Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia.

Recent advances in treatment for childhood acute lymphoblastic leukaemia (ALL) have significantly increased outcome. High-dose methotrexate (MTX) is the most commonly used regimen during the consolidation period, but the optimal dose remains to be defined. We investigated the usefulness of the MTHFR genotype to increase the MTX dosage in the consolidation phase in 141 childhood ALL patients enrolled in the ALL/SHOP-2005 protocol. We also investigated the pharmacogenetic role of polymorphisms in genes involved in MTX metabolism on therapy-related toxicity and survival. Patients with a favourable MTHFR genotype (normal enzymatic activity) treated with MTX doses of 5 g m⁻² had a significantly lower risk of suffering an event than patients with an unfavourable MTHFR genotype (reduced enzymatic activity) that were treated with the classical MTX dose of 3 g m⁻² (P=0.012). Our results indicate that analysis of the MTHFR genotype is a useful tool to optimise MTX therapy in childhood patients with ALL.

[Surgery of lung metastasis]. / La cirugía de las metástasis pulmonares.

INTRODUCTION: The 30-40% of the oncologic patients have pulmonary metastases. Lung can be the only organ affected. In selected patients, exeresis of the pulmonary nodules can mean their healing. MATERIAL AND METHODS: Between 1982-1997, twenty two patients presented metastases, 13 could be operated and 16 thoracotomies were done. There were 53% boys and 47% girls whose ages ranged from 3 to 15 years. We have considered: pulmonary tumour location, disease free interval, number of metastases, surgical technique and incomplete pulmonary tumour resection. RESULTS: Primary tumours were: Wilms tumours 23%, bone tumours 67% (Ewing and osteosarcoma). Disease free interval was < 2 years in 8 patients (61%) and > 2 years in 39%. X-Ray and CT were performed in every case and 66% presented a solitary nodule. Surgical techniques were: metastasectomy in two cases (12%), wedge resection in 8 (50%) and lobectomy in six cases (38%). We made thoracoscopy in two patients. There weren't postoperatory mortality but the patients with tumorectomy had an incomplete surgical resection. The overall survival is 54 percent and the 5 years survival is 23 percent (3 patients). CONCLUSIONS: The patients with a DFI < 2 years have a survival of 25% compared with 100% for patients who have a DFI > 2 years. The pulmonary resection in selected patients can offer better survival. We can use the thoracoscopy in same selected patients.

Ifosfamide-induced renal tubular defect.

We describe 2 cases of proximal tubular defects induced by the administration of ifosfamide at a dosage of 6 g/m2/course over 2 days in children with a diagnosis of malignant mesenchymal tumors. This adverse effect could be minimized dividing dosage of the drug. However at present it is not clear if divided doses are completely safe.

Impaired T cell signal transduction through CD28 in a patient with idiopathic thrombocytopenia.

We describe an infant whose peripheral blood mononuclear cells were unable to proliferate or synthesize IL-2 in response to a mitogenic combination of antibodies directed against CD2 and CD28. This peculiar defect, which has been stable to date, was attributed to an impairment in CD28-mediated T cell activation, because further comitogenic combinations containing anti-CD28 monoclonals also failed to induce normal proliferation of the patient's T cells. In contrast, proliferation after membrane stimulation (with anti-CD2, recombinant IL-2, or certain lectins) or transmembrane activation (with phorbol ester and calcium ionophore) was normal, suggesting that his lymphocytes did not have a general membrane or intracellular signalling impairment. A T cell line derived from the patient confirmed the existence of a severe defect in CD28-mediated T cell proliferation, but also showed a profound impairment in CD3-induced T cell proliferation. Other cell surface molecules like CD2 and CD25 were, in contrast, capable of transducing normal proliferation signals. As all relevant molecules were detectable by cytofluorography and immunoprecipitation, we conclude that the patient's lymphocytes had an intrinsic defect in the delivery of CD28-mediated signals which, in the absence of monocytes, also affected CD3-mediated proliferation. The study of this novel kind of immunodeficiency may help to unravel the complex interactions that take place among CD2, CD3 and CD28 during T cell activation. The presence of an idiopathic thrombocytopenia in the patient suggests the intriguing possibility of a role for CD28 in the maintenance of peripheral blood platelets levels, although alternative interpretations are not ruled out.