http://repub.eur.nl/res/aut/12075/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/30052/ 2008-05-01T00:00:00Z Background: Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure. We developed an isolated hypoxic hepatic perfusion (IHHP) with retrograde outflow without the need for a heart-lung machine. Patients and Methods: Twenty-four consecutive patients with irresectable metastases of various origins were treated. IHHP inflow was via the hepatic artery, outflow via the portal vein with occlusion of the retrohepatic caval vein. Radiolabeled albumine was used for leakage monitoring. Melphalan was used at 1-2 mg/kg. A 25-minute perfusion period was followed by a complete washout. Local and systemic melphalan concentrations were determined. Results: Compared with oxygenated classical IHP, the IHPP procedure reduced operation time from >8 h to 4 hours, blood loss from >4000 to 900 cc and saved material and personnel costs. Leakage was 0% with negligible systemic toxicity and 0% perioperative mortality. Tumor response: complete response (CR) in 4%, partial response (PR) in 58%, and stable disease (SD) in 13%. Median time to progression was 9 months (2-24 months); pharmacokinetics demonstrated intrahepatic melphalan concentrations more than 9 fold higher than postperfusion systemic concentrations. Conclusions: IHPP is a relatively simple procedure with reduced costs, reduced blood loss, no mortality, limited toxicity, and response rates comparable to classic IHP. The median duration of 9 months of tumor control should be improved. Hereto, vasoactive drugs, will be explored in further studies. http://repub.eur.nl/res/pub/36108/ 2007-04-01T00:00:00Z Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting. http://repub.eur.nl/res/pub/13410/ 2004-12-01T00:00:00Z BACKGROUND: Isolated hepatic perfusion for irresectable metastases confined to the liver has reported response rates of 50% to 75%. Magnitude, costs, and nonrepeatability of the procedure are its major drawbacks. We developed a less invasive, less costly, and potentially repeatable balloon catheter-mediated isolated hypoxic hepatic perfusion (IHHP) technique. METHODS: In this phase I and II study, 18 consecutive patients with irresectable colorectal or ocular melanoma hepatic metastases were included. Two different perfusion methods were used, both with inflow via the hepatic artery, using melphalan 1 mg/kg. In the first eight patients, the portal vein was occluded, and outflow was via the hepatic veins into an intracaval double-balloon catheter. This orthograde IHHP had on average 56% leakage. In next 10 patients, we performed a retrograde outflow IHHP with a triple balloon blocking outflow into the caval vein and allowing outflow via the portal vein. The retrograde IHHP still had 35% leakage on average. RESULTS: Although local drug concentrations were high with retrograde IHHP, systemic toxicity was still moderate to severe. Partial responses were seen in 12% and stable disease in 81% of patients. The median time to local progression was 4.8 months. CONCLUSIONS: We have abandoned occlusion balloon methodology for IHHP because it failed to obtain leakage control. We are presently conducting a study using a simplified surgical retrograde IHHP method, in which leakage is fully controlled, which translates into high response rates. http://repub.eur.nl/res/pub/13544/ 2004-11-03T00:00:00Z BACKGROUND: We have previously shown how tumor response of isolated limb perfusion (ILP) with melphalan was improved when tumor necrosis factor alpha (TNF-alpha) was added. Taking into account that other vasoactive drugs could also improve tumor response to ILP, we evaluated histamine (Hi) as an alternative to TNF-alpha. METHODS: We used a rat ILP model to assess the combined effects of Hi and melphalan (n = 6) on tumor regression, melphalan uptake (n = 6), and tissue histology (n = 2) compared with Hi or melphalan alone. We also evaluated the growth of BN-175 tumor cells as well as apoptosis, necrosis, cell morphology, and paracellular permeability of human umbilical vein endothelial cells (HUVECs) after Hi treatment alone and in combination with melphalan. RESULTS: The antitumor effect of the combination of Hi and melphalan in vivo was synergistic, and Hi-dependent reduction in tumor volume was blocked by H1 and H2 receptor inhibitors. Tumor regression was observed in 66% of the animals treated with Hi and melphalan, compared with 17% after treatment with Hi or melphalan alone. Tumor melphalan uptake increased and vascular integrity in the surrounding tissue was reduced after ILP treatment with Hi and melphalan compared with melphalan alone. In vitro results paralleled in vivo results. BN-175 tumor cells were more sensitive to the cytotoxicity of combined treatment than HUVECs, and Hi treatment increased the permeability of HUVECs. CONCLUSIONS: Hi in combination with melphalan in ILP improved response to that of melphalan alone through direct and indirect mechanisms. These results warrant further evaluation in the clinical ILP setting and, importantly, in organ perfusion. http://repub.eur.nl/res/pub/8981/ 1998-01-01T00:00:00Z OBJECTIVE: To validate the methodology of isolated hypoxic hepatic perfusion (IHHP) using balloon catheter techniques and to gain insight into the distribution of tumor necrosis factor-alpha (TNF), melphalan, and mitomycin C (MMC) through the regional and systemic blood compartments when applying these techniques. SUMMARY BACKGROUND DATA: There is no standard treatment for unresectable liver tumors. Clinical results of isolated limb perfusion with high-dose TNF and melphalan for the treatment of melanoma and sarcoma have been promising, and attempts have been made to extrapolate this success to the isolated liver perfusion setting. The magnitude and toxicity of the surgical procedure, however, have limited clinical applicability. METHODS: Pigs underwent IHHP with TNF, melphalan, and MMC using balloon catheters or served as controls, receiving equivalent dosages of these agents intravenously. After a 20-minute perfusion, a washout procedure was performed for 10 minutes, after which isolation was terminated. Throughout the procedure and afterward, blood samples were obtained from the hepatic and systemic blood compartments and concentrations of perfused agents were determined. RESULTS: During perfusion, locoregional plasma drug concentrations were 20- to 40-fold higher than systemic concentrations. Compared with systemic concentrations after intravenous administration, regional concentrations during IHHP were up to 10-fold higher. Regional MMC and melphalan levels steadily declined during perfusion, indicating rapid uptake by the liver tissue; minimal systemic concentrations indicated virtually no leakage to the systemic blood compartment. During isolation, concentrations of TNF in the perfusate declined only slightly, indicating limited uptake by the liver tissue; no leakage of TNF to the systemic circulation was observed. After termination of isolation, systemic TNF levels showed only a minor transient elevation, indicating that the washout procedure at the end of the perfusions was fully effective. CONCLUSIONS: Complete isolation of the hepatic vascular bed can be accomplished when performing IHHP using this balloon catheter technique. Thus, as in extremities, an ideal leakage-free perfusion of the liver can now be performed, and repeated, without major surgery. The effective washout allows the addition of TNF in this setting.