The prognosis for higher risk childhood B-cell non-Hodgkin lymphoma has improved over the past 20 years but the optimal intensity of treatment has yet to be determined. Children 21 years old or younger with newly diagnosed B-cell nonHodgkin lymphoma/B-cell acute lymphoblastic leukemia (B-NHL/B-ALL) with higher risk factors (bone marrow [BM] with or without CNS involvement) were randomized to standard intensity FrenchAmerican-British/Lymphoma Malignancy B (FAB/LMB) therapy or reduced intensity (reduced cytarabine plus etoposide and deletion of 3 maintenance courses M2, M3, M4). All patients with CNS disease had additional high-dose methotrexate (8 g/m 2 ) plus extra intrathecal therapy. Fifty-one percent had BM involvement, 20% had CNS involvement, and 29% had BM and CNS involvement. One hundred ninety patients were randomized. The probabilities of 4-year event-free survival (EFS) and survival (S) were 79% ؎ 2.7% and 82% ؎ 2.6%, respectively. In patients in remission after 3 cycles who were randomized to standard versus reducedintensity therapy, the 4-year EFS after randomization was 90% ؎ 3.1% versus 80% ؎ 4.2% (one-sided P ‫؍‬ .064) and S was 93% ؎ 2.7% versus 83% ؎ 4.0% (onesided P ‫؍‬ .032). Patients with either combined BM/CNS disease at diagnosis or poor response to cyclophosphamide, Oncovin [vincristine], prednisone (COP) reduction therapy had a significantly inferior EFS and S (P < .001). Standardintensity FAB/LMB therapy is recommended for children with high-risk B-NHL (B-ALL with or without CNS involvement).

Summary.One hundred and thirty-four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c-AMB), liposomal amphotericin B 1 mg/kg/d (L-AMB1) or liposomal amphotericin B 3 mg/ kg/d (L-AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38ЊC or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0 . 5 × 10 9 /l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (< 38ЊC) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L-AMB treated patients had a 2-6-fold decrease in the incidence (P 4 0 . 01) of test-drug-related side-effects, compared to c-AMB. Severe trial-drug-related side-effects were seen in 1% of L-AMB treated patients, in contrast to 12% of patients on c-AMB (P < 0 . 01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine level, was not observed in the L-AMB1 arm whereas the incidence was 3% in patients on L-AMB3 and 23% in those on c-AMB (P < 0 . 01). Moreover, time to develop nephrotoxicity was longer in both L-AMB arms than c-AMB (P < 0 . 01). Severe hypokalaemia was observed less frequently in both L-AMB arms (P < 0 . 01).Analysis was by intention-to-treat and included all patients randomized. Success was defined by a minimum of 3 consecutive days with fever (< 38ЊC) continuing to study end indicated by recovery of neutrophils to 0 . 5 × 10 9 /l. Addition of systemic antifungal therapy or development of systemic fungal infection were failures as was persistent fever to study end. Efficacy assessments indicated success in 49% of the total group treated with c-AMB. 58% of patients responded to L-AMB1 and 64% to L-AMB3. A statistically significant difference was found between c-AMB and L-AMB3 (P ¼ 0 . 03) but a Kaplan-Meier analysis of time to deffervescence of fever showed there was no significant difference between the arms.It was concluded that liposomal amphotericin at either 1 or 3 mg/kg/d was significantly safer than conventional amphotericin B in children and adults. The main aim of this open-label study was to compare safety between the three trial arms. However, we provide evidence for an equivalent or possibly superior efficacy of liposomal amphotericin with regard to resolution of fever of unknown origin. Subsequent trials should compare amphotericin preparations in defined fungal infections.

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A long-term follow-up study was carried out to assess ototoxicity in children who had been treated for a malignant tumour with "standard dose" cisplatin (60-100 mg/m2 per course), and were at least 2 years from stopping treatment. The median age at diagnosis was 2 years 2 months (range 1 month to 13.5 years). On the basis of hearing assessment by pure-tone audiometry, a practical grading system of hearing loss from 0 to 4 is proposed. Moderate to severe high-frequency hearing loss (grade 2-4) was found in half the children and 10 require appropriate hearing aids. The risk of developing ototoxicity increased significantly with the cumulative cisplatin dose (P = 0.027), although there was considerable individual susceptibility. Serial follow-up testing, to a median of 4 years after completion of cisplatin treatment, showed no recovery of hearing in any of these children. We suggest careful monitoring of young children by a consultant audiological physician throughout treatment with cisplatin, particularly when doses of 400 mg/m2 and over have been reached. Alternative chemotherapy should be discussed if grade 2 ototoxicity develops.