Surgical Metabolism Section of the Surgery Branch conducts clinical trials evaluating regional cancer treatments for patients with a variety of solid tumor malignancies and provides surgical consultation and treatment for patients with endocrine disorders including parathyroid, thyroid, endocrine pancreas, and adrenal neoplasms. We have actively participated in developing new diagnostic and imaging techniques for patients with endocrine disorders and have established an active program of advanced therapeutic laparoscopic procedures for such patients including laparoscopic partial pancreatectomy, liver resection, or adrenalectomy. The Surgical Metabolism Section is conducting clinical trials evaluating cancer treatments administered via isolated organ perfusion of the limb or liver and regional peritoneal perfusion using biological agents, melphalan, and hyperthermia. Initial results with isolated hepatic or limb perfusion have shown that these procedures can be done with acceptable morbidity and result in substantial and durable regression of locally advanced cancers such as unresectable extremity sarcoma or unresectable cancers of the liver in the majority of patients treated. A major thrust of these clinical trials has been to determine if tumor necrosis factor (TNF), a protein with impressive antitumor effects in experimental models but which is too toxic for systemic administration in humans, has significant antitumor activity when used in isolated organ perfusion. In patients with advanced unresectable liver cancers, isolated hepatic perfusion with TNF and melphalan results in significant regression (> 50% reduction in size) of tumors in 75% of patients. Tumor responses are seen in virtually all histologies treated and occur even in patients with large (>10 cm) lesions, multiple tumors, or those with a significant (>30%) tumor burden in liver. Although variable, the duration of responses can extend well beyond a year particularly when hepatic perfusion is combined with post-perfusion intra arterial FUDR and leucovorin in patients with colorectal cancer. Another major clincial research effort has centered on evaluating the utility of new imaging techniques such as PET scan in detecting occult recurrences in patients with a history of colorectal cancer and who have rising CEA values. PET scan is also being used with new radiopharmaceuticals to quantify changes in tumor viability, metabolism, and blood flow in patients treated with antiangiogenic therapies. Initial results indicate that PET scan is a very sensitive test for detecting occult tumors and may provide valuable insights into the efficacy and mechanisms of action of antiangiogenic therapies. Laboratory research falls into several broad areas that complement the clinical research effort. Adeno- and vaccina virus constructs with reporter or therapeutic genes are being developed to target tumors in experimental models of liver metastases, peritoneal carcinomatosis, and pulmonary metastases. Vaccinia viral (VV) constructs containing either a reporter gene (luciferase) or suicide gene (cytosine deaminase, CD) under the control of a synthetic early/late promoter have been shown to selectively replicate and express the gene of interest in high titer in tumor and intravenous administration VV with CD followed by prodrug treatment with 5-FC results in a significant survival benefit in mice with established liver metastases with long term cures observed in about 25% of treated animals. The unique phenotype of tumor neovasculature is being characterized and explored as an important potential target for cancer therapy. The laboratory has shown that a tumor derived cytokine, endothelial monocyte activating polypeptide (EMAP), will cause procoagulant effects in tumor microvasculature. EMAP expression in tumors correlates with TNF senstivity in vivo. Retroviral transduction of TNF resistant tumors so that they express higher titers of EMAP renders them sensitive to TNF in experimental models. In addition, using a rat aortic ring assay of angiogenesis, the laboratory has showm that EMAP has potent antiangiogenic effects. In order to better understand the mechanisms of antitumor activity in isolated organ perfusion, we have been investigating the effects of melphalan, hyperthermia, and TNF on endothelial cell viability and permeability in vitro and on tumor microvascular permeability in an experimental model of liver metastases and in patients undergoing isolated hepatic perfusion. Early results have indicated that TNF may not be responsible for the marked augmentation in capillary leak in tumor vasculature after perfusion and TNF continues to be critically evaluated to determine its role in isolation perfusion.""""""""
