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1. The aim of this study was to investigate 6-mercaptopurine (6MP) metabolism by human liver cytosol in vitro. 2. Cytosol was prepared from seven human livers (A-G). A single cytosol (C) was used to optimize incubation conditions. 3. Cytosols A-G were incubated with 6MP at 2, 10 and 500 microM for two fixed times (5 and 48 h). Parent drug, thiopurine and thionucleotide metabolites were quantitated by high performance liquid chromatography at all time points. 4. At 5 and 48 h the 2 microM and 10 microM 6MP incubations contained both 6MP and its initial nucleotide metabolite, thioinosine 5'-monophosphate (TIMP). In addition, the 10 microM 6MP 48 h incubates contained small amounts of 6-thioguanine (6TG, median 0.12 microM). At 500 microM 6MP all seven liver incubates produced a range of metabolites. At 48 h these included thiouric acid, 8-hydroxy-6-mercaptopurine and 6-methylmercaptopurine (median 31, 19.5 and 8.8 microM respectively), with TIMP, 6TG, thioxanthine and thioxanthine nucleotide at median concentrations of 61, 0.79, 2.11 and 0.80 microM respectively. Thioguanine nucleotides, major metabolites measured in vivo, were not detected. 5. These results indicate that the human liver 6MP metabolic profile is dependent upon drug concentration.

Early studies indicated that low immunoglobulin (Ig) concentrations at diagnosis predict a worse outlook for children with acute lymphoblastic leukemia (ALL). We re-examined this suggestion in the light of immunophenotypic disease subtyping and more modern therapy. The concentrations of Ig, IgA, and IgM at diagnosis of ALL in 199 children were reviewed. One hundred forty-one (71%) had normal values and 58 (29%) had at least one abnormal value. No obvious pattern of abnormality relating to disease immunophenotype emerged. Disease-free survival (DFS) was not significantly different when simply comparing children with normal and abnormal values. Those with a white blood cell count lower than 20 x 10(9)/L (n = 106) included 22 with at least one low Ig whose 5-year DFS was inferior to the "normal" group (56% vs 83%; P < 0.005). The 140 children with CD10 + B precursor ALL included 31 with one or more low Ig concentrations who also showed an inferior 5-year DFS to the remainder (55% vs 77%; P < 0.02). Minor abnormalities in Ig concentrations are seen in approximately one third of children with ALL regardless of immunologic subtype. Low values may relate to poor outcome in patients with the disease at otherwise good risk.

The clinical usefulness of the measurement of red cell zinc protoporphyrin (ZPP), an indicator of iron-deficient erythropoiesis, was assessed in a group of UK children undergoing investigation for red cell microcytosis. Of 213 children studied, 136 had increased ZPP values. Of these, 86 also had reduced iron stores as indicated by serum ferritin concentration. The 50 children with increased ZPP and normal ferritin values could be divided into two main groups. One group comprised 28 children who had evidence of coexistent infection or inflammatory disease. The other included 21 children who had beta-thalassemia trait (n = 19) or disease (n = 2). Among the 77 children with normal ZPP values, 22 had reduced serum ferritin concentrations and 45 did not, nor did they have evidence of beta-thalassemia. Microcytosis in some of these children could have been due to alpha-thalassemia trait. Measurement of ZPP is a simple, quick, and relatively cheap method of confirming the presence of iron-deficient erythropoiesis even when inflammation makes serum ferritin measurements unreliable. It is not as sensitive as the ferritin assay to the early stages of iron deficiency, and its specificity is reduced by the occurrence of raised values in most children with beta-thalassemia trait. Where there is microcytosis, normal values, together with normal hemoglobin A2 and serum ferritin concentrations, are likely to indicate alpha-thalassemia trait.

Blast cell chromosome abnormalities at presentation in childhood acute lymphoblastic leukemia (ALL) are common, and different patterns are known to be related to outcome. In contrast, the frequency and importance of further changes at the time of relapse remain unclear. Blast cell karyotype evolution was therefore studied in a group of children with recurrent disease. Of 134 consecutive children diagnosed between 1982 and 1992, 31 had a marrow relapse, and 24 had complete cytogenetic studies at both diagnosis and the time of recurrence. Fourteen (58%) of the 24 showed additional chromosomal abnormalities at relapse, 5 (21%) retained abnormalities identical to those seen at diagnosis, and 5 (21%) remained cytogenetically normal. The 14 with additional changes had shorter first remissions and showed shorter survival after relapse compared with the others. These findings indicate that emergency of cytogenetically recognizable subclones during the progression of childhood ALL could be a marker of more resistant disease.

Twenty-one children who suffered an acute encephalopathic illness during induction chemotherapy for ALL are described. Convulsions and coma were a major feature of this illness. In the absence of other predisposing factors we feel that the encephalopathy was secondary to drug toxicity. Two children died, and 4 of the surviving children have also died. Modifications of antileukemic therapy because of encephalopathic illness may have had a part to play in the outcome for some of these children. The surviving children appear to be neurologically and developmentally normal.