Vinca alkaloids (VA) represent a family of closely related molecules, which includes vincristine (VCR), vinblastine (VLB), vindesine (VDS) and navelbine (NVB), a new synthetic VA presently in phase II clinical trial. Development of sensitive and specific analytical tools (polyclonal and monoclonal antibodies) enabled us to investigate the kinetic behavior of VDS and NVB after IV bolus or long term administration. Following IV bolus injection, the mean pharmacokinetic parameters are: total plasma clearance: 0.53 l/h-1kg-1, 0.72 l/h-1kg-1 and apparent elimination half-life: 23.2 h, 39.5 h for VDS and NVB, respectively. Chronic treatment reveals time- and dose-dependence relationships and detailed observations of individual kinetics demonstrate an important interindividual variability for both drugs. Renal excretion of VDS and NVB is low (from 5 to 12% of the total dose), suggesting the important role of the liver in their rapid elimination.

During long-term venous catheter implantation, septic and thrombotic complications are quite frequent. In the case reported, the failure of systemic and local antibiotic therapy during repeated septicaemia due to Bacillus cereus at the time of intensive chemotherapy led to a scanning electron microscopy study of the used silicone catheter. There were marked changes of the inner surface with a lot of cellular remains, in contrast with the usual non thrombogenic property of the silicone. An in vitro study was carried out with antitumour agents. Duration of exposure and drug concentration were identical to those used in in vivo perfusions. There were marked changes of the inner surface, which could lead to important modifications of the properties of the silicone. The damage depended on the drug. Silicone was slightly sensitive to vicristin and carmustin, but highly sensitive to cisplatin and doxorubicin. The compatibility of catheter material with the drugs used, especially for oncologic chemotherapy, must be tested systematically.

Two short-lived vitamin K-dependent factors, factor VII and protein C, were measured by both functional and antigenic techniques in 3 hematological conditions known for their risk of hepatotoxicity: Following use of asparaginase and bisantrene, and patients at high risk of hepatic veno-occlusive disease after allogenic bone marrow transplantation for relapse of acute leukemia of accelerated phase of evoluted chronic myelogenic leukemia. In these 3 conditions functionally measured levels of protein C and factor VII, and antigenically measured levels of both these factors proved to be early markers of incipient hepatic involvement. These tests were easy to use routinely were reproducible, and proved to be predictive of veno-occlusive disease in grafted patients at the preconditioning stage. In the follow-up of bone marrow grafted patients plasma markers of endothelial function (von Willebrand's factor, tissue type plasminogen activator, and plasma activity of angiotensin converting enzyme) were significantly altered at the time of overdose with cyclosporin A, probably due to a drug-induced in vivo lesion of the endothelium. In the search for cytoprotective drugs for the prevention of veno-occlusive disease in bone marrow grafted patients prostaglandin E1 (PGE1) was given prior to and for at least 4 weeks after transplantation and proved to be effective by biological criteria (the level of protein C mainly). This deserves further study in a prospective clinical trial of the potential usefulness of PGE1 in preventing liver veno-occlusive disease in bone marrow grafted patients.

Several new anthracyclines have been recently made available for clinical use or for clinical trials. Each molecule is characterized by original metabolic and pharmacokinetic features, which can be compared to those of the reference anthracyclines, doxorubicin and daunorubicin. Idarubicin is transformed into idarubicinol to a high extent, similarly to the transformation of daunorubicin to daunorubicinol, whereas the 13-dihydroderivatives of esorubicin, epirubicin or pirarubicin are present in plasma at lower levels than the parent drugs. Epirubicin is the only anthracycline able to form glucuronides, and pirarubicin can be transformed into doxorubicin itself. The elimination half-life of epirubicin or esorubicin is similar to that of doxorubicin (30 h) and the elimination half-life of unchanged idarubicin or pirarubicin is shorter (15-20 h). The novel anthracyclines have generally a higher plasma clearance than doxorubicin or daunorubicin, and a higher volume of distribution. Less than 10% of the injected dose of any anthracycline is found in urines, the major elimination pathway being the bile. The knowledge of anthracycline pharmacokinetics may allow the prediction of their behavior when special administrations are used (continuous infusion, locoregional therapy...).

The authors report a case of successful pregnancy 8 years after surgery and chemotherapy for biliary cancer with secondaries in the liver. The authors, in considering this case, have analysed the sequelae of chemotherapy for cancer on fertility. They discuss the need to preserve the ability to produce oocytes in young women who need treatment for cancer.

A paradoxical effect of radiotherapy and chemotherapy for cancer is that some of these treatments can themselves cause new cancers. Most epidemiologic methods can be applied successfully to the investigation of this problem and this paper reviews various approaches that have already been used by various researchers. The authors first review the more traditional methods, i.e., cohort and case-control studies and they then describe designs that have been proposed more recently, such as case-cohort studies. A distinction is established between internal comparisons, carried out within the study population, and external comparisons, in which a general population external to the population under study is used as the reference category. This presentation is mainly aimed at investigators using tumor registry data. However, the general principles formulated here are easily generalized to contexts other than that of registries.

The authors studied distraction osteogenesis in an animal subjected to prolonged anti-mitotic chemotherapy (Methotrexate and Doxorubicin). This chemotherapy decreased osteogenesis (essentially at the expense of external regeneration) though without inhibiting it totally. Distraction bone consolidation is thus possible in the animal, permitting reconstruction of limb segments by mobilization of an axial fragment in accordance with the Ilizarov technique.

110 arteriovenous fistulas made for hemodialysis, chemotherapy and extended parenteral nutrition are studied. For authors, the side-end radial arteriovenous fistula is the main used, followed by the humero-basilic shunt. The immediately functional fistula's percentage was of 81% with a net progress in the last year since it is now at 92%. Thrombosis prevails in early complications. 32% of delayed complications are minutely studied. They include thrombosis, infections, trophic disturbance of hands, secondary stenosis, hyper-flow with cardiac consequences. Others more unusual delayed complications are described ("Stealing" syndrome, no venous distention, bleeding, pseudo-aneurysm). The authors advice the side-end arteriovenous fistula for hemodialysis and humero-basilic shunt with immediately basilic superficialization for infant's hemodialysis, for chemotherapy and parenteral nutrition.

Twenty-six patients with metastatic breast cancer where treated, after failure of a first line chemotherapy including an anthracycline, with a second line combination of vindesine, methotrexate and thiotepa. Overall tolerance of this treatment was good. There were one complete response and two partial responses. The authors conclude that this treatment has a marginal activity.

Intravesical chemotherapy is widely used in the management of superficial urinary bladder tumors. A complete response rate of 30 to 50% is observed in unresected tumors. Prophylactic instillations of the drugs after transurethral resection of the tumors seem able to delay recurrences. BCG can also be as effective, particularly in carcinoma in situ. Confirmation of efficacy of retinoids needs further studies. Invasive or metastatic bladder carcinoma can be responsive to systemic chemotherapy in about 40% of the cases for a period of 6 to 12 months. The value of adjuvant chemotherapy remains to be proved. Enhancement of radiation therapeutic effects by CisPlatinum in an interesting field of clinical research.

Fifteen patients with hepatocellular carcinoma were administered elliptinium acetate in a phase II trial. A dose of 80 mg/m2/day was administered during 3 consecutive days, every 3 weeks. According to WHO criteria regarding response, no objective responses were observed. The major toxicity was dryness of the mouth which occurred in 73% of patients, on addition, one case of hemolysis was documented in spite of a systematic search for anti-elliptinium antibodies prior to each injection. In conclusion, elliptinium acetate has no valuable therapeutic impact on the treatment of hepatocellular carcinoma.

We describe the 4-year follow-up of an endocrine tumour of the pancreas (vipoma-glucagonoma) treated with chemotherapy. To control the endocrine syndrome we used somatostatin 14 by continuous subcutaneous infusion for 1 year, followed by the somatostatin analogue SMS 201-995 administered alone without antitumoral chemotherapy. Under SMS 201-995 (100 micrograms 12-hourly) the endocrine syndrome dramatically improved. This effect persisted for 12 months after which a relative resistance to the drug developed. It was necessary to increase the dosage (300-400 micrograms/24 hours) and to alter the mode of administration (continuous subcutaneous infusion) to obtain a clinical benefit inferior to that obtained during the first year of treatment with SMS 201-995. At present this drug is given combined with recombinant interferon alpha 2A. In spite of computerized tomography, ultrasonography and monitoring of hormone levels we were unable to determine whether or not SMS 201-995 exerted a partial antitumoral effect.

Most experimental data clearly suggest that antitumor agents including DNA intercalative molecules (acridine derivatives, ellipticine and derivatives), or non intercalative ones (epipodophyllotoxines), exert their cytotoxic activity by stabilizing DNA-Topoisomerase II complexes. This phenomenon can be revealed by the presence of DNA breaks upon protein denaturing treatment. In this work, BD-40, an ellipticine analog has been shown to interact in vivo with Topoisomerase II. Moreover, cleavage sites generated by the drug treatment in human proto-oncogene c-myc appear to be mostly localized in the 5' end of the gene locus, which contains regulatory elements. Some of these sites are in a striking correspondence with DNAse I hypersensitive sites, which reportedly reflect the state of activity of genes.