BACKGROUND: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established. METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS. CONCLUSIONS: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

• Klíčová slova
• H3-wild-type and IDH-wild-type, chromosome 6, gliomatosis cerebri, pedHGG_RTK2, pediatric-type glioma, pediatric-type high-grade glioma,
• MeSH
• dítě MeSH
• fenotyp MeSH
• gliom * genetika   patologie   MeSH
• kojenec MeSH
• lidé MeSH
• metylace DNA MeSH
• míra přežití MeSH
• mladiství MeSH
• mutace MeSH
• nádorové biomarkery genetika   MeSH
• nádory mozku * genetika   patologie   MeSH
• následné studie MeSH
• neuroepitelové nádory * patologie   genetika   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• retrospektivní studie 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
• multicentrická studie MeSH
• Názvy látek
• nádorové biomarkery MeSH

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.

• Klíčová slova
• BRAF, Chemotherapy, Child, First-line, MAPK, Pediatric low-grade glioma, Tovorafenib, pLGG,
• MeSH
• dítě MeSH
• gliom * farmakoterapie   genetika   metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy MeSH
• mladý dospělý MeSH
• mutace MeSH
• oximy MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf MeSH
• pyridony MeSH
• pyrimidinony terapeutické užití   MeSH
• světluškovití * metabolismus   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladý dospělý MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• mitogenem aktivované proteinkinasy MeSH
• oximy MeSH
• protoonkogenní proteiny B-Raf MeSH
• pyridony MeSH
• pyrimidinony MeSH

BACKGROUND: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using fresh frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit. METHODS: Analysis of patients aged 0 to 21 years, enrolled in Germany between April 2019 and February 2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing, and RNA-Seq were performed. RESULTS: FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n = 71), BRAF V600E-mutation (n = 12), and alterations in FGFR1 (n = 14) as the most frequent alterations, among other common molecular drivers (n = 12). N = 16 cases (13%) presented rare gene fusions (eg, TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n = 27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 internal tandem duplications (n = 6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols. CONCLUSIONS: The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

• Klíčová slova
• RNA sequencing, actionable drivers, molecular profiling, pLGG, rare gene fusions,
• MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   MeSH
• gliom * patologie   MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• molekulární patologie MeSH
• protoonkogenní proteiny B-Raf * genetika   MeSH
• protoonkogenní proteiny genetika   MeSH
• sekvenování transkriptomu MeSH
• transkripční faktory genetika   MeSH
• tyrosinkinasy MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• protoonkogenní proteiny B-Raf * MeSH
• protoonkogenní proteiny MeSH
• transkripční faktory MeSH
• tyrosinkinasy MeSH
• VGLL1 protein, human MeSH Prohlížeč

BACKGROUND: Childhood thalamopeduncular gliomas arise at the interface of the thalamus and cerebral peduncle. The optimal treatment is total resection but not at the cost of neurological function. We present long-term clinical and oncological outcomes of maximal safe resection. METHODS: Retrospective review of prospectively collected data: demography, symptomatology, imaging, extent of resection, surgical complications, histology, functional and oncological outcome. RESULTS: During 16-year period (2005-2020), 21 patients were treated at our institution. These were 13 girls and 8 boys (mean age 7.6 years). Presentation included progressive hemiparesis in 9 patients, raised intracranial pressure in 9 patients and cerebellar symptomatology in 3 patients. The tumour was confined to the thalamus in 6 cases. Extent of resection was judged on postoperative imaging as total (6), near-total (6) and less extensive (9). Surgical complications included progression of baseline neurological status in 6 patients, and 5 of these gradually improved to preoperative status. All tumours were classified as low-grade gliomas. Disease progression was observed in 9 patients (median progression-free survival 7.3 years). At last follow-up (median 6.1 years), all patients were alive, median Lansky score of 90. Seven patients were without evidence of disease, 6 had stable disease, 7 stable following progression and 1 had progressive disease managed expectantly. CONCLUSION: Paediatric patients with low-grade thalamopeduncular gliomas have excellent long-term functional and oncological outcomes when gross total resection is not achievable. Surgery should aim at total resection; however, neurological function should not be endangered due to excellent chance for long-term survival.

• Klíčová slova
• Childhood glioma, Extent of resection, Low-grade astrocytoma, Survival, Thalamus,
• MeSH
• dítě MeSH
• gliom * komplikace   diagnostické zobrazování   chirurgie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• nádory mozku * komplikace   diagnostické zobrazování   chirurgie   MeSH
• neurochirurgické výkony metody   MeSH
• retrospektivní studie MeSH
• thalamus diagnostické zobrazování   patologie   chirurgie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

• Klíčová slova
• Brain tumor, EWSR1, Gene fusion, MN1, Neuroepithelial, Neurooncology, PATZ1, Pediatric,
• MeSH
• dítě MeSH
• fúzní onkogenní proteiny genetika   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory mozku genetika   patologie   MeSH
• neuroepitelové nádory genetika   patologie   MeSH
• onkogenní fúze MeSH
• předškolní dítě MeSH
• represorové proteiny genetika   MeSH
• transkripční faktory Krüppel-like genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• nádorové biomarkery MeSH
• PATZ1 protein, human MeSH Prohlížeč
• represorové proteiny MeSH
• transkripční faktory Krüppel-like MeSH

A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.

• Klíčová slova
• FGFR, FGFR fusion, cancer, centrosome, centrosome cycle, cilia, fibroblast growth factor receptor, neoplastic transformation, oncogenic driver, primary cilia,
• MeSH
• centrozom metabolismus   MeSH
• cilie * metabolismus   patologie   MeSH
• lidé MeSH
• nádorová transformace buněk patologie   MeSH
• nádory * metabolismus   patologie   MeSH
• onkogenní fúze MeSH
• receptory fibroblastových růstových faktorů metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• receptory fibroblastových růstových faktorů MeSH

PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

• Publikační typ
• časopisecké články 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

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

Zinc ions are essential cofactors of a wide range of enzymes, transcription factors, and other regulatory proteins. Moreover, zinc is also involved in cellular signaling and enzymes inhibition. Zinc dysregulation, deficiency, over-supply, and imbalance in zinc ion transporters regulation are connected with various diseases including cancer. A zinc ion pool is maintained by two types of proteins: (i) zinc-binding proteins, which act as a buffer and intracellular donors of zinc and (ii) zinc transporters responsible for zinc fluxes into/from cells and organelles. The decreased serum zinc ion levels have been identified in patients suffering from various cancer diseases, including head and neck tumors and breast, prostate, liver, and lung cancer. On the contrary, increased zinc ion levels have been found in breast cancer and other malignant tissues. Zinc metalloproteomes of a majority of tumors including brain ones are still not yet fully understood. Current knowledge show that zinc ion levels and detection of certain zinc-containing proteins may be utilized for diagnostic and prognostic purposes. In addition, these proteins can also be promising therapeutic targets. The aim of the present work is an overview of the importance of zinc ions, zinc transporters, and zinc-containing proteins in brain tumors, which are, after leukemia, the second most common type of childhood cancer and the second leading cause of death in children after accidents.

• Klíčová slova
• Cancer, Childhood brain tumors, Metallothioneins, Zinc metalloenzymes, Zinc transporters,
• MeSH
• biologické modely MeSH
• cílená molekulární terapie MeSH
• dítě MeSH
• lidé MeSH
• nádorové proteiny metabolismus   MeSH
• nádory mozku diagnóza   metabolismus   MeSH
• zinek metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• nádorové proteiny MeSH
• zinek MeSH