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Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics. [ABSTRACT FROM AUTHOR]

It is 50 years since the first effective drug for childhood lymphoblastic leukaemia (ALL) was described. At that time the outlook for such children was certain death. Now patients have an odds-on chance of normal health and life expectancy. Although the greatest gains have been made in recent years, the classes of drug that have achieved this have all been available for over 20 years. It is their better deployment and the greater understanding of their pharmacology that have allowed both more effective protocols to be devised and long term adverse effects to be recognised and avoided. Supportive treatment has also improved in parallel. Three major problems remain: how to recognise children in whom conventional therapy will fail; how to prevent failure; and how to treat it if it occurs. Therapy will fail in some children for pharmacological reasons - noncompliance or constitutional (genetic) drug resistance. For such children in vitro drug sensitivity testing and greater pharmacological vigilance may help by identifying those at risk and allowing intervention. In others, treatment will fail because of intrinsically resistant disease that either develops despite therapy or regrows from a minimal residue. Despite wider application of sophisticated immunological and genetic studies both at diagnosis or later, recognising poor-prognosis children prospectively is hampered by the lack of a biological classification system that is sufficiently sensitive and specific to categorise all patients reliably. In those where there is no doubt about high-risk status, treatment failure rates are still unacceptably high whatever therapy is given, and salvage therapy in any child who relapses is a continuing challenge. [ABSTRACT FROM AUTHOR]

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 muM 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 muM and 10 muM 6MP incubations contained both 6MP and its initial nucleotide metabolite, thioinosine 5'-monophosphate (TIMP). In addition, the 10 muM 6MP 48 h incubates contained small amounts of 6-thioguanine (6TG, median 0.12 muM). At 500 muM 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 muM respectively), with TIMP, 6TG, thioxanthine and thioxanthine nucleotide at median concentrations of 61, 0.79, 2.11 and 0.80 muM 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. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the pharmacokinetics of once daily (OD) gentamicin and its effectiveness as part of an OD regimen for the empirical treatment of febrile neutropenia in children with cancer.Subjects: 59 children aged 6 months to 16 years (mean (SD) 5.7 (4) years) with febrile neutropenia (neutrophil count < 0.5 x 10(9)/l) after chemotherapy.Methods: Over one year, 113 febrile neutropenic episodes were treated empirically with an OD antibiotic regimen of ceftriaxone (80 mg/kg; maximum 4 g) and gentamicin (7 mg/kg; infused over 60 minutes, no maximum). The patients were assessed after 48 hours.Results: 86 of the 113 episodes settled with the first line antibiotic regimen. In 29 episodes, blood cultures identified a causative bacterial pathogen; for 17 of these, the first line antibiotic regimen was adequate; in four episodes, although the episode settled, ceftriaxone was replaced by a more appropriate antibiotic and OD gentamicin was continued; in the remaining eight episodes, a glycopeptide antibiotic was deemed necessary. There was no failure of treatment in organisms sensitive to gentamicin, including Pseudomonas aeruginosa. In 27 episodes (24%), resolution was obtained by the empirical introduction of a second line regimen of ceftazidime and a glycopeptide antibiotic, and/or amphotericin. Gentamicin concentrations were measured in 110 episodes and they were all below the 24 hour line indicating that there was no need to change the dosing interval. In two episodes (2%), serum creatinine rose transiently by more than 50% of the baseline concentration. Although there was no vestibular toxicity, three of 30 children who underwent pure tone audiometry reported high frequency hearing loss in one ear.Conclusion: OD gentamicin can be used safely and effectively to treat febrile neutropenia in children with cancer. When used for a short period (< 5 days), in children not receiving other nephrotoxic drugs and who have normal serum creatinine, serum gentamicin estimations are unnecessary. [ABSTRACT FROM AUTHOR]

Fifty consecutive episodes of fever in neutropenic children with malignant disease or aplastic anaemia were randomized to treatment with either ceftazidime alone or a combination of azlocillin and tobramycin, pending the results of bacteriological investigation. More than 90% of organisms isolated from these episodes were sensitive to ceftazidime, which appears to be a non-toxic alternative to aminoglycosides in such circumstances. [ABSTRACT FROM PUBLISHER]