The significance of genetic background in childhood acute lymphoblastic leukemia (ALL) is not well understood. Polymorphisms of genes encoding for xenobiotics and drug transporters are potential factors, which can influence the risk of developing ALL and its clinical outcome. P-glycoprotein (P-gp) is an adenosine triphosphate-binding cassette (ABC)-family transporter involved in protection against xenobiotics and multi-drug resistance. Recently, the single-nucleotide polymorphism C3435T of MDR1 gene has been found to be associated with altered tissue expression and function of P-gp. To evaluate whether C3435T MDR1 polymorphism is associated with the occurrence and outcome of ALL, 113 children with ALL (median age 5.1 yr) and 175 healthy individuals of Polish Caucasian origin were studied by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) assay. The mutant homozygous TT genotype was found to be associated with occurrence of ALL (OR, 95% CI; 1.8, 1.1-3.1; P = 0.037). Besides, the analysis of factors influencing clinical outcome of our ALL patient cohort showed that CC genotype carriers had significantly lower event-free survival probability (pEFS) (0.62 vs. 0.87; P = 0.007) and overall survival probability (pOS) (0.72 vs. 0.91; P = 0.006). The Cox proportional hazards model-based analysis revealed that the hazard ratios for lower pEFS and lower pOS among CC homozygous subjects were 3.9 (P = 0.008) and 3.3 (P = 0.02), respectively. In conclusion, the results of the present study provide evidence that C3435T MDR1 polymorphism may involve both the susceptibility to and the clinical outcome of childhood ALL. Carriers of the TT genotype are more at risk of developing ALL than other individuals, whereas CC genotype carriers are supposed to have worse prognosis.

Children and adolescents with Type 1 diabetes mellitus have a very wide range of insulin sensitivity, which is determined by sex, age, amount of adipose tissue and glycaemic control.

The primary aim of the study was to evaluate the importance of anti-asparaginase antibodies for l-asparaginase activity in children with standard and medium risk acute lymphoblastic leukemia (ALL). Forty-seven children with newly diagnosed ALL were included into the prospective study. Enzyme activity and the presence of anti-asparaginase antibodies (IgG and IgM class) were determined. Anti-asparaginase antibodies were identified in 13/47 (IgM class) and 10/47 (IgG class) patients in the induction and in 19/47 (IgM class) and 20/47 (IgG class) patients in the reinduction phase of treatment. The enzyme activity was lower in patients that were positive for anti-asparaginase antibodies, especially in reinduction phase (median 37 (20 - 180) vs 355 (141 - 499), p = 0.001). An association between anti-asparaginase antibodies and the allergic reaction to the drug was found. Besides, the children who developed anti-asparaginase antibodies in the induction phase of treatment showed lower event-free survival as well as overall survival in comparison with children without antibodies. Since our study was carried out in a small number of patients, this observation is only speculative and needs to be confirmed by a further study on a larger sample size, with multivariable analysis. However, our data suggest that L-asparaginase activity together with anti-asparaginase antibodies measurements may become useful for effective therapy of ALL.

Repeated administration of L-asparaginase leads to the development of specific antibodies and hypersensitivity reactions. The aim of the study was to evaluate a possible cross-reaction of anti-asparaginase antibodies, developed against the native E. coli L-asparaginase (Asparaginase Medac), with other preparations of the enzyme. Sixteen patients with acute lymphoblastic leukemia, in whom in the reinduction phase of treatment hypersensitivity against L-asparaginase was observed and/or the presence of anti-asparaginase antibodies was established were recruited for the present study. Ten out of 16 tested sera showed cross-immunoreactivity to PEG-asparaginase, while no reactivity to L-asparaginase derived from Erwinia chrysantemi was observed. Since cross-reacting antibodies were also found in sera of patients with no overt allergic reaction, L: -asparaginase may undergo silent inactivation during the reinduction phase of therapy. This finding is of clinical importance with regard to appropriate dosage and necessitates careful enzyme activity monitoring in all patients undergoing repeated treatment with various L-asparaginase preparations.

The overrepresentation of phenotypically slow acetylators among patients with atopic allergy has been reported in previous studies. The N-acetyltransferase coding gene has not yet been investigated in allergic diseases. This study was designed to determine the differences in the distribution of mutation frequency and genotypes that encode normal and defective activity of N-acetyltransferase in children with atopic allergies compared with healthy children. In 56 children with documented inhalational, food, or mixed allergies and in 100 healthy control children with no clinical or laboratory signs of allergy, the genotype coding for N-acetyltransferase was identified by means of the polymerase chain reaction followed by analysis of restriction fragment length polymorphism. Nucleotide transitions in the following positions were investigated: 481 C-->T, 590 G-->A, 803 A-->G, and 857 G-->A, which enabled the identification of six genotypes, including the wild-type (wt) allele, and 16 genotypes, including mutated alleles (homozygotic and herterozygotic). The statistical analysis showed significant differences in the distribution of the frequency of the occurrence of mutated alleles and genotypes between the two groups of children. In 51 children (91%) with allergy, genotypes that encode acetylation defect were found; genotypes that code for normal N-acetyltransferase were observed in only five allergic children (9%). In the control group the distribution of genotypes coding for normal and defective N-acetyltransferase activity is 38% and 62%, respectively. Thus study enabled the conclusion that the slow acetylation genotype is a genetic marker of predisposition to atopy.