In a historical cohort study of all singleton live births in Northern Ireland from 1971 -86 (n=434 933) associations between early life factors and childhood acute lymphoblastic leukaemia were investigated. Multivariable analyses showed a positive association between high paternal age (535 years) and acute lymphoblastic leukaemia (relative risk=1.49; 95% confidence interval (CI)=0.96 -2.31) but no association with maternal age. High birth weight (53500 g) was positively associated with acute lymphoblastic leukaemia (relative risk=1.66; 95% CI=1.18 -2.33). Children of mothers with a previous miscarriage or increased gestation (540 weeks) had reduced risks of ALL (respective relative risks=0.49; 95% CI=0.29 -0.80, and 0.67; 95% CI=0.48 -0.94). Children born into more crowded households (51 person per room) had substantially lower risks than children born into less crowded homes with also some evidence of a lower risk for children born into homes with three adults (relative risks=0.56; 95% CI=0.35 -0.91 and 0.58; 95% CI=0.21 -1.61 respectively). These findings indicate that several early life factors, including living conditions in childhood and maternal miscarriage history, influence risk of acute lymphoblastic leukaemia in childhood.

This study explored how fathers of children diagnosed with acute lymphoblastic leukaemia (ALL) perceived and understood the roles they had within their family over the course of their child's illness and treatment. In-depth semi-structured interviews were conducted with five fathers. Transcripts were analysed using interpretative phenomenological analysis (IPA). The major themes that emerged were: adjusting to the diagnosis; the experience of maternal gate-keeping; striving for normalization; experiences of giving and receiving support. Overall, the fathers perceived themselves as having significant responsibility in helping their child and family cope with the illness experience. Clinical implications, including the need for professionals to recognize and more openly acknowledge the father's position, are considered.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 6-Mercaptopurine (6-MP) and azathioprine (AZA) are both inactive prodrugs that require intracellular activation into the active 6-thioguanine nucleotides (6-TGNs).• This metabolic process undergoes three different competitive pathways that are catalysed by three different enzymes; xanthine oxidase (XO), thiopurine methyltransferase (TPMT) and inosine triphosphatase (ITPA), all of which exhibit genetic polymorphisms.• Although the impact of genetic variation in the TPMT gene on treatment outcome and toxicity has been demonstrated, the role of other polymorphisms remains less well known. WHAT THIS STUDY ADDS• New information on the allelic variation of these three enzymes (XO, TPMT and ITPA) and their influence on 6-MP/AZA metabolism and toxicity.• Confirmation of the association of TPMT polymorphism with haematological toxicity.• Identified potential genetic characteristics that may contribute to higher risk of adverse events (such as ITPA IVS2+21A→C mutation). AIMSTo examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD). METHODSClinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94→A and IVS2+21A→C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined. RESULTSThiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A→C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A→C variants with thrombocytopenia (P = 0.012). CONCLUSIONSPharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.