arterial blood gas analysis, exhaled nitric oxide (F(ENO) ) and overnight polysomnography. Linear regression models were used to evaluate the effect of measured variables on the apnoea-hypopnoea index (AHI). Models were cross-validated by bootstrapping.RESULTS:Most of the patients were obese and had severe OSA. FEF(50) /FIF(50) , F(ENO) and an interaction term between smoking and F(ENO) contributed significantly to the predictive model for AHI, in addition to age, neck circumference, body mass index and carboxyhaemoglobin saturation. A nomogram to predict AHI was obtained, which converted the effect of each covariate in the model to a 0-100 scale. The nomogram showed a good predictive ability for AHI values between 25 and 64.CONCLUSIONS:The measurement of F(ENO) and of FEF(50) /FIF(50) improves the ability to predict OSA and may be used to identify patients who require a sleep study.

PURPOSE: Vitamin B12 deficiency causes sensory neuropathy, that might contribute to the pathogenesis of chronic cough and pharyngo-laryngeal dysfunction. Increased nerve growth factor (NGF) levels have been demonstrated in cobalamin deficiency. We investigated upper and lower airway responsiveness and cough threshold to histamine before and after vitamin B12 supplementation (cobalamin 1000 mcg weekly for 2 months) in 40 patients with chronic unexplained cough, 25 with B12 deficiency (serum value below 300 pg/ml) and 15 controls with no nutritional lack. In a subgroup of subjects, NGF expression in pharyngeal mucosa was assessed.

BACKGROUND:Hypoxia and snoring-related mechanical trauma contribute to airway inflammation in obstructive sleep apnoea (OSA). Increased exhaled nitric oxide (FENO), an airway inflammation marker, has been reported in OSA patients. We propose the measure of NO in the oral cavity (oNO) as marker of oropharyngeal inflammation in OSA. METHODS:We compared oNO and FENO of 39 OSA patients with those of 26 mild asthmatics (ASTHMA), 15 patients with chronic rhinitis or rhinosinusitis (CRS) and 24 healthy subjects. A special device was used for oNO measurement. Apnoea/hypopnoea index (AHI), oxygen desaturation index, mean and nadir SaO2 were calculated from the polysomnography. RESULTS:oNO was significantly increased in OSA (104.2 95%CI 80.2-135.5ppb) as compared to ASTHMA (71.9 95%CI 56.3-91.9ppb; p=0.015), CRS (54.4 95%CI 40.2-73.7ppb; p=0.009) and healthy subjects (63.6 95%CI 59-73ppb; p<0.001). oNO was directly related to AHI (r=0.466, p=0.003) and to minutes slept with SaO2 <90% (r=0.471, p=0.011) and it was inversely related to nadirSaO2 (r=-0.393, p=0.018). FENO was highest in asthmatics (40.3 95%CI 32.5-50.1ppb) and only slightly elevated in OSA (23.1 95%CI 19,8-28.3ppb) and CRS (22.8 95%CI 16.8-32.5ppb). CONCLUSIONS:The finding that oral NO is increased in OSA and is related to upper airway obstructive episodes and to hypoxemia severity, strengthens the clinical and pathogenic role of oral inflammation in OSA.

PURPOSE: Upper airway cough syndrome (UACS) is the most frequent cause of chronic cough. It is due to a variety of upper respiratory diseases, that are supposed to sensitize pharyngolaryngeal receptors. The aim of this study was to evaluate the characteristics of UACS as compared to other nonasthmatic causes of chronic cough (no-UACS).

Solar cheilosis (SC), a common precancer of the lower lip with a high potential to progress to invasive squamous cell carcinoma, presents with characteristic morphological vermillion-skin border alterations, like the border retraction.To determine robust macro-morphological descriptors of the vermillion border from non-standardized digital photographs and to exploit a probabilistic model for SC recognition in real clinical environments.Lip borders of 150 individuals (75 SC patients, 75 non-SC controls) were quantified on the basis of the extent of vermillion retraction and the degree of border irregularity employing fractal features and type-P Fourier descriptors. Eight lip border quantifiers were evaluated in terms of their reliability and reproducibility. The probabilistic ‘diagnostic’ model was implemented using the relevance vector machine (RVM) algorithm.Picture acquisition contributes substantially to overall variability of lip border images; however, for the different lip descriptors 33% to 65% of border morphological variability is due to differences among individuals. Different camera operators or the use of cameras with different specifications did not affect significantly the extracted lip features. The proposed RVM probabilistic model yielded a high sensitivity and specificity of 94.6% and 96%, respectively.We explored the use of digital photography within the clinical routine setting to validate a probabilistic model for the assessment of lip conditions like SC. The proposed method opens new perspectives toward a cost effective, non-invasive monitoring of SC to support large scale epidemiological and interventional studies in different clinical environments.