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1 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
LUNG CANCER
Gerard Silvestri
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine
Medical University of South Carolina
Charleston, South Carolina
Dr. Silvestri briefly reviewed the International Early Lung Cancer Action Project (IELCAP) published in the New England Journal of Medicine (1). A more extensive review was presented by Dr. David Lynch in a later session and is summarized later in this issue (see pages 495–496).
The role of lung cancer screening with computed tomography (CT) in at-risk individuals and its impact on outcomes are among the most critical issues in pulmonary medicine. Bach and coworkers (2) performed a longitudinal analysis of 3,246 current or former asymptomatic smokers from three CT screening trials from the United States and Italy. The mean period of follow-up was 3.9 years. The major endpoint was mortality, but a number of other relevant parameters were compared with expected findings from a prediction model. One hundred forty-four individuals were found to have lung cancer; only 44.5 were expected from the model (P < 0.001). There were 109 surgical resections, compared with 10.9 expected resections (P < 0.001). There was no difference in the number of advanced lung cancer cases; there were 42 actual cases versus 33 expected cases. Perhaps most significantly, there was no difference between the number of actual and expected deaths from lung cancer (38 in each group, P = 0.9). This study's findings stand in sharp contrast to the conclusions of the IELCAP. Differences could be explained by population differences, differences in ascertainment of cancer deaths, and the accuracy of the cancer prediction model used by Bach and colleagues, among others. The results of the National Lung Screening Trial comparing CT screening with chest radiograph alone should provide more definitive answers.
Accurate lung cancer staging with the TNM (tumor-node-metastasis) system, which impacts both treatment and prognosis, requires adequate evaluation of mediastinal lymph nodes, specifically with histologic confirmation. Using chart abstraction in 729 hospitals, Little and colleagues at the American College of Surgeons (3) gathered data on 40,900 patients with non–small cell lung cancer to assess patterns of surgical care. Surgery was performed in 11,668 individuals (29.1%), with a mortality rate of 5.2%. Lobectomy was the most common operation, accounting for 70.8% of procedures. Three-fourths of patients had significant comorbidities, whereas 47% were older than 70 years. Surgical margins were positive in 7.8%, but frozen section was only performed in 65% of the procedures. Most germane to the issue of staging was the finding that preoperative mediastinoscopy was only performed in 27% (1,480) of patients, and of those, only 46% had mediastinal lymph node sampling. Because adequate staging is critical, this was believed to be a concerning finding.
Although mediastinoscopy remains the "gold standard" for sampling mediastinal lymph nodes, there are a number of other available techniques, including endobronchial ultrasound (EBUS) with fine needle aspiration (FNA). Herth and collaborators (4) performed EBUS in 502 consecutive patients, resulting in 573 lymph node biopsies via FNA. The mean lymph node diameter was 1.6 cm. Sensitivity and specificity were 94 and 100%, respectively, with no reported complications. In another study cited, Worth and coworkers (5) reported similar sensitivity (92.3%) and sensitivity (100%) compared with surgical staging in 100 patients with lung cancer. EBUS with FNA is a promising diagnostic method for mediastinal lymph nodes that appears superior to conventional transbronchial needle aspiration.
Adjuvant chemotherapy for non–small cell lung cancer is an evolving therapeutic option. The international ANITA (Adjuvant Navelbine International Trialist Association) trial, authored by Doulliard and coworkers (6), compared cisplatin plus vinorelbine to observation in a randomized controlled fashion for the treatment of completely resected stage IB–IIIA lung cancer. From a total of 829 patients, 798 were randomized; 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. All subjects had a high performance status. Three hundred sixty-seven patients were included in the chemotherapy arm. The median survival in the intention-to-treat population after a median period of follow-up of 76 months was significantly higher in the chemotherapy arm versus the observation arm (65.8 vs. 43.8%, P = 0.013). Survival was improved by 8.6% at 5 years in the chemotherapy group, and sustained at 8.4% at 7 years. Cisplatin-based chemotherapy should be considered in patients with stage II–IIIB lung cancer with good performance status and completely resected primary tumors.
Although adjuvant chemotherapy may improve mortality in completely resected stage II–IIIA non–small cell lung cancer, there are no validated clinical or biologic markers of benefit. Excision repair cross-complementation protein (ERCC1) plays a role in DNA repair and has been postulated to be a potential marker of chemotherapy response. Using immunohistochemical analysis, Olaussen and colleagues (7) determined ERCC1 expression in 761 operative specimens of non–small cell lung cancer. Of the tumors, 335 were ERCC1 positive, whereas 426 were negative. In patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors. However, adjuvant chemotherapy significantly prolonged survival among patients with ERCC1-negative tumors (adjusted hazard ratio for death, 0.65; P = 0.002) when compared with observation, but this was not the case among patients with ERCC1-positive tumors. The conclusion drawn from these data is that patients with completely resected non–small cell lung cancer and ERCC1-negative tumors appear to benefit from adjuvant cisplatin–based chemotherapy, whereas patients with ERCC1-positive tumors do not.
The ability to predict lung cancer treatment outcomes remains inadequate. Genomic approaches may be powerful tools. Chen and colleagues (8) identified 16 genes correlated with survival in patients with non–small cell lung cancer and then established a risk score. Five genes, DUSP6, MMD, STAT1, ERBB3, and LCK, were used in a decision-tree analysis, and were found to independently predict relapse and disease-free survival. The five gene signature was validated in a cohort of 60 patients. This study underscores the value of genomics in various aspects of lung cancer, including natural history and prognosis.
INTERVENTIONAL PULMONOLOGY
Daniel H. Sterman
Pulmonary, Allergy, and Critical Care Division
University of Pennsylvania Medical Center
Philadelphia, Pennsylvania
Therapeutic Bronchoscopy for Benign Pulmonary Disease
In patients with moderate–severe asthma, airway hyperresponsiveness (AHR), often accompanied by airway smooth muscle hypertrophy, is believed to play a role in the pathogenesis of exacerbations and chronic airflow limitation. Bronchial thermoplasty (BT) is a novel bronchoscopic technique that delivers thermal energy via a radiofrequency probe to reduce the mass of airway smooth muscle and perhaps decrease bronchoconstriction. Cox and coworkers (9) studied the safety and effect of BT on lung function and AHR in 16 young patients with mild–moderate asthma at two Canadian centers over a 2-year follow-up period. Spirometry and methacholine challenge tests were performed at baseline and at 12 weeks after treatment; medication usage, PEF rates, and respiratory symptoms were recorded on a daily basis. Subjects exhibited a significant improvement in symptom-free days, a significant improvement in PEF rates at 12 weeks, and decreased AHR assessed by increased PC20 (provocative concentration of methacholine causing a 20% fall in FEV1) at 12 weeks and at 1 and 2 years. Prebronchodilator FEV1 was unchanged over 2 years. There were a number of limitations, including a small patient cohort, the potential for placebo effect with symptom reporting, and no longer term follow-up. A larger double-blind, randomized, sham-controlled multicenter trial of BT in moderate–severe asthma has completed accrual and should provide additional insight into the role of BT.
The proven efficacy of lung volume reduction surgery in selected patients with severe emphysema has prompted much interest in less invasive bronchoscopic techniques, particularly the insertion of one-way valves. Wan and colleagues (10) reported a retrospective analysis of the collective multinational endobronchial valve (EBV) experience in 98 patients from nine centers. Inclusion criteria were similar to those used for lung volume reduction surgery; patients with an FEV1 of less than 20% predicted, hypercapnia, pulmonary hypertension, and a DLCO of less than 25% of predicted were excluded. Full pulmonary function and six-minute-walk testing was performed at 30 and 90 days post-procedure. The mean FEV1 at baseline was 30.1 ± 10.7% predicted. At 90 days, there was significant improvement in FEV1 (+10.7% ± 26.2%), FVC, RV, and six-minute-walk test distance. Greater improvement was reported in patients with an FEV1 of less than 30%, and severe hyperinflation with an RV greater than 225% of predicted. A greater trend in improvement was seen in patients treated unilaterally and in panlobular fashion. Serious complications were reported in eight (8.2%) patients within the first 90 days, including one death. The results of a larger clinical trial are expected in the future, but this study documents the feasibility of this therapeutic approach.
Advances in Diagnostic Bronchoscopy
Electromagnetic navigation bronchoscopy is a novel technique using an electromagnetic board, position sensors in the tip of a steerable probe, and an extended working channel, designed to enhance the diagnostic yield of bronchoscopy for peripheral and mediastinal lesions. Gildea and coworkers (11) performed a prospective, single-center, open-label, pilot trial of 60 patients with abnormal CT findings. Mean navigation times were 7 ± 6, and 2 ±2 minutes for peripheral lung and lymph node lesions, respectively. Successful navigation of the steerable probe into the target lesion was accomplished in all cases. A diagnosis was established in 80.3% of patients, including the finding of malignancy in 74.4%. The yield was 74% for peripheral lesions and 100% for lymph node lesions (which had a mean size of 28.1 ± 12.8 mm). Pneumothorax occurred in two patients, but the procedure was otherwise well tolerated. This study showed that electromagnetic navigation bronchoscopy is a safe, high-yield technique, but the upfront cost of the device and the absence of clear-cut superiority over EBUS techniques for lymph node sampling may limit its widespread use.
Fibered confocal fluorescence microscopy (FCCM) is a new technique that produces microscopic imaging of living tissue via a 1-mm probe passed through a fiberoptic bronchoscope. Thiberville and collaborators (12) performed FCCM on two bronchial specimens ex vivo and 29 patients at high risk of lung cancer in vivo, and took biopsies of FCCM-imaged areas using autofluorescence bronchoscopy. Microscopic and spectral analysis showed that the FCCM signal originated from the elastic component of the basement membrane zone. The investigators identified five distinct, reproducible microscopic patterns in the normal tracheobronchial tree extending to the more distal respiratory bronchi. Alterations in the microstructure were seen in a very high number of abnormal biopsies, including 19 of 22 meta- or dysplastic lesions, five of five carcinomas in situ, and two of two invasive lesions. This technique may be helpful in studying bronchial wall structures and improving detection of early central lung cancers, but its small sampling area represents a major limitation.
PEDIATRIC PULMONARY DISEASE
Michelle M. Cloutier
Asthma Center
Connecticut Children's Medical Center
Hartford, Connecticut
Effect of Prematurity on Lung Function in Early Adulthood
As many individuals born prematurely reach adulthood, potential pulmonary function abnormalities may become more clinically relevant. Vrijlandt and coworkers (13) measured pulmonary function by spiromety and whole body plethysmography, and exercise capacity by incremental bicycle ergometry, in a prospective cohort study of 1,338 Danish children born prematurely in 1983. Forty-four patients enrolled in the trial and were compared with age-matched control subjects. Pulmonary function studies, including spirometry, lung volumes, and diffusing capacity, were normal in prematurely born patients, but FEV1, FVC, expiratory flow rates, airway resistance, and diffusing capacity were lower than in control subjects (P < 0.002). Interestingly, there was no difference in pulmonary function between those with or without bronchopulmonary dysplasia during infancy. In addition, exercise capacity was lower in study patients than control subjects, although there was no ventilatory limitation. The differences were attributed to deconditioning. This study suggests that adults born prematurely may be at risk for significant pulmonary impairment at a younger age.
Secondhand Smoke and Lung Function In Children
In a multinational, cross-sectional study of 22,712 schoolchildren, Moshammer and coworkers (14) assessed the impact of secondhand smoke exposure on spirometry. Only 28.7% had no exposure to smoke in utero or during their first 2 years of life. Almost 20% had exposure in utero, 54% had exposure in the first 2 years of life, and 55.6% had ongoing exposure. The effects of secondhand smoke exposure on spirometry was small, but was largest in those with in utero exposure (–1.1% for FEV1 and –5.4% for maximum expiratory flow 25% [MEF25]). In those with current exposure or those in the first 2 years of life, the changes were –0.4 and –0.5%, respectively, for FEV1, and –2.5 and 2.6%, respectively, for MEF25. This study underscores the importance of substantive intervention to decrease exposure to cigarette smoke.
Sickle Cell Disease and Acute Chest Syndrome
Chronic lung disease, whose major risk factor is acute chest syndrome (ACS), is the leading cause of death in patients with sickle cell disease (SCD). Sylvester and colleagues (15) studied the impact of ACS on spirometry and lung volumes in 20 children with SCD in an age-matched case-control study. ACS was defined as chest pain, dyspnea, pyrexia, and new radiographic infiltrates. They found that children with SCD and history of ACS had evidence of airflow obstruction which was unresponsive to bronchodilators. Subjects with SCD and ACS had lower FEV1, FEF75, and FEV1/FVC ratio, and higher airway resistance, TLC, and RV. This small study suggests that these changes may contribute to the development of sickle cell lung disease in adulthood.
Obstructive Sleep Apnea in Children
Obstructive sleep apnea (OSA) is believed to affect about 2% of school-aged children. Risk factors include obesity, adenotonsillar hypertrophy, prematurity, and Hispanic and African-American ethnicity. Spilsbury and colleagues (16) assessed the relationship between OSA and neighborhood socioeconomic status in a cross-sectional study of 843 children, ages 8 to 11 years, from a community-based cohort. The mean age of the children was 9.5 years; 46.3% were born prematurely, 20.3% had asthma, and 15.7% were obese. Forty children had OSA. Living in a severely disadvantaged neighborhood was a risk factor for OSA, with an odds ratio of 5.07. Prematurity, obesity, and African-American ethnicity were other unadjusted risk factors. Even after controlling for known factors associated with OSA, neighborhood socioeconomic status remained an independent risk factor. The factors associated with this association remain unclear, but exposure to environmental neurotoxins, sleep deprivation, and stress have been postulated to be contributing factors.
PULMONARY VASCULAR DISEASE
Gerald Simmonneau
Department of Pulmonary Medicine and Intensive Care Unit
Hopital Antoine Bedere
Clamart, France
Pathophysiology of Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) may result from various etiologies. HIV infection is one of the rare, but well-known causes, with a prevalence of 0.5 per 1,000 individuals. The pathology is quite similar to that of idiopathic PAH. Although the mechanism is unknown, indirect action of viral proteins has been postulated. HIV-1 nef is a viral protein involved in viral replication; it also regulates intracellular membrane trafficking, and leads to endothelial dysfunction and apoptosis. Marecki and colleagues (17) performed a retrospective analysis of nef staining in archived nonhuman primate (macaque) lung tissue from six chimeric SIV (SHIV)-nef–infected and 18 simian HIV (SIV)-infected animals. Staining was also performed on tissue from two humans with HIV-associated PAH and two individuals with idiopathic PAH. Plexiform lesions of PAH were identified in five of six of the chimeric SHIV-nef animals, but in none of the SIV-nef monkeys. There was also an enhanced accumulation of Nef in endothelial cells of plexiform lesions in the two HIV-infected humans but none in patients with idiopathic PAH. This study suggests that Nef plays an important role in the pathophysiology of PAH. In addition, the SHIV-nef–infected macaque animal model is the first to reproduce plexiform lesions and may prove to be crucial in the study of pulmonary arterial disease.
Epidemiology of PAH
Information about the epidemiology and natural history of PAH has come predominantly from a U.S. registry dating to the early 1980s. Since that time, there have been dramatic advances in therapy as well as a new classification system for PAH. Humbert and colleagues (18) reported data collected from a prospective registry of PAH initiated in 17 university hospitals in France in 2002. In a country with an adult population of more than 44 million people, 686 patients with PAH were reported (prevalence, 15.4/1,000,000), including 256 with idiopathic PAH (prevalence, 5.7/1,000,000). Idiopathic PAH was the most common etiology, followed by connective tissue–associated PAH, portal hypertension, congenital heart disease, and anorexigen-induced and HIV-associated PAH. Three-quarters of patients presented with New York Heart Association (NYHA) functional class III or IV at time of diagnosis. The mean pulmonary arterial pressure was 55 ± 15 mm Hg, with a mean total pulmonary resistance of 12.5 ± 7.3 IU. The mean six-minute-walk test distance was 329 ± 109 m. A response to vasodilators was seen in fewer than 8% of subjects. The 1-year survival was 88% in the incident cohort. This registry may provide ongoing insight into the impact of therapy on the natural history of PAH.
Nonmedical Treatment of Pulmonary Hypertension
Pharmacologic therapy for PAH has been the subject of intensive study in the recent past, and several agents are now approved for use. Little is known, however, about the impact of nonpharmacologic measures, such as exercise training. Mereles and coworkers (19) undertook the first prospective, randomized trial assessing the impact of exercise and respiratory training on individuals with PAH. They randomized 30 stable patients with severe symptomatic PAH (NYHA class III or IV) to either a control or primary training group. Patients in the primary training group underwent an initial hospital-based exercise program for 3 weeks, followed by a home-based program for 12 weeks. Patients in the control group underwent nutrition, muscle relaxation, and respiratory training alone. There were 15 individuals in each group. Primary endpoints included changes in six-minute-walk distance from baseline to Week 15, and scores of the Short Form Health Survey quality-of-life tool. Secondary endpoints included changes in World Health Organization functional class, and echocardiographic and gas exchange parameters. Both groups had improvement in six-minute-walk test distance at Week 15, but the mean difference in six-minute-walk test distance between primary training patients and control patients was 111 m (P > 0.001). World Health Organization functional class quality-of-life scores and other exercise parameters also improved, whereas systolic pulmonary arterial pressures did not change. Exercise training was well tolerated. Although the impact on clinical course or survival was not assessed, respiratory and exercise training may be an important adjunct to pharmacologic therapy in patients with PAH.
Medical Therapy for Pulmonary Hypertension
As advances in the treatment of PAH with drugs from different classes have evolved, there is interest in studying combinations of agents. McLaughlin and coworkers (20) evaluated the safety and efficacy of adding inhaled iloprost, a prostacyclin analog, to bosentan in a randomized, multicenter, double-blind, placebo-controlled trial of 67 patients with idiopathic PAH. Iloprost or placebo was added to bosentan for 12 weeks in those already receiving the latter for a minimum of 4 months. At Week 12, there was a mean increase in six-minute-walk test distance of 30 m (P = 0.001), compared with 4 m in the placebo group (P = 0.69). NYHA status improved by one class in 34 and 6% in the iloprost and placebo groups (P = 0.002), respectively. Iloprost delayed the time to clinical worsening; improvements were also reported in postinhalation mean pulmonary artery pressure and pulmonary vascular resistance. Combination therapy was reportedly well tolerated. The study's limitations include a relatively small sample size and short study period, but the study demonstrates the safety and efficacy of an iloprost–bosentan combination in the short term.
FOOTNOTES
Conflict of Interest Statement: G.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
REFERENCES
Related articles in Proceedings of the American Thoracic Society:
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