Leukocyte activation by isolated hyperthermic liver and limb perfusion due to malignancy

Fourteen patients with liver tumor malignancy and sixteen patients with malignant melanoma localized to one limb were studied regarding leukocyte activation with the release of polymorphonuclear neutrophilic (PMN) elastase and of neopterin and formation of cytokines (TNF- and Il-6) during the surgical treatment. Patients undergoing liver resection (n=10), abdominal hysterectomy (n=10), or hip replacement surgery (n=10) served as control groups. Isolated hyperthermic liver perfusion was performed with cytostatic-containing perfusate (melphalan and cisplatinum). Patients with recurrent malignant melanoma confined to one limb underwent isolated hyperthermic limb perfusion with cytostatic-containing perfusate (melphalan). Blood samples for determination of PMN elastase, neopterin, TNF-, and IL-6 were drawn from the patients preoperatively, 1 minute before the start of the perfusion, 60 and 120 minutes after the start of the perfusion, and 24 hours postoperatively. Samples from the perfusate were drawn 60 minutes after the start of the perfusion. High concentrations of plasma PMN clastase were found both in patients undergoing liver and limb perfusion and in patients undergoing liver resection surgery. Elevated concentrations of Il-6 were found in the patients undergoing liver perfusion and in patients undergoing liver resection. In none of the patients were there increased concentrations of neopterin or TNF-. The perfusate contained high concentrations of PMN elastase, neopterin, and IL-6. This study also demonstrated that major surgery leads to elevated concentrations of PMN elastase and IL-6. An increase of PMN elastase and IL-6 was seen in response to perfusion and to surgical trauma.

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Resumen Catorce pacientes con tumores malignos del hígado y 16 pacientes con melanoma maligno localizado en una extremidad fueron estudiados en relación con la activación de leucocitos con liberación de elastasa de PMN y de neopterina y la formación de citocinas (FNT- e IL-6) en el curso del tratamiento quirúrgico. Pacientes sometidos a resección del hígado (n=10), histerectomía abdominal (n=10) y reemplazo de cadera (n=10) sirvieron como grupos control. Se realizó perfusión hipertérmica aislada del hígado con perfusato citostácico (melfalán y cisplatino). Los pacientes con melanoma maligno recurrente confinado a una extremidad fueron sometidos a perfusión hipertérmica aislada de la extremidad con perfusato citostácico (melfalán). Se tomaron muestras de sangre para determinación preoperatoria de elastasa de PMN, neopterina, FNT- e IL-6, un minuto antes de comenzar la perfusión, 60 y 120 minutos después del comienzo de la perfusión y 24 horas después de la operación. Se tomaron muestras del perfusato a los 60 minutos luego del comienzo de la perfusión. Se encontraron altas concentraciones de elastasa de PMN tanto en los pacientes sometidos a perfusión hepática o de la extremidad, como en los pacientes sometidos a resección hepática. Se encontraron concentraciones elevadas de IL-6 en los pacientes sometidos a perfusión hepática y en los pacientes sometidos a resección del hígado. En ningún paciente se encontraron concentraciones aumentadas de neopterina o de FNT-. El perfusato contenía altas concentraciones de elastasa de PMN, neopterina e IL-6. Se encontró un aumento en la elastasa de PMN y en la IL-6 en respuesta a la perfusión y al trauma quirúrgico.

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Résumé Quatorze patients ayant une tumeur maligne du foie et 16 patients ayant un mélanome malin localisé à une extrémité ont été étudiés en ce qui concerne l'activation des leucocytes associée à un relargage d'élastase PMN et de néoptérine ainsi que la formation de cytokinines (TNF- et IL-6) pendant le traitement chirurgical. Trente patients avant eu soit une résection hépatique (n=10), soit une hystérectomie abdominale (n=10) ou une prothèse de hanche (n=10) ont servi de témoins. On a perfusé le foie avec un perfusât de cytostatiques (mélphalane et cis-platine). Les patients ayant un mélanome malin d'une extrémité ont eu une perfusion isolée hyperthermique avec une perfusion de cytostatique (mélphanane). Des échantillons du sang ont été retirés pour déterminer les taux d'élastase PMN, de la néoptérine, du TNF-, et de l'IL-6 en préopératoire, une minute avant le début de la perfusion, 60 et 120 minutes après le début de la perfusion, et 24 heures postopératoirement. Des échantillons ont été retirés 60 minutes après le début de la perfusion. Des concentration élevées d'élastase PMN ont été retrouvées à la fois chez les patients ayant une perfusion hépatique et de l'extrémité et chez les patients ayant eu une résection du foie. Des concentration élevées en IL-6 ont été retrouvées chez le patient ayant une perfusion du foie et chez le patient ayant une résection hépatique. Les concentrations en néoptérine et en TNF- n'étaient pas élevées. Le liquide de perfusion contenait des concentrations élevées en élastase PMN, néoptérine et en IL-6. Cette étude démontre aussi que la chirurgie majeure est associée avec des concentrations élevées en PMN elastase et IL-6. Une augmentation en PMN-élastase et en IL-6 a été retrouvée en réponse à la perfusion et au traumatisme chirurgical.

     

Availability of iron and degree of inflammation modifies the response to recombinant human erythropoietin when treating anemia of chronic disease in patients with rheumatoid arthritis

Forty-six patients with rheumatoid arthritis (RA) and documented anemia of chronic disease (Hb <100/110 g/l) were randomized to receive either human recombinant erythropoietin (r-HuEPO, n = 36, 300 U/kg body weight) or placebo (n = 10) for 12 weeks in a multicenter study. An adequate response was defined as elevation of Hb≥120 g/l. Relevant clinical and laboratory assessments were made to evaluate efficacy and secure safety. A significant elevation in Hb from week 10 onwards was noted in twenty-six patients (five drop-outs) out of nine patients receiving placebo (one drop-out) (12±1.2 g/l vs 4±0.5 g/l; Hb elevation from 95 g/l to 107 g/l vs 93 g/l to 97 g/l, P<0.05). Only 14.6%, however, were considered responders according to preset criteria. In the responders a lower initial CRP, a significant reduction in ESR but not in CRP was seen compared to the remaining r-HuEPO group. A significant elevation of energy level was noted in the r-HuEPO group; otherwise, no differences in clinical variables were seen. No serious adverse effects were noted. When analyzing patients receiving oral iron in combination with r-HuEPO and adding five additional, openly selected patients receiving both adequate iron supplementation and r-HuEPO, there was a significant weekly elevation of Hb from week 8 onwards in favor of combination therapy over the ones only receiving r-HuEPO (18±1.1 g/l vs 7±1.1 g/l, P<0.05). The initial six responders had now reached ten of whom seven belonged to the combination therapy group. Response to r-HuEPO in RA patients appears to be dependent on availability of iron and on the degree of inflammation. If r-HuEPO treatment is considered, iron deficiency should always be corrected and strenous efforts should have been made to control the disease itself. Received: 21 February 1997 / Accepted: 21 April 1997     

Bone mineral density in men with rheumatoid arthritis is associated with erosive disease and sulfasalazine treatment but not with sex hormones

OBJECTIVE: To quantify bone mineral density (BMD) in men with rheumatoid arthritis (RA) and to evaluate the influence of various disease-specific and non-disease-specific variables on bone mass. METHODS: Dual energy x-ray absorptiometry was performed in 104 male patients with RA and BMD was measured in lumbar spine, femoral neck, trochanter, and Ward's triangle. Inflammatory activity, measured as Disease Activity Score including 28 joints (DAS28), degree of functional impairment measured with the Health Assessment Questionnaire, and sex hormones (bioavailable testosterone, DHEAS, estradiol, and estrone) were estimated. Presence of erosions, rheumatoid factor, and current treatment as well as body mass index and smoking habits were recorded. Correlations were performed with nonparametric tests and multiple regression analyses. RESULTS: BMD was reduced in both spine and hip compared to an age matched reference population. Erosive disease was the variable with the strongest correlation with BMD. Treatment with sulfasalazine correlated positively with BMD at 3 of the 5 measured bone sites. However, in multivariate analysis significance was sustained only in the trochanter region. There were no correlations between the degree of inflammation, levels of sex hormones, treatment with corticosteroids, or smoking and BMD at any site measured. CONCLUSION: A large proportion of the men with RA had reduced bone mass. Sex hormone levels and treatment with corticosteroid did not influence BMD, nor did current degree of disease activity. Erosive disease was closely correlated with low BMD, whereas sulfasalazine was associated with high BMD at least in the trochanter region.     

The influence of hepatic artery ligation and of vasopressin on liver tumour blood flow in rats.

The blood flow in an experimental adenocarcinoma in the rat liver was determined with the 133Xe-washout technique before and after hepatic artery ligation (HAL). There was an initial reduction of the washout of 50%. This was further reduced after 1 day by 50%, which was maintained for 7 days. Seven days after HAL or sham procedures the 133Xe-washout was of similar magnitude in the liver tumours, although after the sham procedure the tumours were larger (3.4 g vs. 1.5 g). The estimated tumour blood flow was then approximately 0.04 ml x min-1 x g-1. The influence on normal liver parenchyma of HAL was a reduction at 30 minutes, which was maintained for 7 days. Postacton--a synthetic vasopressin--did not influence the 133Xe-washout in normal liver parenchyma in non-tumour, as well as in tumour-bearing animals. There was no influence of Postacton on the 133Xe-washout in the liver tumours. Thirty minutes after HAL Postacton gave a reduction of blood flow in normal liver parenchyma of tumour-bearing animals, which is thus only from the portal vein. In tumours Postacton did not significantly reduce the tumour blood flow immediately after HAL.     

Treatment of liver cancer with regional intraarterial 5-FU infusion.

The results of a retrospective three year study of forty-six patients with cancer of the liver treated with regional intraarterial infusion of 5-FU are reported. No primary mortality was noted. Oblective overall remission rate was 43 per cent. Overall median survival from onset of treatment was six months. The one year survival rate was 33 per cent and the two year survival rate 11 per cent. Patients with an objective response had a significantly prolonged survival as compared with nonresponders, especially in the colorectal group: sixteen months versus four months. Survival was not related to tumor size and involvement of the liver. During treatment 42 per cent of the patients developed extrahepatic metastases. Quality of life was improved in 63 per cent of the patients. The results indicate that infusion therapy induces reasonable response and palliation but is inadequate for the control of extrahepatic tumor growth.     

Treatment of malignant melanoma with dacarbazin (DTIC-DOME) with special reference to urinary excretion of 5-S-cysteinyldopa

Seventeen patients were given DTIC, 200 mg/m2/day in five-day courses every four to six weeks. In four patients (stage II) treated on an adjuvant basis, tumor recurrence has been verified in three. Four of the palliatively treated patients were also given DTIC by regional intra-arterial infusion with minimal positive tumor effect and minimal toxicity. 5-S-cysteinyldopa excretion in urine was checked continuously in all patients. Tumor recurrence was revealed in two patients given DTIC on an adjuvant basis three and four months before clinical signs of tumor. In the palliatively treated patients, 5-S-cysteinyldopa excretion increased in 5/6 patients judged to have stable disease, before tumor progression was clinically detectable. The use of 5-S-cysteinyldopa examination is a valuable adjunct to the follow-up of the effect of DTIC therapy in melanoma patients.     

A randomized trial of oral 5-fluorouracil versus placebo as adjuvant therapy in colorectal cancer Dukes' B and C: results after 5 years observation time

A double-blind randomized trial of daily oral 5-fluorouracil (5 mg kg-1 bodyweight) for 3 months versus placebo as adjuvant therapy to surgical treatment of colorectal cancer Dukes' B and C was conducted. In total 421 patients were randomized; 198 patients with Dukes' B, 159 with Dukes' C and 64 were referred to a limited resection group. The distribution of prognostic variables was similar in both groups indicating the absence of any bias and the efficacy of the randomization. Disease-free interval and survival time were analysed as end points. After 5 years of follow-up of all patients there was no significant difference between treatment or placebo group in the total material or the subgroups regarding either of the end points. There was no difference in localization of first recurrence between treated and control group. A high withdrawal of therapy was found in the 5-FU group (40 per cent) and in the placebo group (13 per cent).     

Effect of carcinomatosis and intraperitoneal 5-fluorouracil on peritoneal blood flow modulated by vasopressin in the rat as measured with the <Superscript>133</Superscript>Xe-clearance technique

Purpose Intraperitoneal administration of 5-fluorouracil for the treatment of gastrointestinal malignancies results in a greater total drug exposure in the peritoneal fluid than in plasma. Drugs are eliminated from the peritoneal cavity mainly by capillaries leading to the portal venous system and to a lesser extent by lymphatics. The drug itself and the presence of peritoneal carcinomatosis may affect elimination of the drug. The ¹³³Xe-clearance technique allows the influence of a vasoactive agent on the peritoneal blood flow to be estimated with minimal invasiveness. The aim of the present study was to explore whether intraperitoneal 5-FU or peritoneal carcinomatosis affects the peritoneal blood flow and its reactivity to intravenous vasopressin, as measured indirectly with the ¹³³Xe-clearance technique.Methods The animals used in this study were 63 Wistar-Fu (W-Fu) rats and 67 Lister-Hooded (LH) rats. On day 0, either 5-FU at 25 mg/kg body weight in 25 ml/kg isotonic saline was instilled intraperitoneally, or 1×10⁵ syngeneic tumour cells were inoculated intraperitoneally. On days 1, 2 and 3 in the 5-FU-treated rats, and on days 12–16 in rats inoculated with tumour cells, peritoneal blood flow was analysed with the ¹³³Xe-clearance technique, before and during intravenous infusion of vasopressin at 0.07 IU/min/kg body weight.Results The basal ¹³³Xe-clearance before administration of vasopressin was similar in all groups except in the LH rats treated with 5-FU in which it was significantly lower. Infusion of vasopressin induced a significant decrease in ¹³³Xe-clearance of the same magnitude in controls and in tumour-bearing rats. In the rats given intraperitoneal 5-FU, vasopressin did not reduce the ¹³³Xe-clearance the first day after administration of 5-FU.Conclusions Intravenous vasopressin at 0.07 IU/min/kg decreased peritoneal blood flow as measured indirectly with the ¹³³Xe-clearance method. Intraperitoneal 5-FU abrogated the reduction in peritoneal blood flow with intravenous vasopressin the first day after treatment. In contrast, the presence of peritoneal carcinomatosis did not influence peritoneal blood flow, nor the effect of vasopressin