Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon and rapidly fatal tumor.Therapeutic options have traditionally been limited and ineffective.The biologic and molecular events correlated with poor responsiveness to therapy are still poorly understood.In recent years,an innovative treatment approach involving aggressive cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has reportedly resulted in improved outcome,as compared to historical controls.Since 1995,at the National Cancer Institute (NCI) of Milan (Italy),patients with DMPM have been treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC).In the present paper,clinical experiences and basic science investigations on DMPM at Milan NCI are reviewed.Perioperative and long-term outcome results with CRS and HIPEC are presented.Clinico-pathological prognostic factors were investigated by multivariate analysis.The pathologic features and immunohistochemical markers related to DMPM biologic behavior were assessed in a large case-series uniformly treated at our institution.The prevalence and prognostic role of telomere maintenance mechanisms,which account for the limitless cell replicative potential of many malignancies,were studied.The dysregulation of the apoptotic pathways may play a role in the relative chemo-resistance of DMPM and a better understanding of apoptosis-related mechanisms could result in novel targeted therapeutic strategies.On this basis,the expression of survivin and other IAP family members (IAP-1,IAP-2,and X-IAP),the pro-apoptotic protein Smac/DIABLO,and antigens associated with cell proliferation (Ki-67) and apoptosis (caspase-cleaved cytokeratin-18) were analyzed.Finally,analyses of EGFR,PDGFRA and PDGFRB were performed to ascertain if deregulation of RTK could offer useful alternative therapeutic targets. Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon and rapidly fatal tumor. Therapeutic options have traditionally been limited and ineffective. The biologic and molecular events correlated with poor responsiveness to therapy are still poorly understood. Recent years, an innovative treatment approach involving aggressive cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has reportedly resulted in improved outcome, as compared to historical controls .ince 1995, at the National Cancer Institute (NCI) of Milan (Italy), patients with DMPM have been treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) .In the present paper, clinical experiences and basic science investigations on DMPM at Milan NCI are reviewed. Perioperative and long-term outcome results with CRS and HIPEC are presented. Clinico-pathological prognostic factors were investigated by multivariate analysis. pathologic features and immunohistochemical markers related to DMPM bio logic behavior were assessed in a large case-series uniformly treated at our institution. prevalence and prognostic role of telomere maintenance mechanisms, which account for the limitless cell replicative potential of many malignancies, were studied. dysregulation of the apoptotic pathways may play a role in the relative chemo-resistance of DMPM and a better understanding of apoptosis-related mechanisms could result in novel targeted therapeutic strategies. On this basis, the expression of survivin and other IAP family members (IAP-1, IAP-2, and X -IAP), the pro-apoptotic protein Smac / DIABLO, and antigens associated with cell proliferation (Ki-67) and apoptosis (caspase-cleaved cytokeratin-18) .Finally, analyzes of EGFR, PDGFRA and PDGFRB were performed to ascertain if deregulation of RTK could offer useful alternative therapeutic targets.