Real-world safety and efficacy data of immunotherapy in patients with cancer and autoimmune disease: the experience of the Hellenic Cooperative Oncology Group.

BACKGROUND: Data on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with concurrent autoimmune diseases (AID) are limited. METHODS: We performed a retrospective multicenter review of medical records of patients with cancer and underlying AID who received ICI. The primary endpoint was progression-free survival (PFS). RESULTS: Among 123 patients with pre-existing AID who received ICI, the majority had been diagnosed with non-small cell lung cancer (NSCLC, 68.3%) and melanoma (14.6%). Most patients had a rheumatologic (43.9%), or an endocrine disorder (21.1%). Overall, 74 (60.2%) patients experienced an immune-related adverse event (irAE) after ICI initiation, AID flare (25.2%), or new irAE (35%). Frequent irAEs included thyroiditis, dermatitis and colitis. ICI was permanently discontinued due to unacceptable (8.1%) or fatal (0.8%) toxicity. In patients with NSCLC, corticosteroid treatment at the initiation of immunotherapy was associated with poor PFS (HR = 2.78, 95% CI 1.40-5.50, p = 0.003). The occurrence of irAE was associated with increased PFS (HR = 0.48, 95% CI 0.25-0.92, p = 0.026). Both parameters maintained their independent prognostic significance. CONCLUSIONS: ICI in patients with cancer and pre-existing AID is associated with manageable toxicity that infrequently requires treatment discontinuation. However, since severe AID flare might occur, expected ICI efficacy and toxicity must be balanced. CLINICAL TRIAL IDENTIFIER: NCT04805099.

Asthma and rhinitis in Greek furniture workers.

Objective: The detection of asthma and rhinitis in furniture workers exposed to chemicals in the area of Thessaloniki Greece and the determination of the most useful tests for diagnosing the above occupational diseases.Methods: Eighty-three workers (76 men), 35 exposed to chemicals (CW), 23 to wood dust (WW), and 25 office workers (OW), serving as controls, filled in a specialized European Community Respiratory Health Survey (ECRHS) questionnaire for asthma and were submitted to clinical evaluation, spirometry, bronchodilation test, PEF computer algorithm OASYS-2, FeNO, skin prick tests (SPTs), rhinomanometry and methacholine inhalation challenge. Working conditions and protective measurements were also recorded. According to the results of all conducted tests, each subject was distributed to a subgroup: (a) normal, (b) asthma, (c) rhinitis, (d) asthma and rhinitis. Comparisons were performed among work groups.Results: The presence of asthma and/or rhinitis was higher among CW and WW compared to OW (p = 0.004). Significant differences among groups were observed in the questions «better weekend¼ (p < 0.034) and "improvement on vacation¼ (p < 0.000), in OASYS-2 Score (p < 0.000), in ABC Score (p < 0.000), and in methacholine score (p < 0.022). Rhinomanometry, FeNO, spirometry, and spirometry after bronchodilation had no significant differences among groups. Working conditions, ventilation system, work practice, use and type of mask revealed no significant differences.Conclusion: Asthma and rhinitis are significantly common among CW. Protective measurements used were not adequate to prevent asthma and or work related rhinitis. Early diagnosis might contribute to disease prevention and control.

Acute effects of e-cigarette vaping on pulmonary function and airway inflammation in healthy individuals and in patients with asthma.

BACKGROUND AND OBJECTIVE: The acute effects of e-cigarettes have not been scientifically demonstrated yet. The aim of this study was to assess the acute changes in pulmonary function and airway inflammation in patients with asthma after vaping one e-cigarette. METHODS: Twenty-five smokers suffering from stable moderate asthma according to GINA guidelines with no other comorbidities and 25 healthy smokers matched with the baseline characteristics of the asthmatic patients were recruited. PFT, IOS, FeNO and EBC were performed before and after vaping one e-cigarette with nicotine. pH and concentrations of IL-1ß, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17A, TNF-α, ISO8 and LTB4 were measured in EBC. RESULTS: FFEV1/FVC ratio and PEF were reduced in asthmatic patients after e-cigarette. Z5Hz and R5Hz, R10Hz and R20Hz increased in both groups. FeNO and EBC pH increased by 3.60 ppb (P = 0.001) and 0.15 (P = 0.014) in asthmatic patients after e-cigarette, whereas they decreased in control group by 3.28 ppb (P < 0.001) and 0.12 (P = 0.064), respectively. The concentrations of IL-10, TNF-α and ISO8 in EBC increased in asthmatic patients after e-cigarette and the changes in concentrations of IL-1ß and IL-4 differed significantly between the two groups. CONCLUSION: E-cigarette vaping resulted in acute alteration of both pulmonary function and airway inflammation in stable moderate asthmatic patients.

Comparison of Three Screening Questionnaires for Chronic Obstructive Pulmonary Disease in the Primary Care.

BACKGROUND: Even though the diagnosis of chronic obstructive pulmonary disease (COPD) is easy and based mainly on spirometry and symptoms, the prevalence of underdiagnosis is extremely high. The use of simple screening tools (e.g., questionnaires, hand-held spirometers) has been proved to be a simple method for case finding of COPD. Nevertheless the most appropriate target group of the general population has not been specified yet. OBJECTIVES: The aim of the present study was to compare 3 screening questionnaires among smokers aged >40 years in the primary care setting. METHODS: We excluded all subjects with a previous medical diagnosis of bronchial asthma or chronic pulmonary disease other than COPD. All participants were in a stable clinical condition, filled in the International Primary Care Airways Group (IPAG) questionnaire, the COPD Population Screener (COPD-PS) questionnaire, and the Lung Function Questionnaire (LFQ) and underwent spirometry. Medical diagnosis of COPD was established by an experienced pulmonologist. RESULTS: We studied 3,234 subjects during a 3.5-year period. COPD prevalence was 10.9% (52.1% underdiagnosis). All 3 questionnaires showed extremely high negative predictive values (94-96%), so in this case the diagnosis of COPD could be safely excluded. The area under the curve was similar across the 3 questionnaires (AUCROC: 0.794-0.809). The COPD-PS questionnaire demonstrated the highest positive predictive value (41%) compared to the other 2. On the other hand, the IPAG questionnaire and LFQ demonstrated higher sensitivities than COPD-PS resulting in lower percentages of missed cases. CONCLUSIONS: Three validated screening questionnaires for COPD demonstrated different diagnostic characteristics.

Estimating the extent and economic impact of under and overdiagnosis of chronic obstructive pulmonary disease in primary care.

The aim of the present study was to estimate the frequency of under- and over-diagnosis as well as overtreatment and their impact on the financial burden of inhaled drugs for stable chronic obstructive pulmonary disease (COPD). We examined 3200 subjects (65.5% males) of the general population (>40 year old, current or former smokers, and asthma patients were excluded) during a 3-year period. All participants gave detailed medical history, underwent spirometry, and their current and past inhaled medications were registered through the national electronic prescription system. We diagnosed 342 subjects (10.7%) with COPD of whom 180 (52.6%) had no prior medical diagnosis. Overdiagnosis was the case for 306 subjects (9.6%) of whom 35.1% were treated with inhaled drugs during the last year. We calculated that 55.4% of the current cost for inhaled drugs is wasted to overtreatment and overdiagnosis. If there was adherence to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines both for the diagnosis and treatment it would be a net profit of 36,059€ annually, which would be increased to 116,017€ if we had excluded underdiagnosed patients. Under- and over-diagnosis of COPD as well as non-adherence to GOLD guidelines for treatment are common problems in the primary care setting that increase significantly the economic burden of inhaled medications.

Reference Equations for Static Lung Volumes and TLCO from a Population Sample in Northern Greece.

Background: The most commonly used reference equations for the measurement of static lung volumes/capacities and transfer factor of the lung for CO (TLCO) are based on studies around 30-40 years old with significant limitations. Objectives: Our aim was to (1) develop reference equations for static lung volumes and TLCO using the current American Thoracic Society/European Respiratory Society guidelines, and (2) compare the equations derived with those most commonly used. Methods: Healthy Caucasian subjects (234 males and 233 females) aged 18-91 years were recruited. All of them were healthy never smokers with a normal chest X-ray. Static lung volumes and TLCO were measured with a single-breath technique according to the latest guidelines. Results: Curvilinear regression prediction equations derived from the present study were compared with those that are most commonly used. Our reference equations in accordance with the latest studies show lower values for all static lung volume parameters and TLCO as well as a different way of deviation of those parameters (i.e. declining with age total lung capacity, TLCO age decline in both sex and functional residual capacity age rise in males). Conclusions: We suggest that old reference values of static lung volumes and TLCO should be updated, and our perception of deviation of some spirometric parameters should be revised. Our new reference curvilinear equations derived according to the latest guidelines could contribute to the updating by respiratory societies of old existing reference values and result in a better estimation of the lung function of contemporary populations with similar Caucasian characteristics. © 2015 S. Karger AG, Basel.

Effects of particulate air pollution on nasal and lung function development among Greek children: a 19-year cohort study.

The aim was to investigate respiratory symptoms, lung function and nasal airflow development among a cohort of children who were exposed to particulate air pollution. We used questionnaires, spirometry and rhinomanometry, while central-monitored PM10 concentrations were used for exposure assessment. We initially examined 1046 children (10-12 year old) in the heavily polluted town of Ptolemaida, Greece, and 379 children in the cleaner town of Grevena (control group). We re-evaluated 312 of the former and 119 of the latter after 19 years. PM10 concentrations were above permissible levels in Ptolemaida during all study period. At both visits, nasal flow was significantly lower in the study sample. At the follow-up visit, 34.3% had severe nasal obstruction (< 500 ml/s) and 38.5% reported chronic nasal symptoms. Spirometric parameters did not differ compared to the control group. Particulate air pollution had significant and negative effects on nasal but not on lung function development.

Exposure to PM10 as a risk factor for the development of nasal obstruction and chronic obstructive pulmonary disease.

OBJECTIVES: To investigate whether air pollution is a potential risk factor for airways obstruction. METHODS: A prospective cohort study (11.3 +/- 2.9 years) that took place in two areas (Eordea where concentration of PM10 was high and Grevena, Greece). We used the MRC questionnaire, spirometry, and anterior rhinomanometry at both visits. RESULTS: Initially we examined 3046 subjects. After excluding chronic obstructive pulmonary disease (COPD) patients, we re-examined 872 subjects and 168 of them had developed COPD (Grevena: 24.3%, Eordea: 18.5%). Multivariable logistic regression analysis showed that the area of residence and thus exposure to air pollution was not a risk factor for the development of COPD (OR: 0.51, 95% CI: 0.18-1.46, P = 0.21). On the other hand, residence in Eordea was strongly related to the development of severe nasal obstruction (OR: 11.47, 95% CI: 6.15-21.40, P < 0.001). Similar results were found after excluding patients with COPD stage I as well as in the subgroup of never smokers. CONCLUSION: Air pollution was associated with severe nasal obstruction but not with COPD development.

COVID-19 and liver injury: An ongoing challenge.

The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019, in Wuhan, China. The virus was rapidly spread worldwide, causing coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is presented, usually, with typical respiratory symptoms (i.e., dyspnea, cough) and fever, extrapulmonary manifestations are also encountered. Liver injury is a common feature in patients with COVID-19 and ranges from mild and temporary elevation of liver enzymes to severe liver injury and, even, acute liver failure. The pathogenesis of liver damage is not clearly defined; multiple mechanisms contribute to liver disorder, including direct cytopathic viral effect, cytokine storm and immune-mediated hepatitis, hypoxic injury, and drug-induced liver toxicity. Patients with underlying chronic liver disease (i.e., cirrhosis, non-alcoholic fatty liver disease, alcohol-related liver disease, hepatocellular carcinoma, etc.) may have greater risk to develop both severe COVID-19 and further liver deterioration, and, as a consequence, certain issues should be considered during disease management. The aim of this review is to present the prevalence, clinical manifestation and pathophysiological mechanisms of liver injury in patients with SARS-CoV-2 infection. Moreover, we overview the association between chronic liver disease and SARS-CoV-2 infection and we briefly discuss the management of liver injury during COVID-19.

A combination of the IPAG questionnaire and PiKo-6® flow meter is a valuable screening tool for COPD in the primary care setting.

AIMS: To investigate the validity of the International Primary Care Airways Guidelines (IPAG) questionnaire and PiKo-6® (Ferraris Respiratory Europe Ltd.) flow meter as screening tools for diagnosing chronic obstructive pulmonary disease (COPD) in the primary care setting. METHODS: The first 50 patients in 25 general practice offices completed the IPAG questionnaire and underwent spirometry with the handheld PiKo-6® flow meter. The results were compared with official spirometry parameters after bronchodilation. All participants had no previous medical diagnosis of respiratory diseases. RESULTS: Data from 1,078 out of 1,250 subjects (462 males, mean age 65.3 ± 11.4 years) were analysed. The percentage of smokers was 48.4% (38 ± 29 pack-years). COPD was diagnosed in 111 (10.3%) patients. In the subgroup of smokers the sensitivity and specificity for COPD diagnosis were 91% and 49%, respectively, for the IPAG questionnaire; 80% and 95% respectively for the PiKo-6® spirometer; and 72% and 97% for their combination. The negative predictive value of the questionnaire was 97%, whereas the positive predictive value of the questionnaire/ PiKo-6® combination was 82%. Using a cut-off score of 19 points for the IPAG questionnaire, we calculated the best combination of sensitivity (75%) and specificity (72%). CONCLUSIONS: The IPAG questionnaire and the hand-held PiKo-6® spirometer can be used in combination to increase the possibility of an early and accurate diagnosis of COPD in the primary care setting.

Underdiagnosis, false diagnosis and treatment of COPD in a selected population in Northern Greece.

BACKGROUND: In the primary care setting, diagnosis and treatment of COPD is not always consistent with GOLD guidelines. OBJECTIVES: To calculate the prevalence of COPD underdiagnosis, false diagnosis and treatment in the general population of northern Greece. METHODS: Observational study in the context of an early COPD detection and smoking cessation project. Inclusion criteria: >40-year-old, current and former smokers (>10 pack-years) in five primary care centres of northern Greece from 2012 to 2019. Participation was achieved via a campaign (posters and advertisements in the mass media). RESULTS: We examined 5,226 subjects (mean age: 58.2 ± 12.7 years, 61.5% males, current smokers: 56.2%) of whom 564 (10.8%) had symptoms and spirometrically confirmed COPD. There were 5 groups of 'interest:' a) 117/264 (44.3%) with a previous correct diagnosis COPD and correct treatment; b) 139/264 (52.7%) previous correct diagnosis COPD but overtreatment; c) 8/264 (3%) previous correct diagnosis COPD but undertreatment; d) 461 subjects (63.6% of those with previous COPD diagnosis) had previous false diagnosis of COPD (= also overtreatment); e) 300/564 (53.2%) previously not diagnosed COPD (=underdiagnosis and also undertreatment). We found that 322/461 (69.8%) of those with a previous false diagnosis have been prescribed long-acting bronchodilators plus ICS. CONCLUSION: Among the general population subjects in northern Greece, more than 50% of patients with COPD were underdiagnosed, more than 50% of correctly diagnosed COPD patients were overtreated and most patients taking inhaled drugs were those with a false diagnosis of COPD (possibly GOLD stage 0).

Bacteriology, antibiotic resistance and risk stratification of patients with culture-positive, community-acquired pleural infection.

BACKGROUND: Community-acquired pleural infection (CAPI) is a growing health problem worldwide. Although most CAPI patients recover with antibiotics and pleural drainage, 20% require surgical intervention. The use of inappropriate antibiotics is a common cause of treatment failure. Awareness of the common causative bacteria along with their patterns of antibiotic resistance is critical in the selection of antibiotics in CAPI-patients. This study aimed to define CAPI bacteriology from the positive pleural fluid cultures, determine effective antibiotic regimens and investigate for associations between clinical features and risk for death or antibiotic-resistance, in order to advocate with more invasive techniques in the optimal timing. METHODS: We examined 158 patients with culture positive, CAPI collected both retrospectively (2012-2013) and prospectively (2014-2018). Culture-positive, CAPI patients hospitalized in six tertiary hospitals in Greece were prospectively recruited (N=113). Bacteriological data from retrospectively detected patients were also used (N=45). Logistic regression analysis was performed to identify clinical features related to mortality, presence of certain bacteria and antibiotic resistance. RESULTS: Streptococci, especially the non-pneumococcal ones, were the most common bacteria among the isolates, which were mostly sensitive to commonly used antibiotic combinations. RAPID score (i.e., clinical score for the stratification of mortality risk in patients with pleural infection; parameters: renal, age, purulence, infection source, and dietary factors), diabetes and CRP were independent predictors of mortality while several patient co-morbidities (e.g., diabetes, malignancy, chronic renal failure, etc.) were related to the presence of certain bacteria or antibiotic resistance. CONCLUSIONS: The dominance of streptococci among pleural fluid isolates from culture-positive, CAPI patients was demonstrated. Common antibiotic regimens were found highly effective in CAPI treatment. The predictive strength of RAPID score for CAPI mortality was confirmed while additional risk factors for mortality and antibiotic resistance were detected.

An Observational Study to Assess the Molecular Epidemiology and Direct Medical Costs of Epidermal Growth Factor Receptor (EGFR) Mutations in Patients with Advanced EGFR Mutation-Positive Non-Small Cell Lung Cancer Treated with Afatinib in Real-World Clinical Settings in Greece.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line option for patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC). Afatinib, a second-generation irreversible EGFR-TKI, has been extensively used in Greece in this setting; however, real-world data regarding molecular epidemiology and financial implications of afatinib use are lacking. MATERIALS AND METHODS: This was an observational, non-interventional, multicenter, retrospective cohort study, based on real-world data collected from the medical charts/records of patients treated with afatinib between 15/03/2015 and 25/06/2020 and were recorded on a web-based data capture system. Cox models were used to assess the prognostic significance of clinicopathological parameters with respect to clinical outcomes of interest. Cost analysis was conducted from a public third-payer perspective, and only direct medical costs reimbursed by the payer were considered. RESULTS: A total of 59 patients were treated with afatinib for their EGFR mutation-positive advanced NSCLC; the median age was 61 years (range: 37-91). Performance status was zero in 61%, and brain metastases were present in 13.6%. Forty-four patients (74.6%) had a deletion in exon 19 only, while nine (15.3%) had a mutation in exon 21, 8 of them in L858R and one in L861Q. At a median follow-up of 41.8 months (95% CI 35.9-51.4), the median PFS was 14.3 months (95% CI 12.2-16.4), and the median OS was 29 months (95% CI 25.6-33.4). Corresponding values for patients with deletion 19 only were 14.3 months (95% CI 11.5-18.5) and 28.1 months (95% CI 21.1-32.6), respectively. The mean expenditure for the treatment of each patient equals €25,333.68; with €21,865.06 being attributed to drug acquisition costs, €3325.35 to monitoring costs and €143.27 to adverse event treatment-related costs. CONCLUSION: Long-term data in the real-world setting in Greece confirm activity, tolerability and cost-effectiveness of afatinib as first-line treatment of patients with advanced EGFR-mutant NSCLC. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT04640870.

The Role of Immunotherapy in Extensive Stage Small-Cell Lung Cancer: A Review of the Literature.

Lung cancer is the second most common cancer in both sexes worldwide. Small-cell lung cancer (SCLC) is a form of neuroendocrine tumor, which is classified into limited and extensive-stage disease and shows excellent initial response to chemotherapy; however, almost all patients relapse later. During the past few years, several clinical trials have evaluated the effect of addition of immunotherapy to conventional chemotherapy in patients with extensive SCLC. Checkpoint inhibitors are currently under investigation, especially the CTLA-4 and PD-1/PD-L1 inhibitors. Nowadays, evidence show a statistically significant survival benefit of adding atezolizumab, an IgG1 monoclonal antibody targeting against PD-L1, to platinum-based chemotherapy plus etoposide in patients who have not received any previous systemic therapy. Furthermore, the role of nivolumab, an IgG4 anti-PD-1 monoclonal antibody, is significant for the treatment of relapsed SCLC cases. Recently, pembrolizumab was the first immunotherapeutic agent to be approved by the FDA for patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of chemotherapy. Nevertheless, prognostic biomarkers to immunotherapy response remain to be discovered.

Endocrine paraneoplastic syndromes in lung cancer.

Paraneoplastic syndromes are defined as a combination of clinical disorders associated with malignant diseases that are caused by the secretion of various substances by the tumor without, however, being caused by the direct growth and infiltration of the primary tumor, or due to the development of distant metastases. Despite the fact that lung cancer represents the number one cause of death from cancer worldwide, the new methods of treatment increase patient survival and the incidence of paraneoplastic syndromes. The most important ones of these are humoral hypercalcemia of malignancy, syndrome of inappropriate antidiuretic hormone, hyponatremia of malignancy, ectopic Cushing's syndrome, carcinoid syndrome, and hypoglycemia and are usually a poor prognostic marker. Early diagnosis of those syndromes is achieved using specific criteria and may lead to early diagnosis of the underlying malignancy. It is essential to treat them with the overriding objective of improving the patients' quality of life.

Chronic obstructive pulmonary disease in patients with lung cancer: prevalence, impact and management challenges.

Chronic obstructive pulmonary disease (COPD) and lung cancer share a common etiological factor (cigarette smoking) and usually coexist in everyday clinical practice. The prevalence of COPD among newly diagnosed patients with lung cancer sometimes exceeds 50%. COPD is an independent risk factor (2-4 times higher than non-COPD subjects) for lung cancer development. The presence of emphysema in addition to other factors (e.g., smoking history, age) could be incorporated into risk scores in order to define the most appropriate target group for lung cancer screening using low-dose computed tomography. Clinical management of patients with coexistence of COPD and lung cancer requires a multidisciplinary oncology board that includes a pulmonologist. Detailed evaluation (lung function tests, cardiopulmonary exercise test) and management (inhaled drugs, smoking cessation, pulmonary rehabilitation) of COPD should be taken into account for lung cancer treatment (surgical approach, radiotherapy).

Weekly Personal Ozone Exposure and Respiratory Health in a Panel of Greek Schoolchildren.

BACKGROUND: The association of ozone exposure with respiratory outcomes has been investigated in epidemiologic studies mainly including asthmatic children. The findings reported had methodological gaps and inconsistencies. OBJECTIVES: We aimed to investigate effects of personal ozone exposure on various respiratory outcomes in school-age children generally representative of the population during their normal activities. METHODS: We conducted a panel study in a representative sample of school-age children in the two major cities of Greece, Athens and Thessaloniki. We followed 188, 10- to 11-y-old, elementary school students for 5 wk spread throughout the 2013­2014 academic year, during which ozone was measured using personal samplers. At the end of each study week, spirometry was performed by trained physicians, and the fractional concentration of nitric oxide in exhaled air (FeNO) was measured. Students kept a daily time­activity­symptom diary and measured PEF (peak expiratory flow) using peak flow meters. Mixed models accounting for repeated measurements were applied. RESULTS: An increase of 10 µg/m3 in weekly ozone concentration was associated with a decrease in FVC (forced vital capacity) and FEV1 (forced expiratory volume in 1 s) of 0.03 L [95% confidence interval (CI): −0.05, −0.01] and 0.01 L (95% CI: −0.03, 0.003) respectively. The same increase in exposure was associated with a 11.10% (95% CI: 4.23, 18.43) increase in FeNO and 19% (95% CI: −0.53, 42.75) increase in days with any symptom. The effect estimates were robust to PM10 adjustment. No inverse association was found between ozone exposure and PEF. CONCLUSIONS: The study provides evidence that airway inflammation and the frequency of respiratory symptoms increase, whereas lung function decreases with increased ozone exposure in schoolchildren. https://doi.org/10.1289/EHP635.

Effect of Ambient Ozone Exposure Assessed by Individual Monitors on Nasal Function and Exhaled NO Among School Children in the Area of Thessaloniki, Greece.

OBJECTIVES: The study of short-term effects of environmental ozone exposure on nasal airflow, lung function, and airway inflammation. METHODS: Ninety one children-47 underwent rhinomanometry-were included. The study was carried out during the 2013 to 2014 academic year. Activity questionnaires and personal O3 samplers were distributed and 1 week later, respiratory measurements were performed. Daily measurements of outdoor ozone were also considered. RESULTS: A 10 µg/m increase in weekly personal ozone exposure concentrations was associated with a non-statistically significant 12.7% decrease in nasal inspiratory airflow (29.4% during the high ozone period). When the outdoor exposure of the same and the previous day were taken into account the corresponding figures were 13.48% and 43.58% (P = 0.02). CONCLUSIONS: There is an indication for increased risk of nasal obstruction during exposure to high ozone.

Umeclidinium bromide/vilanterol combination in the treatment of chronic obstructive pulmonary disease: a review.

Chronic obstructive pulmonary disease (COPD) is a common disease among the elderly that could be prevented by smoking cessation. As it is characterized by airflow limitation that is not fully reversible, bronchodilator therapy is the first choice of treatment. Symptomatic COPD patients with or without risk for future exacerbations have a strong indication for the permanent use of long- and ultralong-acting ß2-agonists and/or long-acting muscarinic antagonists. Combining bronchodilators is an effective approach, as they demonstrate synergic action at a cellular level and have additive clinical benefits and fewer adverse events compared with increased doses of the monocomponents. Novel fixed-dose combinations of long-acting ß2-agonists/long-acting muscarinic antagonists in one inhaler have been approved for clinical use by the US Food and Drug Administration and the European Medicines Agency. This review focuses on published clinical trials about the fixed-dose combination of umeclidinium/vilanterol trifenatate in patients with COPD. Results from six studies (five of them of 12 weeks' duration and one that lasted 1 year, including more than 6,000 patients in total) showed that umeclidinium/vilanterol trifenatate improved lung function, dyspnea, and health-related quality of life and decreased the exacerbation rate with no serious adverse events. More longstanding trials are needed to evaluate the effect of the drug on disease progression and compare it directly with other fixed-dose combinations.

Mast cells mediate malignant pleural effusion formation.

Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL-1ß, which in turn induced pleural vasculature leakiness and triggered NF-κB activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell-induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenocarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC-dependent effusion formation is therapeutically addressable.