Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors.

Malignant mesothelioma is an aggressive neoplastic proliferation derived from cells lining serosal membranes. The biological and clinical characteristics of epithelial type malignant mesothelioma are distinct from those of biphasic and sarcomatous type tumors. The goal of our study was to examine the molecular basis for this distinction. Microarray analysis confirmed that the molecular signatures of epithelial and biphasic histologic subtypes were distinct. Among the differentially expressed functional gene categories was the ubiquitin-proteasome pathway, which was upregulated in biphasic tumors. Cytotoxicity experiments indicated that 211H cells derived from biphasic tumors were synergistically sensitive to sequential combination regimens containing the proteasome inhibitor bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of epithelial tumor origin, was apoptosis. Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients.

Two-stage operative cytoreduction and intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma: Operative morbidity and mortality in phase I and II trials.

AIMS: The standard of care for diffuse malignant peritoneal mesothelioma involves operative cytoreduction and intraperitoneal chemotherapy. Most centers favor aggressive operative cytoreduction, accepting high morbidity and mortality. In our trials, patients underwent less extensive cytoreduction followed by prolonged intraperitoneal chemotherapy. Patients underwent a second cytoreduction with heated intraperitoneal chemotherapy. We hypothesized this would result in lower operative morbidity and mortality with similar survival. METHODS: Hospital records, discharge summaries, microbiology, radiography, and office records were retrospectively reviewed to supplement a prospective database. 30-day morbidity and mortality were categorized, and classified according to the Clavien methodology. RESULTS: 47 first and 39 second operations were performed with 13% and 26% morbidity, respectively. Mortality was 2%. Infections comprised 59% of the morbidity. Inclusive of both operations, formal peritonectomy was performed in 16% of patients, resection of isolated lesions in less than half, and only 19% had a visceral organs other than the spleen resected. At the completion of the protocol, only 3% of patients had visible intraperitoneal disease. The mean total length of stay for both operations combined was 16 ± 23 days. Overall median survival was 54.9 months, and median survival for the epithelioid subtype was 70.2 months. CONCLUSIONS: A two-stage cytoreduction with intraperitoneal chemotherapy offers median survival comparable to one-stage protocols, with relatively low morbidity, mortality, visceral resections and length of stay despite two operations. This series supports that our protocol is a feasible and safe approach.