The authors present their experience of the use of a totally implanted vascular access system, at the Institut Jules Bordet. Between 1983 and 1988, 296 catheters were implanted in 289 patients. The average venous access period using this system was 232 days. The complication rate was only 0.36/1000 days of venous access. The totally implanted vascular system can provide a comfortable and reliable method of venous access in patients requiring prolonged intravenous chemotherapy.

THP-adriamycin (pirarubicin) is a new anthracycline-analogue. In France, the drug is achieving the phase II studies and the step of phase III studies is going on. As this point of its development, it is already possible to conclude that the drug probably shares the same efficacy as adriamycine, especially in breast cancer, but exhibits a better tolerance in term of alopecia and cardiac toxicity, as predicted by preclinical studies. Its pharmacological properties make the drug an original compound, exciting for investigations in the field of loco-regional therapy.

Navelbine (NVB) (5'-noranhydrovinblastine) is a new semi-synthetic vincaalkaloid (VA) exhibiting a high affinity for tubulin and considerable anticancer activity in patients. A better hematologic tolerance and a weak neurotoxicity have been reported for this drug as compared to other VA. Moreover, NVB presents a relatively high bioavailability and a good digestive tolerance, thus offering original perspectives for the treatment of ambulatory cancer patients. A clinical pharmacokinetic study of NVB was carried out on 12 patients after oral administration of the drug. The pharmacokinetic parameters were similar to those of intravenous administration and also showed a high interindividual variability. Studies on the in vitro metabolism of NVB using hepatic microsomal fractions from 22 different donors demonstrated the formation of 3 metabolites. The biotransformation rate quantitatively varies from one human liver specimen to another, a fact which could be, in part, at the origin of the interindividual variability of the therapeutic response.

The analysis of Phase II trials with regard to brain tumors in children, aiming to test the activity of 1 drug or a combination of drugs is not easy, due to the following reasons: poor selection of patients (clinical and pathological heterogeneity), not always rational choice of the drugs and mostly, variability of the criteria and the methods used to assess the tumor response. When using a single drug, the current most efficient agents seem to be: cisplatinum, carboplatin, cyclophosphamide and etoposide, while nitroso-ureas have not been strictly studied. When using polychemotherapy, the best results have been obtained with the "8 drugs in 1 d" regimen. The most chemo-sensitive tumors are: medulloblastomas, primitive neurectodermal tumors, pinealoblastomas; high grade ependymomas and astrocytomas have been studied less in children than in adults. Present and future strict organisation of Phase II trials in brain tumors is compulsory in order to select the active agents, and to establish the best modalities of administration. The need to assess chemotherapy not only in refractory or relapsing patients, but also at diagnosis in high-risk patients is emphasized (after incomplete surgery and before radiotherapy).

In terms of pharmacology, drug delivery is an important obstacle in the development of brain tumor chemotherapy. The blood-brain barrier limits the drug penetration in normal brain tissue around the tumor and at distant potential metastatic sites. In the tumor, the altered blood-brain barrier, ie blood-tumor barrier, decreases the drug entry in malignant cells. The knowledge of the blood-brain barrier physiology and the definition of the laws that govern the drug delivery to the central nervous system allow the development of new strategies to increase drug delivery to the tumor. In pediatric oncology, the more appropriate methods are the use of anticancer agents that easily cross the blood-brain barrier and the development of high-dose systemic chemotherapy regimens with or without bone marrow rescue.

Reviewing arguments based on the pharmacokinetics of arterial infusions, on literature study results, and on their personal experience with 16 patients, the authors present a case for the administration of antitumoral agents by intra-arterial infusion as a method of dispensing induction chemotherapy to stomatological cancer patients. Utilization of implanted sites and discriminating selection of indications will improve the performance of intra-arterial chemotherapy.

The growth fraction of cancer cells, estimated by the monoclonal antibody Ki-67 labelling, and DNA content were determined simultaneously en K562 human leukemic cells by flow cytometry. Adriamycin, aclacinomycin A and fagaronine induced differentiation, as assessed by benzidine staining and glycophorin A expression. These drugs decreases the fraction of Ki-67 positive cells, Ki-67 negative cells displayed a G1, but also a G2 and a S DNA content in different proportions, indicating that induction of quiescent cells by differentiating agents is not a uniform process and is worthy of interest.

Doxifluridine, a new fluorouracil analog with a low myelosuppressive effect, has recently been subject to various disease-oriented, Phase II trials. For the present evaluation of drug tolerance, the Phase II data of 114 patients having received 376 doxifluridine cycles has been used. The treatment cycles consisted of 5 daily intravenous injections of 4,000 mg/m2 non-pretreated patients, and 3,000 mg/m2 in pretreated patients. Previous observations showing that doxifluridine is less myelotoxic than fluorouracil have been confirmed. 54% of the patients had no leucopenia (maintaining WBC counts over 3,000/mm3 and 90% had no thrombopenia (platelets not lower than 100,000/mm3) throughout treatment. However, a WHO grade 4 hematologic toxicity was observed in 9 patients, and 2 toxic deaths were related to severe granulocytopenia and sepsis. Digestive tract toxicity was similar and equally frequent as the one observed with fluorouracil: mucositis with oral ulcerations (19%), nausea and vomiting requiring specific treatment (8%) and severe but never hemorrhagic diarrhoea (5%). Neurologic toxicity was frequent, with 20% of patients complaining of somnolence and/or peripheral neuropathy, 7% of impaired consciousness and 1% of WHO grade 4 cerebellar ataxia. Among the 10% of patients with cardiac symptoms, 6% were benign and transient arrhythmias, and 4% were severe, including 1 myocardial infarction, 1 spontaneously reversible cardiac arrest and 2 ventricular fibrillations successfully treated with cardioversion. In spite of its encouraging antitumor activity and its good hematologic tolerance, intravenous doxifluridine, as used in this study, cannot be recommended because of the observed neurologic and cardiac toxicity. Oral doxifluridine is presently under investigation with preliminary results suggesting a lack of neuro- or cardiotoxicity.

This review reports on the various studies using fluorine-19 nuclear magnetic resonance spectroscopy (19F NMR) to study the metabolism of antineoplastic or antifungal fluoropyrimidines. It is divided into 2 parts: the first examines ex vivo studies, ie, of biofluids or excised tissue samples from patients. In vivo studies, ie where the biotransformation of the drug is followed by non-invasively both in animals and in humans, are described in the second part. For ex vivo studies, 19F NMR can already be considered as complementary to the classical analytical methodologies used for drug metabolism studies. In vivo 19F NMR spectroscopic studies, especially in humans, are still at an early stage of development. Several improvements, both methodological (development of volume-selective localization techniques and quantification methods) and clinical (more rigorous definition of pathologies under study and administered treatments), are a prerequisite for useful clinical application.

A severe or lengthy disturbance of immunity favors the development of malignant tumors. The increased incidence of lymphomas, leukemias and certain carcinomas in cases of congenital immunodeficiency, as well as of Kaposi's sarcoma and certain lymphomas in the acquired immunodeficiency syndrome (AIDS) are well known. In transplantees, patients undergoing immunosuppressive treatment for autoimmune disorders and cancer patients receiving chemotherapy, the occurrence of secondary neoplasias represents a phenomenon with a specific profile. We have seen 14 solid tumors in patients who were immunosuppressed for one of the 3 above-mentioned reasons. It is a heterogeneous group, both in terms of patient profile and tumor localisation. However, there are certain characteristics of these tumors which distinguish them from similar ones arising in the general population. The advent of more aggressive immunosuppressive therapies, the constant increase in organ transplants and the development of new cancer treatment modalities which influence the patients immune systems explain the importance of this phenomenon. Thus one must constantly be wary of these unusual tumors which occur independently of age and usual risk factors.

Racemic 7-hydroxy-9-oxa-anthracyclinone (5a) has been synthetised in seven steps from quinizarin (6) and its resolution achieved after glycosylation with 3,4-di-O-acetyl-2-deoxy-L-fucose. Chiral pool syntheses of (8S)-8-hydroxymethyl-9-oxa-anthracyclinone (5b) and of (8S,10R) and (8S,10S)-8-hydroxymethyl-10-methyl-9-oxa-anthracyclinones (5c and 5d) have been achieved using (R)-2,3-O-isopropylideneglyceraldehyde (12) and leucoquinizarin (13) as starting materials. Glycosylation of aglycones 5b-5d by either 3,4-di-O-acetyl-2-deoxy-L-fucose or various 3-amino-2,3,6-trideoxy-L-hexoses yielded the corresponding anthracyclines. The synthetic glycosides do not show significant cytotoxic activity at a concentration of 1 microgram/ml against L 1210 cells.

The optimal approach to reduce bacterial infections in granulocytopenic patients is still controversial. Recently, fluoroquinolones have been developed and real progress has been achieved in the prevention of Gram negative bacilli septicemia. This study reports our experience with ciprofloxacin and shows the excellent tolerance of ciprofloxacin by our patients as well as promising data for the reduction of Gram negative bacilli infection. However, practical modalities to prevent infection caused by Gram positive cocci remain to be defined.

A 21-year old male patient with Philadelphia chromosome-positive chronic myeloid leukaemia received an autologous bone marrow transplant in consolidation of the 2nd chronic phase. The bone marrow had been treated with mafosfamide in adequate doses. The post-transplantation course of the disease was marked by an inversion: the duration of the 2nd chronic phase was more than 4 times longer than that of the first one, suggesting some degree of effectiveness of autologous bone marrow transplantation performed in the 2nd chronic phase and/for of the in vitro treatment of the bone marrow with mafosfamide. Cytogenetic monitoring was pursued throughout the course of leukaemia: regression of the Philadelphia chromosome was only partial and transient, and 3 clones appeared, each of them involving chromosome 1, for which mafosfamide was most probably responsible.