Faculty Bibliography

Tumors of the mediastinum represent a wide diversity of disease states. The location and composition of a mass is critical to narrowing the differential diagnosis. The most common causes of an anterior mediastinal mass include the following: thymoma; teratoma; thyroid disease; and lymphoma. Masses of the middle mediastinum are typically congenital cysts, including foregut and pericardial cysts, while those that arise in the posterior mediastinum are often neurogenic tumors. The clinical sequelae of mediastinal masses can range from being asymptomatic to producing symptoms of cough, chest pain, and dyspnea. This article will review the anatomy of the mediastinum as well as the different clinical, radiographic, and prognostic features, and therapeutic options of the most commonly encountered masses.

Given previous work showing that an adenoviral vector expressing IFN-beta (Ad.IFNbeta) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 10(9) plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNbeta intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNbeta were long-term survivors (>120 days; P < 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNbeta induced direct tumor cell killing and that depleting natural killer or CD8+ T cells, but not CD4+ T cells, with antibodies attenuated the effect of Ad.IFNbeta. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNbeta to treat human non-small cell lung cancer.

Malignant mesothelioma is an insidious neoplasm arising from the mesothelial surfaces of the pleural and peritoneal cavities, the pericardium, or the tunica vaginalis. A total of 80% of all cases are pleural in origin. The predominant cause of malignant mesothelioma is inhalational exposure to asbestos, although evidence is increasing to support the hypothesis that simian virus-40 virus plays a role in cocarcinogenesis. Immunohistochemical markers such as calretinin, WT-1, and cytokeratin 5/6 are becoming established diagnostic markers. Preliminary data suggests that a soluble form of mesothelin could serve as a serum marker for established and early cases of mesothelioma. Positron emission tomography with 18-fluorodeoxyglucose in conjunction with computed tomograhy scanning has improved preoperative imaging and staging. Prognostic factors have been identified and verified. Negative indicators include thrombocytosis, high leukocyte counts, poor performance status, and nonepithelial histology. For the first time, there is now evidence that some treatments are increasing the quality and quantity of life for patients with mesothelioma. Chemotherapy, with the new multi-targeted antifolate drug Pemetrexed, combined with cisplatin, has shown superior survival rates in a large phase III trial when compared to cisplatin alone. High-dose intensity-modulated radiotherapy when administered after extrapleural pneumonectomy has resulted in excellent local control. Multimodality treatment programs that combine surgical cytoreduction with novel forms of radiation therapy and more effective chemotherapy combinations may offer significant increases in survival for certain subgroups of mesothelioma patients. Innovative palliative approaches have proved successful in alleviation of the significant symptoms experienced by many mesothelioma patients. Experimental treatments such as immunotherapy and gene therapy present a window of hope for all mesothelioma patients, and in the future, may be combined with 'standard therapy' in multimodality protocols. Patients with adequate performance status should be enrolled into clinical trials where possible. Over the past decade, significant advances have been made on several fronts that have improved the ability to diagnose a stage, define prognosis, and treat malignant pleural mesothelioma.

Immunotherapy against a variety of malignancies, including pleural-based malignancies, has shown promise in animal models and early human clinical trials, but successful efforts will need to address immunosuppressive factors of the tumor and host, particularly certain cytokines and CD4(+) CD25(+) regulatory T cells (Treg). Here, we evaluated the cellular and cytokine components of malignant pleural effusions from 44 patients with previously diagnosed mesothelioma, non-small cell lung cancer (NSCLC), or breast cancer and found significant differences in the immune profile of pleural effusions secondary to mesothelioma vs. carcinoma. Although a high prevalence of functionally suppressive CD4(+) CD25(+) T cells was found in carcinomatous pleural effusions, mesothelioma pleural effusions contained significantly fewer CD4(+) CD25(+) T cells. Activated CD8(+) T cells in pleural fluid were significantly more prevalent in mesothelioma than carcinoma. However, there is clear patient-to-patient variability and occasional mesothelioma patients with high percentages of CD4(+) CD25(+) pleural effusion T cells and low percentages of CD8(+) CD25(+) pleural effusion T cells can be identified. Mesothelioma pleural effusions contained the highest concentrations of the immunosuppressive cytokine transforming growth factor (TGF)-beta. Thus, the contribution of cellular and cytokine components of immunosuppression associated with malignant pleural effusions varies by tumor histology and by the individual patient. These results have implications for the development of immunotherapy directed to the malignant pleural space, and suggest the need to tailor immunotherapy to overcome immunosuppressive mechanisms in tumor environments.

BACKGROUND: Malignant pleural effusions (MPEs) can produce significant respiratory symptoms and diminished quality of life in patients with terminal malignancies. Control of MPEs to palliate respiratory symptoms can be performed via several different approaches. Ideally, a minimally invasive procedure to control MPEs and to provide relief of respiratory symptoms would be optimal. OBJECTIVE: To ascertain if control of MPEs can be achieved by outpatient management via a small-bore pleural catheter (PC) without the need for sclerosing agents. METHODS: Retrospective chart analysis of 24 patients after outpatient insertion of PCs for recurrent, symptomatic MPEs followed by frequent home drainage of pleural fluid to relieve respiratory symptoms. RESULTS: Symptomatic relief of respiratory symptoms was achieved in 100% of patients, while pleurodesis was achieved in 58% of patients in a mean of 39 days. Five patients (6 PCs) expired with the catheters in place. In these patients, all catheters remained in position and functional until the patients ultimately died from nonpleural disease progression. No major complications occurred during insertion of the catheter. Late complications included localized cellulitis and bacterial superinfection in three patients and tumor growth at the catheter site in one patient. CONCLUSIONS: The PCs used in the present study provided an effective modality not only to alleviate respiratory symptoms associated with MPE, but also to achieve pleurodesis in 58% of our patients. These catheters may provide a significantly less invasive outpatient approach to the palliative management of MPEs.

Gene therapy for pulmonary disease, a field still in the experimental stage, has nonetheless progressed considerably in the past decade. There have been significant advances in pre-clinical studies, as well as important developments resulting from multiple early-phase human clinical trials for a variety of respiratory disorders. Although there are several ways of delivering therapeutic genes to the lungs, the primary delivery modality remains flexible bronchoscopy. The flexible bronchoscope, because of its unique access to both large and small airways, serves as an ideal instrument to deliver therapeutic genes to the tracheobronchial tree, even to small airways and alveoli that are beyond the reach of the bronchoscope. In addition, bronchoscopic gene delivery has the capacity to treat pulmonary vascular disorders because delivery of marker and therapeutic genes via the airways has been demonstrated to successfully transduce the pulmonary vascular endothelium. This article describes the various methods and disease targets of bronchoscopically mediated gene therapy, focusing in particular on the results of clinical studies and providing a glimpse into the future of the field.

To evaluate the feasibility, safety, and efficacy of vaccination with autologous tumor cells genetically modified with an adenoviral vector (Ad-GM) to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF), we conducted a phase I/II multicenter trial in patients with early and advanced stage non-small-cell lung cancer (NSCLC). Vaccines were generated from autologous tumor harvests. Intradermal injections were given every 2 weeks for a total of three to six vaccinations. Tumors were harvested from 83 patients, 20 with early-stage NSCLC and 63 with advanced- stage NSCLC; vaccines were successfully manufactured for 67 patients, and 43 patients were vaccinated. The most common toxicity was a local injection-site reaction (93%). Three of 33 advanced-stage patients, two with bronchioloalveolar carcinoma, had durable complete tumor responses (lasting 6, 18, and >or=22 months). Longer survival was observed in patients receiving vaccines secreting GM-CSF at more than 40 ng/24 h per 10(6) cells (median survival = 17 months, 95% confidence interval [CI] = 6 to 23 months) than in patients receiving vaccines secreting less GM-CSF (median survival = 7 months, 95% CI = 4 to 10 months) (P =.028), suggesting a vaccine dose-related survival advantage.

OBJECTIVES: Immuno-gene therapy of mesothelioma with an adenovirus encoding interferon-beta mediated strong antitumor responses in murine models with low but not high tumor burden. Our goals were to determine the mechanisms responsible for this loss of efficacy and to test the hypothesis that the combination of preoperative adenovirus encoding interferon-beta and surgical resection would be effective in treating bulky tumors. METHODS: Flank tumors of a mouse mesothelioma cell line were treated with adenovirus encoding interferon-beta or adenoviral vector encoding the bacterial protein beta-galactosidase. Cytotoxic T lymphocytes and tumor infiltration by T lymphocytes were measured. Tumors were surgically excised 72 hours later and tumor cells were injected in the contralateral flank to create a model of a metastatic focus. Tumor-free survival and distant metastatic disease were assessed. RESULTS: Immuno-gene therapy effectively treated small tumors (<200 mm(3)) but did not reduce the size of large (>800 mm(3)) flank tumors. Although treatment with adenovirus encoding interferon-beta resulted in the generation of tumor-neutralizing splenocytes in large tumors, the number of T cells visualized within the tumors was minimal. Tumors treated with adenovirus encoding interferon-beta (versus adenoviral vector encoding the bacterial protein beta-galactosidase or phosphate-buffered saline solution) prior to debulking increased long-term tumor-free survival and resulted in two- to sixfold smaller foci of implanted tumor cells at 2 weeks postoperatively. CONCLUSIONS: The use of adenovirus encoding interferon-beta or surgical debulking alone is ineffective in treating large tumors, but combining preoperative adenovirus encoding interferon-beta and surgical debulking significantly reduces tumor recurrence and improves long-term tumor-free survival. We postulate that adenovirus encoding interferon-beta amplifies the cytotoxic T-lymphocyte antitumor response, allowing elimination of residual tumor cells.