Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia, tumour necrosis factor alpha and melphalan.

AIMS: To determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan (Alkeran) under mild hyperthermic conditions. METHODS: A phase I trial was performed. Eleven patients with unresectable metastatic malignancies in the liver were pre-treated with 3 x 10(6) U leukocyte IFN daily 2 days before the perfusion. The liver was isolated and inflow catheters inserted in the hepatic artery and the portal vein. The hepatic veins were drained via a catheter in the retrohepatic caval vein. The venous blood flow from the lower extremities and the splanchnic circulation was bypassed to the axillar vein. The liver circuit was perfused with oxygenated blood and 30-200 microg TNF-alpha was added. At 39 degrees C in the liver circuit 0.5 mg/kg melphalan was added and the perfusion was continued for 1 h. RESULTS: Six patients underwent re-operation due to post-operative bleeding. Two patients died of coagulopathy or multiple organ failure within the first post-operative month. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma showed a partial response while no patients with liver metastases from colorectal cancer showed any response. The mean survival time was 20 months, which is within the same range as seen in previous isolated hepatic perfusion (IHP) studies. CONCLUSIONS: IHP with this drug regimen is a method with a considerable toxicity, though it is hard to distinguish between toxicity from TNF-alpha and that from the perfusion procedure itself. The method was not effective in patients with colorectal liver metastasis, but the results in melanoma and leiomyosarcoma patients warrant further studies.

Indication for isolated hyperthermic liver perfusion: a surgeon's view.

Isolated hyperthermic liver perfusion is a transitional therapy, i.e. a therapy between evidence based, standard therapy and experimental therapy. It appears to provide distinct benefits in a number of situations but the scientific evidence is still incomplete. In our view the present indications for use of isolated hyperthermic perfusion of the liver are: to gain more knowledge; nonresectable liver metastases without proven extrahepatic growth from: uveal melanoma, colorectal carcinoma, and ovarian cancer; symptoms related to hepatic metastases from endocrine tumors. A multicenter study aimed at gaining more knowledge is recommended.

In vivo 31P NMR OSIRIS of bioenergetic changes in rabbit kidneys during and after ischaemia: effect of pretreatment with an indeno-indole compound.

Changes in energy phosphates of rabbit kidneys subjected to ischaemia-reperfusion have been measured in vivo with volume selective 31P NMR spectroscopy. The effects of pretreatment with a new lipid peroxidation inhibitor (indeno-indol derivate--code name H290/51) on the bioenergetic changes were analysed. The left kidney was moved to a subcutaneous pocket to facilitate exact positioning over the surface coil. A 1H NMR image was acquired and a 3.5-mL cube selected for 31P NMR spectra. 31P NMR spectra were recorded before occlusion of the left renal artery, during 1 h of ischaemia and 2 hours of reperfusion. Ischaemia induced drastic changes in the levels of inorganic phosphates and ATP as well as intracellular acidosis. A normalization was observed during reperfusion. Two hours after reperfusion significantly higher values for beta-ATP/Pi and intracellular pH were recorded in the animals pretreated with H290/51. The present technique allows quantitative analyses of changes in kidney bioenergetics in vivo during different experimental conditions. The importance of ischaemia-reperfusion induced lipid peroxidation for mitochondrial function is emphasized.

Purine nucleotides and phospholipids in ischemic and reperfused rat skeletal muscle: effect of ascorbate.

The effect of intravenously administered ascorbate on the ischemic and reperfused rat skeletal muscle was investigated. Purine nucleotides and phospholipids in skeletal muscle from rats subjected to 4 h of ischemia followed by 1-h reperfusion were analyzed by high-performance liquid chromatography. In addition, ATP, phosphocreatine (PCr), Pi, and phosphomonoesters (PME) were analyzed by 31P-nuclear magnetic resonance at 202.4 MHz, and individual PME such as glucose-6-phosphate and IMP were quantified. PCr and ATP were exhausted after 4 h of ischemia and recovered poorly upon reperfusion in the soleus and tibialis muscle of untreated rats. Postischemic reperfusion resulted in significant loss of cardiolipin. Treatment with 55 mM ascorbate resulted in total restoration of PCr during reperfusion, and ATP recovered to 42% of control in the soleus. Recovery was improved in the tibialis as well, and the cardiolipin decrease was limited. A lower ascorbate concentration (5 mM) did not enhance postischemic recovery. Our findings show that a high dose of ascorbate improves the energetic state of rat skeletal muscle during postischemic reperfusion, probably due to its antioxidant function.

Isolated hyperthermic liver perfusion with chemotherapy for liver malignancy.

In an open study of unresectable liver tumours, isolated regional perfusion with hyperthermia and cytotoxic drugs has been tested in 29 patients. Four patients had primary hepatocellular cancer, 10 patients had metastases from malignant melanoma, remaining from breast cancer, colorectal cancer, midgut carcinoids and miscellaneous primaries. At laparotomy the proper hepatic artery and portal vein were canulated and connected to a pump oxygenator. The inferior vena cava was canulated with a triple lumen catheter (Perfufix) allowing for porto-caval shunting, drainage of lower body and renal veins to the heart and separate drainage of liver veins to the pump oxygenator. Liver perfusion was performed with a mean flow of 900 ml per min. Melphalan and cis-platinum 0.5 mg/kg body-weight were added to the perfusate for 1 h after liver temperature reached 40 degrees C. Four patients died within 30 days of perfusion due to multiple organ failure. These patients had more than 50% of liver volume occupied by cancer. All surviving patients developed reversible hepato- and renal toxicity. Partial tumour regression was registered in 20% of the patients. Five patients have survived more than three years. Hyperthermic liver perfusion is feasible but in patients with massive liver tumour, there is a significant risk of developing multiple organ failure.

Adjuvant treatment with ursodeoxycholic acid reduces acute rejection after liver transplantation.

Acute rejection, occurring with a reported frequency of 50-70%, is still a dominating problem after liver transplantation. Medication with ursodeoxycholic acid (UDCA) has beneficial effects in different cholestatic conditions and has also been shown to reduce HLA class I antigen expression on hepatocytes in patients with PBC. Since August 1989 we have consecutively treated all patients with primary graft function with UDCA (n = 41). Patients transplanted in the first half of 1989 served as a control group (n = 8). All patients in this study were given sequential quadruple drug immunosuppression. The treatment group were given oral UDCA 10 mg/kg per day. During the first postoperative month, 17% of the UDCA-treated patients had an episode of acute rejection compared with 75% of the control patients (P < 0.01). Liver biochemistry tests 1 month postoperatively were significantly better in patients treated with UDCA. The results suggest that adjuvant treatment with UDCA reduces acute liver graft rejection.

Leg exchange of amino acids during exercise in patients with arterial insufficiency.

Intermittent claudication is associated with adaptation in muscle metabolism. This study has evaluated the metabolism of amino acids at rest and during non-steady state exercise in patients with arterial insufficiency of at least six months duration in comparison with matched control individuals. The exchange of amino acids were measured during two periods of acute exercise; one initial exercise period with a standardized work load and exercise time and a second exercise period which continued until further exercise was impossible due to pain in the patients and exhaustion in the controls. The maximum blood flow was reduced by 40% in the patients but the maximum oxygen uptake per unit power developed was almost the same in patients and controls. The patients had significantly lower concentrations of glutamine, lysine and taurine at rest compared with the controls. The exchange of amino acids across the resting leg did not differ between the two groups. Exercise increased the efflux of amino acids in both patients and controls. The efflux of glutamine (896 +/- 205 vs. 48 +/- 359 nmol/100 ml/min/watt) was higher in the patients compared to the controls at the first exercise period with inverse changes in the opposite direction of asparagine (149 +/- 105 vs. 799 +/- 121 and 27 +/- 70 vs. 633 +/- 334 nmol/100 ml/min/watt at the first and second exercise, respectively. Alanine release did not differ between the groups. The complementary patterns of glutamine and asparagine during hypoxic exercise in the patients may reflect the fact that these amino acids share a common carrier system. The similarity in the efflux of non-metabolized amino acids, such as methionine, phenylalanine, tyrosine and 3-methylhistidine, indicated that muscle hypoxia in claudication patients did not promote net degradation of either globular or myofibrillar proteins, although exercise increased the efflux of 3-methylhistidine three- to fourfold in both patients and control individuals (from 1 +/- 0.4 to 4 +/- 1.8 and from 0 +/- 0.7 to 6 +/- 2.5 nmol/100 ml/min/watt, respectively). The exercise-induced alterations in leg exchange of amino acids were restored within 10-20 min following exercise regardless of hypoxia. The results demonstrate that patients with arterial insufficiency have altered intermediary metabolism of amino acids during exercise. However, muscle hypoxia in such patients does not seem to promote a negative protein balance or induce serious alterations in cell membrane integrity.

Total parenteral nutrition as an adjuvant to patients undergoing chemotherapy for testicular carcinoma: protection of body composition--a randomized, prospective study.

The efficacy of total parenteral nutrition (TPN) in the protection of body composition, when given as an adjuvant to CVB (cisplatin-vinblastine-bleomycin) treatment to patients with testicular teratocarcinoma, was investigated. Twenty-three patients without previous malnutrition were randomized to receive either TPN or spontaneous oral intake only during their hospital stay, in the course of a total treatment period of 10 weeks. The patients spent weeks 1, 4, 7, and 10 in the hospital to undergo chemotherapy. Energy and nitrogen intakes were profoundly decreased in the spontaneous oral-intake group, whereas the intakes decreased in the TPN group only at home when they relied on oral intake. In spite of the cytotoxic drugs, the TPN group remained in nitrogen balance when undergoing TPN at the hospital. However, they lost substantial body weight and body nitrogen over 10 weeks when compared with the oral-intake group. This loss in body mass was mainly a result of the prolonged anorexia that all the patients had after weekly termination of chemotherapy. This study demonstrates that well-nourished patients can use intravenous nutrition even while receiving cytocidal and cytostatic drug administration. However, intermittent periods of adequate nutrition in the hospital had only a marginal impact, since the positive effects of nutrition were offset by the pronounced anorexia that occurred in all patients outside the hospital for a considerable time after cytostatic treatment.