Tiotropium HandiHaler improves the survival of patients with COPD: a systematic review and meta-analysis.

BACKGROUND: Tiotropium HandiHaler (TioH) has been shown to improve lung function, exacerbations, and quality of life when added to the pharmacotherapy of patients with stable chronic obstructive pulmonary disease (COPD). The purpose of this meta-analysis was to synthesize current evidence regarding the impact of TioH on the survival rate of these patients, which is still controversial. METHODS: A systematic search in the electronic databases of the Cochrane Library, Medline, Scopus, EMBASE, PschINFO, CINAHL, and Web of Science was conducted by two independent authors (December 2012). Randomized clinical trials (RCTs) comparing inhaled TioH versus control (placebo or open control) were included. Data on total mortality were extracted, and missing data were obtained from authors. Relative risk (RR) for total mortality was calculated for each study and pooled. Heterogeneity, the risk of bias, and the publication bias were assessed in accordance with Cochrane's guidance. RESULTS: Twenty-eight RCTs, evaluating 33,538 patients, met the inclusion criteria. Data were nonheterogeneous, so fixed-effects model analysis was used. The effect of TioH versus placebo was assessed in 19 RCTs, with a total population of 19,826 patients (31,914 patient years), of whom 1,018 died during the study period. A statistically significant decrease in all-cause mortality was associated with the administration of TioH [RR 0.86, 95% confidence interval (CI) 0.76-0.98]. The number needed to treat to prevent one fatality was estimated to be 64 (95% CI 56-110). Comparisons of tiotropium against six more comparators were identified, but the insufficient sample size did not allow robust comparisons with respect to mortality. CONCLUSION: Our meta-analysis of RCTs showed that TioH prolongs the survival of COPD patients compared with placebo. Further RCTs are needed to confirm the potential superiority of prescriptions with versus without TioH in mortality reduction.

Expression of Bmi1, FoxF1, Nanog, and γ-catenin in relation to hedgehog signaling pathway in human non-small-cell lung cancer.

BACKGROUND: Hedgehog signaling is known to be involved in both lung organogenesis and lung carcinogenesis. The aim of this study was to examine potential downstream targets of the hedgehog signaling pathway in non-small-cell lung cancer. METHODS: Protein expression of Bmi1, FoxF1, Nanog, and γ-catenin was examined by immunohistochemistry in 80 non-small-cell lung cancer samples. Correlations with the previously immunohistochemically recovered results for sonic hedgehog, Ptch1, Smo, Gli1, and Gli2 in the same cohort of tumors as well as the clinicopathological characteristics of the tumors were also evaluated. RESULTS: Bmi1 was expressed in 78/80 (97.5 %) cases of non-small-cell lung cancer and correlated with male gender and expression of Gli1. Positive expression of FoxF1 was found in 62/80 (77.5 %) cases. Expression of FoxF1 correlated with lymph node metastases, Bmi1, and hedgehog pathway activation. Overexpression of Nanog was also noted in 74/80 (92.5 %) tumors and correlated with Bmi1. Cytoplasmic accumulation of γ-catenin was observed in 85 % (68/80) of the tumors and correlated with the expression of Bmi1, FoxF1, and Nanog. CONCLUSION: Several developmental pathways seem to be implicated in non-small-cell lung cancer. It is also suggested that Bmi1 and FoxF1 may cooperate with hedgehog signaling in non-small-cell lung carcinogenesis.

Impact of long-term treatment with low-dose inhaled corticosteroids on the bone mineral density of chronic obstructive pulmonary disease patients: aggravating or beneficial?

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by a low-level systemic chronic inflammatory activity that is responsible for many of the disease's extra-pulmonary manifestations, including osteoporosis and fragility fractures. These manifestations are also well-documented side-effects of oral corticosteroids. It was hypothesized that low levels of inhaled corticosteroids, due to their anti-inflammatory properties and their low circulating levels, might preserve the bone mineral density (BMD) of COPD patients. METHODS: Two hundred and fifty-one male ex-smokers with COPD patients grouped on the basis of their diffusion capacity value as predominantly bronchitic or predominantly emphysematic and 313 male controls with similar age and smoking history were enrolled in the study. Each of the patient's categories was randomized into two separate subgroups. Patients enrolled in subgroups B(neg) (n = 91, 36%) and E(neg) (n = 37, 14.7%) were treated with long-acting ß2-agonists and anticholinergics, while subgroups B(ICS) (n = 87, 35%) and E(ICS) (n = 38, 15.1%) were additionally receiving low-dose inhaled corticosteroids. Patients and controls were evaluated by clinical examination, lung function testing and BMD measurement every 6 months for 4 years. RESULTS: According to the findings, emphysematic patients demonstrated an increased rate of BMD loss compared with bronchitic patients (P = 0.01). Furthermore, a reduction of the annual BMD loss in bronchitic patients on inhaled corticosteroids (P = 0.02) was measured, without a corresponding benefit for the emphysematics (P = not significant). CONCLUSIONS: Long-term administration of low-dose inhaled corticosteroids decelerates the annual BMD loss in bronchitic patients, possibly by reducing both pulmonary and systemic chronic inflammation caused by COPD.

Overexpression of hedgehog pathway molecules and FOXM1 in non-small cell lung carcinomas.

The hedgehog (HH)-signaling pathway is implicated in developmental processes and its aberrant activation in adult tissues has been associated with malignancy. The aim of this study was to determine the expression pattern of HH-signaling molecules in non-small cell lung carcinomas (NSCLC), as well as the involvement of the transcription factor FOXM1, that controls cell proliferation, in this process. Paraffin-embedded tissue sections of 80 NSCLC cases and adjacent non-neoplastic lung parenchyma were immunohistochemically analyzed with anti-SHH, anti-Patched1 (PTCH1), anti-Smoothened (SMO), anti-GLI1, anti-GLI2 and anti-FOXM1 antibodies. Correlations of HH molecules with clinicopathological parameters and FOXM1 expression were evaluated. All the HH-signaling molecules examined were overexpressed in NSCLC compared with the adjacent non-neoplastic lung parenchyma. HH pathway activity and expression of PTCH1 and SMO were significantly higher in squamous cell carcinomas compared to other NSCLC histological types. Activation of HH pathway and PTCH1 expression were correlated with tumor grade being higher in low grade tumors. There was a significant correlation of lymph node metastases with expression of SMO in all NSCLC histological types and with nuclear GLI1 immunolocalization only in adenocarcinomas. Overexpression of FOXM1 in NSCLC was also significantly correlated with PTCH1, SMO and GLI1 expression. In conclusion, HH-signaling pathway is activated in NSCLC and correlates with histological type, prognostic parameters of the tumors as well as with the increased expression of FOXM1.