[Low-dose cytosine arabinoside in the treatment of myeloblastic leukemia].
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Biomedical subjects
Publications and source records attributed to B Chapuis.
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Inheritance of HLA antigens in 55 families of patients with ALL was analyzed. Significantly increased sharing of DR antigens was observed among the parents of the affected children (p = 0.003). A similar increase was noted in the sharing of HLA-B antigens (p = 0.02). The observed number of DR homozygotes among the patients was twice the expected value in families where the parents shared a B and a DR antigen. Segregation analysis of the shared antigens disclosed significant prevalence of heterozygotes among the healthy siblings, which suggested the occurrence of gametic selection in such families. This study indicates that mating of certain shared alleles of the HLA system (especially of the DR locus) is associated with a risk for the offspring to develop ALL in childhood. Restricted heterogeneity of the parental HLA gene pool favours the expression of linked recessive genes and, presumably, of those involved in susceptibility to ALL.
Two out of three patients with acute myeloid leukemia responded to treatment with small subcutaneous doses of cytosine-arabinoside alone. Although marked cytopenia may transiently occur this treatment has no other side effects and is simple to administer. It may therefore be useful for elderly patients. Morphological studies and indirect evidence suggest that this schedule, dosage and route of administration for cytosine-arabinoside may promote differentiation within the malignant clone rather than acting as a cytotoxic agent.
A 1000-fold purification of human T-cell growth factor (TCGF) was achieved starting from supernatants of human spleen cells stimulated with phytohaemagglutinin (PHA) in culture medium containing 0.5% serum. The purification scheme involved precipitation with ammonium sulphate, gel filtration and blue-Sepharose chromatography. The use of polyethylene glycol 6000 (PEG 6000) was critical during the chromatographic steps in order to obtain high final recoveries or activity (40-50%). Purified preparations of TCGF labelled with 125I by the chloramine T method revealed that the activity co-migrated with 2 molecular species of 14,000-17,000 daltons in SDS-PAGE under non-reducing conditions.
Human T cells stimulated in secondary allogeneic mixed lymphocyte culture (MLC) were cloned under limiting conditions in microculture systems using T cell growth factor and irradiated allogeneic cells. Clones with lytic activity against either phytohemagglutinin-induced blast cells bearing the stimulating alloantigen(s) (cytotoxic T lymphocyte [CTL] activity), L1210 mouse lymphoma cells coated with rabbit antibody (antibody-dependent cell-mediated cytotoxicity [ADCC]), or K562 human target cells were selected, expanded, and then analyzed for different surface markers, including rosette formation with sheep erythrocytes (E rosettes), receptors for the fc portion of IgG or IgM (Fc gamma R and Fc mu R), and a group of antigens recognized by monoclonal antibodies including Ia, 4F2, OKT8,a nd OKT4. All the cytotoxic cells were E rosette+, Ia+ and 4f2+. Expression of Fc gamma R was restricted to the clones active in ADCC. CTL clones were either OKT8+ or OKT8-. Furthermore, three of the OKT8- CTL clones were OKT4+. In addition, some cytolytic clones devoid of specific CTL activity were OKT8+. It thus appears that the claim that human CTL are OKT8+, OKT4-, and Ia- is not supported by the analysis of their phenotype at the clonal level.
Human spleen cells were tested for the ability to produce T cell growth factor (TCGF) upon stimulation with PHA. Quantitative analysis of the amounts of TCGF produced under optimal conditions indicated that supernatants obtained from spleen cell cultures were approximately five times more active than those derived from peripheral blood leucocytes (PBL). Moreover, in contrast to PBL, there was no significant difference in TCGF production between individual spleen cell populations. Among splenic T cells, TG-depleted cell fractions were superior to TG-enriched cell fractions in producing TCGF upon PHA stimulation. These supernatants induced intense proliferation of blast cell populations isolated from mixed leucocyte-tumour cell cultures (MLTC) established with PBL and irradiated allogeneic myelogenous leukaemic cells. Within 7 days of culture in TCGF, the number of MLTC blast cells increased approximately 300-fold. Concomitantly, the lytic activity (on a per-cell basis) of these populations against the corresponding myelogenous leukaemic cell targets increased approximately 80-fold.
Circulating immune complexes (CIC) have been studied in one or several serum samples obtained from 249 patients with cancer. 42.4% of patients with evolutive tumors and 26.9% of patients in complete remission have elevated levels of CIC. It appears that, in approximately one case out of 3, the presence of CIC is not necessarily in relationship with the tumor, but could be the consequence of other clinical factors. In some instances, repeated plasmapheresis results in decreased CIC levels. The specificity of the antibodies present in CIC is not yet known.
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The goal of cancer immunotherapy is to achieve cure when the more usual means of treatment fail to do so. This can be achieved in some animal models where tumor rejection antigens have been demonstrated. In man, the contribution of immunotherapy to the treatment of minimal residual but disseminated disease has been exceedingly poor. This discrepancy should be analyzed, in an effort to detect and define in vitro putative tumor rejection antigens in human tumors.
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One hundred and thirty-nine untreated patients with acute myelogenous leukaemia (AML) were admitted between August 1970 and December 1973 and allocated into two remission treatment regimens: one to receive chemotherapy alone and the other chemotherapy with immunotherapy. Of the patients who attained remission. 22 were in the chemotherapy group and in September 1975 2 remained alive, the median survival time being 270 days and after relapse 75 days. Twenty-eight patients received immunotherapy during remission, and 5 remained alive; the median survival time of the group being 510 days and after relapse 165 days. Ongoing acturial analysis precisely predicted early in the study the median survival of the two groups, but it took a 2-year follow-up after entry of the last patient before it became clear that there were very few long-term survivors. The increase in survival time produced by the immunotherapy is apparently made up of two components: prolongation of the first remission and length of survival after the first relapse. It must be notted that the chemotherapy for this study was devised 6 years ago and the results of the control arm (chemotherapy alone) may be poorer than those obtained in contemporary studies.
Fifteen patients with acute myelogenous leukaemia were studied to determine if their remission blood leucocytes could be stimulated into taking up [3H] thymidine after in vitro culture with their own cryo-preserved irradiated AML leukaemia cells. In 6/15 patients it was possible to show autologous recognition and equal recognition of their stored leukaemia cells, even when they had previously been maintained in in vitro proliferative cultures in liquid suspension and undergoing myeloid maturation for one week. After in vitro proliferative culture, 4 populations of leukaemia cells produced material in the supernatant media between 3 and 7 days capable of inducing [3H] thymidine uptake in autologous (2 pts, 5 supernatants) and allogeneic (2 pts, 2 supernatants) AML remission lymphocytes, but not in normal donor lymphocytes. The relevance of these observations to tumour-associated AML antigen is discussed.
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