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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)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: The contribution of tumor type, multimodal treatment, and other patient-related factors upon long-term cognitive sequelae in infant brain tumor survivors remains undefined. We add our retrospective analysis of neuropsychological and quality of survival (QoS) outcome data of survivors of atypical teratoid/rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors of the soft tissues (eMRT) and kidneys (RTK) treated within the same framework. Neuropsychological data from children with ATRT were compared to data from children with non-irradiated low-grade glioma (LGG)., Patients and Methods: Following surgery, patients (0-36 months at diagnosis) had received radio-chemotherapy (up to 54 Gy; ATRT: n = 13; eMRT/RTK: n = 7), chemotherapy only (LGG: n = 4; eMRT/RTK: n = 1) or had been observed (LGG: n = 11). Neuropsychological evaluation employing comparable tests was performed at median 6.8 years (ATRT), 6.6 years (eMRT/RTK), and 5.2 years (LGG) post diagnosis., Results: We detected sequelae in various domains for all tumor types. Group comparison showed impairments, specifically in fluid intelligence (p = .041; d = 1.11) and visual processing (p = .001; d = 2.09) in ATRT patients when compared to LGG patients. Results for psychomotor speed and attention abilities were significantly below the norm for both groups (p < .001-.019; d = 0.79-1.90). Diagnosis predicted impairments of cognitive outcome, while sex- and age-related variables did not. QoS outcome for all rhabdoid patients displayed impairments mainly in social (p = .008; d = 0.74) and school functioning (p = .048; d = 0.67), as well as lower overall scores in psychosocial functioning (p = .023; d = 0.78) and quality of life (p = .006; d = 0.79) compared to healthy controls., Conclusion: Survivors of infant ATRT experience various late effects in cognition and QoS following multimodal treatment, while infant LGG patients without radiotherapy demonstrated comparable impairments in psychomotor and attention abilities. Early onset and multimodal treatment of rhabdoid tumors require close monitoring of neuropsychological and QoS sequelae., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding hGFAP-cre::Trp53 Fl/Fl ::lsl-MYCN mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from., (© 2023. The Author(s).)

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology., (© 2023. The Author(s).)

Immunologic treatment strategies are under investigation for high-grade gliomas. Determining relevant immunologic pathways is required for invigorating a tumor-specific immune response. We therefore investigated the immunologic phenotypes within different subgroups of high-grade gliomas, with a focus on rare genetic subgroups of pediatric and adolescent patients to identify potentially targetable mechanisms. We gathered published gene-expression data from 1,135 high-grade glioma patients and applied a machine-learning technique to determine their transcriptional (mesenchymal, classic, neural, and proneural) and mutational [K27, G34, IDH, and wild type (WT)] subtypes. Gene signatures of infiltrating immune cells and functional immune pathways were evaluated in correlation to histologic diagnosis, age, and transcriptional and mutational subgroups. Our analysis identified four distinct microenvironmental signatures of immune cell infiltration (immune 1-4), which can be stratified into vascular, monocytic/stromal, monocytic/T-cell-, and antigen-presenting cell (APC)/natural killer (NK) cell/T-cell-dominated immune clusters. Immune cell expression profiles correlated with transcriptional and mutational subgroups but were independent of age and histologic diagnosis. By including functional pathways and correlating the expression of immunostimulatory and -inhibitory receptor-ligand interactions, we were able to define the immunologic microenvironment and identify possible immunologic subtypes associated with poor prognosis. In addition, comparison of overall survival with the immunologic landscape and with checkpoint molecules revealed correlations within the transcriptional and mutational subgroups, highlighting the potential application of PD-1/PD-L1 checkpoint inhibition in K27-mutated tumors. Our study shows that transcriptional and mutational subgroups are characterized by distinct immunologic tumor microenvironments, demonstrating the immunologic heterogeneity within high-grade gliomas and suggesting an immune-specific stratification for upcoming immunotherapy trials., (©2019 American Association for Cancer Research.)

Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence., Methods: The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m 2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3)., Results: All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression., Conclusions: Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.

We conducted a phase II study to test methotrexate (5 g/m(2)), as a single agent prior to radiochemotherapy for pediatric high-grade glioma and diffuse intrinsic pontine glioma. Thirty patients (19 male, median age 10.8) were enrolled. Tumors were located as follows: cortex 10, pons 7, other 13. Tumor resection was classified as gross total in 6, subtotal in 6, partial in 4, biopsy in 11 and not performed in 3. WHO grading of the histology was: IV: 11, III: 12 and II: 3. Patients received methotrexate 5 g/m(2) in 24-hour infusions on days 1 and 15. Subsequently 54 Gy radiation was administered with simultaneous chemotherapy including cisplatin, etoposide, vincristine and ifosfamide as previously described. Eight 6-weeks cycles of maintenance chemotherapy consisted of vincristine 1.5 mg/m(2) on days 1, 8 and 15; lomustine 100 mg/m(2) on day 2 and prednisone 40 mg/kg on days 1-17. Event-free survival rates in the whole group of 30 patients were: 43, 20, and 13% after 1, 2 and 5 years, respectively. The response evaluation after methotrexate was available in 19 of the 24 patients who started treatment with measurable disease: CR: 0, PR: 1, SD 18, PD: 0. After radiochemotherapy the response of 24 patients with measurable disease was CR: 1, PR 10, SD 12, PD 1. Both response and event-free survival were superior to the control group of 330 patients treated in various protocols of the same cooperative group. In subgroup analyses the use of dexamethasone during early treatment was linked to poor event free survival. Giving two cycles of high-dose methotrexate prior to radiochemotherapy was feasible, and the approach was taken forward to a randomized phase III trial.

Background: The quality of care for children with brain tumors might be higher in large medical centers; however, it may be possible to improve the quality of care received in smaller centers if they join an effective network., Aim: This study used the HIT-GBM® database to compare the quality of care provided to pediatric high-grade glioma and diffuse intrinsic pontine glioma patients among various medical centers of differing sizes., Patients and Methods: Overall survival was used as a defining parameter. Indirect measures were the time intervals between the first clinical signs of cancer, initial diagnostic imaging, surgery, or chemotherapy and radiation., Results: From 1995 to 2003, 310 children (137 girls and 173 boys, aged 3 to 18 years old) were registered from 72 medical centers in Europe. Center sizes differed from 1 to 17 registered patients. Center size did not affect survival, nor any of the time intervals studied., Conclusion: There was no evidence that the quality of care differed between smaller and larger centers.

Background: The authors hypothesized that intensified chemotherapy in protocol HIT-GBM-C would increase survival of pediatric patients with high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG)., Methods: Pediatric patients with newly diagnosed HGG and DIPG were treated with standard fractionated radiation and simultaneous chemotherapy (cisplatin 20 mg/m2 x 5 days, etoposide 100 mg/m2 x 3 days, and vincristine, and 1 cycle of cisplatin + etoposide + ifosfamide 1.5 g/m x 5 days [PEI] during the last week of radiation). Subsequent maintenance chemotherapy included further cycles of PEI in Weeks 10, 14, 18, 22, 26, and 30, followed by oral valproic acid., Results: Ninety-seven (pons, 37; nonpons, 60) patients (median age, 10 years; grade IV histology, 35) were treated. Resection was complete in 21 patients, partial in 29, biopsy only in 26, and not performed in 21. Overall survival rates were 91% (standard error of the mean [SE] +/- 3%), 56%, and 19% at 6, 12, and 60 months after diagnosis, respectively. When compared with previous protocols, there was no significant benefit for patients with residual tumor, but the 5-year overall survival rate for patients with complete resection treated on HIT-GBM-C was 63% +/- 12% SE, compared with 17% +/- 10% SE for the historical control group (P = .003, log-rank test)., Conclusions: HIT-GBM-C chemotherapy after complete tumor resection was superior to previous protocols., (Copyright 2009 American Cancer Society.)

Valproic acid (VPA) inhibits histone deacetylase and has been reported to induce apoptosis in glioma. We report 44 heavily pretreated pediatric patients with high-grade glioma or diffuse intrinsic pontine glioma who received VPA as oral continues maintenance treatment with individual dose adaptation. The tumor status when starting the drug was: no measurable disease in 12, measurable but stable disease in 12, and measurable progressive disease in 22 patients. Average trough blood levels of VPA were 99 mg/l. The most frequent complaint was somnolence (three patients), but no severe toxicity was reported. One relapse patient responded, early progression of disease was observed in three frontline patients and in six relapsed patients. Median overall survival duration for all patients was 1.33 years, with large differences between first-line (5-year overall survival, 44%) and relapse therapy (5-year overall survival, 14%). This shows that valproate is safe in this patient population. The moderate tumor efficacy encourages studying the drug further as an element of multi-agent protocols.

In children, treatment regimen for high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) are generally not stratified according to disease stage. The hypothesis was that secondary disseminating disease (SDD) in children with HGG is related to an even worse outcome. Description of SDD pattern was performed. In total, 270 children with newly diagnosed HGG or DIPG were eligible for retrospective analysis of SDD. Medical and computer records of these patients were reviewed for demographic characteristics, sites of dissemination, prognostic variables. Forty-six (17%) of the 270 patients had developed SDD. The median time to SDD was 8.2 months. The median overall survival (OS) after dissemination was 3.2 months. The SDD was located parenchymal in the supratentorial (34.8%), infratentorial (6.5%), supratentorial and infratentorial (19.6%), spinal (10.9%), spinal and cerebral (6.5%) regions of the CNS, or leptomeningeal (21.7%). For HGG patients, the median OS was shorter among patients with SDD than among patients without SDD (1.02 vs 1.41 years, P=0.0495). In the group of patients with SDD, patients with cerebrospinal fluid dissemination had a worse outcome compared with patients with parenchymal metastases. Summarising, SDD is a negative prognostic factor for patients with HGG outside the pons. Treatment stratification should be considered.

The present study was performed to investigate the prognostic impact of tumor resection on survival in children and adolescents with malignant gliomas. From the HIT-GBM data base of the Gesellschaft für Paediatrische Onkologie und Haematologie (GPOH), 85 pediatric patients with malignant non-pontine gliomas were analyzed. Histological diagnosis and extent of tumor resection had been confirmed by central neuropathological review and post-surgical imaging. The extent of tumor resection represented the most prominent prognostic factor for overall (OS) and event-free survival (EFS) in univariate and Cox regression analyses. Four-year survival after gross total tumor resection was 48.0 +/- 12.0% (OS) and 14.1 +/- 8.9% (EFS), after non-total resection 13.2 +/- 6.1% and 2.9 +/- 2.8%, respectively. From several clinical parameters, only histological grading displayed a similar statistical significance in Cox regression analysis. In conclusion, gross total tumor resection improves survival in pediatric patients with malignant gliomas and should always be attempted when possible.

Background: Pontine gliomas are the subgroup of brainstem gliomas with the worst prognosis. Controversial treatment approaches are discussed., Patients and Methods: Data of children with pontine gliomas treated in different prospective multi-center studies who were registered in the HIT-GBM database were pooled and analyzed addressing prognostic factors and the relevance of intensive treatment using contingency tables, Kaplan-Meier curves and Cox regression analyses., Results: From 1983 to 2001, 153 patients (74 males, 79 females, mean age: 8.1 years) with pontine gliomas were registered. Twenty-one tumors were low-grade and 60 were high-grade gliomas (72 undefined histology: 67 no surgery, 5 incomplete data). Sixteen tumors were partially resected, and 125 were irradiated. Ninety children received chemotherapy according to the "HIT-GBM" protocols ("Hirntumor-Glioblastoma multiforme"). The one-year overall survival rate (1YOS) of all patients with pontine glioma was 39.9+/-4.3%. None of the surviving patients had an observation time longer than 3.9 years. Favorable prognostic factors seemed to be age younger than 4 years, low-grade histology and smaller tumor. All three major treatment modalities including resection, irradiation and chemotherapy had prognostic relevance in univariable analysis. Chemotherapy remained beneficial, even if the analysis was restricted to the subgroup of irradiated tumors (1YOS 45.8+/-5.4% vs. 34.4+/-13.5%, P=0.030)., Conclusion: Irradiation is an effective element for the treatment of pontine gliomas. Intensive chemotherapy seems to be important in achieving a better OS.

Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden. [ABSTRACT FROM AUTHOR]