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Mesothelioma and New Comprehensive Approach of Cytoreductive Surgery
Another interesting study is called, "Abdominal computed tomography scans in the selection of patients with malignant peritoneal mesothelioma for comprehensive treatment with cytoreductive surgery and perioperative intraperitoneal chemotherapy" by
Tristan D. Yan M.D., Namic Haveric M.D., Carlos P. Carmignani M.D., David Chang M.S., Paul H. Sugarbaker M.D. – Cancer Volume 103, Issue 4, pages 839–849, 15 February 2005. Here is an excerpt: "Abstract – BACKGROUND - Malignant peritoneal mesothelioma is a rare and fatal disease. Until recently, the treatment options were very limited and ineffective. The new comprehensive approach of cytoreductive surgery with perioperative intraperitoneal chemotherapy offers improved survival rates at a cost of considerable morbidity and mortality as in other peritoneal surface malignancies. The outcome after these treatments is predominantly dependent on adequate cytoreduction. The aim of the current study was to identify computed tomography (CT) scan images that are useful in patient selection for this comprehensive approach.
METHODS - An analysis of the preoperative CT scans of 30 patients with peritoneal mesothelioma treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy at a single institution was performed. Based on the size of residual tumor nodules after cytoreductive surgery, patients were divided into 2 groups: those with residual lesions ≤ 2.5 cm (adequate cytoreduction) and those with residual lesions > 2.5 cm (suboptimal cytoreduction). The CT scans for each patient were evaluated by a standardized scoring system with the reader blinded to the operative findings. Thirty-nine CT scan parameters were obtained and statistically analyzed to determine their association with the study outcome variables, namely, adequacy of cytoreduction.
RESULTS - Seven patients (64%) in the suboptimal cytoreduction group and 2 patients (11%) in the adequate cytoreduction group had a > 5-cm tumor mass in the epigastric region (P = 0.004). Nine patients (82%) in the suboptimal group and 2 patients (11%) in the adequate cytoreduction group had CT scans that showed loss of normal architecture of the small bowel and its mesentery (P < 0.001). In a composite analysis of these 2 radiologic features, none of the patients with a > 5-cm tumor mass in the epigastric region and loss of normal architecture of the small bowel and its mesentery had an adequate cytoreduction. Patients who lacked these two preoperative CT scan findings had a 94% probability of an adequate cytoreduction.
CONCLUSIONS - CT scans effectively identified large peritoneal mesothelioma tumors at crucial anatomic sites. Because adequate cytoreduction is necessary to achieve prolonged survival, CT scans became an accurate prognostic radiologic test for patient selection for comprehensive treatment.
Another interesting study is called, "Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12." By Caminschi I, Venetsanakos E, Leong CC, Garlepp MJ, Robinson BW, Scott B. Am J Respir Cell Mol Biol. 1999 Sep;21(3):347-56. Department of Medicine, University of Western Australia; Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, Nedlands, Australia. Here is an excerpt: "Abstract - Malignant mesothelioma (MM) is a solid tumor of the mesothelium for which there is no curative treatment. MM appears to be sensitive to immunotherapeutic approaches, and one of the most powerful immunomodulatory cytokines with antitumor effects is interleukin (IL)-12. We have previously shown in a murine model of MM that systemic administration of recombinant IL-12 induces a potent anti-MM immune response. The nature and accessibility of MM tumors means that they are suitable candidates for direct cytokine and gene-transfer therapeutic approaches. Therefore, we undertook a study to assess the antitumor effects induced by the local production of IL-12 within MM tumors by transfecting a murine MM line with the genes for IL-12. The IL-12 transfectant (AB1-IL-12) did not produce tumors in normal mice, but did so in athymic nude mice, implicating T cells in the prevention of MM tumor growth. In mixing experiments, paracrine IL-12 production inhibited growth of untransfected MM cells provided that cells producing IL-12 represented more than 50-80% of the inoculum. Furthermore, BALB/c mice previously challenged with AB1-IL-12 were protected against rechallenge with parental AB1 tumor, indicating that the transfectant induced long-term immunity. AB1-IL-12 induced systemic immunity that was effective at reducing the incidence of parental AB1 tumor at a distal site, but its effects were dose-dependent. Though both CD4(+) and CD8(+) cells infiltrated the rejecting tumor, CD8(+) effector cells were essential for protection against development of parental AB1 tumor. This study shows that paracrine secretion of IL-12, generated by gene transfer, can induce immunity against MM that can act locally and also at a distant site. In addition, there was no evidence of toxicity, which has been associated with the systemic administration of IL-12, indicating that this cytokine is a good candidate for experimental gene therapy in MM."
Another interesting study is called, "Anti-Tumor Activity of K1-LysPE38QQR, an Immunotoxin Targeting Mesothelin, a Cell-Surface Antigen Overexpressed in Ovarian Cancer and Malignant Mesothelioma" by Hassan, Raffit; Viner, Jaye L; Wang, Qing-Cheng; Margulies, Inger; Kreitman, Robert J; Pastan, Ira - Journal of Immunotherapy:
July/August 2000 - Volume 23 - Issue 4 - pp 473-479. Here is an excerpt: "Abstract - Mesothelin, a differentiation antigen, is a 40-kD glycosylphosphatidylinositol-linked cell-surface glycoprotein, that is present on the surface of normal mesothelium and is overexpressed in many patients with epithelial ovarian cancer and malignant mesotheliomas. Monoclonal antibody K1 is a murine immunoglobulin G1 that recognizes mesothelin. LysPE38QQR is a truncated form of Pseudomonas exotoxin that lacks the cell-binding domain, but retains the translocation and adenosine diphosphate-ribosylation domains. It has a single lysine residue near the amino terminus that is available for conjugation to antibodies. To prevent chemical conjugation of the antibody to lysine residues at the C-terminus of Pseudomonas exotoxin, the two lysine residues at positions 590 and 606 were mutated to glutamine, and the lysine residue at position 613 was mutated to arginine. Monoclonal antibody K1 was chemically conjugated with LysPE38QQR , by modifying the antibody with sulfo-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate and coupling it with SPDP N-succinimidyl 3-(2-pyridyldithio)propionate-modified LysPE38QQR. The resulting immunotoxin K1-LysPE38QQR was highly toxic to A431-K5 cells (a human epidermoid carcinoma cell line transfected with a mesothelin expression plasmid) with a half-maximal inhibitory concentration of 3-6 ng/mL. The immunotoxin had negligible activity against A431 cells, which do not express mesothelin (median inhibitory concentration > 100 ng/mL). This immunotoxin also caused complete regression of tumors in nude mice that received xenografts of mesothelin-positive human carcinomas. These results show that immunotoxins directed against mesothelin are a therapeutic option that merits further investigation for the treatment of ovarian cancer and malignant mesotheliomas."
About the Author
Monty Wrobleski is the author of this article. For more information please click on the following links
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