Faculty Bibliography

The potassium channel activator nicorandil, under evaluation for antianginal management, has been shown to decrease neutrophil respiratory burst. Since our laboratory has demonstrated that reactive oxygen species (ROS) increase tumor necrosis factor (TNF) production, we hypothesized that nicorandil might decrease TNF production from a lipopolysaccharide (LPS) challenge via reduction of respiratory burst. Macrophage viability and TNF production were determined after an 18-hr exposure to 5.0 micrograms/ml LPS and varying concentrations of nicorandil. Nicorandil was not toxic to macrophages below 12 mM (94 +/- 3% viability versus control) and decreased ROS and TNF production. Intracellular superoxide production decreased from 164 +/- 24 OD550 to 99 +/- 6 OD550 with 10 mM nicorandil and extracellular superoxide decreased from 3108 +/- 111 to 1760 +/- 210 nM. Hydrogen peroxide production was also decreased by 10 mM nicorandil. TNF production in response to 5 micrograms/ml LPS decreased from 6.8 +/- 0.6 to 2.7 +/- 0.4 ng/ml with 10 mM nicorandil. Northern and slot blot analyses demonstrate that nicorandil acts at a post-transcriptional site. These data imply that nicorandil decreases macrophage TNF production from an LPS challenge, possibly through a reduction in respiratory burst. Such compounds may prove useful in the treatment of conditions thought to be associated with free radical-lymphokine interactions such as ischemia-reperfusion injury, oxygen toxicity, adult respiratory distress syndrome, and septic shock

Two markers for the progenitor cells of peripheral airways and their tumors are the 10 kilodalton (kd) Clara cell protein and the major surfactant associated protein-A (SP-A). We used the RNA-RNA in situ hybridization technique to study expression of the genes encoding these proteins at the cellular level in 19 pairs of non-neoplastic and neoplastic tissues from resected human lungs. Our results show that in non-neoplastic lung tissue, the Clara 10 kd protein gene was expressed in nonciliated cells of both bronchial and bronchiolar epithelium, indicating that, in contrast to previous assumptions, cells with Clara cell-like differentiation in humans may not be restricted to bronchiolar cells. The incidence of Clara 10 kd protein gene expression, as detected in lung carcinomas (1 out of 19 cases positive) was less than expected based on previous ultrastructural reports. The SP-A gene was strongly expressed in normal alveolar type II cells in non-neoplastic lung and, at higher levels, in hyperplastic cells. In addition, SP-A mRNA expression was observed in scattered bronchial and bronchiolar epithelial cells in 40% of the airways examined. Five out of 17 lung tumors, all of which were adenocarcinomas, were positive for SP-A expression, albeit generally less intense than type II cells. This expression was seen in carcinomas with papillolepidic as well as solid and glandular growth patterns. Our findings provide new insights into the peripheral airway cell differentiation

Immunoperoxidase histochemical staining of cryostat sections from human tumor tissues revealed that a murine monoclonal antibody (MAb), K1, can distinguish epithelial mesotheliomas from lung adenocarcinomas. All of 15 epithelial-type mesotheliomas and all four mixed type mesothelioma samples, but none of 23 lung adenocarcinomas with different degrees of histologic differentiation demonstrated reactivity with antibody K1. Of the cell populations in each mesothelioma tested, 80% to 100% showed strong and homogeneous staining with MAb K1. Immunofluorescence analysis of live cultured cells from an epithelioid mesothelioma (H-meso) and several lung carcinoma cell lines as well as a pleural effusion of a patient with mesothelioma also showed selective reactivity of K1 with the mesothelioma cells. These data indicate that K1 can be useful as a mesothelial cell marker for the differential pathological diagnosis of the epithelial form of mesothelioma; K1 may also be useful in the study of the pathogenesis, immunodiagnosis, and immunotherapy of epithelial-type and mixed-type human malignant mesothelioma

Based upon the radiation sensitization properties of the halogenated pyrimidines, 5-iododeoxyuridine (IdUrd) and 5-bromodeoxyuridine, long term i.v. infusions of halogenated pyrimidines in conjunction with fractionated radiation therapy have been evaluated in the treatment of a variety of human malignancies. While clinical studies have attempted to measure the halogenated pyrimidine incorporation, few have successfully related tumor response to the incorporation of IdUrd by the tumor. The present study reports the continuous IdUrd labeling index (number of cells labeled) and the IdUrd corrected replacement (percentage of thymidine replacement in the labeled cells of the population) from the tumors of 17 patients who received continuous infusions of IdUrd (1000 mg/m2/24 h). The tumors treated included four high grade gliomas, five head and neck tumors, four high grade sarcomas, and five other tumors of varying types. Less than 25% of the cells in three of four gliomas incorporated IdUrd after 5-7-day IdUrd infusion time. Corrected replacement for the gliomas ranged from 0 to 4%. In contrast, 63-85% of the cells in the head and neck biopsies were labeled with IdUrd after 3-7-day IdUrd infusions suggesting that these large tumors (3-12 cm diameter) have a high fraction of dividing cells. Corrected replacements values for the head and neck tumor patients ranged from 2.9 to 26.3%. The high grade sarcomas also demonstrated a high percentage of IdUrd labeled cells (57-79%) with three patients having corrected replacements of 7.5-14.2%. The continuous labeling and thymidine replacement data for four patients from whom serial biopsies were taken during IdUrd infusion demonstrated both an increasing IdUrd replacement and continuous labeling index with an increasing duration of IdUrd infusion. The clinical response of both the high grade glioma and head and neck tumor patients indicate that the IdUrd replacement and labeling data may provide some important predictive information with regard to the successful use of the halogenated pyrimidines in clinical radiation trials

Persistent primary hyperparathyroidism due to mediastinal parathyroid adenoma was effectively treated by either angiographic ablation or median sternotomy in this study of 49 patients managed at the National Institutes of Health since 1977. Each patient presented here with symptomatic persistent primary hyperparathyroidism after failed initial surgical procedures done at other institutions. Each patient underwent extensive parathyroid localization procedures, including selective angiography, and most had a parathyroid adenoma localized to the mediastinum. Angiographic ablation, the deliberate injection of large doses of contrast material into the artery that selectively perfuses the adenoma, was initially successful in 22 of 30 procedures (73%) in 27 patients. Long-term control of persistent primary hyperparathyroidism was achieved in 17 of 27 patients (63%) by angiographic ablation. Each unsuccessful ablation could be easily salvaged by surgical resection. Surgical resection of the parathyroid adenoma by median sternotomy achieved immediate success in 24 of 24 procedures (p2 less than 0.02 versus ablation), and long-term cure in 23 of 23 evaluable patients (p2 less than 0.001 versus ablation). However, ablation did have benefits for the patients in whom it was successfully performed. It was associated with a significantly shorter hospital stay (median, 6 days versus 9 days for sternotomy, p2 less than 0.003), much less pain, and easier recuperation. Complications of each procedure were transient and similar in both groups. Operative resection is the most effective single means to eradicate mediastinal parathyroid adenoma; however, angiographic ablation can provide similar long-term control of hyperparathyroidism in 63% of patients with less pain and shorter convalescence than that seen in patients after median sternotomy. Our results suggest that angiographic ablation should be attempted as the initial procedure for patients with persistent primary hyperparathyroidism caused by an angiographically identified mediastinal parathyroid adenoma. Operation can be reserved for those who fail ablation

The sensitivity of magnetic resonance (MR) imaging for detection of pulmonary metastases in 11 patients scheduled for thoracotomy and curative resection of metastases was evaluated with a prospective, controlled study. MR imaging performed at 0.5 T was compared with chest radiography, computed tomography (CT), and thoracotomy in 12 cases. (One patient had two separate occurrences of pulmonary metastases.) All images were interpreted in blinded fashion. When all MR sequences were interpreted together, MR imaging enabled correct identification of all patients with pulmonary nodules (100%). CT enabled detection of at least one nodule in all 12 cases (100%) by design; the sensitivity of chest radiography was only 64%. For individual nodules, MR imaging was at least as sensitive as CT (P2 less than .25 [two-sided value]) and significantly more sensitive than chest radiography (P2 less than .01). Among all MR sequences, short inversion time inversion-recovery sequences had the highest sensitivity for detection of individual nodules (82%)

Exophiala dermatitidis, one of the saprophytic dematiaceous fungi, is a rare cause of human infection that, when invasive, is nearly always fatal. Besides the more common subcutaneous infection usually caused by traumatic inoculation, infection can also spread hematogenously, in which case the organism has a distinct neurotropism. A patient with autosomal recessive chronic granulomatous disease of childhood who was found to have a progressive pulmonary and central nervous system infection with E. dermatitidis responded to an aggressive, multifaceted therapeutic approach. Scanning electron microscopy of the cultured conidiogenous cells confirmed that the manner of conidiogenesis is typical of the genus Exophiala. We report the first successful treatment of an infection involving the lungs and central nervous system by a combination of surgical resection of the pulmonary source and medical therapy with amphotericin B, flucytosine or ketoconazole, and transfused white cells, followed by a prolonged course of fluconazole

The tolerance of mediastinal structures to intraoperative radiotherapy (IORT) was investigated in 3 separate animals trials using 49 adult foxhounds and one limited Phase I trial in 4 patients with Stage II or III non-small cell lung cancer (NSCLC). The 1- to 2-year results of these trials have been previously reported with significant toxicity found at dose levels over 20 Gy. We now report the results of five dogs reserved for long term studies and one Stage II NSCLC patient alive at 5 years. Two dogs received 20 Gy IORT and one received 30 Gy IORT to the esophagus, all three to a single 6 cm field with 9 MeV electrons. One control dog underwent surgery without irradiation. One dog received 20 Gy IORT to a single 5 cm mediastinal field with 13 MeV electrons following left pneumonectomy. At 5 years, all five dogs reserved for a long term evaluation were alive and evaluable with minimal endoscopic and radiographic abnormalities. The one patient alive at 5 years for evaluation received 25 Gy IORT to two matched 6 cm fields with 13 MeV electrons. She has stable dyspnea on exertion and there is no evidence of cancer by endoscopy. We conclude, based on these limited data, that IORT in the mediastinum may be safe at dose levels that do not exceed 20 Gy, and further careful evaluation at these lower treatment doses is warranted to determine efficacy

Selected immunotherapies (tumor necrosis factor, interleukin-1, interleukin-2, and gamma interferon), chemotherapeutic agents (mitomycin, platinum, doxorubicin [Adriamycin], and bleomycin), and radiation therapy have been described to exert cytotoxicity through the generation of reactive oxygen species, including superoxide and hydrogen peroxide. Tumor necrosis factor, however, has been shown to impart increased resistance in vitro and in vivo against reactive oxygen species stress, including radiation therapy and oxygen toxicity, possibly because of the induction of increased cellular buffering capacities. It is unknown whether the sensitivity of a lung cancer cell to reactive oxygen species therapy is altered by tumor necrosis factor through the induction of free radical scavenging enzymes such as manganese superoxide dismutase. This question was investigated as follows: A549 lung adenocarcinoma cells, exposed for 24 hours to 0, 0.1, 1.0, or 10 micrograms/ml concentrations of tumor necrosis factor, were exposed to hypoxanthine plus xanthine oxidase, a superoxide generating system, for varying intervals. The number of cells surviving 5 days after the stress was determined, and cells exposed to tumor necrosis factor were examined by Northern Blot analysis for induction of the manganese superoxide dismutase gene. The hypoxanthine-xanthine oxidase stress alone caused a time-dependent decrease in survival; however, pretreatment with tumor necrosis factor increased cell survival significantly. Moreover, the cells exposed to tumor necrosis factor had a fivefold increase in the number of manganese superoxide dismutase transcripts. These findings suggest that tumor necrosis factor may confer resistance of lung cancer cells to subsequent reactive oxygen species-based therapies, and the resistance of these cells may be due to increased expression of manganese superoxide dismutase. Clinical treatment failures may result, especially if tumor necrosis factor is given concurrently with other therapies

We report two cases of allergic bronchopulmonary fungal disease (ABPFD) caused by Curvularia sp and associated with allergic fungal sinusitis (AFS). Curvularia lunata was cultured in one case and Curvularia senegalensis was cultured in the other. Based on these cases and a review of the literature, we discuss unusual clinical and pathologic features that can occur in ABPFD. Unusual clinical aspects of ABPFD include associated AFS, absence of asthma, progression to Churg-Strauss angiitis and granulomatosis, concomitant hypersensitivity pneumonitis, and underlying cystic fibrosis. Atypical pathologic features that may occur in ABPFD include follicular bronchiolitis, xanthomatous bronchiolitis, limited tissue invasion, fungus balls, and association with unusual fungi. Prominent follicular bronchiolitis and xanthomatous bronchiolitis were misleading histologic features in one of our cases and led to a delay in recognition of the diagnosis. Both patients presented primarily with AFS; ABPFD was detected subsequently. This suggests that a small subset of patients with AFS may be at risk for ABPFD. The goal of this review is to increase awareness of unusual clinical and pathologic manifestations of ABPFD. It is hoped that this will result in accurate diagnosis and proper therapy, especially for patients who present with atypical features. Unusual fungal species should be considered in patients who have clinical findings compatible with ABPFD but who do not demonstrate immunologic reactivity to Aspergillus sp, especially Aspergillus fumigatus. In addition, ABPFD should be considered in patients with AFS who develop new pulmonary lesions