Faculty Bibliography

RATIONALE: Whether histologic subtype of non-small cell lung cancer (NSCLC) has an important effect on prognosis after surgery is unknown. OBJECTIVES: We hypothesized that we could predict mortality more effectively by integrating precise tumor size and histology rather than relying on conventional staging. METHODS: We used the SEER (Surveillance, Epidemiology, and End Results) registry. Inclusion criteria were as follows: (1) primary squamous cell or adenocarcinoma; (2) potentially curative surgery, defined as a lobectomy or bilobectomy; (3) lymph node dissection performed; and (4) pathologic stage IA or IB. MEASUREMENTS AND MAIN RESULTS: From 1988 to 2000, 7,965 patients were included. For both all-cause and lung cancer-associated mortality, tumor size demonstrated the strongest association (log-rank P < 0.0001 for each). When tumors were small (</=2 cm), lung cancer-associated mortality was similar for adenocarcinoma when compared with squamous cell carcinoma. When tumors were 3 cm or larger in size, lung cancer-associated mortality was higher for adenocarcinoma. The increased risk of lung cancer-associated mortality with adenocarcinoma was more pronounced in those younger than 65 years. Survival prediction using precise size and histology had much better discriminatory power than conventional TNM (tumor-node-metastasis) staging (P = 0.005). CONCLUSIONS: Staging that takes into account size, histology, late recurrence risk, and patient age is more accurate than the current TNM system and is clinically relevant because improved prediction can facilitate better decisions on the use of adjuvant chemotherapy

Lung cancer causes over one million deaths per year worldwide and cigarette smoking, the proximate cause, results in a field cancerization of the respiratory track. Lung cancer cells or premalignant cells may be susceptible to apoptosis or necrosis-inducing agents. Statins inhibit the acetyl coenzyme A pathway reducing L-mevalonate that is a precursor to isoprenoids necessary for post-translational processing, resulting in apoptosis. Lovastatin was added to four lung cancer cell lines and normal human bronchial epithelial cells followed by Western blots to evaluate proteins in the cell cycle, oxidant, and apoptotic pathways. Flow cytometry revealed significant increases in three of four lung cancer cell lines in apoptosis and necrosis after lovastatin treatment at 10 microM for 72 h. Lovastatin adversely affected lung cancer cell survival with increases in cell-cycle check-point inhibitors p21WAF and/or p27KIP and a decrease in cyclin D1. All four lung cancer cell lines had a decrease in glutathione after lovastatin treatment consistent with reduced protection against reactive oxidant species. Three of four lung cancer cell lines had increased cytochrome c release with reduced pro-caspase-3 and increases in activated caspase-3. Lovastatin induces apoptosis and necrosis in lung cancer cell lines by causing alterations in the cell cycle, reducing glutathione, and activating p53, Bax protein, and caspases while increasing cytochrome c in apoptosis pathways. Targeting HMG-CoA reductase may represent an approach to lung cancer chemotherapy, e.g., reversing ground glass opacities detected on CT scans or resolving airway preneoplasias detected by bronchoscopy before they progress to malignant transformation

The host response to Mycobacterium tuberculosis includes macrophage activation, inflammation with increased immune effector cells, tissue necrosis, and cavity formation, and fibrosis, distortion, and bronchiectasis. To evaluate the molecular basis of the immune response in the lungs of patients with active pulmonary tuberculosis (TB), we used bronchoalveolar lavage to obtain cells at the site of infection. Affymetrix GeneChip microarrays and cDNA nylon filter microarrays interrogated gene expression in bronchoalveolar lavage (BAL) cells from 11 healthy controls and 17 patients with active pulmonary TB. We found altered gene expression for 69 genes in TB versus normal controls that included cell surface markers, cytokines, chemokines, receptors, transcription factors, and complement components. In addition, TB BAL cell gene expression patterns segregated into 2 groups: one suggestive of a T helper type 1 (Th1) cellular immune response with increased signal transducer and activator of transcription-4 (STAT-4), interferon-gamma (IFN-gamma receptor), and monokine induced by IFN-gamma (MIG) expression with increased IFN-gamma protein levels in BAL fluid; the other group displayed characteristics of Th2 immunity with increased STAT-6, CD81, and IL-10 receptor expression. We were able to demonstrate that a Th2 presentation could change to a Th1 pattern after anti-tuberculous treatment in 1 TB patient studied serially. These gene expression data support the conclusion that pulmonary TB produces a global change in the BAL cell transcriptome with manifestations of either Th1 or Th2 immunity

Consistent with the hypothesis that pulmonary epithelial apoptosis is the key to the acute exacerbation of idiopathic pulmonary fibrosis (IPF), we conducted serological identification of Ags by recombinant expression cloning (SEREX) analysis using type II alveolar cell carcinoma (A549) cell lines to identify disease-related Abs. In a survey of Abs to the recombinant autoantigens identified by SEREX analysis, five Abs were identified as novel candidates for the acute exacerbation of IPF. Abs to annexin 1 were detected in 47 and 53% of the sera and bronchoalveolar lavage materials from patients with acute exacerbation of IPF. Some identical TCR Vbeta genes were identified in sequential materials obtained at 1-3 mo in all 10 acute exacerbation IPF cases, suggesting that some infiltrating CD4-positive T cells sharing limited epitopes expand by Ag-driven stimulation during disease extension. The CDR3 region of these identical TCR Vbeta genes showed high homology with the N-terminal portion of annexin 1, including in the HLA-DR ligand epitopes predicted by TEPITOPE analysis. By Western blotting analysis and observation of the CD4-positive T cell responses in bronchoalveolar lavage samples, the N-terminal portion of annexin 1 was cleaved and found to induce marked proliferative responses of CD4-positive T cells in three patients. Our study demonstrates that annexin 1 is an autoantigen that raises both Ab production and T cell response in patients with acute exacerbation of IPF, and that the N-terminal portion of annexin 1 plays some role in the pathogenesis of acute exacerbation in IPF patients

In September 2004 the American Thoracic Society released a revised set of guidelines for the clinical diagnosis of nonmalignant asbestos-related disease (Am J Resp Crit Care Med. 2004;170:691-715). The conditions of concern are asbestosis, pleural disorders, and chronic airways obstruction. The criteria are evidence of structural lesion consistent with asbestos-related disease, evidence of causation by asbestos, and exclusion of alternative diagnoses. Findings that satisfy each are described. These guidelines are an extension of the 1986 ATS criteria and expand on them by establishing three explicit criteria, accommodating newer diagnostic modalities, recommending evaluation of impairment appropriate to the diagnosis, and outlining initial management measures following diagnosis. A history of significant asbestos exposure obligates the responsible physician to provide a management plan for the patient that takes into consideration current disease, impairment, and future risk. Persons identified as having asbestos-related disease or having significant exposure histories may benefit from management directed at preserving lung function, preventing complications, reducing the risk of lung cancer, and screening for potentially treatable asbestos-related disease including malignancies. Various issues arising since the publication of the guidelines are addressed, including evidence for pleural plaques being a marker of risk for lung disease apart from history of asbestos exposure; evidence against smoking being associated with a greater frequency of pleural plaques; an association between asbestos exposure and colon cancer; the diagnostic sensitivity of the chest film in smokers; and affirming the adequacy of findings on plain chest films as sufficient for the diagnosis of nonmalignant asbestos-related disease but not always sufficient to rule it out.

Leprosy or Hansen's disease is a chronic infectious disease caused by an acid-fast bacillus, Mycobacterium leprae (M. leprae). The bacilli proliferate in macrophages infiltrating the skin and gain entry to the dermal nerves via the laminar surface of Schwann cells where they replicate. After entry, the Schwann cells proliferate and then die. Conclusive identification of M. leprae DNA in a sample can be obtained by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the heat shock 65 gene (hsp65). Molecular epidemiology will make it possible to study the global distributions of M. leprae, explore the relationship between genotypes-incidence rates, mode of transmission, and the type of disease (tuberculoid vs. lepromatous). We amplified DNA using PCR for the hsp65 gene from 24 skin lesions from patients diagnosed with various types of leprosy. Fifteen out of 24 were positive for the hsp65 gene. Digestion with HaeIII-PAGE for the RFLP confirmation of the presence of M. leprae DNA showed the typical pattern in 5 out of 24 and 2 novel patterns in 10 out of 24 patients. We confirmed the presence of M. leprae DNA by sequencing the genes for gyraseA or B and folP, which contained only M. leprae specific single nucleotide polymorphisms (SNPs). Thus, we describe novel hsp65 RFLPs for M. leprae found in a high frequency making them ideal for future epidemiology and transmission studies