Bellini A, Pötschger U, Bernard V, et al. - Among high-risk (HR) neuroblastoma (NB) patients on the HR-NBL1/SIOPEN trial, this inquiry was conducted to analyze anaplastic lymphoma kinase (ALK) genetic alterations, as well as their frequency, correlation with clinical parameters, and prognostic influence. Researchers obtained diagnostic tumor samples from 1,092 HR-NBL1/SIOPEN patients to ascertain ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). Total 4.5% of cases (41 out of 901) showed presence of genomic ALK amplification (ALKa), all except one with MYCN amplification (MNA). Presence of ALK mutations (ALKm) at a clonal level (> 20% mutated allele fraction) and at a subclonal level (mutated allele fraction 0.1%-20%) was found in 10% of cases (76 out of 762) and in 3.9% of patients (30 out of 762), respectively, with a strong correlation between the presence of ALKm and MNA. Findings showed that a poorer survival was independently predicted by genetic alterations of ALK (clonal mutations and amplifications) in HR-NB. These results offer a rationale for combination of ALK inhibitors in upfront therapy of HR-NB with ALK alterations.