RESUMO
Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing. DNA and/or RNA sequencing revealed recurrent fusions involving the capicua transcriptional repressor (CIC) gene in 10/10 tumor samples analyzed, with the most common fusion being CIC::LEUTX (n = 9). In addition, a CIC::NUTM1 fusion was detected in one of the tumors. Apart from the detected fusion events, no additional oncogenic alteration was identified in these tumors. The histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. All tumors were located in the supratentorial compartment, occurred during childhood (median age 8.5 years) and typically showed early relapses. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC. Downstream functional consequences of the fusion protein CIC::LEUTX and potential therapeutic implications need to be further investigated.
RESUMO
Background: Osteonecrosis (ON) is a recognized complication of childhood ALL, but its optimal management remains unestablished. This study evaluated the effect of bisphosphonate (BP) treatment on the evolution of ON lesions in childhood ALL.Material and Methods: We included a national cohort of ALL patients diagnosed with symptomatic ON before 18 years of age and treated with BPs (N = 10; five males). Patients were followed both clinically and with serial MRIs. ON lesions were graded according to the Niinimäki classification.Results: The 10 patients had a total of 55 ON lesions. The median age was 13.3 years at ALL diagnosis and 14.8 years at ON diagnosis. Four patients had received HSCT before the ON diagnosis. BPs used were pamidronate (N = 7), alendronate (N = 2) and ibandronate (N = 1). The duration of BP treatment varied between 4 months and 4 years. In 4/10 patients, BP treatment was given during the chemotherapy. BPs were well-tolerated, with no severe complications or changes in kidney function. At the end of follow up 13/55 (24%) ON lesions were completely healed both clinically and radiographically; all these lesions were originally graded 3 or less. In contrast, ON lesions originally classified as grade 5 (joint destruction; N = 4) remained at grade 5. All grade 5 hip joint lesions needed surgical treatment. During BP treatment, the pain was relieved in 7/10 patients. At the end of follow-up, none of the patients reported severe or frequent pain.Conclusion: BP treatment was safe and seemed effective in relieving ON-induced pain in childhood ALL. After articular collapse (grade 5) lesions did not improve with BP treatment. Randomized controlled studies are needed to further elucidate the role of BPs in childhood ALL-associated ON.
