For pediatric patients with high-grade gliomas, standard-ofcare treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high-grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3-year-old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal-parietal-temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling Figure 2. Therapeutic course and serial neuroimaging studies. (A): Schematic illustrating the timing of tumor resection and treatments for the patient. (B): Contrast MRI (top) and fluid-attenuated inversion recovery MRI (bottom) images during the course of treatment from
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.
Choroid plexus carcinoma (CPC) is a rare malignant tumor arising from the epithelium of the choroid plexus of the brain. More than 80 % of CPCs occur in children. Mutations in the TP53 gene is played the main role in the pathogenesis of these tumors. Choroid plexus carcinomas in 40 % of cases are associated with Li–Fraumeni syndrome. Survival rates in patients with CPC and Li–Fraumeni syndrome are extremely low. The standards of the therapy for patients with CPC are not defined. The extent of surgical resection and treatment modality correlate with prognosis. The role of adjuvant therapy in CPC remains unclear: doses and volumes of radiation therapy (RT), combinations of chemotherapeutic drugs, timing, and a combination of RT and chemotherapy (CT) have not been identified. Also, there is neither a standard CT regimen nor a prospective international study assessing the efficacy and toxicity of various combinations of cytostatics in patients with CPC. The article presents an overview of the existing molecular genetic changes, existing methods for the diagnosis and treatment of choroid plexus carcinoma.
BACKGROUND/OBJECTIVES
Treatment of children with CNS NGGCT remains challenge: 5y OS is 60 – 80%; relapses are very aggressive.
DESIGN/METHODS
Between 2003 and 2019, 14 children (median age 10.5, range 4 – 16 years) with localized intracranial NGGCT were treated with RT after induction chemotherapy (focal – 4, WVI+boost – 6, WBI+boost – 3, CSI+boost – 1). Tumor markers were elevated in 13 patients: 6 – AFP, 5 – HCG, 2 – both. One patient with level of HCG 72049 IU/l in serum and 121451 IU/l in CSF received 4 cycles of PEI + CSI 30 Gy with boost 54Gy.
RESULTS
At a median follow-up of 4,7 years (range 1 – 16,25 years), 12 patients are alive. 5-year PFS and OS are 77,1% and 85,7%, respectively. Two patients (both AFP and HCG) progressed during RT (1 – focal, 1 – WBI+boost), both died. Two patients with high level of HCG recurred after therapy (WVI+boost – 1, focal – 1), both are alive. The first of them at recurrence (mts of lateral ventricle) received 4 cycles of PEI and RT (WBI+boost). The second patient had level of HCG 620IU/l and initially received focal irradiation 54Gy. At recurrence with distant spinal mts he received HD-CHT with auto-SCT, surgical resection of residual tumor and CSI with boost.
CONCLUSIONS
Good results of treatment of localized CNS NGGCT with CSI, WBI or WVI in compare with focal RT show advantages of extended irradiation field. CSI should be considered for patients with extremely high levels of tumor markers and respectively poor prognostic histology.
Low grade gliomas (LGGs) are the most common brain tumors in children. Our retrospective-prospective study of biological characteristics of sporadic LGGs (not associated with neurofibromatosis type I) included 233 patients aged 0 to 18 years who had been diagnosed and/or treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology in the period from 2009 to 2021. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. The median age at the diagnosis was 5 years 4 months (2 months – 17 years). Among the LGGs, the following histological variants were identified: pilocytic astrocytoma (n = 191; 82%), pleomorphic xanthoastrocytoma (n = 16; 7%), ganglioglioma (n = 7; 3%), desmoplastic infantile ganglioglioma (n = 4; 2%), diffuse leptomeningeal glioneuronal tumor (n = 5; 2%), dysembryoplastic neuroepithelial tumor (n = 2, 1%), and diffuse astrocytoma (n = 1; 0,5%). The tumors were located in: the suprasellar region (n = 98; 42%), the brainstem (n = 40; 17%), the cerebellum (n = 35; 15%), the hemispheres (n = 34; 15%) etc. The KIAA1549-BRAF fusion was the most common molecular genetic alteration (n = 107; 46%). The second most frequent genetic aberration was the BRAF V600E mutation (n = 44; 19%). Rare molecular genetic events leading to the activation of the MAPK signaling pathway were detected in 13 (6%) patients. The H3 K27M mutation associated with an aggressive clinical course was identified in three patients with brainstem LGGs (1%). These findings point to the importance of molecular profiling of pediatric LGGs for the selection of an effective strategy for molecular diagnosis and optimal clinical care.
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