[The medical oncology clinic]. / La Clinique d'Oncologie Médicale.

The clinic of medical oncology is mainly devoted to the development of new anticancer treatments based on molecular biology and immunology. The clinic was the first in Belgium to start a protocol of gene therapy. Scientific contributions deal with the role of various oncogens in cell transformation, the interaction between cancer and the immune system and, new tools for the molecular diagnosis of cancers. Focus was particularly put on the development of new vectors for gene therapy and antitumor cell vaccines for cell therapy.

[Anti-tumor immunotherapy based on dendritic cells]. / L'immunothérapie anti-tumorale à base de cellules dendritiques.

In cancer immunotherapy, the use of dendritic cells (DC) loaded with tumor-associated antigens (TAA) emerged as a promising strategy. We initiated 3 pilot clinical trials with immunological endpoints using TAA loaded autologous DC. These trials showed that this approach was safe and associated with the induction of potent TAA specific IFN-gamma responses, which were transient despite the providing a further help through KLH presentation. Subcutaneous (s.c.) IL-2 administration was associated with long-lasting TAA specific IL-5 production. Clinical responses were observed in about 1/3 of the patients. Further improvements will take advantage of the use of a new type of DC cells (IL-3/IFN-beta DC) and of tumor cell-DC hybrids.

Transient expansion of peptide-specific lymphocytes producing IFN-gamma after vaccination with dendritic cells pulsed with MAGE peptides in patients with mage-A1/A3-positive tumors.

Assessment of T-cell activation is pivotal for evaluation of cancer immunotherapy. We initiated a clinical trial in patients with MAGE-A1 and/or -A3 tumors using autologous DC pulsed with MAGE peptides aimed at analyzing T-cell-derived, IFN-gamma secretion by cytokine flow cytometry and ELISPOT. We also tested whether further KLH addition could influence this response favorably. Monocyte-derived DC were generated from leukapheresis products. They were pulsed with the relevant MAGE peptide(s) alone in group A (n=10 pts) and additionally with KLH in group B (n=16 pts). A specific but transient increase in the number of peripheral blood T lymphocytes secreting IFN-gamma in response to the vaccine peptide(s) was observed in 6/8 patients of group A and in 6/16 patients of group B. We conclude that anti-tumor vaccination using DC pulsed with MAGE peptides induces a potent but transient anti-MAGE, IFN-gamma secretion that is not influenced by the additional delivery of a nonspecific, T-cell help.

[Novel autograft method using positive selection of CD34 stem cells]. / Méthode nouvelle d'autogreffe par sélection positive de cellules souches sanguines CD34.

High dose chemotherapy with autologous blood stem cell rescue becomes widely used for patients with hematologic malignancies and solid tumors. Recently, it has been demonstrated that stem cells characterized by the CD34 antigenic marker could be positively selected using an anti CD34 monoclonal antibody and an avidin biotin immunoabsorption device. We report our experience of twelve selections and ten grafts. A CD34+ cells enrichment of 1.9 log (purity: 72%) and a CFU-GM cells concentration of 1.6 log have been obtained. In ten transplanted patients, the hematological recovery was similar to that obtained with non selected blood stem cells. The CD34+ cells purification allows mini graft infusion and purge of residual tumor cells implicated in relapse after autologous stem cells transplantation.

Supportive care of neurologic complications.

Approximately one cancer patient in five will suffer from injuries to either the central or peripheral nervous system. These complications occur preferentially in the advanced stages of neoplastic disease, and their management is an important aspect of the supportive care of these patients. The most common neurologic complications seen in patients with cancer are related to metastases or to local tumor spread. Antineoplastic treatments, mainly chemotherapy or radiotherapy, account for more than 10% of these complications. A much smaller percentage (probably less than 1%) are paraneoplastic manifestations. In this review, we discuss the most recent developments in the management of neurologic complications specifically related to cancer as well as some less specific problems such as thromboembolic complications and the use of steroids.

Metabolism of almitrine in extensive and poor metabolisers of debrisoquine/sparteine.

1. Almitrine bismesylate displays wide inter-subject variation in peak plasma concentrations and can induce peripheral polyneuropathy. 2. The phenotyped volunteer panel approach was used to examine whether almitrine oxidation displayed a genetic polymorphism of the debrisoquine/sparteine type. 3. There was no difference between poor and extensive metabolisers of debrisoquine with respect to the pharmacokinetics and metabolism of almitrine.

Amiodarone-induced thyrotoxicosis suggestive of thyroid damage.

Amiodarone-induced thyrotoxicosis (AIT) is generally believed to result from increased hormonal synthesis related to the iodine overload. Thyroid damage has recently been incriminated as a pathophysiological mechanism. We report 3 cases of AIT associated with clinical and/or biochemical features consistent with thyroid damage. This hypothesis was supported by a painful thyroid (case 1), transient high serum Tg (case 2), a transient (case 2) or persistent (case 3) hypothyroid phase and an undetectable technetium thyroid uptake during the hypothyroid period (case 3). These clinical observations support the previous histological data indicating that thyroid follicular disruption might contribute to the pathogenesis of AIT.

Penetration of ciprofloxacin into human pleural fluid.

The concentrations of ciprofloxacin (1.5 mg/kg of body weight) in serum and in uninfected pleural exudates were studied after one and three intravenous injections had been given at 8-h intervals. The drug was assayed in serum and in pleural fluid by high-performance liquid chromatography. The peak concentrations in pleural fluid 1.5 h after one and three injections were (mean +/- standard error of the mean) 0.52 +/- 0.09 and 0.77 +/- 0.15 mg/liter, respectively; the corresponding 8-h concentrations were 0.19 +/- 0.05 and 0.39 +/- 0.10 mg/liter. At 1 and 8 h, the ratios of mean concentrations in pleural fluid to mean concentrations in serum were 112 and 158%, respectively, after one injection and 77 and 122% after three injections. This study suggested that there is a satisfactory pleural penetration of ciprofloxacin after intravenous injection.

Penetration of ciprofloxacin in bronchial secretions after intravenous administration.

Ciprofloxacin concentrations in serum and in bronchial secretions were studied after single and multiple intravenous administrations for two days in ten patients. The dose given was either 0.75 or 1.5 mg/kg. With the lower dose, the peak concentrations in the bronchial secretions were (mean +/- S.D.) 0.40 +/- 0.29 mg/l after the first injection and 0.35 +/- 0.25 mg/l after the fourth injection. With the higher dose, the corresponding mean peak bronchial concentrations were 0.84 +/- 0.58 and 1.16 +/- 0.86 mg/l respectively. The half-lives of the drug in bronchial secretions ranged from 2.13 to 3.72 h. The penetration of ciprofloxacin into bronchial secretions was excellent as demonstrated by the high ratios of the areas under the concentration curves obtained in the serum and in bronchial secretions which ranged from 0.79 to 1.11.

The pharmacokinetics of oxybutynin in man.

We have studied the pharmacokinetics of oxybutynin (Ditropan) after single oral (5 mg) and intravenous administration (1 and 5 mg), and after repeated oral administration in healthy volunteers. Oxybutynin was rapidly absorbed, maximum plasma concentrations (8 ng.ml-1) being reached in less than 1 h. The absolute systemic availability averaged 6% and the tablet and solution forms displayed similar relative systemic availability. Plasma concentrations of oxybutynin fell biexponentially, the elimination half-life being about 2 h. There was a large interindividual variation in oxybutynin plasma concentrations. Almost no intact drug could be recovered in the urine. During repeated oral administration steady-state was reached after eight days of treatment. The low absolute systemic availability of oxybutynin, the large interindividual variability in its plasma concentrations, and the apparent absence of intact oxybutynin in the urine suggest that its major pathway of elimination is hepatic metabolism.

Acute pancreatitis as presenting symptom and sole manifestation of small cell lung carcinoma.

A 58-year-old man with no sign of pulmonary disease and a normal chest x-ray presented with acute pancreatitis resistant to conventional medical management and a mass in the head of the pancreas. The presumptive diagnosis was pancreatic cancer with tumor-induced pancreatitis. However, endoscopic retrograde cholangiopancreatography suggested metastatic rather than primary tumor, so that an extrapancreatic primary was actively sought. Further lung work-up demonstrated a small cell carcinoma of the lung. This case indicates that metastasis-induced acute pancreatitis can be the presenting symptom and sole manifestation of lung cancer.

[Surgical treatment of cutaneous ulcerations related to anticancer chemotherapy]. / Traitement chirurgical des ulcérations cutanées liées à la chimiothérapie anticancéreuse.

Surgical treatment of skin ulcers from extravasation of chemotherapeutic agents produces a chronic ulcer. The origin of the disease and the techniques of wide local excision and of skin cover are discussed.

Treatment of hairy-cell leukemia with recombinant alpha 2-interferon.

Eleven patients with hairy-cell leukemia (eight with progressive and three with non-progressive disease) were treated with low dose recombinant human alpha 2-interferon. After a 3-month treatment period, nine patients showed an improvement and one patient a partial remission. By then, transfusions were not required any more and serious infections were no longer encountered. Four patients were further treated: three for a total period of 9 months and one for 6 months; all of them reached a partial or complete remission. The treatment was equally effective in patients with both progressive and non-progressive disease. Previous absence of response to splenectomy did not preclude a positive effect of IFN therapy. In two patients, IFN dose reduction was necessary due to unremitting flu-like symptoms.

Trisomy 11 in preleukemia.

The clinical and cytogenetic findings of a patient with a preleukemic state and trisomy 11 are reported. Trisomy 11 was present as the sole karyotypic alteration at the time of overt leukemia. Trisomy 11 presents an additional chromosomal abnormality not previously described in preleukemia.

Therapeutic effect of human recombinant interferon-alpha-2C in essential thrombocythaemia.

Human recombinant interferon-alpha 2C was given to 4 patients with essential thrombocythaemia. Three patients achieved a complete remission on day 19 +/- 1 and the 4th achieved a partial remission. After 4 weeks of induction therapy, a maintenance therapy of twice weekly intramuscular injections of 5 X 10(6) or 10 X 10(6) IU was instituted but did not maintain the remission.

Probenecid inhibition of methotrexate cytotoxicity in mouse L1210 leukemia cells.

The effect of probenecid on methotrexate cytotoxicity has been measured using mouse L1210 leukemia cells in vitro. Cytotoxic effects were measured using a soft agar cloning technique. Cell exposure to varying concentrations of methotrexate at fixed concentrations of probenecid resulted in increased cell survival when compared with exposure to methotrexate alone. Cell exposure to a fixed concentration of methotrexate and varying concentrations of probenecid showed this effect to be dependent on the concentration of probenecid. Intracellular methotrexate concentrations were unchanged by the presence of probenecid. However, there was an effect of probenecid on progression of cells through the cell cycle which would tend to decrease the number of cells susceptible to the cytotoxic effects of methotrexate.

Study of the influence of nifedipine on the pharmacokinetics and pharmacodynamics of propranolol, metoprolol and atenolol.

The influence of chronic therapy with nifedipine on the pharmacokinetics of propranolol 80 mg twice daily, metoprolol 100 mg twice daily and atenolol 100 mg once daily was investigated in eight healthy volunteers. Nifedipine 10 mg three times daily did not affect the pharmacokinetics of metoprolol and atenolol whereas nifedipine shortened the time to peak plasma concentration for propranolol by about 1 h. Propranolol, metoprolol and atenolol provoked comparable decreases in heart rate measured at rest and during exercise. The beta-adrenoceptor blocking properties of propranolol, metoprolol and atenolol were not affected by concomitant therapy with nifedipine. The present study did not show significant pharmacokinetic and pharmacodynamic interactions between nifedipine and lipophilic beta-adrenoceptor blockers.

Rectus sheath hematoma mimicking acute splenic disease.

In patients with hematological malignancies and splenomegaly, acute abdominal pain in the left upper quadrant is highly suspicious of splenic disease (i.e., hematoma, infarction, or rupture). We report the case of a patient with chronic myelogenous leukemia and splenomegaly who presented an unusual abdominal condition causing pain in the left upper quadrant, with a clinical presentation mimicking acute splenic disease. The diagnostic dilemma was resolved by ultrasonography, demonstrating a rectus sheath hematoma.