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- Acute Eosinophilic and Neutrophilic Pneumonia following Transarterial Chemoembolization with Drug-Eluting Beads Loaded with Doxorubicin for Hepatocellular Carcinoma: A Case Report. [JOURNAL ARTICLE]
- Respiration 2014 Oct 23.:426-429.
At an intermediate or advanced stage, i.e. stage B or C, based on the Barcelona Clinic Liver Cancer classification of hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) may be offered as a treatment of palliative intent. We report the case of a patient suffering from acute respiratory distress syndrome after TACE with drug-eluting beads loaded with doxorubicin for HCC. To our knowledge, this is the first case described where a bronchoalveolar lavage was performed, and where significant levels of alveolar eosinophilia and neutrophilia were evident, attributed to a pulmonary toxicity of doxorubicin following liver chemoembolization. © 2014 S. Karger AG, Basel.
- Exercise Training-Based Pulmonary Rehabilitation Program Is Clinically Beneficial for Idiopathic Pulmonary Fibrosis. [JOURNAL ARTICLE]
- Respiration 2014 Oct 23.:378-388.
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, interstitial lung disease, with few therapeutic options. IPF is characterized by pulmonary restriction, dyspnea, hypoxemia, exercise intolerance and poor quality of life (QOL). Objectives: We aimed to examine the effect of exercise training (ET) on clinical outcomes in IPF patients. Methods: A randomized controlled study included thirty-two IPF patients (aged 68 ± 8 years) who were allocated either to the ET group (n = 15), participating in a 12-week, twice-weekly 60-min supervised ET-based pulmonary rehabilitation program, or to a control group (n = 17) continuing with regular medical treatment alone. Cardiopulmonary exercise test, 6-min walking distance (6MWD) test, 30-second chair-stand test, pulmonary function tests, dyspnea and QOL were assessed at baseline and at the end of the 12-week intervention. Results: Significant differences were observed between the ET and the control groups in raw mean deltas (Δ = post- - pre-intervention): Δ6MWD, 81 m, p < 0.001; ΔVO2 peak, 2.6 ml/kg/min, p = 0.002; Δwork rate, 22 W, p < 0.001; Δanaerobic threshold, 3.1 ml/kg/min, p < 0.001, and ΔFVC % predicted, 6%, p = 0.038. Dyspnea, QOL and 30-second chair-stand were also improved significantly following the program. Conclusions: ET improves exercise tolerance, functional capacity, pulmonary function, dyspnea and QOL in patients with IPF, suggesting a short-term treatment efficacy for clinical improvement, and should be considered the standard care for IPF. © 2014 S. Karger AG, Basel.
- Benefits of an Oxygen Reservoir Cannula versus a Conventional Nasal Cannula during Exercise in Hypoxemic COPD Patients: A Crossover Trial. [JOURNAL ARTICLE]
- Respiration 2014 Oct 16.
Background: The Oxymizer® is a special nasal cannula that provides a higher luminal diameter in combination with an incorporated oxygen (O2) reservoir. It is assumed that a higher O2 concentration can be delivered breath by breath in order to increase oxygenation. Objective: We aimed to investigate the effects of the Oxymizer on endurance time in comparison to a conventional nasal cannula (CNC). Methods: Forty-three patients with severe chronic obstructive pulmonary disease (COPD, age 60 ± 9 years, FEV1 37 ± 16% pred.) and indications for LTOT were recruited during pulmonary rehabilitation for this cross-over study. After an initial maximal incremental cycle test, all patients performed 4 cycling endurance time tests at 70% of their peak work rate (twice with the Oxymizer and twice with a CNC, in reverse order). Results: The endurance time was significantly higher when patients cycled while using the Oxymizer in comparison to while using the CNC [858 ± 754 vs. 766 ± 652 s; between-group difference 92 s (95% confidence interval 32-152), p < 0.001]. In addition to a longer cycling duration, O2 saturation at isotime was significantly higher with the Oxymizer (93.5 ± 5.4 vs. 90.4 ± 5.3%; p = 0.027). Furthermore, there was a positive correlation (r = 0.427, p = 0.002) between the O2 flow rate and improvements in the constant work rate test, showing greater improvements in favor of the Oxymizer in patients with a higher demand for O2 (≥4 liters/min). Conclusion: We show that O2 delivery via the Oxymizer is superior to a CNC with regard to endurance capacity and oxygenation during exercise in patients with severe COPD. It seems that patients with a higher demand for O2 (≥4 liters/min), in particular, may benefit more from the use of the Oxymizer. © 2014 S. Karger AG, Basel.
- Stent-Mediated Gene Delivery for Site-Specific Transgene Administration to the Airway Epithelium and Management of Tracheobronchial Tumors. [JOURNAL ARTICLE]
- Respiration 2014 Oct 16.
Background: Gene therapy is currently under investigation as a means of managing a variety of pulmonary diseases. Unfortunately, gene transfer to bronchial epithelium has been hampered by the lack of stable and efficient transduction. Recent studies have shown that gene vectors could be tethered to the metallic surfaces of intra-arterial stents. This approach enables efficacious and site-specific adenoviral gene delivery to the vascular endothelium. Objectives: We hypothesized that airway mesh stents impregnated with viral gene vectors could be used for local gene delivery to benign and malignant bronchial epithelium. Methods: Serotype 5 adenoviral vectors (Ad5, E1-/E3-) containing the reporter genes green fluorescent protein (Ad.GFP) or β-galactoside/LacZ (Ad.LacZ), or a therapeutic gene, Ad.INF-β, were coupled to either metallic mesh disks or stents via anti-Ad knob antibodies. These platforms were assessed for their ability to transfect bronchial epithelial cells from both rats and humans, as well as murine (L1C2) and human (A549) lung cancer cell lines. Gene transfer was quantified by fluorescent microscopy, scanning fluorimetry for Ad.GFP, and light microscopy studies assessing β-galactosidase staining for Ad.LacZ. Metallic mesh and stent-mediated gene transfer was also performed in a murine flank tumor model and in a rat endotracheal tumor model in order to evaluate the therapeutic potential. Results: In these studies, murine and human non-small cell lung cancer (NSCLC) cells were successfully transfected with reporter genes in vitro. Ad.LacZ-complexed mesh successfully transfected reporter genes into established murine flank NSCLC tumors. In addition, Ad.LacZ-tethered stents could effectively transfect both tracheobronchial epithelium and submucosal glands in rats. Similar epithelial transfection was achieved in ex vivo human bronchial epithelium. Pilot in vivo experimentation provided data supporting the concept that therapeutic genes could also be delivered with this technology. In additional pilot in vivo experiments, the growth of murine flank tumors was inhibited by placement of mesh disks coupled with Ad.muINF-β, and rats bearing endotracheal tumors demonstrated a trend towards prolonged survival with insertion of Ad.ratINF-β-tethered stents. Conclusions: Stent-mediated gene delivery successfully enabled site-specific vector administration to target rat and human airway cells in cell culture, organ culture and in vivo. Local tracheobronchial gene delivery via stents could provide a viable clinical solution for overcoming the difficulties encountered with vector delivery within the lungs, in particular by lowering requisite vector titers and by directing desired vectors to areas of interest. This strategy may prove valuable for treating tumors involving the tracheobronchial tree, as well as other nonmalignant tracheobronchial disorders. © 2014 S. Karger AG, Basel.
- Suitability of Small Bronchoscopic Tumour Specimens for Lung Cancer Genotyping. [JOURNAL ARTICLE]
- Respiration 2014 Oct 9.
Background: Biomarker-driven clinical trials in advanced non-small cell lung cancer (NSCLC) usually accept biopsy specimens only, as cytology specimens are supposed to be more challenging due to low neoplastic cell content and suboptimal DNA quantity. Objectives: We aimed to evaluate 2 aspects of bronchoscopic biopsy and cytology specimens: (1) the proportion of neoplastic cells and quantity of DNA extracted, and (2) the detection limit of the Scorpion amplification refractory mutation system on endoscopic samples obtained in daily clinical practice. Methods: We screened 679 patients with advanced-stage NSCLC for the presence of an activating EGFR mutation according to the guidelines of the European Society of Medical Oncology. Their diagnostic tumour tissue samples were characterized. A dilution experiment was performed to determine the minimal proportion of neoplastic cells for a reliable test result. Results: Surgical biopsies, bronchoscopic forceps biopsy samples and needle aspiration cytology specimens exhibited a median tumour cell proportion of 70 versus 30 versus 20% and a DNA quantity of 2,500 versus 1,610 versus 1,440 ng, respectively. The overall EGFR mutation rate was 11%, with no differences between different sample types. Dilution experiments showed that the detection limit depends on the type of mutation. A neoplastic cell content of at least 10 and 25% for exon 19 deletions and exon 21 L858R point mutation, respectively, was required for a true negative result. Conclusions: Bronchoscopic forceps biopsy and needle aspiration cytology specimens are suitable for accurate EGFR mutation analysis using single-gene quantitative real-time polymerase chain reaction. Technologies with a better analytical sensitivity are evolving and should consider these endoscopic tumour specimens. © 2014 S. Karger AG, Basel.
- Overexpression of Matrix Metalloproteinases in Lung Tissue of Patients with Primary Spontaneous Pneumothorax. [JOURNAL ARTICLE]
- Respiration 2014 Oct 7.
Background: Although blebs and bullae are frequently found in the apexes of lungs of patients with primary spontaneous pneumothorax (PSP), its pathogens remain unclear. Objectives: To examine the role of proteases [matrix metalloproteinase (MMP)-2, MMP-7 and MMP-9] and antiproteases [tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4] in the pathogenesis of PSP. Method: Fifty consecutive PSP patients who received standard surgical care were enrolled in the study. Lung tissues from 20 patients with stage I non-small cell lung cancer were used as a control. Immunohistochemistry (IHC), reverse transcription-polymerase chain reaction (RT-PCR) and gelatin zymography were used to evaluate the expression of MMP and TIMP in the lung tissue of patients with PSP. Results: Overexpression of MMP-2, MMP-7 and MMP-9 was found in the afflicted lung by IHC, zymography and RT-PCR. By IHC, higher expression of MMP-2 and MMP-9 in PSP patients was identified in alveolar macrophages and type II pneumocytes (88 and 92% of patients in macrophages, and 72 and 70% of patients in type II pneumocytes, respectively). MMP-2, MMP-7 and MMP-9 expression in patients was higher in mesothelial cells (66, 76 and 76%). Overexpression of TIMP-2 was detected in the extracellular matrix around bullae and blebs. Expression levels of TIMP-1, TIMP-3 and TIMP-4 were negligible (<10% of cells) in both PSP patients and controls. Conclusions: MMP-2, MMP-9, MMP-7 and TIMP-2 were upregulated in PSP lesions. These results suggest that an imbalance between the expression of proteases and antiproteases may be involved in the pathogeneses of PSP. © 2014 S. Karger AG, Basel.
- Cost-Effectiveness of Endobronchial Valve Therapy for Severe Emphysema: A Model-Based Projection Based on the VENT Study. [JOURNAL ARTICLE]
- Respiration 2014 Sep 30.
Background: Endobronchial valve (EBV) therapy is an innovative treatment that has been shown to be safe and effective in selected subgroups of patients with severe emphysema. Objectives: The objective of our study was to assess the cost-effectiveness of EBV therapy compared to the medical management of patients with high heterogeneity, complete fissures and lobar exclusion in the context of the German health-care system. Methods: Clinical data from a subset of VENT (Endobronchial Valve for Emphysema Palliation Trial) provided information about clinical events, health-related quality of life, and disease staging for 12 months. This information was subsequently used to project long-term disease progression, mortality, and health resource utilization. We computed the 5- and 10-year incremental cost-effectiveness ratio (ICER) in euros per quality-adjusted life year (QALY). Costs and effects were discounted at 3% per year. Results: EBV therapy led to clinically meaningful disease restaging at 12 months (37.8% of the cohort improved staging, compared to 0% in the controls). Over 5 years, EBV therapy was projected to increase survival from 66.4 to 70.7%, and to add 0.22 QALYs. Costs were estimated to increase by EUR 10,299, resulting in an ICER of EUR 46,322 per QALY. Over 10 years, 0.41 QALYs were gained at an additional cost of EUR 10,425, yielding an ICER of EUR 25,142 per QALY. Conclusions: Our model-based analysis suggests that EBV therapy leads to clinically meaningful changes in disease staging and progression when compared to medical management, with resulting gains in unadjusted and quality-adjusted life expectancy. Our results indicate that EBV therapy is cost-effective in the German health-care system. © 2014 S. Karger AG, Basel.
- Targeting Inhaled Therapy beyond the Lungs. [JOURNAL ARTICLE]
- Respiration 2014 Sep 24.
Pulmonary disease has been the primary target of inhaled therapeutics for over 50 years. During that period, increasing interest has arisen in the use of this route of administration to gain access to the systemic circulation for the treatment of a number of diseases beyond the airways. In order to effectively employ this route, the barriers to transport from the lungs following deposition of aerosols must be considered, including the nature of the disease (whether proximal, as in pulmonary hypertension, or distal, as in diabetes). Delivery to the systemic circulation begins with the efficiency of aerosol generation and subsequent deposition in the airways and proceeds to the influence of mechanisms of clearance, including absorption, metabolism, and mucociliary and cell-mediated transport, on the residence time of the drugs in the lungs. The nature of the drug (small or large molecules/low or high molecular weight), susceptibility to degradation and general physicochemical properties play a role in the chemistry of its formulation, physics of aerosol delivery and biology of disposition. © 2014 S. Karger AG, Basel.
- Predictors of Hospital Admission Two Months after Emergency Department Evaluation of COPD Exacerbation. [JOURNAL ARTICLE]
- Respiration 2014 Sep 10.
Background: Limited information is available regarding the factors related to short-term hospital admission following an exacerbation of chronic obstructive pulmonary disease (eCOPD). Objectives: The aim of this study was to identify variables related to short-term admission in patients with an eCOPD. Methods: This was a prospective cohort study of patients with an eCOPD who attended an emergency department (ED) at 1 of 16 hospitals. Information on possible predictor variables was recorded during the ED stay, 24 h after admission to the hospital or after ED discharge home, and at hospital discharge or 1 week later if discharged home from the ED. An admission after an eCOPD within 2 months was the outcome of interest. Multivariate models were employed for patients admitted to the hospital or discharged home from the ED. Results: For patients discharged home from the ED, eCOPD-related hospital admissions in the previous year [odds ratio (OR) 1.98 and 2.33], pCO2 at ED admission (ORs 2.02 and 2.90), the number of ED visits within 1 week of the index ED visit (OR 5.14) and dyspnea level 1 week after the index ED visit (ORs 2.66 and 1.40) were predictors of short-term admission [area under the curve (AUC) 0.82]. For patients admitted to the hospital during the index ED visit, baseline FEV1% (ORs 1.32 and 1.88), eCOPD-related hospital admissions in the previous year (ORs 1.28 and 2.51), severe baseline dyspnea (OR 2.57) and dyspnea level 1 week after the index ED visit (ORs 2.15 and 1.74) were predictors of short-term readmission (AUC 0.73). Conclusions: Just a few easily recorded parameters may allow clinicians to identify patients at a higher risk of short-term readmission and establish preventive strategies. © 2014 S. Karger AG, Basel.
- Disability and recovery of independent function in obstructive lung disease: the cardiovascular health study. [Journal Article]
- Respiration 2014; 88(4):329-38.
Chronic obstructive lung disease frequently leads to disability. Older patients may experience transitions between states of disability and independence over time.To identify factors associated with transition between states of disability and independent function in obstructive lung disease.We analyzed data on 4,394 participants in the Cardiovascular Health Study who completed prebronchodilator spirometry. We calculated the 1-year probability of developing and resolving impairment in ≥1 instrumental activity of daily living (IADL) or ≥1 activity of daily living (ADL) using transition probability analysis. We identified factors associated with resolving disability using relative risk (RR) regression.The prevalence of IADL impairment was higher with moderate (23.9%) and severe (36.9%) airflow obstruction compared to normal spirometry (22.5%; p < 0.001). Among participants with severe airflow obstruction, 23.5% recovered independence in IADLs and 40.5% recovered independence in ADLs. In the adjusted analyses, airflow obstruction predicted the development of IADL, but not ADL impairment. Participants with severe airflow obstruction were less likely to resolve IADL impairment [RR 0.67 and 95% confidence interval (CI) 0.49-0.94]. Compared to the most active individuals (i.e. who walked ≥28 blocks per week), walking less was associated with a decreased likelihood of resolving IADL impairment (7-27 blocks: RR 0.81 and 95% CI 0.69-0.86 and <7 blocks: RR 0.73 and 95% CI 0.61-0.86). Increased strength (RR 1.16 and 95% CI 1.05-1.29) was associated with resolving IADL impairment.Disability is common in older people, especially in those with severe airflow obstruction. Increased physical activity and muscle strength are associated with recovery. Research is needed on interventions to improve these factors among patients with obstructive lung disease and disability. © 2014 S. Karger AG, Basel.