Influence of hepatic artery occlusion and desferrioxamine on liver-tumour growth

Thde mechanisms behind tumour regression during ischaemic therapy of liver malignancy are not thoroughlhd elucidated. Ischaemia-reperfusion injury and release of free radicals is one mechanism suggested. The aim of the present study was to explore whether inhibition of hydroxyl radicals, by complex binding Fe⁺⁺⁺ with desferrioxamine (DFO), counteracted the retardation in tumour growth rate after HAL and whether DFO in itself had an effect on tumour growth in 2 experimental rat liver tumours. Rats with a hepatoma or an adenocarcinoma were subjected to HAL or to a sham procedure with or without additional injections of DFO daily for 2 or 7 days. HAL had an inhibitory effect on tumour growth rate. The effect of HAL was not counteracted by DFO, while DFO alone caused a decrease in tumour volume. There was an additive effect of DFO and HAL on tumour growth rate in both tumour systems. In vitro there was a growth inhibitory effect of DFO in both tumours, more pronounced in the hepatoma than in the adenocarcinoma. Our findings indicate that the effect of HAL is not mediated by release of oxygen free radicals. In the adenocarcinoma system, an additive effect of DFO and HAL was seen. As a rate-limiting enzyme for DNA synthesis is dependent on iron, depletion of iron can decrease mitotic activity, a mechanism that could explain the effect of DFO on tumour growth.     

Dacarbazine versus dacarbazine-vindesine in disseminated malignant melanoma: a randomized phase II study

In a phase II study 119 patients with disseminated malignant melanoma were randomized to receive treatment with dacarbazine alone or in combination with vindesine. The study was designed to reveal an additive response rate when the drugs were combined. Dacarbazine was given i.v. at 250 mg m-2 per day X V every 4 weeks. In the combination regimen vindesine given at 3 mg m-2 per week was included. One hundred and ten patients were available for evaluation of response. With dacarbazine 4/51 patients obtained a complete remission (8%) and 5/51 patients a partial remission (10%). Overall response rate was 18%. With dacarbazine-vindesine 8/59 patients obtained a complete remission (13%) and 7/59 patients a partial remission (12%). Overall response rate was 25%. The difference in response rates observed between the treatment arms is not statistically significant. Median response duration was 123 days for dacarbazine patients and 171 days for patients receiving dacarbazine-vindesine (difference not statistically significant).     

Effect on liver tumor growth in rats of allopurinol and 5-fluorouracil in combination with hepatic artery ligation

Summary Rats with an experimental solitary liver tumor of a nitrosoguanidine-induced colonic adenocarcinoma were subjected to hepatic artery ligation (HAL) alone or in combination with 5-fluorouracil (5-FU) in three different doses, with or without the addition of allopurinol. The drugs were injected i.p. on 3 consecutive days before or after the HAL procedure. HAL alone significantly reduced the tumor growth compared with the control procedure (P<0.001). This observation was correlated with a significantly prolonged survival for the ligated animals (P<0.01). The administration of a low dose of 5-FU (15 mg/kg per day) in combination with allopurinol (100 mg/kg per day) enhanced tumor growth compared with that in animals treated with 5-FU only (P<0.01) or nontreated animals (P<0.05). A significant increase in survival was observed in animals given a high dose of 5-FU (60 mg/kg per day) after HAL compared with nontreated animals (P<0.001) as well as animals subjected to HAL alone (P<0.02). All animals receiving more than 15 mg/kg per day 5-FU before HAL succumbed within 10 days. The addition of allopurinol did not protect the animals against this mortality. These observations indicate that the effect of HAL followed by 5-FU is dose-dependent and that, at least in this treatment modality, allopurinol does not modulate the toxicity of 5-FU.This study was supported by Swedish Medical Research Council grants B85-17X-07184-01A, B86-04X-07155-02B, and B87-04X-07155-03A and the Wellcome Foundation     

Effects of human interferon preparations on neutrophil function

We have studied effects of two partially purified human leukocyte (alpha) interferon (IFN) preparations (PIF-A and PIF-B) and a highly purified fibroblast (beta) IFN on the functional activity of normal human neutrophils (PMNs). In vitro, PIF-B conferred a significant and dose-dependent enhancement of chemiluminescence (CL) induced both by phagocytosis and a soluble stimulus, f-Met-Leu-Phe, and decreased killing of Staph. aureus. In contrast, PIF-A caused only a slight inhibition of bactericidal activity and had no effects on CL. beta-IFN had no effects on either bactericidal activity or CL. Migration under agarose was decreased with all of the IFN but phagocytosis and release of enzymes was not affected. PMNs from seven patients treated with PIF-A for multiple myeloma exhibited increased CL responses but no other PMN functions were affected. The findings that human IFN preparations affect PMN functions indicate that high-dose IFN therapy of immunocompromised patients should be carefully evaluated for the possibility of increased infectious complications.     

Quantitative measurements of collateral arterial blood flow in nonarterialized rat liver grafts

The early development of arterial blood flow in the grafted liver after orthotopic liver transplantation in the rat without reconstruction of the hepatic artery was studied. Arterial liver blood flow was measured on day 21 after transplantation with NEN-TRAC microspheres (size 15.5±0.1 m) and labelled with ¹⁰³Ru. The arterial liver blood flow in the grafted liver was 0.778±0.247 ml/min per gram for transplanted rats after 21 days. One day after transplantation, the blood flow was only 0.006±0.002 ml/min per gram. The results of this study demonstrate that there was no arterial blood flow on day 1 after transplantation, as expected, but that there was a high arterial blood flow in the transplanted liver by day 21. This was also supported by the angiographic findings. The early development of arterial blood flow via collaterals may account for the excellent results that we and others have attained in orthotopic liver transplantation without rearterialization in the rat.     

Liver metastases found by follow-up of patients operated on for colorectal cancer.

One hundred and twenty-six patients earlier operated on for colorectal cancer were followed-up once yearly with serum screening tests. The activities of alkaline phosphatase (AP) and gammaglutamyltranspeptidase (GT) were recorded. 58 patients had positive tests. The majority of the patients with liver metastases (20/21) was possible to encircle with these simple serum tests. 38 of the 58 "screening positive patients" were further investigated with celiac angiography and/or liver scintigraphy and liver metastases were very suspect in 29 of these patients. 18 of them were laparotomized and the suspicion was verified in 8.7 of these patients could be subjected to surgery against their liver tumours and 2 of them have then survived more than 2 years. The authors suggest a follow-up system with shorter interval between the examinations.     

Lymphoscintigraphy in patients with malignant melanoma: A quantitative and qualitative evaluation of its usefulness

Lymphoscintigraphy using ^99mTcSb₂S₃ colloid was performed in 32 patients with malignant melanoma. Subcutaneous injections were made peritumorally in 20 patients and dorsopedally in 12 patients. Regional lymph node dissections were carried out on the following day in 16 patients and the resected lymph nodes were weighed, measured for radioactivity, and examined by light microscopy.Lymph flow to regional lymph nodes was shown in all but 2 patients. Twenty-nine of 239 lymph nodes contained metastases. Radioactivity was demonstrated in 17 of these nodes. In 5 of 11 patients with metastatic disease, the highest uptake was found in cancerous lymph nodes. The specific activity-uptake distribution in isolated ilio-inguinal lymph nodes after a dorsopedal injection was log-normal with a mean of 0.05%/g indicating a good saturation of colloid particles.This investigation concludes that the observed lymph flow directions in patients injected peritumorally are of value for the follow-up. Quantitative lymphoscintigraphy in patients with melanoma of the lower extremities is, however, of no value for excluding ilio-inguinal lymph node metastases.     

Postoperative radiation therapy in mammary carcinoma stage II. Target volume, organs at risk, absorbed dose, time-dose schedule, and dose to organs at risk in a prospective investigation

A standardized programme for postoperative radiation therapy of carcinoma of the breast stage II is reported. The target volume and the organs at risk are defined, and the target absorbed dose and fractionation are specified. The irradiation techniques is briefly described.     

Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous Vasopressin in non-resectable pancreas cancer

Background: Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity.Aim: To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer.Patients/methods: Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal5-FU instillation 750–1500 mg/m² and intravenous Leucovorin 100 mg/m² for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed.Results: The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8–54.1+), and median survival was 8.0 months (0.8–54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4 ± 2.5 and 6.1 ± 5.4 mol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment.Conclusion: Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.