Faculty Bibliography

BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with >/= 10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90alpha, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC. CONCLUSIONS/SIGNIFICANCE: This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer

INTRODUCTION: Traditionally, Mycobacterium abscessus pulmonary disease has poor long term response to current antibiotic regimens. The data regarding the clinical efficacy of linezolid and aerosolized amikacin in M. abscessus pulmonary disease is limited. CASE PRESENTATION: A 52 year-old Caucasian female presented in 2004 with scant hemoptysis and intermittent night sweats. Her past medical history was unremarkable. She denied history of pneumonias. She did not smoke tobacco. She worked as a middle school secretary. Computed tomographic (CT) evaluation of the chest showed significant bronchiectasis in the right middle lobe with irregular opacities throughout the right upper lobe and right lower lobe. She was treated empirically with levofloxacin for recurrent episodes of infection with a presumed response. In 2007, she had more severe hemoptysis with several teaspoons of bright red blood that woke her up from sleep at night. M. chelonae and M. abscessus were identified in her sputum and she was started on clarithromycin combined with ciprofloxacin. In 2008, pulmonary function tests showed evidence of decreasing diffusing capacity. Chest CT showed interval increase in the nodular densities primarily in the right middle lobe and many were cavitating. She required hospitalization in 2009 for increasing hemoptysis and underwent IR embolization of branches of the right bronchial artery and right internal mammary artery. Nebulized amikacin 250 mg daily was started along with linezolid 600 mg daily. After 6 months of moxifloxacin, clarithromycin, nebulized amikacin, and linezolid, chest CT in late 2009 showed improvement and there was no further hemoptysis. DISCUSSIONS: Intermittent courses of parenteral therapy combined with and followed by an oral macrolide, aerosolized amikacin, and linezolid may be used to suppress infection and control disease progression of M. abscessus pulmonary disease. (1) Cost and side effects may limit the feasibility of prolonged treatment with parenteral antibiotic therapy. Aminoglycosides exhibit significant concentration-dependent bactericidal activity against nontuberculous mycobacteria. Extended parenteral therapy with aminoglycosides has been avoided due to the substantial risks of nephrotoxicity, ototoxicity, and vestibular toxicity. Aerosolized antibiotic delivery offers the potential advantage of achieving high drug concentrations in the lung with low systemic absorption and diminished risk of systemic toxicities. Aerosolized antibiotics have been used with notable success in the treatment of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis. In an observational case series, six HIV-negative patients with Mycobacterium avium intracellulare pulmonary infections who had failed standard therapy were administered aerosolized amikacin at 15 mg/kg daily in addition to standard multi-drug macrolide-based oral therapy. Five responded to therapy and achieved symptomatic improvement. Four were sputum culture negative after 6 months of therapy. (2) Approximately 50% of M. abscessus isolates are susceptible or exhibit intermediate susceptibility in vitro to the oxazolidinone linezolid. A small number of patients with M. abscessus lung disease have been treated with linezolid and a companion drug, usually a macrolide, with varied results. Impediments to long-term use of linezolid include the cost and potential side effects of chronic therapy which include peripheral neuropathy and anemia. Once daily dosing of linezolid 600mg instead of the traditional twice daily dosing is currently used by some to treat mycobacterial disease with seemingly fewer side effects and retained antimycobacterial activity. CONCLUSION: Preliminary case series suggest that nonparenteral agents including oral macrolides, aerosolized amikacin, and linezolid may be effective for the treatment of M. abscessus pulmonary disease

Tools for effective TB control have been available for years. Case finding, active medications, case management and directly observed therapy are the foundations for the management of TB. The current TB epidemic, centered in resource-limited settings is fueled by the HIV-1 epidemic. Lack of ability to diagnose and treat drug-resistant TB has led to development of more extensive patterns of resistance. Among the currently available drugs, there is reason to hope that rifamycins paired with fluoroquinolones will lead to shorter treatment regimens for drug-susceptible TB. As the result of novel public-private collaborations and investments of resources, new drugs are being developed. These include TMC207, already shown to have activity early in the treatment of multidrug-resistant TB and others that are likely to be active against persistor organisms, and have the prospect to dramatically shorten treatment courses for active and latent TB. Given that these drugs have novel mechanisms of action, combinations have the prospect to be highly active even against multidrug-resistant organisms

BACKGROUND: The World Trade Center (WTC) collapse produced a massive exposure to respirable particulates in New York City Fire Department (FDNY) rescue workers. This group had spirometry examinations pre-September 11, 2001, and post-September 11, 2001, demonstrating declines in lung function with parallel declines in FEV(1) and FVC. To date, the underlying pathophysiologic cause for this has been open to question. METHODS: Of 13,234 participants in the FDNY-WTC Monitoring Program, 1,720 (13%) were referred for pulmonary subspecialty evaluation at a single institution. Evaluation included 919 full pulmonary function tests, 1,219 methacholine challenge tests, and 982 high-resolution chest CT scans. RESULTS: At pulmonary evaluation (median 34 months post-September 11, 2001), median values were FEV(1) 93% predicted (interquartile range [IQR], 83%-101%), FVC 98% predicted (IQR, 89%-106%), and FEV(1)/FVC 0.78 (IQR, 0.72-0.82). The residual volume (RV) was 123% predicted (IQR, 106%-147%) with nearly all participants having normal total lung capacity, functional residual capacity, and diffusing capacity of carbon monoxide. Also, 1,051/1,720 (59%) had obstructive airways disease based on at least one of the following: FEV(1)/FVC, bronchodilator responsiveness, hyperreactivity, or elevated RV. After adjusting for age, gender, race, height and weight, and tobacco use, the decline in FEV(1) post-September 11, 2001, was significantly correlated with increased RV percent predicted (P < .0001), increased bronchodilator responsiveness (P < .0001), and increased hyperreactivity (P = .0056). CT scans demonstrated bronchial wall thickening that was significantly associated with the decline in FEV(1) post-September 11, 2001 (P = .024), increases in hyperreactivity (P < .0001), and increases in RV (P < .0001). Few had evidence for interstitial disease. CONCLUSIONS: Airways obstruction was the predominant physiologic finding underlying the reduction in lung function post-September 11, 2001, in FDNY WTC rescue workers presenting for pulmonary evaluation

Specimen collection is an integral component of clinical research. Specimens from subjects with various stages of cancers or other conditions, as well as those without disease, are critical tools in the hunt for biomarkers, predictors, or tests that will detect serious diseases earlier or more readily than currently possible. Analytic methodologies evolve quickly. Access to high-quality specimens, collected and handled in standardized ways that minimize potential bias or confounding factors, is key to the 'bench to bedside' aim of translational research. It is essential that standard operating procedures, 'the how' of creating the repositories, be defined prospectively when designing clinical trials. Small differences in the processing or handling of a specimen can have dramatic effects in analytical reliability and reproducibility, especially when multiplex methods are used. A representative working group, Standard Operating Procedures Internal Working Group (SOPIWG), comprised of members from across Early Detection Research Network (EDRN) was formed to develop standard operating procedures (SOPs) for various types of specimens collected and managed for our biomarker discovery and validation work. This report presents our consensus on SOPs for the collection, processing, handling, and storage of serum and plasma for biomarker discovery and validation