http://repub.eur.nl/res/aut/7568/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/32736/ 2010-04-22T00:00:00Z Background: Necrotizing pancreatitis with infected necrotic tissue is associated with a high rate of complications and death. Standard treatment is open necrosectomy. The outcome may be improved by a minimally invasive step-up approach. Methods: In this multicenter study, we randomly assigned 88 patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue to undergo primary open necrosectomy or a step-up approach to treatment. The step-up approach consisted of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy. The primary end point was a composite of major complications (new-onset multiple-organ failure or multiple systemic complications, perforation of a visceral organ or enterocutaneous fistula, or bleeding) or death. Results: The primary end point occurred in 31 of 45 patients (69%) assigned to open necrosectomy and in 17 of 43 patients (40%) assigned to the step-up approach (risk ratio with the step-up approach, 0.57; 95% confidence interval, 0.38 to 0.87; P = 0.006). Of the patients assigned to the step-up approach, 35% were treated with percutaneous drainage only. New-onset multiple-organ failure occurred less often in patients assigned to the step-up approach than in those assigned to open necrosectomy (12% vs. 40%, P = 0.002). The rate of death did not differ significantly between groups (19% vs. 16%, P = 0.70). Patients assigned to the step-up approach had a lower rate of incisional hernias (7% vs. 24%, P = 0.03) and new-onset diabetes (16% vs. 38%, P = 0.02). Conclusions: A minimally invasive step-up approach, as compared with open necrosectomy, reduced the rate of the composite end point of major complications or death among patients with necrotizing pancreatitis and infected necrotic tissue. (Current Controlled Trials number, ISRCTN13975868.). Copyright http://repub.eur.nl/res/pub/9540/ 2000-01-01T00:00:00Z OBJECTIVE: To evaluate the potential of isolated limb perfusion (ILP) for efficient and tumor-specific adenovirus-mediated gene transfer in sarcoma-bearing rats. SUMMARY BACKGROUND DATA: A major concern in adenovirus-mediated gene therapy in cancer is the transfer of genes to organs other than the tumor, especially organs with a rapid cell turnover. Adjustment of the vector delivery route might be an option creating tumor specificity in therapeutic gene expression. METHODS: Rat hind limb sarcomas (5-10 mm) were transfected with recombinant adenoviruses. Intratumoral luciferase expression after ILP was compared with systemic administration, regional infusion, or intratumoral injection using a similar dose of adenoviruses carrying the luciferase marker gene. Localization studies using lacZ as a marker gene were performed to evaluate the intratumoral distribution of transfected cells after both ILP and intratumoral injection. RESULTS: Intratumoral luciferase activity after ILP or intratumoral administration was significantly higher compared with regional infusion or systemic administration. After ILP, luciferase gene expression was minimal in extratumoral organs, whether outside or inside the isolated circuit. Localization studies demonstrated that transfection was confined to tumor cells lying along the needle track after intratumoral injection, whereas after ILP, lacZ expression was found in viable tumor cells and in the tumor-associated vasculature. CONCLUSIONS: Using ILP, efficient and tumor-specific gene transfection can be achieved. The ILP technique might be useful for the delivery of recombinant adenoviruses carrying therapeutic gene constructs to enhance tumor control. http://repub.eur.nl/res/pub/17509/ 1998-11-04T00:00:00Z Isolated limb perfusion (lLP) with high dose TNFa in combination with IFNr and melphalan in patients with melanoma in transit metastases confined to the limb has recently been reported to result in much higher complete tumor response rates than after the standard therapy of ILP with melphalan alone: 90 % vs 54 % complete remissionl .'. Moreover the same protocol of ILP when applied as an induction bio-chemotherapy in patients with irresectabIe extremity soft tissue sarcomas. was reported to result in about 85 % response rates rendering most tumors resectable and resulting in a > 80% limb salvage rate'·'. The tumor response in many patients in both patient groups was characterized by an immediate (within 3 days) and grossly visible reaction to treatment, which shows a remarkable similarity to that observed in animal tumor models after systemic administration of TNFa. ILP became the first setting, in which effective concentrations of TN Fa could be reached and a reproducible antitumor effect could be measured. In patients Lv. administration of TN Fa is limited to much lower doses than the effective doses in mice, since TNFa causes severe hypotension in man and is known to play a key role as a mediator in septic shock. Pathophysiologically, TNFa is a paracrine (and autocrine) mediator that is released at the inflammation site, with severe hypotensive effects when it is released systemically. Therefore the trials of systemic administration of TNFa, either alone or in combination with other cytokines or chemotherapy had marginal results.