High-dose methotrexate pharmacokinetics and its impact on prognosis of paediatric acute lymphoblastic leukaemia patients: A population pharmacokinetic study.

This study delivers a comprehensive evaluation of the efficacy and pharmacokinetics of high-dose methotrexate (HDMTX) in a large cohort of Chinese paediatric acute lymphoblastic leukaemia patients. A total of 533 patients were included in the prognostic analysis. An association was observed between lower steady-state MTX concentrations (<56 µmol/L) and poorer outcomes in intermediate-/high-risk (IR/HR) patients. Subgroup analysis further revealed that this relationship between concentrations and prognosis was even more pronounced in patients with MLL rearrangements. In contrast, such an association did not emerge within the low-risk patient group. Additionally, utilizing population pharmacokinetic modelling (6051 concentrations from 815 patients), we identified the significant impact of physiological maturation, estimated glomerular filtration rate, sex and concurrent dasatinib administration on MTX pharmacokinetics. Simulation-based recommendations include a reduced dosage regimen for those with renal insufficiency and a specific 200 mg/kg dosage for infants under 1 year. The findings underscore the critical role of HDMTX in treating IR/HR populations and call for a reassessment of its application in lower-risk groups. An individualized pharmacokinetic dosage regimen could achieve the most optimal results, ensuring the largest proportion of steady-state concentrations within the optimal range.

The association of miR34b/c and TP53 gene polymorphisms with Wilms tumor risk in Chinese children.

Wilms tumor is the most common pediatric malignancy in the kidney. The miR34b/c is a downstream target gene of the transcription factor p53. The important role of TP53 mutations, the methylation of miR34b/c, and the interaction between these two molecules in tumorigenesis have been well documented. Due to the biological connection between p53 and miR34b/c, in the present study, we investigated the association between polymorphisms in these two molecules and Wilms tumor susceptibility through genotyping two important functional polymorphisms (miR34b/c rs4938723 T>C and TP53 rs1042522 C>G) in 183 cases and 603 controls. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) derived from the logistic regression analysis were used to assess the correlation of miR34b/c rs4938723 and TP53 rs1042522 polymorphisms with Wilms tumor risk. Our results indicated that the association of miR34b/c rs4938723 and TP53 rs1042522 polymorphisms with Wilms tumor susceptibility was not statistically significant. Stratified analysis by age, gender, and clinical stage, as well as combined effect analysis were also performed, yet, no significant association was found. In conclusion, our study indicated a lack of association between the two selected polymorphisms and Wilms tumor susceptibility. Our findings need to be verified in studies with larger sample size in the future.

Polymorphisms in MYCN gene and neuroblastoma risk in Chinese children: a 3-center case-control study.

INTRODUCTION: Neuroblastoma is an embryonal tumor of the sympathetic nervous system. The MYCN oncogene is amplified in some neuroblastoma patients and correlated with poor prognosis. However, less is known regarding the relationship between MYCN gene single-nucleotide polymorphisms (SNPs) and neuroblastoma risk. PATIENTS AND METHODS: To investigate the contribution of MYCN gene polymorphisms to neuroblastoma risk, we performed a 3-center case-control study by genotyping 4 SNPs in the MYCN gene from 429 cases and 884 controls. RESULTS: The results showed that only rs57961569 G>A was associated with neuroblastoma risk (GA vs GG: adjusted odds ratio =0.76, 95% confidence interval =0.60-0.98, P=0.033), while the other 3 SNPs were not (rs9653226 T>C, rs13034994 A>G, and rs60226897 G>A). Stratified analysis revealed that rs57961569 GG carriers were more likely to develop neuroblastoma in the following subgroups: children older than 18 months, tumor derived from the adrenal gland, and clinical stages III + IV. The increased neuroblastoma risk associated with the rs9653226 variant CC genotypes was more evident in the following subgroups: females, tumor derived from the adrenal gland, and clinical stages III + IV. The presence of 2-3 risk genotypes had a significant relationship with the following subgroups: tumor derived from the adrenal gland and clinical stages III + IV. CONCLUSION: This study demonstrates a weak impact of MYCN gene polymorphisms on neuroblastoma risk, which should be further validated.