Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study

BACKGROUND: We have previously shown that nuclear factor (NF)-κB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-κB activation and not proliferation specifically inhibits MPE formation by LLC cells. RESULTS: Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-κB activation and NF-κB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-κB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation. CONCLUSIONS: These studies indicate that proteasome inhibition tailored to block NF-κB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE

Static and dynamic mechanics of the murine lung after intratracheal bleomycin

<p>Abstract</p> <p>Background</p> <p>Despite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure.</p> <p>Methods</p> <p>Single intratracheal injections of saline (50 μL) or bleomycin (2 mg/Kg in 50 μL saline) were administered to C57BL/6 (<it>n </it>= 40) and Balb/c (<it>n </it>= 32) mice. Injury/fibrosis score, tissue volume density (TVD), collagen content, airway resistance (<it>R_N</it>), tissue damping (<it>G</it>) and elastance coefficient (<it>H</it>), hysteresivity (<it>η</it>), and area of pressure-volume curve (PV-A) were determined after 7 and 21 days (inflammation and fibrosis stage, respectively). Statistical hypothesis testing was performed using one-way ANOVA with LSD <it>post hoc </it>tests.</p> <p>Results</p> <p>Both C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and <it>G </it>and <it>H </it>non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. <it>G </it>and <it>H</it>, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, <it>H </it>and <it>G </it>was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls.</p> <p>Conclusions</p> <p>Lung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than forced oscillations at detecting inflammation and fibrosis.</p

Smoking cessation treatment in a real-life setting: the Greek experience

Objectives: The aim of this study was to estimate the clinical efficacy of counseling combined with currently used pharmacotherapy for smoking cessation (bupropion SR and nicotine replacement therapy, NRT) in actual clinical practice, and to identify predictors of successful abstinence at the end of therapy, as well as predictors of sustained abstinence in one year. Methods: 895 smokers, self—motivated to quit, received bupropion SR for 7 or 19 weeks and/or nicotine replacement therapy (NRT) (nicotine patch) for 9 weeks in combination with individual behavioural therapy. An intensive program including repetitive visits and telephone contacts during treatment and one year's follow-up period was available for supporting and motivating smokers to prevent relapse. Results: Post-treatment abstinence rates were 71.6% and 53.2% in bupropion SR groups for 7 and 19 weeks of treatment, respectively, ( p < 0 . 001), 63.4% in bupropion SR plus nicotine patch group and 45% ( p < 0 . 001) in nicotine patch group. One year's follow-up abstinence rates were 43.1%, 29.6%, 30.4% and 18.4% ( p < 0 . 05), respectively. Predictors of successful abstinence at the end of therapy included (a) bupropion SR, (b) lower DSM IV symptom score, and (c) lower nicotine addiction, while predictors for sustained abstinence in one year included: (a) bupropion SR, (b) lower nicotine addiction, and (c) smoker's motivation. Conclusions: Smoking cessation interventions implementing intensive multi-component programs and constant smokers' motivation in health care settings of actual practice seem promising for increasing short and long-term abstinence rates

Exercise testing and exercise-limiting factors in patients with bilateral bronchiectasis

SUMMARY. Introduction: Exercise capacity is reduced in many patients with bronchiectasis, but there is little information available regarding exercise responses in these patients. Objectives: The aim of this study was to investigate exercise capacity and exercise responses in patients with bilateral bronchiectasis in order to identify possible exercise-limiting factors. Population and Methods: Fifteen patients with bronchiectasis aged 50±16 years underwent lung function testing, including assessment of tidal expiratory flow limitation (EFL), and performed a maximum incremental (20 watts/min) symptom-limited bicycle exercise test. Results: Exercise performance was reduced in 7 of the 15 patients, particularly in those with a greater degree of impairment of lung function, and specifically lower FEV1 (p<0.001) and FVC (p<0.001). EFL was detected in 5 of the 7 patients with exercise limitation and absent in all with normal exercise capacity. Patients with reduced exercise capacity exhibited significantly lower maximal ventilation (V.Emax %pred; p<0.001), maximal tidal volume (VTmax; p= 0.03), breathing reserve (higher V.Emax/MVV; p<0.001), peak-exercise oxygen saturation measured by pulse oximetry (SpO2, p<0.001), O2-pulse (p<0.001) and anaerobic threshold (AT, p<0.001) and perceived a higher degree of dyspnoea (Borg score; p=0.007). The best correlate of maximal work rate (WRmax, %pred) was the AT (r= 0.90, r2 = 0.81, p<0.001), while for peak oxygen uptake (V.O2max, %pred) the most significant correlation was the peak-exercise SpO2 (r=0.83, r2 = 0.69, p<0.001). Conclusions: Patients with bronchiectasis who have tidal EFL and a low FEV1 exhibit a reduction in exercise capacity. Ventilatory limitation, desaturation and impaired O2-transport/utilization to the periphery appear to be the principal factors limiting exercise. V.O2max can be predicted accurately from parameters obtained by simple means, such as peak-exercise SpO2 obtained by pulse oximetry. Pneumon 2009, 22(4):296-314

The Angiopoietin/Tie2 Axis Mediates Malignant Pleural Effusion Formation1

PURPOSE: Angiopoietins and their receptor, Tie2, participate in angiogenesis, regulation of vascular permeability, and inflammation, all central to the pathogenesis of malignant pleural effusions (MPEs). In the present study, we aimed to examine the role of the angiopoietin/Tie2 axis in MPE pathogenesis. EXPERIMENTAL DESIGN: MPE was induced by intrapleural injection of murine adenocarcinoma cells in C57BL/6 mice. Animals were given twice-weekly intraperitoneal injections of 40 mg/kg MuTekdeltaFc or vehicle. MuTekdeltaFc is a soluble Tie2 (sTie2) receptor that binds murine angiopoietins thereby disrupting their interaction with Tie2 receptors expressed on tissues. Animals were killed on day 14. RESULTS: Angiopoietin/Tie2 axis blockade significantly reduced pleural fluid volume and pleural tumor foci. The mean ± SEM pleural fluid volumes were 617 ± 48 μl and 316 ± 62 μl for the control and treated groups, respectively (P = .001), whereas the mean ± SEM tumor foci were 7.3 ± 1.0 and 3.0 ± 0.52 for the control and treated groups, respectively (P = .001). In addition, tumor-associated cachexia, tumor angiogenesis, pleural vascular permeability, recruitment of inflammatory cells to the pleural cavity, and local elaboration of vascular endothelial growth factor and interleukin 6 were also downregulated, and tumor cell apoptosis was induced in animals treated with the inhibitor. CONCLUSIONS: Our results indicate that the angiopoietin/Tie2 axis is an important component of MPE pathogenesis. Further studies are required to determine whether therapeutic interventions targeting this pathway could be beneficial for patients with MPE