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Medulloblastoma (MB) is the most common embryonal brain tumor in children, characterized by a high level of heterogeneity within this entity. Four major molecular groups have been defined - WNT, Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4) - differing widely in genetic alterations and patient outcomes. Targeted treatment approaches are limited for high-risk MB including MYC-amplified G3, G4, or MYCN/GLI2-amplified SHH. Based on earlier studies describing the inhibition of cell cycle regulation as a therapeutic vulnerability in high-risk MB, we aimed to explore the efficacy and mode of action of approved CDK4/6 inhibitors in aggressive MB. First the in vitro sensitivity of pediatric G3 (n=5) MB cell models against palbociclib, ribociclib and abemaciclib was evaluated and compared to adult SHH (n=2) cells serving as MYC-negative controls. Abemaciclib most effectively reduced cell viability, exhibiting a mean IC50 value of 0.9 M in G3 compared to 2.1 M in SHH cells (p=0.007). Upon long-term exposure (7-10 days), again abemaciclib most potently decreased clonogenic survival already at 250nM in G3 MB cells. We observed a G1/S phase cell cycle arrest upon abemaciclib treatment and confirmed this by Western blot analyses, showing decreased Rb phosphorylation accompanied by reduced MAPK signaling. Interestingly, abemaciclib treatment distinctly reduced MYC protein and gene expression levels in MYC-amplified G3 cell models. In addition, exposure to abemaciclib decreased GLI2 and TERT mRNA levels, which was accompanied by induction of cellular senescence. Within the ITCC-P4 project, single mouse trials are currently being performed including abemaciclib treatment in orthotopic MB models. The detailed investigation of the precise mode of action in vitro and in vivo is ongoing. Summarizing, the CDK4/6 clinically approved inhibitor abemaciclib shows promising efficacy against high-risk MB in vitro.

BACKGROUND: Childhood cerebellar pilocytic astrocytomas harbour excellent overall survival rates after surgical resection, but the patients may exhibit specific cognitive and behavioural problems emphasising our current understanding of the cerebellar role in cognition. Functional MRI has catalysed the mechanistic insights into brain functional systems and has already been linked with the neuropsychological performance. We aimed to exploit the question whether functional MRI can be used as a surrogate measure for the cognitive outcome assessment of these patients. METHODS: We investigated 13 patients (median age 22.0 years, range 15.2 – 31.7) after a median interval between surgery and examination of 15.0 years (range 4.2 – 20.8) and 16 matched controls. All subjects underwent a functional 3T MRI scans in a resting state condition and a battery neuropsychological tests. RESULTS: Patients showed a significantly increased functional connectivity in the precuneus compared to controls (p

BACKGROUND High-grade gliomas are among the most aggressive brain tumors across all age groups. BRAF is within the most frequently altered genes in pediatric glioma, sometimes connected with telomerase reverse transcriptase (TERT) promoter mutations, predicting a particularly aggressive course of disease. Precision medicine approaches targeting the MAPK pathway have shown promising results in patients with BRAF-mutated glioma. Although acquired insensitivity to BRAF inhibitors appears as major issue for therapy failure, underlying molecular mechanisms are still poorly understood. METHODS Cell models from an anaplastic pleomorphic xanthoastrocytoma with BRAF V600E and TERT promoter mutations and the recurrent tumor, operated following MAPK pathway-targeting therapy, were established. Furthermore, a dabrafenib-resistant subline of the recurrent tumor was generated. The patient-derived cell models were genetically characterized using array-based genomic hybridization (aCGH). Sensitivity of the cells towards different MAPK pathway inhibitors was tested. Basal expression and activation of MAPK pathway and downstream signals were analyzed by qRT-PCR and Western blots. RESULTS Screening a panel of both primary and immortalized glioma cell models with different BRAF and TERT promoter status revealed significantly induced MAPK pathway activation and enhanced TERT levels in BRAF V600E and TERT promoter double-mutant gliomas. Furthermore, cells with both mutations were hyper-sensitive towards BRAF-targeting agents and BRAF inhibition resulted in reduced TERT levels. ETS1 expression was strongly increased in the recurrent tumor and identified as important player in telomerase re-activation. aCGH revealed gains of chromosomal regions encoding for different ETS-factors in the dabrafenib-resistant subline. Western blot analyses suggested a BRAF/ERK-independent survival mechanism in the dabrafenib-resistant subline. Accordingly, dabrafenib insensitivity triggered cross-resistance towards the MEK inhibitor trametinib. Uncoupled from the MAPK pathway, ETS1 expression was further upregulated in the dabrafenib-resistant subline. CONSLUSION: Taken together, our data demonstrate that MAPK-independent ETS transcription factor upregulation is a central mechanism of BRAF inhibitor therapy failure in BRAF-mutated pediatric glioma patients.

BACKGROUND Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNET) are glioneural tumors associated with treatment refractory seizures, especially in younger patients. Because there is a relative paucity of data on which factors predispose patients for recurrences, we analyzed our own cohort treated over the last 25 years. MATERIAL AND METHODS We performed a retrospective analysis of all patients undergoing resection of a glioneural tumor with a minimum follow up of one year. Surgery type, histological findings, and seizure outcome were extracted from patient records. Recurrence was defined as new tumor lesions in previously unremarkable parenchyma or tumor growth of a residual lesion. We performed a Mann-Whitney-U test to determine statistical significance of differences in continuous variables and Fisher’s exact test in categorical. RESULTS In total, 109 patients were operated between March 1994 to March and followed for a median of 62.4 months (range 12–281 months). The average age of patients at the time of surgery was 21.2 years with 60 patients belonging to the pediatric population. Complete lesionectomies were the goal in 72 cases, extended resections in 10, and partial resection due to proximity of eloquent areas was performed in 27 cases. 77 tumors were classified histologically as a GG and 32 as a DNET. The temporal lobe was the most common site of origin with 65 tumors (59.6%) being found there. On postoperative MRI, complete resection was achieved in 76 cases. Local tumor recurrences were seen in 14 patients (12 GG and 2 DNET), 9 of which occurred in patients with apparently complete resection. Overall, only one malignant transformation of a GG was observed. Age at surgery was significantly lower for patients with later recurrence (11.9 yrs vs. 22.6 yrs for patients without recurrence, p=0.0047). A second surgery was performed in 11 patients with previously incomplete resections (33%) and 7 patients with complete resection (9.2%), p=0.0038. 95 patients (87.2%) had preoperative seizures for a median of 26 months before surgery. One year after surgery, a documented ILAE outcome was available for 90 of these patients and 63 (70%) were seizure free one year after surgery. While 45 patients with epilepsy (47.4%) had at least one seizure relapse after surgery - most often associated with AED withdrawal or tumor recurrence - medical therapy and repeat resection allowed 76 patients (80%) to be seizure free for over one year at their last follow up. Age at surgery was not a significant predictor of seizure freedom. CONCLUSION Glioneural tumors are highly epileptogenic but neurosurgical resection allows seizure freedom in the large majority of these patients. Tumor recurrences were more likely in younger patients and incomplete resections predisposed patients to need another surgery. Resection extent on MRI does not appear to be a reliable marker for future recurrence risk.

Background The intratumoral heterogeneity of oxygen metabolism in combination with variable patterns of neovascularization (NV) as well as reprogramming of energy metabolism affects the landscape of tumor microenvironments (TMEs) in glioblastoma. Knowledge of the hypoxic and perivascular niches within the TME is essential for understanding treatment failure. Methods Fifty-two patients with untreated glioblastoma (isocitrate dehydrogenase 1 wild type [IDH1wt]) were examined with a physiological MRI protocol including a multiparametric quantitative blood oxygen level dependent (qBOLD) approach and vascular architecture mapping (VAM). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of 6 different TMEs: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation (OxPhos), and glycolysis with/without neovascularization. Association of the different TME volume fractions with progression-free survival (PFS) was assessed using Kaplan–Meier analysis and Cox proportional hazards models. Results A common spatial structure of TMEs was detected: central necrosis surrounded by tumor hypoxia (with defective and functional neovasculature) and different TMEs with a predominance of OxPhos and glycolysis for energy production, respectively. The percentage of the different TMEs on the total tumor volume uncovered 2 clearly different subtypes of glioblastoma IDH1wt: a glycolytic dominated phenotype with predominantly functional neovasculature and a necrotic/hypoxic dominated phenotype with approximately 50% of defective neovasculature. Patients with a necrotic/hypoxic dominated phenotype showed significantly shorter PFS (P = 0.035). Conclusions Our non-invasive mapping approach allows for classification of the TME and detection of tumor-supportive niches in glioblastoma which may be helpful for both clinical patient management and research.

Patients with malignancy, particularly patients with high-grade glioma (HGG; WHO grade III/IV), have an increased risk of venous thromboembolism (VTE). It has been suggested that VTE predicts survival in cancer patients. The aim of our study was to investigate the occurrence of symptomatic VTE and its impact on survival in patients with HGG. Consecutive patients (n = 63; 36 female, 27 male; median age, 58 years) who had neurosurgical intervention between October 2003 and December 2004 were followed after surgery until October 2005. Objectively confirmed VTE was recorded as an event. All patients had received thrombosis prophylaxis with low-molecular-weight heparin (LMWH) during the immediate postoperative period. Subsequently, 56 patients received radiochemotherapy, 6 radiotherapy, and 1 chemotherapy only. Patients were followed over a median time period of 348 days. Fifteen patients (24%) developed VTE. Pulmonary embolism was diagnosed in nine patients (60%) and was fatal twice. The cumulative probability of VTE was 21% after three months and 26% after 12 months. The highest frequency of VTE was observed in patients with biopsy and subtotal tumor resection (n = 37; multivariate hazard ratio, 3.58; 95% CI = 0.98-13.13; P = 0.054) compared with patients with total resection. Survival did not significantly differ among patients with and without VTE and was 53% after 12 months in both groups. Patients with HGG, particularly those with biopsy and subtotal resection, are at high risk to develop VTE postoperatively. Thrombosis was not associated with a significant reduction of survival.

OBJECTIVE: Gangliogliomas (GG) are among the most common lesions causing medically refractory epilepsy. Incomplete resection or early recurrences are common in patients with eloquent located tumours resulting in persistent epilepsy. Neuronavigation combined with intraoperative high-field MR imaging (iopMRI) may improve complete resection even in eloquent located tumours and contribute to a better surgical and seizure outcome. METHODS: We retrospectively identified fifty-two patients (25 female, 27 male, mean age 31.7 ± 14.8 years) with gangliogliomas and lesional epilepsy operated at our clinic. Forty-one (78.8%) were located in the temporal lobe, 11 (21.2%) extratemporally. Additionally to neuronavigation and intraoperative 1.5-Tesla MR imaging, we implemented DTI tractography (visual-, speech- and pyramidal tracts) in 15 and functional MRI (Wernickés area, motor cortex) in 10 patients. Tailored resections were performed in 12 patients using intraoperative electrocorticography (ECoG). RESULTS: The registration accuracy of neuronavigation was 1.5 ± 0.7 mm. The first MRI scan before closing revealed complete resection of the lesion in only 31 of 52 patients (59.6%). Consequently, remnant tumour was identified in 21 patients. After re-segmentation of the residual tumour and update of neuronavigation, total resection rate was improved by 12 patients to 43/52 (82.7%). The remaining patients had subtotal resections due to the vicinity to eloquent brain areas. Follow-up was available for 37 patients to date, who showed excellent seizure control with 31/37 (83.8%) patients having an Engel Class 1 outcome (Engel 1A in 28/37 or 75.7% of all patients) after a mean time period of 60 ± 44 months. Four out of six patients with a permanent neurological deficit presented with short and long term memory decline (7.7%), two had visual field deficits (3.8%). CONCLUSION: Neuronavigation and intraoperative MR imaging increased complete resections in our series of ganglioglioma patients with medically refractory epilepsy by 20%, leading to an excellent seizure control and a low complication rate.