Ware G. Kuschner

Test Performance of Positron Emission Tomography and Computed Tomography for Mediastinal Staging in Patients with Non–Small-Cell Lung Cancer: A Meta-Analysis

Context Is computed tomography (CT) or positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) better for mediastinal staging of nonsmall-cell lung cancer? Contribution This synthesis of 39 studies found that FDG-PET was more accurate than CT for identifying lymph node involvement. Positron emission tomography with 18-fluorodeoxyglucose was more sensitive but less specific when CT showed enlarged nodes than when CT showed no node enlargement. Implications Positron emission tomography with 18-fluorodeoxyglucose is more accurate than CT for mediastinal staging. Because FDG-PET has more true-positive and false-positive findings in patients with enlarged nodes, positive findings warrant biopsy confirmation. Interpretation of negative FDG-PET findings should rely heavily on pretest probability of metastasis regardless of CT findings. The Editors Accurate mediastinal staging is crucial in managing patients with nonsmall-cell lung cancer. Regional lymph node status is an important determinant of prognosis, and decisions about treatment depend critically on tumor stage. Conventional methods for mediastinal staging include computed tomography (CT) and various biopsy procedures. However, CT has poor sensitivity and specificity for identifying mediastinal metastases (1-3), and biopsy procedures are inconvenient and potentially risky. Positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) is a promising but expensive functional imaging test that is rapidly gaining acceptance as a tool for lung cancer staging (4, 5). Positron emission tomography with 18-fluorodeoxyglucose identifies malignant cells in tumors and lymph nodes on the basis of their increased metabolic rate (6). In the past decade, several studies of PET imaging for mediastinal staging were published. These studies suggested that FDG-PET is more accurate than CT for identifying mediastinal metastases. However, most were small and potentially limited by other methodologic shortcomings. In addition, previous studies have not systematically addressed the conditional test performance of FDG-PET and CT. Conditional test performance refers to the possibility that the sensitivity and specificity of 1 test might differ depending on the results of the other test (7). The results of FDG-PET and CT might be mutually dependent, despite the fact that they identify malignant lymph nodes by different mechanisms. In a preliminary analysis, we found that FDG-PET was more sensitive but less specific in patients with lymph node enlargement on CT (8). If confirmed, this finding has important implications for selecting and interpreting tests in mediastinal staging. For example, if FDG-PET is more sensitive when lymph node enlargement is present on CT, then a negative PET result would rule out disease more reliably (because its negative predictive value would be higher). Consequently, confirmatory mediastinal biopsy might not be necessary in some of these patients, especially when pretest probability is low. We performed this meta-analysis to compare the accuracy of FDG-PET and CT for identifying mediastinal metastasis in patients with nonsmall-cell lung cancer. We also aimed to determine whether the results of FDG-PET and CT are conditionally dependent, that is, whether the sensitivity and specificity of FDG-PET depend on the presence or absence of lymph node enlargement on CT. Finally, we explored whether various aspects of study methods affected diagnostic accuracy. Methods We used systematic review methods to identify potentially relevant studies, assess studies for eligibility, evaluate study quality, and derive summary estimates of diagnostic test performance (9-12). We previously used similar methods to evaluate the accuracy of FDG-PET imaging for diagnosis of pulmonary nodules and mass lesions (13). Additional details about our methods can be found in the Appendix. Study Identification We attempted to identify all published studies that examined FDG-PET imaging for mediastinal staging in patients with known or suspected nonsmall-cell lung cancer. We sought studies that evaluated both FDG-PET and CT, but we did not attempt to identify studies that examined only CT for mediastinal staging. An investigator and a professional librarian searched MEDLINE, CancerLit, and EMBASE databases in August 2001 and repeated searches in June 2002 (Appendix Table 1). We updated the literature search in MEDLINE, EMBASE, Current Contents, and BIOSIS through 27 March 2003 as part of a technology assessment performed for the U.S. Department of Veterans Affairs (Appendix Table 2). We augmented our computerized literature searches by manually reviewing the reference lists of identified studies and review articles. We included studies published in any language but did not include abstracts. For English-language studies, 2 investigators independently evaluated studies for inclusion, rated the methodologic quality of included studies, and abstracted relevant data. Disagreements were resolved by discussion. One reviewer performed these tasks for non-English-language studies. Reviewers were blinded to journal, author, institutional affiliation, and date of publication. Study Eligibility We included studies that examined FDG-PET imaging for mediastinal lymph node staging in patients with known or suspected nonsmall-cell lung cancer; enrolled at least 10 participants, including at least 5 participants with lymph node metastases; and provided enough data to permit calculation of sensitivity and specificity for identifying malignant lymph node involvement. Study Quality We adapted an existing instrument (11, 13) to examine 7 aspects of study quality: technical quality of the index tests, technical quality and application of the reference test, independence of test interpretation, description of the study population, cohort assembly, sample size, and unit of analysis (Appendix Table 3). Data Abstraction We abstracted data about the demographic characteristics of participants, the prevalence of malignant lymph node involvement, and the sensitivity and specificity of CT and FDG-PET for identifying malignant lymph nodes. For studies that reported results by using the patient as the unit of analysis, we determined the ability of CT and FDG-PET to distinguish ipsilateral or contralateral mediastinal lymph node involvement (N2 or N3) from hilar, intrapulmonary, or no lymph node involvement (N0 or N1). This distinction is critical because involvement of N2 or N3 nodes usually indicates non-surgically treatable disease. When it was not possible to make this distinction, we determined test sensitivity and specificity for distinguishing N0 lymph node status from N1, N2, or N3 lymph node status. For studies in which the individual patient was not the unit of analysis, we determined the test sensitivity and specificity for identifying malignant lymph nodes or lymph node stations. Because observations are not independent when several lymph nodes from the same patient are analyzed separately, these studies may yield biased estimates of diagnostic test performance. Therefore, we analyzed data from these studies separately. To determine whether the sensitivity and specificity of FDG-PET depended on the presence or absence of enlarged nodes on CT, we recorded the results of FDG-PET, CT, and the reference test or tests for each patient. This enabled us to derive separate estimates for the sensitivity and specificity of FDG-PET in patients with and without lymph node enlargement on CT. Data Synthesis and Statistical Analysis For each study, we constructed 2 2 contingency tables in which all participants were classified as having positive (N2 or N3) or negative (N0 or N1) results and as having or not having mediastinal lymph node involvement as determined by the reference test or tests. We calculated the true-positive rate (true-positive rate = sensitivity), the false-positive rate (false-positive rate = 1 specificity), and the log odds ratio (log odds true-positive rate log odds false-positive rate) for CT and FDG-PET. The log odds ratio is a measure of diagnostic test performance that accounts for the correlation between the true-positive rate and the false-positive rate. We calculated exact 95% CIs for the true-positive rate and the false-positive rate on the basis of the binomial distribution (14). To derive summary estimates of diagnostic test performance, we constructed summary receiver-operating characteristic (ROC) curves by using the method of Moses (12, 13, 15, 16), which confirmed that the curves were symmetrical and could be described by a single parameter, the summary log odds ratio. Because this method requires the use of a correction factor when the reported sensitivity or specificity is 100%, we calculated the summary diagnostic odds ratios by using a fixed-effects model (17), or a random-effects model when there was evidence of heterogeneity (18), and reported results derived from these models. Because the summary log odds ratio is difficult to interpret clinically, we express our results in terms of the maximum joint sensitivity and specificity (12), a transformation of the summary log odds ratio that is a global measure of diagnostic accuracy, similar to the area under the ROC curve. The maximum joint sensitivity and specificity is the point on the summary ROC curve at which sensitivity and specificity are equal. It varies from 0.5 for a test that provides no diagnostic information to 1.0 for a test that is perfect. We used meta-regression to make all statistical comparisons (19), with 1 exception. To compare the sensitivity and specificity of FDG-PET in patients with and without lymph node enlargement, we used discriminant function analysis (20) and a nonparametric permutation test (21). We considered a 2-sided P value less than 0.05 to be significant for all statistical tests. Sensitivity Analysis In prespecified analyses, we examined the effect of year of publication, language, and

Dose-dependent cigarette smoking-related inflammatory responses in healthy adults

The aim of this study was to determine the dose-response relationship between cigarette smoke exposure and pulmonary cell and cytokine concentrations in bronchoalveolar lavage (BAL). BAL cells and BAL supernatant concentrations of tumour necrosis factor-alpha (TNF alpha), interleukin (IL)-1 beta, IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 from 14 healthy smokers and 16 healthy nonsmokers were quantified. Statistically greater concentrations of neutrophils, macrophages, IL-1 beta, IL-6, IL-8 and MCP-1 were observed among smokers compared with nonsmokers (p < or = 0.0007 in all cases). Cigarette smoking, categorized ordinally as: less than one pack, one pack, or greater than one pack per day, was predictive of BAL macrophages (p < 0.0001), neutrophils (p = 0.015), IL-1 beta (p < 0.001) and IL-8 (p = 0.02). We conclude that concentrations of macrophages, neutrophils, IL-1 beta and IL-8 are elevated in the pulmonary microenvironment of smokers in a cigarette dose-dependent manner. Based on the present findings, we would caution against simple analyses that treat current smokers as a homogeneous group and which do not account for smoking intensity.

Accuracy of transbronchial needle aspiration for mediastinal staging of non-small cell lung cancer: a meta-analysis

Background: The reported accuracy of transbronchial needle aspiration (TBNA) for mediastinal staging in non-small cell lung cancer (NSCLC) varies widely. We performed a meta-analysis to estimate the accuracy of TBNA for mediastinal staging in NSCLC. Methods: Medline, Embase, and the bibliographies of retrieved articles were searched for studies evaluating TBNA accuracy with no language restriction. Meta-analytical methods were used to construct summary receiver-operating characteristic curves and to pool sensitivity and specificity. Results: Thirteen studies met inclusion criteria, including six studies that surgically confirmed all TBNA results and enrolled at least 10 patients with and without mediastinal metastasis (tier 1). Methodological quality varied but did not affect diagnostic accuracy. In tier 1 studies the median prevalence of mediastinal metastasis was 34%. Using a random effects model, the pooled sensitivity and specificity were 39% (95% CI 17 to 61) and 99% (95% CI 96 to 100), respectively. Compared with tier 1 studies, the median prevalence of mediastinal metastasis (81%; p = 0.002) and pooled sensitivity (78%; 95% CI 71 to 84; p = 0.009) were higher in non-tier 1 studies. Sensitivity analysis confirmed that the sensitivity of TBNA depends critically on the prevalence of mediastinal metastasis. The pooled major complication rate was 0.3% (95% CI 0.01 to 4). Conclusions: When properly performed, TBNA is highly specific for identifying mediastinal metastasis in patients with NSCLC, but sensitivity depends critically on the study methods and patient population. In populations with a lower prevalence of mediastinal metastasis, the sensitivity of TBNA is much lower than reported in recent lung cancer guidelines.

Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review

Background: Idiopathic pulmonary fibrosis (IPF) profoundly affects the quality of patients’ lives. A systematic review was performed to evaluate critically the published literature and to examine what is known about health-related quality of life (HRQL) in patients with IPF. Methods: The MEDLINE, EMBASE, Health and Psychosocial Instruments, and Cochrane Library databases were searched to 1 April 2004. Abstracts and bibliographies of published articles were scanned and contact was made with investigators. Included studies analysed HRQL (or quality of life) in at least 10 patients with IPF. Two reviewers independently selected studies, evaluated their quality according to predetermined criteria, and abstracted data on study design, patients’ demographic and clinical characteristics, and quality of life outcome measures. Results: Seven studies met the inclusion criteria. The studies enrolled 512 patients with IPF and used three different instruments to measure HRQL. All studies had important limitations in methodological quality; none measured longitudinal changes in HRQL over time. Patients reported substantially impaired HRQL, especially in domains that measured physical health and level of independence. Patients with IPF appear to have similar impairments in HRQL to those with chronic obstructive pulmonary disease. Measures of dyspnoea were moderately correlated with scores from domains that measured physical health (R2 = 0.03–0.66) and energy/fatigue/pep (R2 = 0.19–0.55), but measures of pulmonary function and gas exchange did not correlate as strongly with these and other domains. Conclusion: Studies of HRQL in patients with IPF suggest that, in addition to the obvious effect on physical health, general health, energy level, respiratory symptoms, and level of independence are also impaired. Variability in HRQL among patients is not fully explained by measures of dyspnoea or pulmonary function, suggesting that HRQL measures provide unique information. More research is needed to identify or design appropriate measurement instruments for patients with IPF and to examine changes in HRQL over time or in response to specific treatments.

Use of herbal products, coffee or black tea, and over-the-counter medications as self-treatments among adults with asthma☆☆☆★★★

BACKGROUND There are few data on the use of alternative therapies in adult asthma and their impact on health outcomes. OBJECTIVE The objective of this study was to study the prevalence and morbidity of asthma self-treatment with herbs, coffee or black tea, and over-the-counter (OTC) medications containing ephedrine or epinephrine. METHODS We carried out a cross-sectional analysis of interview data for 601 adults with asthma recruited from a random sample of pulmonary and allergy specialists. We estimated the 12-month prevalence of reported use of herbal products, coffee or black tea, or OTC products to self-treat asthma and their association with emergency department visits and hospitalization. RESULTS Herbal asthma self-treatment was reported by 46 (8%; 95% confidence interval [CI] 6% to 10%); coffee or black tea self-treatment by 36 (6%; 95% CI 4% to 8%), epinephrine or ephedrine OTC use by 36 (6%; 95% CI 4% to 8%), and any of the three practices by 98 subjects (16%; 95% CI 13% to 19%). Adjusting for demographic and illness covariates, herbal use (odds ratio [OR] 2.5; 95% CI 1.1 to 5.6) and coffee or black tea use (OR 3.1; 95% CI 1.2 to 7.8) were associated with asthma hospitalization; OTC use was not (OR 0.8; 95% CI 0.3 to 2.5). CONCLUSIONS Even among adults with access to specialty care for asthma, self-treatment with nonprescription products was common and was associated with increased risk of reported hospitalization. This association does not appear to be accounted for by illness severity or other disease covariates. It may reflect delay in utilization of more efficacious treatments.

Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study

We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.

Electronic cigarettes and thirdhand tobacco smoke: two emerging health care challenges for the primary care provider

Primary care providers should be aware of two new developments in nicotine addiction and smoking cessation: 1) the emergence of a novel nicotine delivery system known as the electronic (e-) cigarette; and 2) new reports of residual environmental nicotine and other biopersistent toxicants found in cigarette smoke, recently described as “thirdhand smoke”. The purpose of this article is to provide a clinician-friendly introduction to these two emerging issues so that clinicians are well prepared to counsel smokers about newly recognized health concerns relevant to tobacco use. E-cigarettes are battery powered devices that convert nicotine into a vapor that can be inhaled. The World Health Organization has termed these devices electronic nicotine delivery systems (ENDS). The vapors from ENDS are complex mixtures of chemicals, not pure nicotine. It is unknown whether inhalation of the complex mixture of chemicals found in ENDS vapors is safe. There is no evidence that e-cigarettes are effective treatment for nicotine addiction. ENDS are not approved as smoking cessation devices. Primary care givers should anticipate being questioned by patients about the advisability of using e-cigarettes as a smoking cessation device. The term thirdhand smoke first appeared in the medical literature in 2009 when investigators introduced the term to describe residual tobacco smoke contamination that remains after the cigarette is extinguished. Thirdhand smoke is a hazardous exposure resulting from cigarette smoke residue that accumulates in cars, homes, and other indoor spaces. Tobacco-derived toxicants can react to form potent cancer causing compounds. Exposure to thirdhand smoke can occur through the skin, by breathing, and by ingestion long after smoke has cleared from a room. Counseling patients about the hazards of thirdhand smoke may provide additional motivation to quit smoking.

A sensitive new bioassay for tumor necrosis factor

Tumor necrosis factor is an important cytokine involved in inflammation and assay of this cytokine in biological fluids may be important in the understanding of several disease processes. This report describes an improved TNF bioassay employing a newly isolated subclone of the cell line NCTC-clone 929 as well as a novel fluorescence indicator system for detecting viability of the target cells. The limit of detection for the TNF hypersensitive cell line with this fluorescence viability assay was 68 +/- 2.5 fg/ml, which is approximately 3 x more sensitive than the parental clone and approximately 10 x more sensitive than that reported by Branch et al. (1991) using the neutral red indicator system. The hypersensitivity of the clone gradually declined over a 45-day period and at regular intervals new cells were cultivated from frozen stocks. Two different serum sources, bovine fetal serum and horse serum, and four different serum concentrations (5, 10, 15, 20%) were evaluated to optimize sensitivity. No difference was found between serum sources but sensitivity was significantly reduced if < 15% serum was used.

The Effect of an Inhaled Corticosteroid on Glucose Control in Type 2 Diabetes

Objective: To determine the effect of inhaled corticosteroid (ICS) therapy on glucose control in adults with type 2 diabetes mellitus and coexisting asthma or chronic obstructive pulmonary disease (COPD). Design: A prospective randomized, double-blind, double-dummy placebo-controlled, crossover investigation of inhaled steroids and oral leukotriene blockers. Setting: A United States Department of Veterans Affairs Health Care System outpatient setting. Participants: Adults with type 2 diabetes and asthma or COPD. Methods: Subjects (n=12) were randomized to receive either inhaled fluticasone propionate (440 μg twice daily) and oral placebo, or inhaled placebo and oral montelukast (10 mg/day). After 6 weeks, subjects were switched to the opposite therapy for 6 weeks. The primary outcome measure was the change in the percentage of glycosylated hemoglobin (%HbA1c) at 6 weeks relative to the baseline value. Results: Ten patients completed the study. The difference between the mean within-subject changes in %HbA1c associated with 6-week periods of fluticasone and the mean changes associated with montelukast therapy was small but statistically significant (mean difference=0.25; P<0.025). Neither fluticasone nor oral montelukast therapy for 6 weeks led to a significantly different mean % HbA1c compared with the relevant baseline (mean differences=0.11 and −0.14, respectively). Conclusion: The absence of a clinically significant within-subject difference in the changes in %HbA1c associated with fluticasone versus oral montelukast therapy, or between either therapy or baseline does not warrant recommending changes in therapy for asthma or diabetes in patients with these co-morbid conditions. However, we suggest that clinicians carefully monitor blood glucose control when diabetic patients initiate ICS, especially with higher dosages.

Circulating Tumor Microemboli Diagnostics for Patients with Non–Small-Cell Lung Cancer

Introduction: Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non–small-cell lung cancer (NSCLC) patients undergoing imaging evaluation. Methods: First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group. Results: We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value = 0.001) and for stage I patients alone (AUC = 0.87, p value = 0.002). Conclusion: CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.