Faculty Bibliography

We have confirmed in a second set of patients having human pleural mesothelioma that DNA for regions of the amino terminus of SV40 Tag can be amplified by the polymerase chain reaction. Moreover, other regions, including the carboxy terminus for Tag, and the regulatory region of SV40, are present in these specimens

A SV40 murine tumor model was developed and characterized involving intravenous inoculation of BALB/c mice with syngeneic SV40-transformed kidney fibroblasts (mKSA cells). Following intravenous inoculation with mKSA cells, viable tumor cells were recovered from primary organ cell culture of the brain, spleen, lungs, and kidneys of tumor bearing mice. The presence of mKSA tumor cells in these tissues was confirmed by morphological identification and by immunofluorescence directed to SV40 large tumor antigen (T-ag). Additionally, a computer assisted method was used to enumerate and quantitate the size of tumor foci. Tumor foci were observed in the lungs and were quantifiable based on both size and number. The number and size of foci observed in the lungs of tumor bearing mice was dependent on the dose of mKSA cells and time post-inoculation. Ultimately, the tumor burden in inoculated mice was found to be lethal. Quantification of tumor foci in the lung, survival data, and detection of metastasis to organs at sites distal to tumor cell inoculation, provides specific reference points for use in examining the mechanism(s) of the immune response to tumors expressing viral antigen and in evaluating immunologic based therapies within this new SV40 murine tumor model. The methods described herein can be applied for the development of new animal models of metastasis that express viral encoded tumor-specific antigens

BACKGROUND: Patients with malignant pleural mesothelioma (MPM) usually die of progressive local disease. This report describes the results of a Phase III trial comparing maximum debulking surgery and postoperative cisplatin, interferon alpha-2b, and tamoxifen (CIT) immunochemotherapy with and without intraoperative photodynamic therapy (PDT) to determine (1) whether such a multimodal approach can be performed with minimum morbidity and mortality in malignant pleural mesothelioma (MPM), and (2) whether first-generation (i.e., 630-nm laser light, Photofrin II) intrapleural PDT impacts on local recurrence of survival. METHODS: From July 1993 to June 1996, 63 patients with localized MPM were randomized to either PDT or no PDT. The tumors of 15 patients could not be debulked to 5 mm. Patients assigned to PDT (n = 25) and no PDT (n = 23) were similar with respect to age, sex, tumor volume, and histology. RESULTS: The type of resection (11 pleurectomies and 14 pneumonectomies vs. 12 pleurectomies and 11 pneumonectomies), length postoperative stay, and ICU time were comparable (PDT vs. no PDT). There was one operative death (hemorrhage), and each group had two bronchopleural fistulas. Postoperative staging divided patients into the following categories: stage I: PDT, 2, no PDT, 2; stage II: PDT, 2, no PDT, 2; stage III, PDT, 21; no PDT, 17; stage IV, PDT, 0; no PDT, 2. Comparable numbers of CIT cycles were delivered. Median survival for the 15 non-debulked patients was 7.2 months, compared to 14 months for the 48 patients on protocol. There were no differences in median survival (14.4 vs. 14.1 months) or median progression-free time (8.5 vs. 7.7 months), and sites of first recurrence were similar. CONCLUSIONS: Aggressive multimodal therapy can be delivered for patients with higher stage MPM. First-generation PDT does not prolong survival or increase local control for MPM

Therapeutic and diagnostic aspiration of Echinococcus granulosus liver cysts, but not pulmonary cysts, are increasingly being performed. Documented herein is the utility of percutaneous drainage and of albendazole treatment in a patient with a large recurrent, isolated, pulmonary echinococcal cyst for whom traditional therapy would have resulted in severe morbidity. Therapeutic options and possible complications are discussed

PURPOSE: Spontaneous regression of pulmonary metastases from renal cell carcinoma is a rare but well documented event. We present 2 recent cases that were radiographically consistent with pulmonary metastases from renal cell carcinoma but were pathologically shown to be pulmonary infarcts with no evidence of metastatic cells. Stable pulmonary infarcts can be misconstrued as metastatic disease in patients with renal cell carcinoma while resolving pulmonary infarcts may represent a subpopulation of patients with apparent spontaneous regression. Clinical implications of these findings are discussed. MATERIALS AND METHODS: Clinical and pathological data from 2 patients with large primary renal tumors, venous thrombi and lung masses were reviewed. Data from these cases, as well as pertinent urological and pathological literature, are presented. RESULTS: Although preoperative assessment was consistent with stage IV renal cell carcinoma, pathological examination of the lung masses in these patients showed no evidence of tumor cells. CONCLUSIONS: Pulmonary infarcts may mimic resolving or stable pulmonary metastasis in patients with renal cell carcinoma. Accurate clinical staging is crucial for the prognosis and treatment of renal cell carcinoma. Mistaking pulmonary infarcts for metastatic lesions can lead to inaccurate prognoses and inappropriate treatment

PURPOSE: We defined the outcome of a strategy using cytoreductive surgery before high dose interleukin-2 (IL-2) therapy in patients with metastatic renal cell carcinoma. MATERIALS AND METHODS: During an 11-year period, 195 patients underwent cytoreductive surgery as preparation for high dose IL-2 based therapy. The renal primary and locoregional metastatic disease that could be safely resected was removed. RESULTS: Because of the large size 176 of 195 renal tumors (90%) were resected through transabdominal incision and in 45 patients (23%) a second additional significant procedure was performed. Five cases (2.6%) were unresectable and 2 (1%) perioperative deaths occurred. After surgery 121 of 195 patients (62%) were eligible for treatment with high dose IL-2 based protocols. Overall response rate to IL-2 based protocols was 18%. CONCLUSIONS: Cytoreductive surgery can be performed safely in patients with metastatic renal cell carcinoma. Although the impact of cytoreductive surgery on response to immunotherapy remains undefined, this combination of primary debulking and systemic IL-2 can result in durable complete tumor regression in some patients with metastatic renal cell carcinoma

Recently, wild-type SV40 and/or DNA sequences indistinguishable from SV40 have been detected in specific types of human tumors: ependymoma and choroid plexus tumors, mesothelioma, osteosarcoma and sarcoma. The same tumor types will develop in hamsters after injection with SV40. These findings are interesting in themselves for they could shed light on the pathogenesis of these tumors. These findings also have public health implications. SV40 was found to have contaminated the poliovaccines and the adenovaccines from 1955 until 1963, therefore resulting in the inadvertent injection of millions of people with this tumor virus. Moreover, our society pays a high cost for asbestos causality, a carcinogen associated with the development of mesothelioma. In addition to asbestos, the potential impact of finding another possible cause for mesothelioma (i.e., SV40), as well as the possible pathogenic role of the contaminated poliovaccines, has generated considerable public interest and concern. To discuss these recent findings, the NIH (National Institutes of Health) and the FDA (Food and Drug Administration), organized an International Conference at the NIH, Bethesda, MD, January 27-28, 1997. The association of SV40 with human mesothelioma was also discussed in a special session at the IV International Mesothelioma Conference that was held at the University of Pennsylvania, Philadelphia, PA, May 13-16, 1997. The purpose of this review is to summarize data, from the discovery of the contaminated poliovaccines, to the most recent findings presented at the meetings in Bethesda and Philadelphia, to discuss technical and other problems associated with this research, and the potential for using these findings to develop new diagnostic and therapeutic approaches for SV40-associated malignancies

The oncoprotein of simian virus-40, SV40 large T-antigen (Tag), is reported to target and to inactivate growth suppressive proteins such as the retinoblastoma family and p53 (ref. 4, 5), leading to transformation of human cell lines in vitro, tumor production in rodents, and detection of Tag in several human cancers including mesotheliomas. The retinoblastoma family contains three members, pRb, p107 and pRb2/p130 (ref. 9), that are phosphorylated in a cell cycle-dependent manner, have cell growth suppressive properties and bind to specific members of the E2F family and various cyclins. Even though mesotheliomas are among the most aggressive human cancers, alterations of important cell-cycle 'controllers,' such as the Rb family genes, have never been reported in these tumors. We found the presence of SV40-like sequences in 86% of 35 archival specimens of mesothelioma. We also demonstrated that SV40 Tag, isolated from frozen biopsies of human mesothelioma, binds each of the retinoblastoma family proteins, pRb, p107 and pRb2/p130, in four of four specimens. We propose that the tumorigenic potential of SV40 Tag in some human mesotheliomas may arise from its ability to interact with and thereby inactivate several tumor and/or growth suppressive proteins

We found that simian virus 40 (SV40) induces mesotheliomas in hamsters and that 60% of human mesotheliomas contain and express SV40 sequences, results now confirmed by others [ref. 3-5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallE, and H.I.P. at 'Simian virus 40: A possible human polyoma virus,' NIH workshop, 27-28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington, DC 20008)]. Mesothelioma, an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardial and peritoneal cavities. The incidence of mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. However, at least 20% of mesotheliomas in the United States are not associated with asbestos exposure, and only a minority of people exposed to high concentrations of asbestos develop mesothelioma. Thus, other carcinogens may induce mesothelioma in individuals not exposed to asbestos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expression of the SV40 large T-antigen (Tag) interferes with the normal expression of the tumor suppressor gene p53 in human mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a cellular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate that the possibility that SV40 contributes to the development of human mesotheliomas should be carefully investigated