Potential interactions with anticancer agents: a cross-sectional study.

BACKGROUND: Patients with cancer are particularly susceptible to drug interactions (DIs), but the extent of the problem has received limited attention. We aimed to evaluate the frequency of interactions with anticancer agents in a group of cancer patients. METHODS: The study was performed in a Belgian teaching hospital. One hundred and twenty-two patients with solid malignancies were included. A comprehensive drug history was performed by a clinical pharmacist. Three renowned DI compendia were used to identify DIs. RESULTS: Forty-one potential interactions involving an anticancer agent and considered to be clinically significant were identified among 25% of patients. The anticancer drugs mostly involved were cisplatin and methotrexate, and the most frequent co-medications involved were vitamin K antagonists, proton pump inhibitors and diuretics. In the majority of cases, the potential adverse consequence was increased toxicity of the anticancer agent and/or of the co-medication. Less than 10% of DIs were identified by the three compendia. CONCLUSIONS: Preventive measures should be taken to avoid increased toxicity or decreased efficacy of the drugs. Most of the time, this simply involves surveillance of biological or clinical parameters. Collaboration with a clinical pharmacist may be useful for the prescribing physician.

Antibody producing human-human hybridomas. I. Technical aspects.

Technical aspects of generation of antibody-secreting human-human hybridomas are evaluated as based on 100 human-human fusions with a human B-lymphoma cell line (RH-L4) or the SKO-007 myeloma cell line as malignant fusion partners, and compared with similar fusion conditions in the mouse hybridoma system. The yield of hybrids was significantly lower when normal peripheral blood lymphocytes were used as fusion partners as compared with spleen lymphocytes, but could be substantially improved by increasing the amount of mitotic active B-lymphocytes by mitogen stimulation of the lymphocytes, preferably in HAT medium, prior to fusion. Furthermore, human hybrids grew slower and had a higher degree of chromosomal instability than usually observed in the mouse hybridoma system. Thus, out of 72 fusions, only 3 stable hybrids with antibody production against a predefined antigen were established. The importance of improved sources of human B-lymphocytes for human-human hybridoma production is discussed and methods of obtaining such improvement suggested.

[Familial Alzheimer's disease: a study of HLA markers]. / Alzheimer familial: étude des marqueurs HLA.

We have studied HLA markers in family with 2 "Probable" and 2 "possible" cases of Alzheimer disease over 3 generations. Three of them (two brothers and the father) present A29 C-B12 DR2 haplotype. It seems that it exists an association between HLA system and Alzheimer disease but we cannot define the character of this genetic linkage; the study of many families and sporadic cases will allow to define it.

HLA-A, B, C, DR antigens, Bf, C4 and glyoxalase I (GLO) polymorphisms in French Basques with insulin-dependent diabetes mellitus (IDDM).

The Basques were previously shown to present a high frequency of HLA-B18 and BfF1, which are known to be associated with insulin dependent diabetes mellitus (IDDM). During the VIII International Histocompatibility Workshop, we studied HLA-A, B, C, DR; Bf, C4 and GLO.I polymorphisms in 51 unrelated French Basque IDDM patients and in 50 controls. Haplotypes were established by family studies in all controls and some patients. Two haplotypes were frequently found in the controls: HLA-A1, Bw57, BfS, C4 F1S, DR7 and HLA-Aw30, Cw5, B18, Bf F1, C4Fs degree, DR3. The first one was not found in the patients. All the components of the second haplotype had increased frequencies possibly as a consequence of linkage disequilibrium with HLA-DR3: a highly significant association between IDDM and HLA-DR3 was observed (90.2% vs 24.0%, relative risk (RR) = 29.1, P less than 10(-11)). The HLA-DR4 frequency was slightly increased (37.3% vs 16.0%), and HLA-DR2 was not found. The silent allele C4s degree was particularly associated with early diagnosed IDDM (86.7% in patients with age at onset under 20 years vs 57.1% in other patients, P less than 0.02). The high relative risk for HLA-DR3/DR4 heterozygous vs that of individuals, possibly HLA-DR3 homozygous, supported the hypothesis that two HLA-DR linked genetic factors could be involved in the inheritance of IDDM susceptibility.

High frequency of the properdin factor Bf F1 and its linkage to HLA in French Basques.

We studied 201 unrelated French Basque individuals for HLA and Bf polymorphisms. The haplotypes of eighty-seven of them were deduced from family studies. The results show the frequency of the Bf F1 allele (0.1393) which is the highest one currently reported. They confirm the high frequencies of HLA-Aw19.2 and B18 previously reported in that population and show that a whole haplotype with strong linkage disequilibria, namely Aw19.2, Cw5, B18, Bf F1, DRw3 is frequent. On the other hand, the gene frequency of Bf S is decreased (0.5497) as compared with the other European Caucasoïd populations, while a slight increase in the Bf F gene frequency (0.2960) appears. These results point out that it is of importance to consider the genetic background choosing the population where linkage disequilibria are to be studied.

HLA-a, B typing in Basque and other Pyrenean populations.

Fourteen HLA-A and 18 HLA-B antigens were studied in three samples of Pyrenean populations: 198 unrelated individuals of a "Pays Basque" group; 212 non-Basque individuals from a valley in Bearn, l'Ouzom; and 73 non-Basque individuals from the neighboring valley of Bareges. The results in the Basque and the non-Basque people from l'Ouzom were comparable: the gene frequencies of HLA-A29, Aw19.2, B17 were increased and the haplotypes HLA-Aw19.2, B18; A29, B12; A2, B5; A1, B17 were found frequently with a striking linkage disequilibrium; HLA-B18 had an increased gene frequency in all these Pyrenean populations, while Bw35 was frequent in l'Ouzom and Bareges, but not among the Basques. The characteristics of Bareges were very different: the gene frequencies of HLA-A2, A11, B7 were increased while the frequency of HLA-B5 was low; the most characteristic haplotypes were HLA-A2, B12; A2, B18; A11, Bw35; A11, B27. It is interesting to note discrepancies between ethnic and HLA classification of the Basques and the non-Basque population of l'Ouzom. The HLA characteristics are quite different in the Hareges sample, more closely resembling those of Northern Europe.

Genetic linkage between Bf S0.7 (Bf S1) and HLA-Bw50.

Two hundred and one unrelated French Basque individuals were studied for HLA-A, B, C, DR and Bf polymorphisms. The results show that the Bf S0.7 (Bf S1) variant, which is known to be associated with HLA-Bw21, presents a highly significant linkage disequilibrium with a subtypic specificity, i.e., Bw50 (delta = 0.0123, delta S=100%, P less than 10(-8)). As neither Bf S0.7 variant nor Bw50 antigen is found in Mongoloid populations, it is suggested that in evolutionary terms, the Bf S0.7 mutation is a more recent event than the HLA-Bw21 split.

Lymphocytotoxic antibodies and antiglobulins in renal allograft recipients. Correlative study with acute rejection.

In 45 patients who received kidney transplants, both homologous and heterologous human antiglobulins (anti-Ig) and HLA cytotoxic antibodies have been studied before and after transplantation and in some cases after nephrectomy. A similar study has been performed in a control group of 1,019 healthy blood donors and in 130 patients with acute or chronic glomerulonephritis. After transplantation, homologous anti-IgG were found in 60% of the patients, as compared with 3.5% in the healthy blood donors and 21% in patients with various forms of glomerulonephritis. This difference is particularly striking in sera obtained prior to nephrectomy; the presence of anti-IgG and cytotoxic antibodies in the same patient being significantly associated with early transplant failure. Anti-IgA were found in 75% of the patients with transplants and in 37% of the patients with glomerulonephritis. There was no relationship between the anti-IgA and the outcome of the graft. On the other hand, heterologous anti-Ig were unchanged in the three groups investigated. The mechanism of formation of the anti-IgG is not clear. They are probably antibodies against antigenic structures of the patient's own antibodies, previously combined with a soluble antigen or an antigen on the transplant that has undergone molecular transformation in the course of this reaction. Their pathogenic role, although not demonstrated, can be strongly suspected, and, in a practical way, screening for the anti-Ig in kidney transplant recipients could be of value as a prognostic test.

[Practical interest of a micromethod for neuraminidase treatment of lymphocytes in transplantation immunology (author's transl)]. / Intérêt pratique du traitement sur plaque des lymphocytes par la neuraminidase en immunologie de transplantation

Vibrio cholerae neuraminidase treatment increases the cell sensitivity to complement and antibodies cytotoxic action. This property can be applied to the microlymphocytotoxicity technic for antibodies study in dialysed and kidney transplanted patients and for pretransplantation cross-matches. The enzymatic treatment usually employed needs a great deal of lymphocytes submitted in a second step to antibodies cytotoxic action. But this method appeared difficult to be routinely applied. We developed a simpler method consisting in treating only the lymphocytes needed to perform the test, on the reaction plate itself. This method gives the same results as the classical enzymatic treatment: the intensity of the weakly positive reaction is strongly increased, after pretreatment of cells; in certain cases, it allows one to detect cytotoxic antibodies not revealed without neuraminidase. These antibodies can be related (or not) to HLA system but practically the more important fact is the ability of this method to reveal an eventual incompatibility.

[Lymphocytes HLA antigens expressivity after neuraminidase treatment (author's transl)]. / Action de la neuraminidase sur l'expressivité des antigénes HLA lymphocytaires

Neuraminidase treatment of lymphoid cells increases the cytotoxic action of antibodies and complement on these cells. We have studied the action of 25 human alloantisera on lymphocytes of 26 healthy subjects by the Trypan blue lymphocytotoxicity technic, before and after neuraminidase treatment of cells. The results show, as a rule, an increased cytotoxicity of sera, with a higher titer and/or a more important number of positive cells. In some sera a specific cytotoxic activity is found only with neuraminidase treated cells. The antibodies often reveal an anti-HLA specificity: that specificity was previously known in the serum or, in several cases, has been found only with neuraminidase treated cells. But in some cases the new specificity does not seem to be related to the HLA system. Different hypotheses are discussed in order to explain these results and the action of neuraminidase on membranes; lastly, applications of our neuraminidase treatment method to practical problems are presented.