Ependymomas are among the most enigmatic tumors of the central nervous system, posing enormous challenges for pathologists and clinicians. Despite the efforts made, the treatment options are still limited to surgical resection and radiation therapy, while none of conventional chemotherapies is beneficial. While being histologically similar, ependymomas show considerable clinical and molecular diversity. Their histopathological evaluation alone is not sufficient for reliable diagnostics, prognosis, and choice of treatment strategy. The importance of integrated diagnosis for ependymomas is underscored in the recommendations of Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. These updated recommendations were adopted and implemented by WHO experts. This minireview highlights recent advances in comprehensive molecular-genetic characterization of ependymomas. Strong emphasis is made on the use of molecular approaches for verification and specification of histological diagnoses, as well as identification of prognostic markers for ependymomas in children.
Cell-free DNA (cfDNA) in body fluids is invaluable for cancer diagnostics. Despite the impressive potential of liquid biopsies for the diagnostics of central nervous system (CNS) tumors, a number of challenges prevent introducing this approach into routine laboratory practice. In this study, we adopt a protocol for sensitive detection of the H3 K27M somatic variant in cerebrospinal fluid (CSF) by using digital polymerase chain reaction (dPCR). Optimization of the protocol was carried out stepwise, including preamplification of the H3 target region and adjustment of dPCR conditions. The optimized protocol allowed detection of the mutant allele starting from DNA quantities as low as 9 picograms. Analytical specificity was tested using a representative group of tumor tissue samples with known H3 K27M status, and no false-positive cases were detected. The protocol was applied to a series of CSF samples collected from patients with CNS tumors (n = 18) using two alternative dPCR platforms, QX200 Droplet Digital PCR system (Bio-Rad) and QIAcuity Digital PCR System (Qiagen). In three out of four CSF specimens collected from patients with H3 K27M-positive diffuse midline glioma, both platforms allowed detection of the mutant allele. The use of ventricular access for CSF collection appears preferential, as lumbar CSF samples may produce ambiguous results. All CSF samples collected from patients with H3 wild-type tumors were qualified as H3 K27M-negative. High agreement of the quantitative data obtained with the two platforms demonstrates universality of the approach.
Infant high grade gliomas (HGG) are the most frequent tumors of the central nervous system in children below 1 year of age. Standard therapy involves surgical resection and chemotherapy. Prognosis in infant HGG is better than in older patients, however, the absence of effective regimens of anti-recurrence therapy and the impossibility of radiation therapy implementation predetermine a negative prognosis in the group of infant gliomas in case of disease progression. In most patients with infant HGG of hemispheric localization, gene rearrangements of receptor tyrosine kinases – NTRK1/2/3 (24%), ALK (41%), ROS1 (28%), MET (7%) are described. The results of tyrosine kinase inhibitor administration show high efficacy and safety in the treatment of patients with NTRK-positive gliomas. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The paper presents two examples of the successful use of targeted therapy in patients with infant HGG lacking the efficacy of the standard chemotherapy. In both cases, a persistent response was obtained: in the first case, a complete response to therapy was achieved, the duration of treatment is currently 1 year, in the second case – there is no progression of the disease during 20 weeks of therapy. Of the adverse events (AE) of targeted therapy in patients, only transitory neutropenia was noted in the first case, in the second case, AEs were not detected. In order to expand therapeutic options and prescribe targeted therapy drugs, a molecular genetic investigation of tumor tissue is mandatory for patients with hemispheric infant gliomas. The parents of the patients agreed to use the information, including photos of children, in scientific research and publications.
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