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Abstract Introduction Neurosurgery is considered the mainstay of treatment for pediatric low‐grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long‐term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. Patients and Methods Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1‐5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1‐status, sex, and age. Results The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p

Rhabdoid tumors (RT) are aggressive paediatric cancers with yet unknown cells of origin. Here, the authors establish genetically engineered mouse models of RT and, using single-cell RNA-seq and epigenomics, identify potential cells of origin for the SHH and MYC subtypes.

Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), CSF cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined. We recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other Response Assessment in Neuro-Oncology recommendations, these need to now be prospectively validated in clinical trials.

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Gorlin syndrome is a genetic condition associated with the occurrence of SHH activated medulloblastoma, basal cell carcinoma, macrocephaly and other congenital anomalies. It is caused by heterozygous pathogenic variants in PTCH1 or SUFU. In this study we included 16 patients from the HIT2000, HIT2000interim, I-HIT-MED, observation registry and older registries such as HIT-SKK87, HIT-SKK92 (1987 – 2020) with genetically confirmed Gorlin syndrome, harboring 10 PTCH1 and 6 SUFU mutations. Nine patients presented with desmoplastic medulloblastomas (DMB), 6 with medulloblastomas with extensive nodularity (MBEN) and one patient with classic medulloblastoma (CMB); all tumors affected the cerebellum, vermis or the fourth ventricle. SHH activation was present in all investigated tumors (14/16); DNA methylation analysis (when available) classified 3 tumors as iSHH-I and 4 tumors as iSHH-II. Age at diagnosis ranged from 0.65 to 3.41 years. All but one patient received chemotherapy according to the HIT-SKK protocol. Ten patients were in complete remission after completion of primary therapy; four subsequently presented with PD. No patient received radiotherapy during initial treatment. Five patients acquired additional neoplasms, namely basal cell carcinomas, odontogenic tumors, ovarian fibromas and meningioma. Developmental delay was documented in 5/16 patients. Overall survival (OS) and progression-free survival (PFS) between patients with PTCH1 or SUFU mutations did not differ statistically (10y-OS 90% vs. 100%, p=0.414; 5y-PFS 88.9% ± 10.5% vs. 41.7% ± 22.2%, p=0.139). Comparing the Gorlin patients to all young, SHH activated MBs in the registries (10y-OS 93.3% ± 6.4% vs. 92.5% ± 3.3%, p=0.738; 10y-PFS 64.9%+-16.7% vs. 83.8%+-4.5%, p=0.228) as well as comparing Gorlin M0 SKK-treated patients to all young, SHH activated, M0, SKK-treated MBs in the HIT-MED database did not reveal significantly different clinical outcomes (10y-OS 88.9% ± 10.5% vs. 88% ± 4%, p=0.812; 5y-PFS 87.5% ± 11.7% vs. 77.7% ± 5.1%, p=0.746). Gorlin syndrome should be considered in young children with SHH activated medulloblastoma, especially DMB and MBEN but cannot be ruled out for CMB. Survival did not differ to patients with SHH-activated medulloblastoma with unknown germline status or between PTCH1 and SUFU mutated patients. Additional neoplasms, especially basal cell carcinomas, need to be expected and screened for. Genetic counselling should be provided for families with young medulloblastoma patients with SHH activation.

Introduction: Neurosurgery is considered the mainstay of treatment for pediatric low‐grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long‐term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. Patients and Methods: Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1‐5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1‐status, sex, and age. Results: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. Conclusions: The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1‐status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals. [ABSTRACT FROM AUTHOR]

Abstract Introduction Risk stratification of children with ependymomas of the posterior fossa in current therapeutic protocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease entity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of patients treated according to the German HIT protocols. Methods Tumor samples of 134 patients aged 0.2–15.9 years treated between 1999 and 2010 according to HIT protocols were analyzed for histological features including mitotic activity, necrosis and vascular proliferation and genomic alterations by SNP and molecular inversion probe analysis. Survival analysis was performed by Kaplan-Meier method with log rank test and multivariate Cox regression analysis. Results Residual tumor after surgery, chromosome 1q gain and structural genomic alterations were identified as predictors of significantly shorter event-free (EFS) and overall survival (OS). Furthermore, specific histological features including vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. Multivariate Cox regression revealed residual tumor, chromosome 1q gain and mitotic activity as independent predictors of both EFS and OS. Using these independent predictors of outcome, we were able to build a 3-tiered risk stratification model that separates patients with standard, intermediate and high risk, and which outperforms current stratification procedures. Conclusion The integration of defined clinical, histological and genetic parameters led to an improved risk-stratification model for posterior fossa ependymoma of childhood. After validation in independent cohorts this model may provide the basis for risk-adapted treatment of children with ependymomas of the posterior fossa.

Objective: Quality of life (QoL) is frequently impaired in childhood-onset craniopharyngioma (CP) by hypothalamic syndrome. The debate, whether pretreatment hypothalamic involvement (HI) has apriori prognostic impact or surgical hypothalamic lesions (HL) determine outcome, is controversial. Design: Survival and outcome of CPs recruited between 2007 and 2014 in KRANIOPHARYNGEOM 2007 were analyzed with regard to reference-confirmed presurgical HI and surgical HL. Methods: Radiological findings, BMI and QoL were assessed at diagnosis and during follow-up. QoL was assessed using Pediatric Quality of Life (PEDQOL) questionnaire. Results: One hundred sixty-nine CPs were included presenting with no HI (n = 11), anterior (n = 49) and anterior + posterior (a + p) HI (n = 109) prior to surgery. The latter 109 were analyzed for postoperative HL (no lesion: n = 23, anterior HL: n = 29, a + pHL: n = 57). Progression-free survival (PFS) was higher after complete resection. The highest PFS was observed in CP with a + pHL, especially when compared between non-irradiated subgroups (P = 0.006). Overall survival (OS) rates were 1.0 in all subgroups. CP with a + pHL developed higher BMI (P ≤ 0.001) during follow-up compared between subgroups. 55/109 pts with a + pHI completed PEDQOL at diagnosis (48/109 at 3 years follow-up). QoL was worse for a + pHL patients in terms of physical, social and emotional functionality when compared with the anterior HL and no HL subgroup. BMI development and QoL during follow-up were similar for patients with anterior HL and without HL. Conclusions: Posterior hypothalamus-sparing surgical strategies are associated with higher QoL, decreased development of obesity and lower PFS in CP.

Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.

Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs., Author(s): Julia E Neumann [1, 2, 3]; Annika K Wefers [1, 4, 5, 6]; Sander Lambo [7]; Edoardo Bianchi [1]; Marie Bockstaller [1]; Mario M Dorostkar [1, 8]; Valerie Meister [...]