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1.  Perfusion Scintigraphy and Patient Selection for Lung Volume Reduction Surgery 
Rationale: It is unclear if lung perfusion can predict response to lung volume reduction surgery (LVRS).
Objectives: To study the role of perfusion scintigraphy in patient selection for LVRS.
Methods: We performed an intention-to-treat analysis of 1,045 of 1,218 patients enrolled in the National Emphysema Treatment Trial who were non–high risk for LVRS and had complete perfusion scintigraphy results at baseline. The median follow-up was 6.0 years. Patients were classified as having upper or non–upper lobe–predominant emphysema on visual examination of the chest computed tomography and high or low exercise capacity on cardiopulmonary exercise testing at baseline. Low upper zone perfusion was defined as less than 20% of total lung perfusion distributed to the upper third of both lungs as measured on perfusion scintigraphy.
Measurements and Main Results: Among 284 of 1,045 patients with upper lobe–predominant emphysema and low exercise capacity at baseline, the 202 with low upper zone perfusion had lower mortality with LVRS versus medical management (risk ratio [RR], 0.56; P = 0.008) unlike the remaining 82 with high perfusion where mortality was unchanged (RR, 0.97; P = 0.62). Similarly, among 404 of 1,045 patients with upper lobe–predominant emphysema and high exercise capacity, the 278 with low upper zone perfusion had lower mortality with LVRS (RR, 0.70; P = 0.02) unlike the remaining 126 with high perfusion (RR, 1.05; P = 1.00). Among the 357 patients with non–upper lobe–predominant emphysema (75 with low and 282 with high exercise capacity) there was no improvement in survival with LVRS and measurement of upper zone perfusion did not contribute new prognostic information.
Conclusions: Compared with optimal medical management, LVRS reduces mortality in patients with upper lobe–predominant emphysema when there is low rather than high perfusion to the upper lung.
doi:10.1164/rccm.201001-0043OC
PMCID: PMC2970864  PMID: 20538961
perfusion; computed tomography; emphysema; mortality; lung volume reduction surgery
2.  Effect of Lung Volume Reduction Surgery on Resting Pulmonary Hemodynamics in Severe Emphysema 
Rationale: To determine the effect of medical treatment versus lung volume reduction surgery (LVRS) on pulmonary hemodynamics.
Methods: Three clinical centers of the National Emphysema Treatment Trial (NETT) screened patients for additional inclusion into a cardiovascular (CV) substudy. Demographics were determined, and lung function testing, six-minute-walk distance, and maximum cardiopulmonary exercise testing were done at baseline and 6 months after medical therapy or LVRS. CV substudy patients underwent right heart catheterization at rest prerandomization (baseline) and 6 months after treatment.
Measurements and Main Results: A total of 110 of the 163 patients evaluated for the CV substudy were randomized in NETT (53 were ineligible), 54 to medical treatment and 56 to LVRS. Fifty-five of these patients had both baseline and repeat right heart catheterization 6 months postrandomization. Baseline demographics and lung function data revealed CV substudy patients to be similar to the remaining 1,163 randomized NETT patients in terms of age, sex, FEV1, residual volume, diffusion capacity of carbon monoxide, PaO2, PaCO2, and six-minute-walk distance. CV substudy patients had moderate pulmonary hypertension at rest (\documentclass[10pt]{article} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{pmc} \usepackage[Euler]{upgreek} \pagestyle{empty} \oddsidemargin -1.0in \begin{document} \begin{equation*}\overline{Ppa}\end{equation*}\end{document}, 24.8 ± 4.9 mm Hg); baseline hemodynamic measurements were similar across groups. Changes from baseline pressures to 6 months post-treatment were similar across treatment groups, except for a smaller change in pulmonary capillary wedge pressure at end-expiration post-LVRS compared with medical treatment (−1.8 vs. 3.5 mm Hg, p = 0.04).
Conclusions: In comparison to medical therapy, LVRS was not associated with an increase in pulmonary artery pressures.
doi:10.1164/rccm.200608-1114OC
PMCID: PMC1994220  PMID: 17496227
emphysema; LVRS; lung volume reduction
3.  A Clinician's Guide to the Use of Lung Volume Reduction Surgery 
The primary purpose of the National Emphysema Treatment Trial (NETT) was to evaluate the clinical efficacy of lung volume reduction surgery (LVRS) compared with medical therapy as a treatment for advanced emphysema. Transitioning the results of a complex multicenter long-term clinical trial into routine clinical practice is challenging, particularly when the therapy examined is controversial, as was the case in NETT. Aspects of the “clinical art” used by the study investigators to select and treat patients are not always transparent to practitioners reading study publications. At the last NETT Steering Committee meeting, a roundtable discussion was held with investigators, coordinators, Steering Committee leadership, and Data Coordinating Center staff regarding the clinical aspects of patient evaluation and selection and performance of LVRS in advanced emphysema. The questions posed to the meeting participants were ones that are commonly asked by patients and their treating physicians who are considering LVRS and included the following: Why recommend LVRS to a patient? When should LVRS be recommended to a patient? What types of patients are candidates for LVRS? What are the important barriers to performing LVRS? What are the major messages delivered by NETT? It is hoped that answers from NETT investigators to some of these commonly encountered questions will provide clarity and guidance to clinicians faced with the responsibility of considering and discussing LVRS with their patients. NETT investigators were also queried regarding the future directions of research in emphysema and the role that NETT played in shaping that future. The following article is a summary of the highlights of these discussions.
doi:10.1513/pats.200709-151ET
PMCID: PMC2645320  PMID: 18453356
emphysema; chronic obstructive pulmonary disease; lung volume reduction surgery; clinical trial; randomized trial
4.  Genetic Determinants of Emphysema Distribution in the National Emphysema Treatment Trial 
Rationale: Computed tomography (CT) scanning of the lung may reduce phenotypic heterogeneity in defining subjects with chronic obstructive pulmonary disease (COPD), and allow identification of genetic determinants of emphysema severity and distribution.
Objectives: We sought to identify genes associated with CT scan distribution of emphysema in individuals without α1-antitrypsin deficiency but with severe COPD.
Methods: We evaluated baseline CT densitometry phenotypes in 282 individuals with emphysema enrolled in the Genetics Ancillary Study of the National Emphysema Treatment Trial, and used regression models to identify genetic variants associated with emphysema distribution.
Measurements and Main Results: Emphysema distribution was assessed by two methods—assessment by radiologists and by computerized density mask quantitation, using a threshold of −950 Hounsfield units. A total of 77 polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. GSTP1, EPHX1, and MMP1 polymorphisms were associated with the densitometric, apical-predominant distribution of emphysema (p value range = 0.001–0.050). When an apical-predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 single-nucleotide polymorphisms were found to be significantly associated. In a case–control analysis of COPD susceptibility limited to cases with densitometric upper-lobe–predominant cases, the EPHX1 His139Arg single-nucleotide polymorphism was associated with COPD (p = 0.005).
Conclusions: Apical and basal emphysematous destruction appears to be influenced by different genes. Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution, and these findings may lead to further insight into genetic determinants of emphysema.
doi:10.1164/rccm.200612-1797OC
PMCID: PMC2049064  PMID: 17363767
COPD; genetics; association analysis; computed tomography; emphysema
5.  Genetic association analysis of COPD candidate genes with bronchodilator responsiveness 
Respiratory medicine  2008;103(4):552-557.
Airflow limitation in COPD patients is not fully reversible. However, there may be large variability in bronchodilator responsiveness (BDR) among COPD patients, and familial aggregation of BDR suggests a genetic component. Therefore we investigated the association between six candidate genes and BDR in subjects with severe COPD. A total of 389 subjects from the National Emphysema Treatment Trial (NETT) were analyzed. Bronchodilator responsiveness to albuterol was expressed in three ways: absolute change in FEV1, change in FEV1 as a percent of baseline FEV1, and change in FEV1 as a percent of predicted FEV1. Genotyping was completed for 122 single nucleotide polymorphisms (SNPs) in six candidate genes (EPHX1, SFTPB, TGFB1, SERPINE2, GSTP1, ADRB2). Associations between BDR phenotypes and SNP genotypes were tested using linear regression, adjusting for age, sex, pack-years of smoking, and height. Genes associated with BDR phenotypes in the NETT subjects were assessed for replication in 127 pedigrees from the Boston Early-Onset COPD (EOCOPD) Study. Three SNPs in EPHX1 (p = 0.009 – 0.04), three SNPs in SERPINE2 (p = 0.004 – 0.05) and two SNPs in ADRB2 (0.04 – 0.05) were significantly associated with BDR phenotypes in NETT subjects. BDR. One SNP in EPHX1 (rs1009668, p = 0.04) was significantly replicated in EOCOPD subjects. SNPs in SFTPB, TGFB1, and GSTP1 genes were not associated with BDR. In conclusion, a polymorphism of EPHX1 was associated with bronchodilator responsiveness phenotypes in subjects with severe COPD.
doi:10.1016/j.rmed.2008.10.025
PMCID: PMC2745950  PMID: 19111454
bronchodilator responsiveness; chronic obstructive pulmonary disease; genetics; association analysis
6.  Longitudinal Change in the BODE Index Predicts Mortality in Severe Emphysema 
Rationale: The predictive value of longitudinal change in BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index has received limited attention. We hypothesized that decrease in a modified BODE (mBODE) would predict survival in National Emphysema Treatment Trial (NETT) patients.
Objectives: To determine how the mBODE score changes in patients with lung volume reduction surgery versus medical therapy and correlations with survival.
Methods: Clinical data were recorded using standardized instruments. The mBODE was calculated and patient-specific mBODE trajectories during 6, 12, and 24 months of follow-up were estimated using separate regressions for each patient. Patients were classified as having decreasing, stable, increasing, or missing mBODE based on their absolute change from baseline. The predictive ability of mBODE change on survival was assessed using multivariate Cox regression models. The index of concordance was used to directly compare the predictive ability of mBODE and its separate components.
Measurements and Main Results: The entire cohort (610 treated medically and 608 treated surgically) was characterized by severe airflow obstruction, moderate breathlessness, and increased mBODE at baseline. A wide distribution of change in mBODE was seen at follow-up. An increase in mBODE of more than 1 point was associated with increased mortality in surgically and medically treated patients. Surgically treated patients were less likely to experience death or an increase greater than 1 in mBODE. Indices of concordance showed that mBODE change predicted survival better than its separate components.
Conclusions: The mBODE demonstrates short- and intermediate-term responsiveness to intervention in severe chronic obstructive pulmonary disease. Increase in mBODE of more than 1 point from baseline to 6, 12, and 24 months of follow-up was predictive of subsequent mortality. Change in mBODE may prove a good surrogate measure of survival in therapeutic trials in severe chronic obstructive pulmonary disease.
Clinical trial registered with www.clinicaltrials.gov (NCT 00000606).
doi:10.1164/rccm.200709-1383OC
PMCID: PMC2542428  PMID: 18535255
chronic obstructive pulmonary disease; survival; multidimensional index
7.  Association of COPD candidate genes with CT emphysema and airway phenotypes in severe COPD 
The principal determining factors influencing the development of the airway disease and emphysema components of COPD have not been clearly defined. Genetic variability in COPD patients might influence the varying degrees of involvement of airway disease and emphysema. Therefore, we investigated genetic association of SNPs in COPD candidate genes for association with emphysema severity and airway wall thickness phenotypes.
Polymorphisms in six candidate genes were analyzed in 379 subjects of the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study with quantitative chest CT data. Genetic association with percent of lung below −950 hounsfield units (LAA950), airway wall thickness (WT), and derived square root wall area of 10 mm internal perimeter airways (SRWA) were investigated.
Three SNPs in EPHX1, five SNPs in SERPINE2, and one SNP in GSTP1 were significantly associated with LAA950. Five SNPs in TGFB1, two SNPs in EPHX1, one SNP in SERPINE2, and two SNPs in ADRB2 were associated with airway wall phenotypes in NETT.
In conclusion, several COPD candidate genes showed evidence for association with airway wall thickness and emphysema severity using CT in a severe COPD population. Further investigation will be required to replicate these genetic associations for emphysema and airway wall phenotypes.
doi:10.1183/09031936.00173009
PMCID: PMC3074301  PMID: 20525719
Airway; chronic obstructive pulmonary disease; computed tomography; emphysema; genetic association
8.  Genetic Associations With Hypoxemia and Pulmonary Arterial Pressure in COPD* 
Chest  2008;135(3):737-744.
Background
Hypoxemia, hypercarbia, and pulmonary arterial hypertension are known complications of advanced COPD. We sought to identify genetic polymorphisms associated with these traits in a population of patients with severe COPD from the National Emphysema Treatment Trial (NETT).
Methods
In 389 participants from the NETT Genetics Ancillary Study, single-nucleotide polymorphisms (SNPs) were genotyped in five candidate genes previously associated with COPD susceptibility (EPHX1, SERPINE2, SFTPB, TGFB1, and GSTP1). Linear regression models were used to test for associations among these SNPs and three quantitative COPD-related traits (Pao2, Paco2, and pulmonary artery systolic pressure). Genes associated with hypoxemia were tested for replication in probands from the Boston Early-Onset COPD Study.
Results
In the NETT Genetics Ancillary Study population, SNPs in microsomal epoxide hydrolase (EPHX1) [p = 0.01 to 0.04] and serpin peptidase inhibitor, clade E, member 2 (SERPINE2) [p = 0.04 to 0.008] were associated with hypoxemia. One SNP within surfactant protein B (SFTPB) was associated with pulmonary artery systolic pressure (p = 0.01). In probands from the Boston Early-Onset COPD Study, SNPs in EPHX1 and in SERPINE2 were associated with the requirement for supplemental oxygen.
Conclusions
In participants with severe COPD, SNPs in EPHX1 and SERPINE2 were associated with hypoxemia in two separate study populations, and SNPs from SFTPB were associated with pulmonary artery pressure in the NETT participants.
doi:10.1378/chest.08-1993
PMCID: PMC2906241  PMID: 19017876
case-control studies; COPD; genetics; phenotype; single-nucleotide polymorphism
9.  Integrating Health Status and Survival Data 
Rationale: In studies that address health-related quality of life (QoL) and survival, subjects who die are usually censored from QoL assessments. This practice tends to inflate the apparent benefits of interventions with a high risk of mortality. Assessing a composite QoL-death outcome is a potential solution to this problem.
Objectives: To determine the effect of lung volume reduction surgery (LVRS) on a composite endpoint consisting of the occurrence of death or a clinically meaningful decline in QoL defined as an increase of at least eight points in the St. George's Respiratory Questionnaire total score from the National Emphysema Treatment Trial.
Methods: In patients with chronic obstructive pulmonary disease and emphysema randomized to receive medical treatment (n = 610) or LVRS (n = 608), we analyzed the survival to the composite endpoint, the hazard functions and constructed prediction models of the slope of QoL decline.
Measurements and Main Results: The time to the composite endpoint was longer in the LVRS group (2 years) than the medical treatment group (1 year) (P < 0.0001). It was even longer in the subsets of patients undergoing LVRS without a high risk for perioperative death and with upper-lobe-predominant emphysema. The hazard for the composite event significantly favored the LVRS group, although it was most significant in patients with predominantly upper-lobe emphysema. The beneficial impact of LVRS on QoL decline was most significant during the 2 years after LVRS.
Conclusions: LVRS has a significant effect on the composite QoL-survival endpoint tested, indicating its meaningful palliative role, particularly in patients with upper-lobe–predominant emphysema.
doi:10.1164/rccm.200809-1383OC
PMCID: PMC2724716  PMID: 19483114
chronic obstructive pulmonary disease; outcome assessment; palliative care; quality of life; survival; emphysema
10.  The National Emphysema Treatment Trial (NETT) 
Substantial information regarding the role of lung volume reduction surgery (LVRS) in severe emphysema emanates from the National Emphysema Treatment Trial (NETT). The NETT was not a crossover trial and therefore was able to examine the effects of optimal medical management and LVRS on short- and long-term survival, as well as lung function, exercise performance, and quality of life. The NETT generated multiple insights into the preoperative, perioperative, and postoperative management of patients undergoing thoracotomy; described pain control techniques that were safe and effective; and emphasized the need to address nonpulmonary issues to optimize surgical outcomes. After the NETT, newer investigation has focused on bronchoscopic endobronchial interventions and other techniques less invasive than LVRS to achieve lung reduction. In this review, we summarize what we currently know about the role of LVRS in the treatment of severe emphysema as a result of insights gained from the NETT and provide a brief review of the newer techniques of lung volume reduction.
doi:10.1164/rccm.201103-0455CI
PMCID: PMC3208657  PMID: 21719757
emphysema; COPD; lung volume reduction surgery
11.  Lung Volume Reduction Surgery 
The objective of lung volume reduction surgery (LVRS) is the safe, effective, and durable palliation of dyspnea in appropriately selected patients with moderate to severe emphysema. Appropriate patient selection and preoperative preparation are prerequisites for successful LVRS. An effective LVRS program requires participation by and communication between experts from pulmonary medicine, thoracic surgery, thoracic anesthesiology, critical care medicine, rehabilitation medicine, respiratory therapy, chest radiology, and nursing. The critical analysis of perioperative outcomes has influenced details of the conduct of the procedure and has established a bilateral, stapled approach as the standard of care for LVRS. The National Emphysema Treatment Trial (NETT) remains the world's largest multi-center, randomized trial comparing LVRS to maximal medical therapy. NETT purposely enrolled a broad spectrum of anatomic patterns of emphysema. This, along with the prospective, audited collection of extensive demographic, physiologic, radiographic, surgical and quality-of-life data, has positioned NETT as the most robust repository of evidence to guide the refinement of patient selection criteria for LVRS, to assist surgeons in providing optimal intraoperative and postoperative care, and to establish benchmarks for survival, complication rates, return to independent living, and durability of response. This article reviews the evolution of current LVRS practice with a particular emphasis on technical aspects of the operation, including the predictors and consequences of its most common complications.
doi:10.1513/pats.200803-023ET
PMCID: PMC2645317  PMID: 18453353
emphysema; surgery; complications; outcomes
12.  Combined Analysis of EPHX1, GSTP1, GSTM1 and GSTT1 Gene Polymorphisms in Relation to Chronic Obstructive Pulmonary Disease Risk and Lung Function Impairment 
Disease markers  2011;30(5):253-263.
Smoking is considered as the major causal factor of chronic obstructive pulmonary disease (COPD). Nevertheless, a minority of chronic heavy cigarette smokers develops COPD. This suggests important contribution of other factors such as genetic predisposing. Our objective was to investigate combined role of EPHX1, GSTP1, M1 and T1 gene polymorphisms in COPD risk, its phenotypes and lung function impairment. Prevalence of EPHX1, GSTP1, M1 and T1 gene polymorphisms were assessed in 234 COPD patients and 182 healthy controls from Tunisia. Genotypes of EPHX1 (Tyr113His; His139Arg) and GSTP1 (Ile105Val; Ala114Val) polymorphisms were performed by PCR-RFLP, while the deletion in GSTM1 and GSTT1 genes was determined using multiplex PCR. Analysis of combinations showed a significant association of 113His/His EPHX1/null-GSTM1 (OR = 4.07) and null-GSTM1/105Val/Val GSTP1 (OR = 3.56) genotypes with increased risk of COPD (respectively P=0.0094 and P=0.0153). The null-GSTM1/ null-GSTT1, 105Val/Val GSTP1/null GSTT1, 113His/His EPHX1/null-GSTM1 and null-GSTM1/105Val/Val GSTP1 genotypes were related to emphysema (respectively P = 0.01; P = 0.009; P = 0.008 and P = 0.001). Combination of 113His/His EPHX1/null-GSTM1 genotypes showed a significant association with the decrease of ΔFEV1 in patients (P = 0.028).
In conclusion, our results suggest combined EPHX1, GSTP1, GSTM1 and GSTT1 genetic polymorphisms may play a significant role in the development of COPD, emphysema and decline of the lung function.
doi:10.3233/DMA-2011-0782
PMCID: PMC3825482  PMID: 21734345
Chronic obstructive pulmonary disease; microsomal epoxide hydrolase; glutathione S-transferase; emphysema; genetic polymorphism
13.  Lung volume reduction surgery for the treatment of severe emphysema: a study in a single Canadian institution 
Canadian Journal of Surgery  2000;43(5):369-376.
Objective
To evaluate lung volume reduction surgery (LVRS) and its effectiveness in improving pulmonary function, exercise capacity and quality of life in a population of emphysema patients referred to and screened in a single centre.
Design
A prospective case series.
Setting
A Canadian tertiary care hospital.
Patients
Patients with severe emphysema, significant dyspnea and impaired exercise capacity interfering with quality of life.
Interventions
Bilateral LVRS was performed through a median sternotomy.
Main outcome measures
Pulmonary function tests (preoperative forced expiratory volume in the first second [FEV1], residual volume [RV]), 6-minute walk (6MW) distance, quality of life (Medical Outcomes Study 36-item short-form health survey) and degree of dyspnea (Medical Research Council of Great Britain dyspnea scale and the baseline and transitional dyspnea indices) were assessed before LVRS and at 6 and 12 months after.
Results
Fifty-seven patients were assessed for LVRS, of whom 10 were selected for surgery. Homogeneous distribution of disease was the most common reason for exclusion. Of the 10 patients operated upon, 1 died of acute cor pulmonale on the fourth postoperative day and 1 died of recurrent exacerbations of chronic obstructive pulmonary disease and chronic respiratory failure at 315 days postoperatively. In the surviving patients, the mean preoperative FEV1 increased from 0.70 L before surgery to 0.90 L at 1 year, with a mean relative increase of 33.4%. The mean RV decreased from 5.57 L to 4.10 L, with a mean relative decrease of 27.6%. The 6MW distance increased from 302.7 m to 356.9 m at 1 year, with a mean relative increase of 21.6%. Quality of life and degree of dyspnea were improved significantly at 1 year after LVRS. Of the 5 patients on oxygen at home before surgery, 4 were able to reduce their requirements but not to discontinue oxygen.
Conclusions
LVRS is an effective palliative treatment for dyspnea and poor exercise tolerance in highly selected patients. Although the duration of palliation is unknown, our results show that improvements in pulmonary function, exercise, quality of life and degree of dyspnea are preserved over the first year. Only a minority of the patients screened were eligible for surgery. The 2 deaths in our series emphasize the need for even further delineation of selection criteria.
PMCID: PMC3695144  PMID: 11045096
14.  Lung Volume Reduction as an Alternative to Transplantation for COPD 
Clinics in chest medicine  2011;32(2):379-397.
Emphysema is disabling and progressive and hallmarked by decreased exercise tolerance and impaired quality of life. Hyperinflation is the sentinel physiological characteristic of emphysema that is responsible for exercise intolerance, dyspnea, impaired quality of life and high mortality. Medical treatment does not alter the progression of emphysema and has little effect on palliating dyspnea or improving functional performance or quality of life. Surgical interventions that reduce lung volume have been the focus of multiple interventions for decades; however, until recently, limited evidence has documented their effectiveness. Lung volume reduction surgery (LVRS) underwent rigorous study in the National Emphysema Treatment Trial (NETT), which demonstrated its short and long term effectiveness, associated morbidity and mortality and the essential factors that predict LVRS success or failure. Current investigation focuses on the use of less invasive techniques, predominantly bronchoscopic techniques that reduce lung volume without open thoracotomy. Herein, I summarize the major results of the NETT and briefly review newer bronchoscopic lung volume reduction techniques that show promise as alternative treatments for select COPD patients undergoing consideration for lung transplantation.
doi:10.1016/j.ccm.2011.02.014
PMCID: PMC3086781  PMID: 21511097
15.  Radiographic Evaluation of the Potential Lung Volume Reduction Surgery Candidate 
Delineating the extent and distribution of emphysema is an essential component of the evaluation of candidates for lung volume reduction surgery (LVRS). Imaging also may identify contraindications to LVRS, including bronchiectasis and pleural scarring. The chest X-ray is of limited utility in LVRS evaluation. Chest computed tomography (CT) scanning is an essential component of the evaluation, demonstrating the presence of emphysema and its amount and distribution. Clinical experience has shown that a substantial minority of chest CT scans will also demonstrate pulmonary nodules, some of which represent lung cancers. Published series, including the National Emphysema Treatment Trial, consistently demonstrate that patients with upper lobe predominant or heterogeneous emphysema are most likely to benefit from LVRS. Heterogeneity and distribution can also be assessed by radionuclide ventilation perfusion scanning, but this modality adds little additional information to CT scanning.
doi:10.1513/pats.200802-017ET
PMCID: PMC2645313  PMID: 18453349
emphysema; lung volume reduction surgery; CT scanning; pulmonary nodule; preoperative evaluation
16.  Physiological and Computed Tomographic Predictors of Outcome from Lung Volume Reduction Surgery 
Rationale: Previous investigations have identified several potential predictors of outcomes from lung volume reduction surgery (LVRS). A concern regarding these studies has been their small sample size, which may limit generalizability. We therefore sought to examine radiographic and physiologic predictors of surgical outcomes in a large, multicenter clinical investigation, the National Emphysema Treatment Trial.
Objectives: To identify objective radiographic and physiological indices of lung disease that have prognostic value in subjects with chronic obstructive pulmonary disease being evaluated for LVRS.
Methods: A subset of the subjects undergoing LVRS in the National Emphysema Treatment Trial underwent preoperative high-resolution computed tomographic (CT) scanning of the chest and measures of static lung recoil at total lung capacity (SRtlc) and inspiratory resistance (Ri). The relationship between CT measures of emphysema, the ratio of upper to lower zone emphysema, CT measures of airway disease, SRtlc, Ri, the ratio of residual volume to total lung capacity (RV/TLC), and both 6-month postoperative changes in FEV1 and maximal exercise capacity were assessed.
Measurements and Main Results: Physiological measures of lung elastic recoil and inspiratory resistance were not correlated with improvement in either the FEV1 (R = −0.03, P = 0.78 and R = –0.17, P = 0.16, respectively) or maximal exercise capacity (R = –0.02, P = 0.83 and R = 0.08, P = 0.53, respectively). The RV/TLC ratio and CT measures of emphysema and its upper to lower zone ratio were only weakly predictive of postoperative changes in both the FEV1 (R = 0.11, P = 0.01; R = 0.2, P < 0.0001; and R = 0.23, P < 0.0001, respectively) and maximal exercise capacity (R = 0.17, P = 0.0001; R = 0.15, P = 0.002; and R = 0.15, P = 0.002, respectively). CT assessments of airway disease were not predictive of change in FEV1 or exercise capacity in this cohort.
Conclusions: The RV/TLC ratio and CT measures of emphysema and its distribution are weak but statistically significant predictors of outcome after LVRS.
doi:10.1164/rccm.200906-0911OC
PMCID: PMC2830400  PMID: 19965810
17.  Several clinical interests regarding lung volume reduction surgery for severe emphysema: meta-analysis and systematic review of randomized controlled trials 
Objectives
We aim to address several clinical interests regarding lung volume reduction surgery (LVRS) for severe emphysema using meta-analysis and systematic review of randomized controlled trials (RCTs).
Methods
Eight RCTs published from 1999 to 2010 were identified and synthesized to compare the efficacy and safety of LVRS vs conservative medical therapy. One RCT was obtained regarding comparison of median sternotomy (MS) and video-assisted thoracoscopic surgery (VATS). And three RCTs were available evaluating clinical efficacy of using bovine pericardium for buttressing, autologous fibrin sealant and BioGlue, respectively.
Results
Odds ratio (95%CI), expressed as the mortality of group A (the group underwent LVRS) versus group B (conservative medical therapies), was 5.16(2.84, 9.35) in 3 months, 3(0.94, 9.57) in 6 months, 1.05(0.82, 1.33) in 12 months, respectively. On the 3rd, 6th and 12th month, all lung function indices of group A were improved more significantly as compared with group B. PaO2 and PaCO2 on the 6th and 12th month showed the same trend. 6MWD of group A on the 6th month and 12th month were improved significantly than of group B, despite no difference on the 3rd month. Quality of life (QOL) of group A was better than of group B in 6 and 12 months. VATS is preferred to MS, due to the earlier recovery and lower cost. And autologous fibrin sealant and BioGlue seems to be the efficacious methods to reduce air leak following LVRS.
Conclusions
LVRS offers the more benefits regarding survival, lung function, gas exchange, exercise capacity and QOL, despite the higher mortality in initial three postoperative months. LVRS, with the optimization of surgical approach and material for reinforcement of the staple lines, should be recommended to patients suffering from severe heterogeneous emphysema.
doi:10.1186/1749-8090-6-148
PMCID: PMC3226652  PMID: 22074613
LVRS; emphysema; meta-analysis; systematic review
18.  Lung volume reduction surgery: results of a Canadian pilot study 
Canadian Journal of Surgery  2000;43(5):377-384.
Objective
To present preliminary experience with lung volume reduction surgery (LVRS) before the institution of the Canadian LVRS trial.
Design
A prospective case series between December 1995 and January 1997.
Setting
University hospitals in London and Hamilton, Ont.
Patients
Forty-nine patients who had disabling dyspnea or emphysema with hyperinflation, able to participate in respiratory rehabilitation. Twenty-three patients were excluded because of comorbid conditions precluding surgery, pulmonary hypertension, excessive steroid dependence, malnutrition, obesity, previous thoracotomy, large solitary bullae, concurrent malignant disease, chronic bronchitis, hypercapnia or psychiatric illness.
Interventions
Preoperative respiratory rehabilitation followed by LVRS via median sternotomy.
Main outcome measures
Impairment, disability and handicap were assessed before and 12 months after LVRS. Impairment was assessed by changes in pulmonary function test results and blood gas measurements, disability by the 6-minute walk test and cardiopulmonary exercise test, and handicap by the disease-specific chronic respiratory disease questionnaire (CRQ), the generic medical outcomes survey short form 36 (SF-36) and the generic health utilities index mark III (HUI-III).
Results
Two patients died of respiratory failure while in rehabilitation. Twenty-four patients (17 men, 7 women) successfully completed rehabilitation and underwent LVRS. The mean age was 63 years (range from 49 to 78 years) and the median length of hospital stay was 12.5 days (range from 7 to 90 days). Two patients (8%) died in the early postoperative period (within 30 days) of pneumonia. One patient died of respiratory failure 8 months after LVRS after a difficult 90-day postoperative hospital stay. There were 27 major complications. There was a 36% relative increase in the mean forced expiratory volume in the first second (p = 0.01) and a 10% relative increase in the 6-minute walk test (p = 0.06). The mean CRQ dyspnea score increased 2.3 points (p = 0.01), and the SF-36 general health domain increased 20 points (p = 0.01). There was no significant change in the HUI-III (p = 0.73).
Conclusion
LVRS appears to lessen the respiratory impairment and handicap for at least 1 year in selected patients with advanced emphysema.
PMCID: PMC3695145  PMID: 11045097
19.  Selection of patients for lung volume reduction surgery using a power law analysis of the computed tomographic scan 
Thorax  2003;58(6):510-514.
Background: A study was undertaken to test the hypothesis that patients respond better to lung volume reduction surgery (LVRS) if their emphysema is confluent and predominantly located in the upper lobes.
Methods: A density mask analysis was used to identify voxels inflated beyond 10.2 ml gas/g tissue (-910 HU) on preoperative and postoperative CT scans from patients receiving LVRS. These hyperinflated regions were considered to represent emphysematous lesions. A power law analysis was used to determine the relationship between the number (K) and size (A) of the emphysematous lesions in the whole lung and two anatomical regions using the power law equation Y=KA-D.
Results: The analysis showed a positive correlation between the change in the power law exponent (D) and the change in exercise (Watts) after surgery (r=0.47, p=0.03). There was also a negative correlation between the power law exponent D in the upper region of the lung preoperatively and the change in exercise following surgery (r=-0.60, p<0.05).
Conclusions: These results confirm that patients with large upper lobe lesions respond better to LVRS than patients with small uniformly distributed disease. Power law analysis of lung CT scans provides a quantitative method for determining the extent and location of emphysema within the lungs of patients with COPD.
doi:10.1136/thorax.58.6.510
PMCID: PMC1746695  PMID: 12775863
20.  Cognitive and Psychological Issues in Emphysema 
Various psychological and cognitive difficulties have been documented in patients with emphysema. The aim of this article is to review prior literature on the prevalence of these difficulties in emphysema, as well as identify specific studies demonstrating improvement in these areas after therapy. Traditional therapies such as continuous and intermittent oxygen therapy and comprehensive pulmonary rehabilitation are reviewed. In general, these studies demonstrate reductions in symptoms of depression and anxiety as well as specific improvements in complex attention and verbal fluency. In a more recent study, patients with emphysema who underwent lung volume reduction surgery (LVRS) demonstrated improved psychomotor speed, verbal memory, and naming skills at 6 months compared with patients with emphysema who were in comprehensive rehabilitation only. The patients with emphysema who had LVRS also demonstrated greater decline in depressive symptoms compared with the rehabilitation patients at 6 months. There were no associations between improved neuropsychological tests and changes in depression, exercise tests, pulmonary function, oxygenation, or quality of life scores, and thus the mechanism of behavioral improvement identified in the patients who underwent LVRS remained unclear. Overall, studies suggest that psychological and cognitive improvements occur subsequent to a variety of medical and behavioral treatment therapeutic approaches, and that LVRS appears to have an advantage for some patients with emphysema.
doi:10.1513/pats.200708-123ET
PMCID: PMC2645335  PMID: 18453371
chronic obstructive pulmonary disease; lung volume reduction surgery; neurobehavioral
21.  Improved Health-Related Quality of Life After Lung Volume Reduction Surgery and Pulmonary Rehabilitation 
Purpose: It has been hypothesized that lung volume reduction surgery (LVRS) and pulmonary rehabilitation improve health-related quality of life (HRQOL). The purpose of this study was to test the hypothesis by examining the long-term functional consequences and general health status of patients with emphysema who have undergone LVRS and pulmonary rehabilitation. Methods: Forty-nine subjects with severe emphysema, aged 51 to 84 years old, post-LVRS and pulmonary rehabilitation participated in this study. Subjects reported changes in physical and mental domains on the Medical Outcomes Study 36-Item Short Form Health Survey (MOS SF-36) over 3 time periods: prior to surgery, 6 months postsurgery, and 18 months postsurgery. The population as a whole was studied and both gender and age were analyzed as subsets. Subjects participated in an intensive 2-week (10 daily sessions) pulmonary rehabilitation program following LVRS. Results: Subjects showed significant improvements in both the physical and mental component summaries at Time 2 (3 months post-LVRS through 6 months post-LVRS) and Time 3 (12 months post-LVRS through 18 months post-LVRS) when compared to Time 1 (pre-LVRS). On the mental component summary scale, subjects younger than 65 years old had significant improvement compared to subjects 65 years and older at Time 3 (P < .05). Women significantly improved more than men at Time 3 on the physical component summary scale (P < .05). Conclusions: Lung volume reduction surgery and 2 weeks (10 daily sessions) of intensive pulmonary rehabilitation appears to improve HRQOL in people with emphysema up to at least 18 months postsurgery. What these data further suggest is that even after declines in health, women can improve HRQOL later in life, and that greater focus should be given to the emotional needs of our older patients.
PMCID: PMC2845245  PMID: 20467519
lung volume reduction surgery; rehabilitation; quality of life
22.  Efficacy of bronchoscopic lung volume reduction: a meta-analysis 
Background
Over the last several years, the morbidity, mortality, and high costs associated with lung volume reduction (LVR) surgery has fuelled the development of different methods for bronchoscopic LVR (BLVR) in patients with emphysema. In this meta-analysis, we sought to study and compare the efficacy of most of these methods.
Methods
Eligible studies were retrieved from PubMed and Embase for the following BLVR methods: one-way valves, sealants (BioLVR), LVR coils, airway bypass stents, and bronchial thermal vapor ablation. Primary study outcomes included the mean change post-intervention in the lung function tests, the 6-minute walk distance, and the St George’s Respiratory Questionnaire. Secondary outcomes included treatment-related complications.
Results
Except for the airway bypass stents, all other methods of BLVR showed efficacy in primary outcomes. However, in comparison, the BioLVR method showed the most significant findings and was the least associated with major treatment-related complications. For the BioLVR method, the mean change in forced expiratory volume (in first second) was 0.18 L (95% confidence interval [CI]: 0.09 to 0.26; P<0.001); in 6-minute walk distance was 23.98 m (95% CI: 12.08 to 35.88; P<0.01); and in St George’s Respiratory Questionnaire was -8.88 points (95% CI: −12.12 to −5.64; P<0.001).
Conclusion
The preliminary findings of our meta-analysis signify the importance of most methods of BLVR. The magnitude of the effect on selected primary outcomes shows noninfe-riority, if not equivalence, when compared to what is known for surgical LVR.
doi:10.2147/COPD.S63378
PMCID: PMC4027920  PMID: 24868153
emphysema; endobronchial valves; sealants; stents; coils
23.  Genetic Association Analysis of Functional Impairment in Chronic Obstructive Pulmonary Disease 
Rationale: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions.
Objectives: To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms.
Methods: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test–replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study.
Results: The test–replication approach identified four genes—microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-β binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-β1 (TGFB1)—that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p ⩽ 0.03) and in LTBP4 (p ⩽ 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p ⩽ 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p ⩽ 0.04). Three SNPs in TGFB1 were associated with dyspnea (p ⩽ 0.002), one of which replicated in the family study (p = 0.02).
Conclusions: Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV1. These associations may identify genes in pathways important for COPD pathogenesis.
doi:10.1164/rccm.200509-1452OC
PMCID: PMC2662917  PMID: 16456143
dyspnea; emphysema; exercise tolerance; genetic association; pulmonary function tests
24.  Altered thoracic gas compression contributes to improvement in spirometry with lung volume reduction surgery 
Thorax  2005;60(4):288-292.
Background: Thoracic gas compression (TGC) exerts a negative effect on forced expiratory flow. Lung resistance, effort during a forced expiratory manoeuvre, and absolute lung volume influence TGC. Lung volume reduction surgery (LVRS) reduces lung resistance and absolute lung volume. LVRS may therefore reduce TGC, and such a reduction might explain in part the improvement in forced expiratory flow with the surgery. A study was conducted to determine the effect of LVRS on TGC and the extent to which reduced TGC contributed to an improvement in forced expiratory volume in 1 second (FEV1) following LVRS.
Methods: The effect of LVRS on TGC was studied using prospectively collected lung mechanics data from 27 subjects with severe emphysema. Several parameters including FEV1, expiratory and inspiratory lung resistance (Rle and Rli), and lung volumes were measured at baseline and 6 months after surgery. Effort during the forced manoeuvre was measured using transpulmonary pressure. A novel method was used to estimate FEV1 corrected for the effect of TGC.
Results: At baseline the FEV1 corrected for gas compression (NFEV1) was significantly higher than FEV1 (p<0.0001). FEV1 increased significantly from baseline (p<0.005) while NFEV1 did not change following surgery (p>0.15). TGC decreased significantly with LVRS (p<0.05). Rle and maximum transpulmonary pressure (TPpeak) during the forced manoeuvre significantly predicted the reduction in TGC following the surgery (Rle: p<0.01; TPpeak: p<0.0001; adjusted R2 = 0.68). The improvement in FEV1 was associated with the reduction in TGC after surgery (p<0.0001, adjusted R2 = 0.58).
Conclusions: LVRS decreased TGC by improving expiratory flow limitation. In turn, the reduction in TGC decreased its negative effect on expiratory flow and therefore explained, in part, the improvement in FEV1 with LVRS in this cohort.
doi:10.1136/thx.2004.033589
PMCID: PMC1747381  PMID: 15790983
25.  Multiple Analytical Approaches Reveal Distinct Gene-Environment Interactions in Smokers and Non Smokers in Lung Cancer 
PLoS ONE  2011;6(12):e29431.
Complex disease such as cancer results from interactions of multiple genetic and environmental factors. Studying these factors singularly cannot explain the underlying pathogenetic mechanism of the disease. Multi-analytical approach, including logistic regression (LR), classification and regression tree (CART) and multifactor dimensionality reduction (MDR), was applied in 188 lung cancer cases and 290 controls to explore high order interactions among xenobiotic metabolizing genes and environmental risk factors. Smoking was identified as the predominant risk factor by all three analytical approaches. Individually, CYP1A1*2A polymorphism was significantly associated with increased lung cancer risk (OR = 1.69;95%CI = 1.11–2.59,p = 0.01), whereas EPHX1 Tyr113His and SULT1A1 Arg213His conferred reduced risk (OR = 0.40;95%CI = 0.25–0.65,p<0.001 and OR = 0.51;95%CI = 0.33–0.78,p = 0.002 respectively). In smokers, EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms reduced the risk of lung cancer, whereas CYP1A1*2A, CYP1A1*2C and GSTP1 Ile105Val imparted increased risk in non-smokers only. While exploring non-linear interactions through CART analysis, smokers carrying the combination of EPHX1 113TC (Tyr/His), SULT1A1 213GG (Arg/Arg) or AA (His/His) and GSTM1 null genotypes showed the highest risk for lung cancer (OR = 3.73;95%CI = 1.33–10.55,p = 0.006), whereas combined effect of CYP1A1*2A 6235CC or TC, SULT1A1 213GG (Arg/Arg) and betel quid chewing showed maximum risk in non-smokers (OR = 2.93;95%CI = 1.15–7.51,p = 0.01). MDR analysis identified two distinct predictor models for the risk of lung cancer in smokers (tobacco chewing, EPHX1 Tyr113His, and SULT1A1 Arg213His) and non-smokers (CYP1A1*2A, GSTP1 Ile105Val and SULT1A1 Arg213His) with testing balance accuracy (TBA) of 0.6436 and 0.6677 respectively. Interaction entropy interpretations of MDR results showed non-additive interactions of tobacco chewing with SULT1A1 Arg213His and EPHX1 Tyr113His in smokers and SULT1A1 Arg213His with GSTP1 Ile105Val and CYP1A1*2C in nonsmokers. These results identified distinct gene-gene and gene environment interactions in smokers and non-smokers, which confirms the importance of multifactorial interaction in risk assessment of lung cancer.
doi:10.1371/journal.pone.0029431
PMCID: PMC3242784  PMID: 22206016

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