Roger A. Maxfield

Prediction of lung cancer using volatile biomarkers in breath1

BACKGROUND Normal metabolism generates several volatile organic compounds (VOCs) that are excreted in the breath (e.g. alkanes). In patients with lung cancer, induction of high-risk cytochrome p450 genotypes may accelerate catabolism of these VOCs, so that their altered abundance in breath may provide biomarkers of lung cancer. METHODS VOCs in 1.0 L alveolar breath were analyzed in 193 subjects with primary lung cancer and 211 controls with a negative chest CT. Subjects were randomly assigned to a training set or to a prediction set in a 2:1 split. A fuzzy logic model of breath biomarkers of lung cancer was constructed in the training set and then tested in subjects in the prediction set by generating their typicality scores for lung cancer. RESULTS Mean typicality scores employing a 16 VOC model were significantly higher in lung cancer patients than in the control group (p<0.0001 in all TNM stages). The model predicted primary lung cancer with 84.6% sensitivity, 80.0% specificity, and 0.88 area under curve (AUC) of the receiver operating characteristic (ROC) curve. Predictive accuracy was similar in TNM stages 1 through 4, and was not affected by current or former tobacco smoking. The predictive model achieved near-maximal performance with six breath VOCs, and was progressively degraded by random classifiers. Predictions with fuzzy logic were consistently superior to multilinear analysis. If applied to a population with 2% prevalence of lung cancer, a screening breath test would have a negative predictive value of 0.985 and a positive predictive value of 0.163 (true positive rate =0.277, false positive rate =0.029). CONCLUSIONS A two-minute breath test predicted lung cancer with accuracy comparable to screening CT of chest. The accuracy of the test was not affected by TNM stage of disease or tobacco smoking. Alterations in breath VOCs in lung cancer were consistent with a non-linear pathophysiologic process, such as an off-on switch controlling high-risk cytochrome p450 activity. Further research is needed to determine if detection of lung cancer with this test will reduce mortality.

Detection of lung cancer using weighted digital analysis of breath biomarkers

BACKGROUND A combination of biomarkers in a multivariate model may predict disease with greater accuracy than a single biomarker employed alone. We developed a non-linear method of multivariate analysis, weighted digital analysis (WDA), and evaluated its ability to predict lung cancer employing volatile biomarkers in the breath. METHODS WDA generates a discriminant function to predict membership in disease vs no disease groups by determining weight, a cutoff value, and a sign for each predictor variable employed in the model. The weight of each predictor variable was the area under the curve (AUC) of the receiver operating characteristic (ROC) curve minus a fixed offset of 0.55, where the AUC was obtained by employing that predictor variable alone, as the sole marker of disease. The sign (+/-) was used to invert the predictor variable if a lower value indicated a higher probability of disease. When employed to predict the presence of a disease in a particular patient, the discriminant function was determined as the sum of the weights of all predictor variables that exceeded their cutoff values. The algorithm that generates the discriminant function is deterministic because parameters are calculated from each individual predictor variable without any optimization or adjustment. We employed WDA to re-evaluate data from a recent study of breath biomarkers of lung cancer, comprising the volatile organic compounds (VOCs) in the alveolar breath of 193 subjects with primary lung cancer and 211 controls with a negative chest CT. RESULTS The WDA discriminant function accurately identified patients with lung cancer in a model employing 30 breath VOCs (ROC curve AUC=0.90; sensitivity=84.5%, specificity=81.0%). These results were superior to multilinear regression analysis of the same data set (AUC=0.74, sensitivity=68.4, specificity=73.5%). WDA test accuracy did not vary appreciably with TNM (tumor, node, metastasis) stage of disease, and results were not affected by tobacco smoking (ROC curve AUC=0.92 in current smokers, 0.90 in former smokers). WDA was a robust predictor of lung cancer: random removal of 1/3 of the VOCs did not reduce the AUC of the ROC curve by >10% (99.7% CI). CONCLUSIONS A test employing WDA of breath VOCs predicted lung cancer with accuracy similar to chest computed tomography. The algorithm identified dependencies that were not apparent with traditional linear methods. WDA appears to provide a useful new technique for non-linear multivariate analysis of data.

A Multicenter Pilot Study of a Bronchial Valve for the Treatment of Severe Emphysema

Background: Chronic obstructive pulmonary disease (COPD) affects millions of people and has limited treatment options. Surgical treatments for severe COPD with emphysema are effective for highly selected patients. A minimally invasive method for treating emphysema could decrease morbidity and increase acceptance by patients. Objective: To study the safety and effectiveness of the IBV® Valve for the treatment of severe emphysema. Methods: A multicenter study treated 91 patients with severe obstruction, hyperinflation and upper lobe (UL)-predominant emphysema with 609 bronchial valves placed bilaterally into ULs. Results: Valves were placed in desired airways with 99.7% technical success and no migration or erosion. There were no procedure-related deaths and 30-day morbidity and mortality were 5.5 and 1.1%, respectively. Pneumothorax was the most frequent serious device-related complication and primarily occurred when all segments of a lobe, especially the left UL, were occluded. Highly significant health-related quality of life (HRQL) improvement (–8.2 ± 16.2, mean ± SD change at 6 months) was observed. HRQL improvement was associated with a decreased volume (mean –294 ± 427 ml, p = 0.007) in the treated lobes without visible atelectasis. FEV1, exercise tests, and total lung volume were not changed but there was a proportional shift, a redirection of inspired volume to the untreated lobes. Combined with perfusion scan changes, this suggests that there is improved ventilation and perfusion matching in non-UL lung parenchyma. Conclusion: Bronchial valve treatment of emphysema has multiple mechanisms of action and acceptable safety, and significantly improves quality of life for the majority of patients.

Effect of Endobronchial Coils vs Usual Care on Exercise Tolerance in Patients With Severe Emphysema: The RENEW Randomized Clinical Trial

IMPORTANCE Preliminary clinical trials have demonstrated that endobronchial coils compress emphysematous lung tissue and may improve lung function, exercise tolerance, and symptoms in patients with emphysema and severe lung hyperinflation. OBJECTIVE To determine the effectiveness and safety of endobronchial coil treatment. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted among 315 patients with emphysema and severe air trapping recruited from 21 North American and 5 European sites from December 2012 through November 2015. INTERVENTIONS Participants were randomly assigned to continue usual care alone (guideline based, including pulmonary rehabilitation and bronchodilators; n = 157) vs usual care plus bilateral coil treatment (n = 158) involving 2 sequential procedures 4 months apart in which 10 to 14 coils were bronchoscopically placed in a single lobe of each lung. MAIN OUTCOMES AND MEASURES The primary effectiveness outcome was difference in absolute change in 6-minute-walk distance between baseline and 12 months (minimal clinically important difference [MCID], 25 m). Secondary end points included the difference between groups in 6-minute walk distance responder rate, absolute change in quality of life using the St Georges Respiratory Questionnaire (MCID, 4) and change in forced expiratory volume in the first second (FEV1; MCID, 10%). The primary safety analysis compared the proportion of participants experiencing at least 1 of 7 prespecified major complications. RESULTS Among 315 participants (mean age, 64 years; 52% women), 90% completed the 12-month follow-up. Median change in 6-minute walk distance at 12 months was 10.3 m with coil treatment vs -7.6 m with usual care, with a between-group difference of 14.6 m (Hodges-Lehmann 97.5% CI, 0.4 m to ∞; 1-sided P = .02). Improvement of at least 25 m occurred in 40.0% of patients in the coil group vs 26.9% with usual care (odds ratio, 1.8 [97.5% CI, 1.1 to ∞]; unadjusted between-group difference, 11.8% [97.5% CI, 1.0% to ∞]; 1-sided P = .01). The between-group difference in median change in FEV1 was 7.0% (97.5% CI, 3.4% to ∞; 1-sided P < .001), and the between-group St Georges Respiratory Questionnaire score improved -8.9 points (97.5% CI, -∞ to -6.3 points; 1-sided P < .001), each favoring the coil group. Major complications (including pneumonia requiring hospitalization and other potentially life-threatening or fatal events) occurred in 34.8% of coil participants vs 19.1% of usual care (P = .002). Other serious adverse events including pneumonia (20% coil vs 4.5% usual care) and pneumothorax (9.7% vs 0.6%, respectively) occurred more frequently in the coil group. CONCLUSIONS AND RELEVANCE Among patients with emphysema and severe hyperinflation treated for 12 months, the use of endobronchial coils compared with usual care resulted in an improvement in median exercise tolerance that was modest and of uncertain clinical importance, with a higher likelihood of major complications. Further follow-up is needed to assess long-term effects on health outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01608490.

Respiratory failure in patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia.

Seven patients with acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia were studied to define the pathophysiology of their respiratory failure. The patients had fever, cough, dyspnea, hypoxemia, and diffuse infiltrates on chest x-ray. Biopsies revealed a spectrum of alveolar filling, interstitial edema and infiltration, and fibrosis. The patients were studied on mechanical ventilation to assess the effect of positive end-expiratory pressure (PEEP) and supplemental oxygen on shunt fraction. Mean anatomic shunt (measured on 100% oxygen) was 34 ± 8%, which increased significantly (p < .001) to 43 ± 9% when the FIO2 was decreased to 40% to 60% (physiologic shunt), indicating ventilation/perfusion (V/Q) imbalance or impaired diffusion. Increasing PEEP by 9 ± 2 cm H2O reduced the anatomic shunt to 30 ± 7% (p < .01) and the physiologic shunt to 37 ± 7% (p < .02). There was a similar decrease in anatomic and physiologic shunts in five studies, a greater decrease in physiologic shunt in four, and a greater decrease in anatomic shunt in two. Evidence of alveolar recruitment with PEEP, measured by an increase in static thoracic compliance, was found in only one study. There was no correlation between the effect of PEEP on compliance and its effect on shunt. The data suggest that in patients with AIDS and P. carinii pneumonia, PEEP can decrease shunt by reducing the anatomic shunt, improving V/Q imbalance, and converting areas of anatomic shunt to areas of low V/Q. P. carinii pneumonia in patients with AIDS can produce a clinical and pathophysiologic pattern similar to that described in the adult respiratory distress syndrome.

Lung Volume Reduction Surgery Using the NETT Selection Criteria

BACKGROUND The National Emphysema Treatment Trial (NETT) proved that lung volume reduction surgery (LVRS) was safe and effective in patients with certain clinical characteristics and using defined inclusion-exclusion criteria. Based on the selection criteria developed in that trial, we performed bilateral LVRS on 49 patients during the period of February 2004 until May 2009. METHODS Forty-nine patients underwent lung volume reduction by either median sternotomy (10) or video-assisted thoracoscopic surgery (39) selected according to NETT described parameters. Preoperative characteristics were the following: mean (±SD) age 62.5±6.6 years, preoperative FEV1 (forced expiratory volume in the first second of expiration) 691 cc (±159), % of predicted FEV1 25.3 (±6.2), preoperative Dlco (diffusing capacity of lung for carbon monoxide) 7.6 (±2.7), and % of predicted DLCO 27% (±7.3). All patients had upper lobe predominant disease and either low exercise capacity (n=23) or high exercise capacity (n=26) as defined by the NETT. RESULTS There was no operative or 90-day mortality. Median length of stay was 8 days (interquartile range=6 to 10). Two patients required reintubation and tracheostomy but were decannulated prior to discharge. The BODE index (body mass index, airflow obstruction, dyspnea, and exercise capacity), a multidimensional predictor of survival in chronic obstructive pulmonary disease, improved -2.3 (±1.5, p<0.0001) (missing data: 5 of 42, 11.9%) and the FEV1 improved 286 cc (±221, p<0.0001), both 1 year after surgery. Probability of survival was 0.98 (95% CI [confidence interval]=0.94 to 1) at 1 year, and 0.95 (95% CI=0.88 to 1) at 3 years. CONCLUSIONS Surgical lung volume reduction for emphysema can be performed in patients using selection criteria developed by the NETT with very low surgical risk and excellent midterm results. Surgical LVRS is the standard against which other nonsurgical treatments for advanced emphysema should be judged.

Molecular testing guidelines for lung adenocarcinoma: Utility of cell blocks and concordance between fine-needle aspiration cytology and histology samples.

Background: Lung cancer is a leading cause of mortality, and patients often present at a late stage. More recently, advances in screening, diagnosing, and treating lung cancer have been made. For instance, greater numbers of minimally invasive procedures are being performed, and identification of lung adenocarcinoma driver mutations has led to the implementation of targeted therapies. Advances in molecular techniques enable use of scant tissue, including cytology specimens. In addition, per recently published consensus guidelines, cytology-derived cell blocks (CBs) are preferred over direct smears. Yet, limited comparison of molecular testing of fine-needle aspiration (FNA) CBs and corresponding histology specimens has been performed. This study aimed to establish concordance of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) virus homolog testing between FNA CBs and histology samples from the same patients. Materials and Methods: Patients for whom molecular testing for EGFR or KRAS was performed on both FNA CBs and histology samples containing lung adenocarcinoma were identified retrospectively. Following microdissection, when necessary, concordance of EGFR and KRAS molecular testing results between FNA CBs and histology samples was evaluated. Results: EGFR and/or KRAS testing was performed on samples obtained from 26 patients. Concordant results were obtained for all EGFR (22/22) and KRAS (17/17) mutation analyses performed. Conclusions: Identification of mutations in lung adenocarcinomas affects clinical decision-making, and it is important that results from small samples be accurate. This study demonstrates that molecular testing on cytology CBs is as sensitive and specific as that on histology.

Management of Patients with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that is often viewed as untreatable. Although no specific treatment for this disease is available, there are important treatable diseases to be considered in the differential and treatable conditions that co-exist or complicate the course of the illness. In this article, we review our current management of patients with ALS.