INTRODUCTION: Pediatric low-grade gliomas arising from the thalamus or thalamopeduncular junction are rare. Prognostic factors are thus seldom reported in the literature. RESEARCH QUESTION: This systematic review aims to define the factors influencing the prognosis of pediatric patients with thalamic and thalamopeduncular low-grade gliomas. MATERIAL AND METHODS: An extensive literature search in adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed and included Web of Science, Scopus, and OVID interface (Medline and Embase). Original articles were selected if they provided data on 10 or more patients under 18 years old with separate or retrievable data for thalamic or thalamopeduncular low-grade gliomas, as well as at least one prognostic factor and its corresponding outcome. The risk of bias and applicability were assessed using The Quality Assessment of Prognostic Accuracy Studies criteria. RESULTS: The study selection process resulted in the inclusion of 14 articles out of the initial pool of 876 references. These 14 articles encompassed data from 446 patients. The prognostic factors reported were the extent of resection in ten studies, age and radiotherapy in four studies, bilateral involvement and molecular genetics in two studies, and sex and dissemination in one study each. Significant prognostic factors included the extent of resection, bilateral involvement, histology, and radiotherapy. DISCUSSION AND CONCLUSION: The reported factors considered significant for prognosis align with previously published data. The maximal safe resection, as a potentially curative modality for thalamic low-grade glioma, and the multidisciplinary approach to each patient should be a standard of care. Given the excellent long-term outlook of these patients, the extent of resection should not be pursued at the risk of neurological function since additional therapeutic possibilities are available today, such as molecular-targeted agents.

• Klíčová slova
• Low-grade glioma, Outcome, Pediatric, Prognosis, Thalamic, Thalamopeduncular,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management. However, the optimal strategy for monitoring gliomas by LB remains to be determined. In this study, we analyzed circulating tumor DNA (ctDNA) from 78 liquid biopsies (plasma n = 44, cerebrospinal fluid n = 34 (CSF)) of 35 glioma patients, determining H3F3A K28M (K27M) and BRAF V600E mutation allele frequency using droplet digital PCR (ddPCR). All results were correlated to clinically relevant parameters including diagnostic imaging and CSF aspiration site (ventricular vs lumbar) with respect to tumor localization. Regarding diagnostic accuracy, the calculated sensitivity score in the H3F3A K27M cohort was 84.61% for CSF and 73.68% for plasma. In the BRAF V600E cohort, we determined a sensitivity of 83.3% in plasma and 80% in CSF. The overall specificity was 100%. With respect to the CSF aspiration, the intra-operatively obtained CSF demonstrated 100% detection rate, followed by ventricular CSF obtained via Ommaya Reservoir/shunt puncture (93%) and CSF obtained via lumbar puncture (66%). Notably, this further correlated with the proximity of the CSF site to tumor localization. Longitudinal CSF monitoring demonstrated a good correlation to clinical and radiological disease evolution. Importantly, we show for the first time that monitoring BRAF V600E by ddPCR could serve as treatment response assessment in gliomas. In summary, our observation may inform recommendations with regard to location of CSF aspiration when incorporating LB into future treatment protocols.

• Klíčová slova
• CSF sampling site, Droplet digital PCR, Glioma, Liquid biopsy, Longitudinal monitoring, Targeted therapy,
• MeSH
• cirkulující nádorová DNA mozkomíšní mok   genetika   MeSH
• dítě MeSH
• dospělí MeSH
• gliom * genetika   patologie   diagnóza   MeSH
• histony * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace MeSH
• nádorové biomarkery * genetika   mozkomíšní mok   MeSH
• nádory mozku * genetika   diagnóza   patologie   MeSH
• předškolní dítě MeSH
• protoonkogenní proteiny B-Raf * genetika   MeSH
• tekutá biopsie metody   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• cirkulující nádorová DNA MeSH
• H3-3A protein, human MeSH Prohlížeč
• histony * MeSH
• nádorové biomarkery * MeSH
• protoonkogenní proteiny B-Raf * MeSH

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

• Klíčová slova
• RAS/MAPK pathway, brain tumor, low-grade glioma, molecular diagnostics, neurooncology, pediatric, risk stratification,
• MeSH
• dítě MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genová přestavba * MeSH
• gliom klasifikace   genetika   patologie   MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy genetika   MeSH
• mladiství MeSH
• mutace * MeSH
• nádorové biomarkery genetika   MeSH
• nádory mozku klasifikace   genetika   patologie   MeSH
• neurofibromin 1 genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• Ras proteiny genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• stanovení celkové genové exprese MeSH
• variabilita počtu kopií segmentů DNA * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• BRAF-KIAA1549 fusion protein, human MeSH Prohlížeč
• fúzní onkogenní proteiny MeSH
• mitogenem aktivované proteinkinasy MeSH
• nádorové biomarkery MeSH
• neurofibromin 1 MeSH
• NF1 protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH
• Ras proteiny MeSH

Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.

• Klíčová slova
• H3K27M, comprehensive molecular profiling, diffuse midline glioma, pediatric oncology, precision medicine,
• Publikační typ
• časopisecké články MeSH

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

• MeSH
• diencefalon enzymologie   patologie   MeSH
• dítě MeSH
• gliom enzymologie   genetika   patologie   terapie   MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mutace MeSH
• nádory mozkového kmene enzymologie   genetika   patologie   terapie   MeSH
• nádory mozku enzymologie   genetika   patologie   terapie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• stupeň nádoru MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH