Faculty Bibliography

INTRODUCTION: Acute exacerbation of IPF is increasingly being recognized as a common clinical event in the IPF population. The exact etiology remains unknown. Previous reports have shown an association between lung surgery, bronchoalveolar lavage, and surgical lung biopsies as a potential trigger for exacerbations of IPF. To our knowledge, there are no known cases in the literature reporting an exacerbation of IPF following a non-thoracic surgical procedure. We report a case of acute exacerbation of IPF following orthopedic surgery. CASE PRESENTATION: 78 year old male with a history of COPD (thirty pack year smoking history) and severe osteoarthritis was admitted to the NYU Hospital for Joint Diseases to undergo evaluation for total hip arthroplasty. Pre-operative evaluation was significant for a restrictive pattern with low DLCO on pulmonary function testing, as well increased interstitial markings on chest x-ray concerning for a fibrotic process. The patient reported no pulmonary symptoms, and underwent successful total hip arthroplasty without complication. On Post op day #6, the patient developed dyspnea on exertion and at rest, requiring increasing amounts of oxygen supplementation. A Chest CT was negative for pulmonary embolism, however did show bronchiectasis and evidence of fibrosis. An echocardiogram did not show evidence of heart failure. The patient was started on broad spectrum antibiotics with Vancomycin, Zosyn and Azithromycin. He also was started on high dose IV steroids (Solumedrol 60mg IV every 6 hours) for a potential COPD exacerbation. Sputum culture was positive only for Candida glabrata, and the patient completed a course of Anidulafungin. However, the patient's respiratory status continued to deteriorate, eventually requiring noninvasive positive pressure ventilation. High dose steroids were continued, as well as therapeutic anticoagulation. A repeat CT chest showed increased groundglass opacities, worsening bronchiectasis and fibrosis diffusely in a UIP pattern. A repeat echocardiogram showed new evidence for pulmonary hypertension, however otherwise normal. A trial of diuretics was initiated without a response. The patient eventually required intubation and tracheostomy, and later passed away. An autopsy revealed evidence for diffuse alveolar damage on a background of honeycombing and bronchiectasis. DISCUSSION: The etiology and pathogenesis of IPF exacerbations remains unknown. One hypothesis involves the loss of alveolar cell integrity following injury, leading to extrusion of fibrin into the alveolar spaces and remodeling. Fibrocytes can be recruited in response to chemokines generated by infection and injury and may potentiate fibrogenesis, leading to diffuse alveolar damage. This process may be triggered by pulmonary procedures, as previously reported. However, a similar inflammatory response may occur after a non-thoracic procedure, leading to the fibrogenic process. The above patient suffered an unexplained worsening fibrotic process, as evidenced by imaging, respiratory failure, and autopsy findings. Alternative causes, such as left heart failure and pulmonary embolism, were excluded. Potential infections were treated with antibiotics. Commonly proposed diagnostic criteria for IPF exacerbation were met. This is the first case to our knowledge of a non-pulmonary procedure triggering the disease process. Cases such as this are likely more common than realized and remain underreported. Clinicians should be aware of the potential for exacerbation of IPF following non-thoracic surgical procedures. CONCLUSIONS: Acute exacerbation of IPF is increasingly being recognized as a common clinical event and may occur after non-thoracic procedures, such as orthopedic surgery

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

We have recently developed a novel optical technology, partial wave spectroscopic (PWS) microscopy, which is exquisitely sensitive to the nanoarchitectural manifestation of the genetic/epigenetic alterations of field carcinogenesis. Our approach was to screen for lung cancer by assessing the cheek cells based on emerging genetic/epigenetic data which suggests that the buccal epithelium is altered in lung field carcinogenesis. We performed PWS analysis from microscopically normal buccal epithelial brushings from smokers with and without lung cancer (n = 135). The PWS parameter, disorder strength of cell nanoarchitecture (L(d)), was markedly (>50%) elevated in patients harboring lung cancer compared with neoplasia-free smokers. The performance characteristic was excellent with an area under the receiver operator characteristic curve of >0.80 and was equivalent for both disease stage (early versus late) and histologies (small cell versus non-small cell lung cancers). An independent data set validated the findings with only a minimal degradation of performance characteristics. Our results offer proof of concept that buccal PWS may potentially herald a minimally intrusive prescreening test that could be integral to the success of lung cancer population screening programs

PURPOSE: Aberrant promoter hypermethylation of tumor suppressor genes is a promising marker for lung cancer detection. We investigated the likelihood of detecting aberrant DNA methylation of tumor suppressor genes in plasma samples of patients with abnormalities of the lung detected upon computed tomography (CT) scan. EXPERIMENTAL DESIGN: In a small evaluation cohort, four gene promoters (DCC, Kif1a, NISCH, and Rarb) were found to be methylated with increased frequency in samples from cancer patients specifically. We then examined DNA from 93 plasma samples from patients with abnormal findings in the lung detected upon CT scan for aberrant methylation of these four gene promoters by quantitative fluorogenic real-time PCR. The patients were divided into two groups, ground glass opacity (n = 23) and cancerous tumors (n = 70). Plasma DNA from age-matched nodule-free individuals were used as controls (n = 80). RESULTS: In plasma, 73% of patients with cancerous tumors showed methylation of at least one gene with a specificity of 71% (P = 0.0001). Only 22% patients with ground glass opacity exhibited methylation of at least one gene. When smoking history was taken into account, 72% of cancer patients with no smoking history or those who smoked <20 pack-years showed methylation of at least one gene with 100% specificity (P = 0.05) when compared with matched controls. Among heavy smokers with 20+ pack-years of smoking history, 30% of the control group and 73% of the patients with cancerous tumors showed methylation (P = 0.0001). CONCLUSIONS: These biomarkers can distinguish between cancerous and noncancerous abnormal CT findings.

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: Sera from lung cancer patients contain autoantibodies that react with tumor associated antigens (TAAs) that reflect genetic over-expression, mutation, or other anomalies of cell cycle, growth, signaling, and metabolism pathways. METHODS: We performed immunoassays to detect autoantibodies to ten tumor associated antigens (TAAs) selected on the basis of previous studies showing that they had preferential specificity for certain cancers. Sera examined were from lung cancer patients (22); smokers with ground-glass opacities (GGOs) (46), benign solid nodules (55), or normal CTs (35); and normal non-smokers (36). Logistic regression models based on the antibody biomarker levels among the high risk and lung cancer groups were developed to identify the combinations of biomarkers that predict lung cancer in these cohorts. RESULTS: Statistically significant differences in the distributions of each of the biomarkers were identified among all five groups. Using Receiver Operating Characteristic (ROC) curves based on age, c-myc, Cyclin A, Cyclin B1, Cyclin D1, CDK2, and survivin, we obtained a sensitivity = 81% and specificity = 97% for the classification of cancer vs smokers(no nodules, solid nodules, or GGO) and correctly predicted 31/36 healthy controls as noncancer. CONCLUSION: A pattern of autoantibody reactivity to TAAs may distinguish patients with lung cancer versus smokers with normal CTs, stable solid nodules, ground glass opacities, or normal healthy never smokers