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Background/Aims: The success of ana our extensive experience with TNF alpha-based isolated limb perfusions in patients with unresectable extremity soft tissue sarcomas made us explore the possibilities for a similar approach for the treatment of hepatic metastases. After experience with the classic surgical isolated hepatic perfusion in pigs and in patients, we concluded that the classic surgical approach was associated with serious drawbacks i.e., magnitude of the procedure with morbidity, lack of repeatability of the procedure, complexity and costs. These problems were addressed in a program aimed at developing a repeatable method of isolated perfusion of the liver with minimally invasive techniques. Methodology: We validated the methodology of isolated hypoxic hepatic perfusion using balloon catheter techniques in pigs. Results: The excellent pharmacokinetic profile of the procedure, resulting in very high regional drug concentrations and negligible systemic drug concentrations, allowed us to move on to the clinic and start to study and further develop this method in a phase I-II study using the drug melphalan, in patients with irresectable hepatic metastases. Conclusions: We aim to develop step by step a fully percutaneous approach for isolated hypoxic hepatic perfusion.

Administration of liposome-encapsulated immunomodulating agents muramyl tripeptide phosphatidyl ethanolamine (LE-MTPPE) or interferon-gamma (LE-IFN-gamma), or co-encapsulated MTPPE and IFN-gamma (LE-(MTPPE/IFN-gamma)) resulted in a dramatic increase of the nonspecific antimicrobial resistance in mice, as shown before. This kind of treatment is especially of use in immunocompromised hosts who are prone to severe infections. Application of these immunomodulators might protect these patients, e.g., transplant recipients, from opportunistic infections. However, accelerated rejection of the graft, resulting from augmentation of the antimicrobial defense in a nonspecific way, has to be avoided. In this study, the effect of treatment with LE-MT-PPE, LE-IFN-gamma, or LE-(MTPPE/IFN-gamma) on skin graft rejection in mice was investigated. It was found that prophylactic treatment of skin-grafted mice with immunomodulating formulations did not influence rejection of the graft. Moreover, in T cell-depleted mice, which showed a prolonged graft survival compared with immunocompetent recipients, the administration of immunomodulators did not change the survival time of the grafts compared with T cell-depleted mice that did not receive immunomodulators. The results clearly show that, in this experimental setting, application of the antimicrobial resistance-enhancing formulations (LE-MTPPE, LE-IFN-gamma, and LE-(MTPPE/IFN-gamma)) is allowed in graft-bearing recipients, without influencing graft survival.