RESUMO
Patients with ALK-driven neuroblastoma may respond to tyrosine kinase inhibitors, but resistance to treatment occurs and methods currently used for detection of residual disease have limited sensitivity. Here we present a national unselected cohort of five patients with relapsed or refractory ALK-driven neuroblastoma treated with lorlatinib as monotherapy, and test the potential of targeted circulating tumor DNA (ctDNA) analysis as a guide for treatment decisions in these patients. We developed a sequencing panel for ultrasensitive detection of ALK mutations associated with neuroblastoma or resistance to tyrosine kinase inhibitors and used it for ctDNA analysis in 83 plasma samples collected longitudinally from the four patients who harbored somatic ALK mutations. All four patients with ALK p.R1275Q experienced major responses and were alive 35-61 months after starting lorlatinib. A fifth patient with ALK p.F1174L initially had a partial response but relapsed after 10 months of treatment. In all cases, ctDNA was detected at the start of lorlatinib single agent treatment and declined gradually, correlating with clinical responses. In the two patients exhibiting relapse, ctDNA was increased nine and three months before clinical detection of disease progression, respectively. In one patient harboring HRAS p.Q61L in the relapsed tumor, retrospective ctDNA analysis showed that the mutation appeared de novo after eight months of lorlatinib treatment. We conclude that some patients with relapsed or refractory high-risk neuroblastoma show durable responses to lorlatinib as monotherapy, and targeted ctDNA analysis is effective for evaluation of treatment and early detection of relapse in ALK-driven neuroblastoma.
RESUMO
Objective: The objective of this study was to investigate odds ratios of overweight/obesity in children with ADHD and to compare the change in body mass index (BMI) after initiation of methylphenidate treatment in normal versus overweight/obese children. Method: This population-based study included 724 children (<18 years), of whom 197 were girls. Odds ratios for overweight and obesity were calculated, comparing the study group with a reference group from the same area. After initiation of methylphenidate treatment, changes in BMI were assessed for up to 3 years. Results: Children with ADHD had an odds ratio of 1.87 (95% confidence interval [CI]: [1.60, 2.19]) for overweight/obesity. A decrease in BMI standard deviation score was identified 1 to 3 years into treatment. The decrease was beneficially greater in overweight/obese as compared with normal weight children-mean (SD) -0.64 (0.80) versus -0.39 (0.68); p = .001-and greater in girls. Conclusion: Medication with methylphenidate may facilitate favorable weight development in children with ADHD and overweight/obesity.