Faculty Bibliography

STUDY OBJECTIVE:s: Although pulmonary mycetoma has been well-described in immunocompetent hosts, the only description in HIV-infected patients has been of 10 patients from our institution, from 1992 to 1995. To further investigate the impact of HIV status on the presentation and course of pulmonary mycetoma, we conducted a follow-up study. DESIGN: Retrospective review of all cases of pulmonary mycetoma at Bellevue Hospital from 1992 to 1999. SETTING: Patients were evaluated on the inpatient chest service and in the outpatient chest and HIV clinics of Bellevue Hospital in New York City. PATIENTS: We identified 74 patients with pulmonary mycetoma; 20 of them were HIV-infected (27%). INTERVENTIONS: The 20 HIV-infected patients were treated with antiretroviral and/or antifungal therapy. MEASUREMENTS AND RESULTS: Predisposing diseases were pulmonary tuberculosis (TB), Pneumocystis carinii pneumonia (PCP), or both TB and PCP. Seventeen patients had a CD4+ cell count of < 100 cells/ micro L at presentation. Hemoptysis was present in 13 patients, but was massive in only 1 patient. Cough was common. Of the 18 patients for whom follow-up was available, 11 received antifungal treatment and 7 were observed without therapy. Six patients received both antiretroviral and antifungal therapy. Disease progression occurred in 50%. Only five patients exhibited radiographic or clinical improvement. All five were treated with both antiretroviral and antifungal therapy. CONCLUSIONS: PCP is a risk factor for pulmonary mycetoma in the HIV-infected individual. HIV-infected patients with mycetomas have a significant rate of disease progression, although they rarely have life-threatening hemoptysis. A combination of antifungal and antiretroviral therapy may improve the clinical outcome in HIV-infected patients with pulmonary mycetoma

Glucocorticoids inhibit the proliferation of various cell types, but the mechanism of this inhibition remains unclear. We investigated the effect of dexamethasone on non-small cell lung cancer cell growth and cell cycle progression. We showed that dexamethasone suppresses the proliferation of A549 and Calu-1 cells, with accumulation of cells in G1/G0 stage of the cell cycle, as determined by fluorescence-activated cell sorter analysis. Western blot analysis confirmed that this is associated with hypophosphorylation of retinoblastoma protein. Using Western blot analysis and in vitro kinase assays, we found that dexamethasone results in decreased activity of CDK2 and 4, decreased levels of cyclin D, E2F, and Myc, and increased levels of the CDK inhibitor p21(Cip1). In addition, we found that dexamethasone decreases activity of extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK). The kinetics of all these changes indicate that inhibition of the ERK/MAPK pathway precedes the cell cycle effects, suggesting that regulation of this MAPK-signaling pathway may be an alternative mechanism for glucocorticoid-induced cell cycle arrest and growth inhibition

The mitogen-activated protein kinase (MAPK) pathways transmit signals from the cell membrane to the nucleus. Activation of MAPK cascades may play a role in malignant transformation. We hypothesized that enhanced expression of one or more of these pathways would occur in human lung cancers. Using Western blot analysis of tissue homogenates from resected non- small cell lung cancers and matched non-neoplastic lung tissue, we determined that only activated p38 was consistently increased in tumor compared with normal tissue. In vitro kinase assays confirmed that the levels of activated MAPK correlated with the activity of the enzymes, and immunohistochemical analysis confirmed the cellular localization of the activated MAPKs. We incubated a lung cancer cell line in a hypoxic chamber to simulate the hypoxic environment in solid lung tumors, but found no increase in p38 activation. Contrary to our expectations, ERK and JNK, the MAPK pathways traditionally associated with cell growth and perhaps malignant transformation, were not consistently activated in the human lung tumor samples. However, p38, a MAPK usually associated with stress responses, growth arrest, and apoptosis, was activated in all of the human lung cancer samples, suggesting an additional role for this pathway in malignant cell growth or transformation

Lung cancer is the leading cause of cancer deaths worldwide. If we can define and detect preneoplastic lesions, we might have a chance of improving survival. The World Health Organization has defined three preneoplastic lesions of the bronchial epithelium: squamous dysplasia/carcinoma in situ; atypical adenomatous hyperplasia; and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. These lesions are believed to progress to squamous cell carcinoma, adenocarcinoma and carcinoid tumors, respectively. In this review we summarize the data supporting the preneoplastic nature of these lesions, and delve into some of the genetic changes found in atypical adenomatous hyperplasia and squamous dysplasia/carcinoma in situ