SummaryGenotyping of TPMT prior to 6-mercaptopurine (6-MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6-MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6-MP toxicity-related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6-MP dose reduction, therapy interruption and event-free survival. The allele frequency of rs116855232 was 0Á16, and leucopenia was more common in carriers of the T allele (odds ratio, 7Á20; 95% confidence interval, 2Á49-20Á80; P = 2Á7 9 10 À4). As leucopenia results in 6-MP dose reduction, we observed average doses during maintenance therapy of 40Á7, 29Á3 and 8Á8 mg/m 2 for patients with CC, CT and TT genotypes, respectively (P < 0Á001). Hepatotoxicity was observed only in CC genotype patients. Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. Considerations for clinical application may be warranted.

BackgroundThe PedsQL 3.0 Cancer Module is a widely used instrument to measure pediatric cancer specific health-related quality of life (HRQOL) for children aged 2 to 18 years. We developed the Japanese version of the PedsQL Cancer Module and investigated its reliability and validity among Japanese children and their parents.MethodsParticipants were 212 children with cancer and 253 of their parents. Reliability was determined by internal consistency using Cronbach's coefficient alpha and test-retest reliability using intra-class correlation coefficient (ICC). Validity was assessed through factor validity, convergent and discriminant validity, concurrent validity, and clinical validity. Factor validity was examined by exploratory factor analysis. Convergent and discriminant validity were examined by multitrait scaling analysis. Concurrent validity was assessed using Spearman's correlation coefficients between the Cancer Module and Generic Core Scales, and the comparison of the scores of child self-reports with those of other self-rating depression scales for children. Clinical validity was assessed by comparing the on- and off- treatment scores using Kruskal-Wallis and Mann-Whitney U tests.ResultsCronbach's coefficient alpha was over 0.70 for the total scale and over 0.60 for each subscale by age except for the 'pain and hurt' subscale for children aged 5 to 7 years. For test-retest reliability, the ICC exceeded 0.70 for the total scale for each age. Exploratory factor analysis demonstrated sufficient factorial validity. Multitrait scaling analysis showed high success rates. Strong correlations were found between the reports by children and their parents, and the scores of the Cancer Module and the Generic Core Scales except for 'treatment anxiety' subscales for child reports. The Depression Self-Rating Scale for Children (DSRS-C) scores were significantly correlated with emotional domains and the total score of the cancer module. Children who had been off treatment over 12 months demonstrated significantly higher scores than those on treatment.ConclusionsThe results demonstrate the reliability and validity of the Japanese version of the PedsQL Cancer Module among Japanese children.

The OS of patients in the JWiTS-1 study were comparable with the results of other multicenter studies in the USA and Europe. The outcome for patients with nephroblastoma and CCSK was fair. In contrast, the cure rate for those with RTK was not satisfactory. New treatment strategies are needed for patients with RTK.

The WT1 gene essential for the embryonic kidney development is mutated in 15-25% of Wilms tumors (WTs). To clarify whether genetic subtypes of WT1 abnormalities are correlated with IGF2 or CTNNB1 alterations or clinicopathological characteristics, we performed comprehensive WT1, IGF2, and CTNNB1 analyses of 36 WTs with WT1 abnormalities using single nucleotide polymorphism arrays, and methylation analysis of the IGF2-H19 differentially methylated region. The tumors were classified into three subtypes based on WT1 abnormalities: 13 with WT1 deletion, 12 with WT1 mutation, and 11 with both deletion and mutation. IGF2 alterations were found in 50% (18/36), paternal uniparental disomy (UPD) of 11p13-11p15 in 13 tumors, UPD limited to 11p15 in 3, and loss of IGF2 imprinting in 2. Quantitative RT-PCR analysis showed that tumors with IGF2 alteration had higher levels of IGF2 mRNA than tumors without IGF2 alteration (P = 0.02). WT1 mRNA levels were very low in six of eight WTs with WT1 deletion, whereas four of eight WTs with WT1 mutation or both deletion and mutation showed higher levels of WT1 mRNA than fetal kidneys. WTs with WT1 mutations occurred in younger patients (P < 0.01), and WTs with mutations or both deletion and mutation (12/23) were more frequent in syndromic patients than WTs (1/13) with the deletion (P = 0.02). WTs with WT1 mutations or both deletion and mutation had the triphasic histological-type (15/23; P = 0.03) and CTNNB1 mutation (17/23; P = 0.03) more frequently than WTs with the deletion (2/13 and 4/13). Thus, three WT1 subtypes were correlated with certain genetic and clinicopathological characteristics.

BACKGROUND Familial hemophagocytic lymphohistiocytosis HLH (FHL) is fatal, unless patients are rescued with hematopoietic stem cell transplantation (SCT). Although the molecular identification of FHL now is possible at least in part from perforin gene study, many cases escape detection or never are tested due to the lack of specific hallmarks, making diagnosis difficult. To the authors' knowledge, it remains to be determined whether persistently low natural killer cell (NK) activity and a high incidence of central nervous system (CNS) disease increase the probability of FHL. METHODS The authors analyzed 42 HLH patients age < 2 years, 13 of whom developed overt CNS disease and 5 of whom demonstrated persistently deficient NK activity (Group 1). The remaining 24 patients had no CNS disease and had NK activity of moderate decrease to within the normal range (Group 2). RESULTS In Group 1, CNS symptoms were detected in 6 cases within 1 month and between 4.5–9 months in 6 other patients. In these cases, spotty lesions demonstrating a high T2 signal in the white matter were noted on brain magnetic resonance imaging. The survival was significantly poor for patients in Group 1 unless they were rescued with SCT, which was performed in 5 of the 13 patients with CNS disease and in all 5 patients with persistent NK activity deficiency. SCT was successful in 9 patients, with no CNS sequelae reported after the transplantation. Conversely, the prognosis of the 24 patients in Group 2 was better and only 1 patient required SCT. CONCLUSIONS Very young HLH patients (age < 2 years) who are at high risk of fatal FHL with persistently deficient NK activity and/or overt CNS disease require appropriate SCT to reverse CNS disease and achieve a complete cure. Cancer 2002;94:3023–31. © 2002 American Cancer Society. DOI 10.1002/cncr.10515