The majority of paediatric B precursor acute lymphoblastic leukaemias in children are derived from a single transformed haematopoietic cell with complete or partial VDJ recombination within the immunoglobulin heavy chain gene. A high frequency of patients also show rearrangements within TCRdelta and TCRgamma loci and in up to 40% of children there is an excess of immune system gene rearrangements compared with the number of identified alleles of immune system genes, suggesting the presence of multiple leukaemic subclones -clonal diversity. It has been observed by us and other investigators that in individual patients the pattern of immune system gene rearrangements often changes between presentation and relapse. In order to explore the possibility that clonal diversity plays a biological role during disease progression we optimised methods for subclone detection and analysed the prognostic significance of clonal diversity among 75 children with B precursor-ALL. Our results suggest that clonal diversity plays a role in disease progression as patients with oligoclonal disease showed a significantly shorter disease free survival than patients with monoclonal disease. This trend was of particular importance in the 'standard risk' group of ALL where aggressive disease could not be recognised by other means. In addition, generation of independent subclones from an early, non-rearranged tumour progenitor appears to be a common feature among leukaemias with aggressive clinical behaviour. We speculate on the type of genetic factors which may participate both in the generation of subclones and also in wider genomic instability and which are likely to be required for the aggressive clinical phenotype in children with ALL.
The purpose of this study was to evaluate the psychological impact of autoantibody screening and its results on at-risk individuals and family members. Individuals who were antibody positive (AP) were identified through a large-scale screening program conducted at our institute. The sample consisted of nine families in whom 10 AP youngsters (7 M, 3 F) were identified, ranging in age from 6-18 years (mean 11.8, median 10 yr). Seventeen parents and eight diabetic youngsters (mean age 15.2, median 16 yr) participated in the study. Reaction to autoantibody positivity was assessed with the Impact of Event scale (IES). The IES was answered twice: within a week from the disclosure of the AP status, and 3 months later. Parents scored higher than their diabetic children and AP children on both measures of the IES, Intrusion and Avoidance. Three months later both scores were significantly reduced in both the parents and the AP children; however, parents still scored significantly higher on both scores than the AP children. The results suggest that learning one's AP status induces significant anxiety, especially in parents of AP youngsters. Although this initial anxiety dissipates over time it still remains quite high after 3 months. The results highlight the importance of psychosocial counseling for all members of diabetes mellitus screening and prevention trials.
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