• BT317, reactive oxygen species
• CT-L proteasome
• Glioblastoma
• LonP1
• Malignant astrocytoma

• Animals
• Humans
• Cell Line, Tumor
• Proteasome Endopeptidase Complex/metabolism
• Apoptosis/drug effects
• Astrocytoma/drug therapy
• Astrocytoma/pathology
• Astrocytoma/metabolism
• Astrocytoma/enzymology
• Mitochondrial Proteins/antagonists & inhibitors
• Mitochondrial Proteins/metabolism
• Mitochondrial Proteins/genetics
• Brain Neoplasms/drug therapy
• Brain Neoplasms/pathology
• Brain Neoplasms/metabolism
• Brain Neoplasms/enzymology
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Reactive Oxygen Species/metabolism
• ATP-Dependent Proteases/metabolism
• ATP-Dependent Proteases/genetics
• ATP-Dependent Proteases/antagonists & inhibitors
• Mitochondria/drug effects
• Mitochondria/enzymology
• Mice
• Xenograft Model Antitumor Assays
• Temozolomide/pharmacology

• Brain tumors
• Cancer stem cells
• Glial cells
• Glioma
• Immunotherapy
• Neural stem cells
• Neuron

• P30 CA062203 NCI NIH HHS

• medulloblastoma
• radiotherapy
• re-irradiation
• recurrence
• resection

• DKS 2006.01, DKS 2008.17, DKS 2012.03, DKS 2015.02, DKS 2017.12, DKS 2020.02 German Children Cancer Foundation

• CNS tumors
• brain tumor
• childhood
• clinical characteristics
• low and middle income countries
• medulloblastoma
• survival

• Sonic Hedgehog Inhibition
• intraventricular therapy
• medulloblastoma
• targeted treatment

• Humans
• Mice
• Animals
• Child
• Medulloblastoma/drug therapy
• Medulloblastoma/genetics
• Medulloblastoma/metabolism
• Hedgehog Proteins/metabolism
• Anilides/pharmacology
• Anilides/therapeutic use
• Disease Models, Animal
• Cerebellar Neoplasms/pathology
• Pyridines

• Mildred Scheel Cancer Career Center Hamburg/Deutsche Krebshilfe
• Fördergemeinschaft Kinderkrebszentrum Hamburg
• Gesellschaft für Kinderkrebsforschung
• Hamburger Krebsgesellschaft
• German Children's Cancer Foundation
• Hubertus Wald Tumorzentrum, University Cancer Center Hamburg
• German Society for Pediatric Oncology and Hematology
• German Children’s Cancer Foundation

• blood-brain barrier
• central nervous system
• chemotherapy
• oncology
• pediatric brain tumor

• Child
• Humans
• Blood-Brain Barrier
• Quality of Life
• Brain Neoplasms/drug therapy
• Brain Neoplasms/radiotherapy
• Antineoplastic Agents/therapeutic use

• K23 AI134307 NIAID NIH HHS
• K23 MH125734 NIMH NIH HHS
• National Institute of Allergy and Infectious Diseases
• National Institute of Mental Health

• Chemotherapy
• DIPG
• MYB-altered glioma
• MYB::QKI fusion
• Pediatric pontine glioma

• Humans
• Infant
• Brain Stem Neoplasms/diagnostic imaging
• Brain Stem Neoplasms/drug therapy
• Brain Stem Neoplasms/genetics
• Astrocytoma/diagnostic imaging
• Astrocytoma/drug therapy
• Astrocytoma/genetics
• Glioma/diagnostic imaging
• Glioma/drug therapy
• Glioma/genetics
• Histones/genetics
• Pons/pathology

• 204220 Grantová Agentura, Univerzita Karlova
• PRIMUS/19/MED/06 Grantová Agentura, Univerzita Karlova
• LX22NPO5102 The project National Institute for Cancer Research (Programme EXCELES)
• MH CZ-DRO,00064203 University Hospital Motol
• Charles University

• Medulloblastoma
• infants
• molecular
• radiation-sparing
• risk-stratification
• young children

• Child
• Infant
• Humans
• Adolescent
• Child, Preschool
• Medulloblastoma/diagnosis
• Medulloblastoma/genetics
• Medulloblastoma/therapy
• Cerebellar Neoplasms/genetics
• Cerebellar Neoplasms/therapy
• Hedgehog Proteins/genetics
• Hedgehog Proteins/therapeutic use
• Neoplasm Recurrence, Local
• Recurrence

• P30 CA021765 NCI NIH HHS

• brain tumors
• chemotherapy
• medulloblastoma
• pediatrics
• radiotherapy

• MYC amplification
• cerebrospinal fluid
• droplet digital PCR
• group 3
• liquid biopsy
• medulloblastoma
• minimal residual disease
• pediatric oncology
• therapy monitoring

• J 4353 Austrian Science Fund FWF

Medulloblastoma (MB) is considered the commonest malignant brain tumor in children. Multimodal treatments consisting of surgery, radiation, and chemotherapy have improved patients’ survival. Nevertheless, the recurrence occurs in 30% of cases. The persistent mortality rates, the failure of current therapies to extend life expectancy, and the serious complications of non-targeted cytotoxic treatment indicate the need for more refined therapeutic approaches. Most MBs originating from the neurons of external granular layer line the outer surface of neocerebellum and responsible for the afferent and efferent connections. Recently, MBs have been segregated into four molecular subgroups: Wingless-activated (WNT-MB) (Group 1); Sonic-hedgehog-activated (SHH-MB) (Group 2); Group 3 and 4 MBs. These molecular alterations follow specific gene mutations and disease-risk stratifications. The current treatment protocols and ongoing clinical trials against these molecular subgroups are still using common chemotherapeutic agents by which their efficacy have improved the progression-free survival but did not change the overall survival. However, the need to explore new therapies targeting specific receptors in MB microenvironment became essential. The immune microenvironment of MBs consists of distinctive cellular heterogeneities including immune cells and none-immune cells. Tumour associate macrophage and tumour infiltrating lymphocyte are considered the main principal cells in tumour microenvironment, and their role are still under investigation. In this review, we discuss the mechanism of interaction between MB cells and immune cells in the microenvironment, with an overview of the recent investigations and clinical trials

• Medulloblastoma
• Tumour microenvironment
• Tumour associated macrophages
• Tumour infiltrating lymphocyte
• Immunotherapies

Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis.

Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production.

Low concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages.

These data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours.

This study was funded by institutional grants and charities.

• hyperfractionation
• medulloblastoma
• neurocognitive
• radiotherapy
• survival

• CNS embryonal tumor
• medulloblastoma
• pediatric brain tumor
• vorinostat

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.

• Gorlin
• PTCH1
• SUFU
• childhood cancer predisposition syndrome
• medulloblastoma

• CpG ODNs
• anti-PD-L1
• postoperative adjuvant immunotherapy
• recurrence and metastasis
• sodium alginate hydrogel

The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.

• MYCN
• PROTACs
• immunotherapy
• medulloblastoma
• metabolism
• targeted therapy

• chemotherapy
• medulloblastoma
• radiotherapy
• secondary malignancy risk incidence ratios

• Innovative imaging methods
• MRI
• Medulloblastoma
• Multimodal neuroimaging
• Neurocognition
• Neurocognitive outcomes
• Pediatric
• Systematic review

Despite progress in the biology and upfront treatment of childhood medulloblastoma, relapse is almost universally fatal. No standardized treatment has so far been established for these patients. By determining which characteristics are prognostic after relapse, treatment strategies may be optimized for each of these children. We demonstrated that molecular subgroup at diagnosis is a relevant prognostic factor of outcome after relapse. Moreover, we showed that time to relapse and the use of salvage radiotherapy at relapse might have a potential impact on post-relapse survival. Our data suggest that ongoing efforts toward a better understanding of the biology, timing and type of relapse would be important to understand the determinants of tumor behavior at relapse. This could help us address more specific questions on the best surveillance strategies after completion of the treatment and the introduction of risk-stratified second-line treatment strategies.

Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4–12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2–87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (>12 months) might also have a potential impact on post-relapse survival.

• molecular subgrouping
• outcome after relapse
• pediatric
• recurrent medulloblastoma
• salvage radiotherapy
• time to relapse

• Medulloblastomas
• ependymomas
• paediatric neurosurgery
• pilocytic astrocytomas
• resection rates

• Drug repurposing
• Medulloblastoma
• Signaling pathway
• Therapeutic targets

Medulloblastoma (MB) is the most common malignant childhood tumor of the brain. Multimodal treatment consisting of surgery, radiation therapy, and chemotherapy reduced cumulative incidence of late mortality but increased the incidence of subsequent neoplasms and severe, incapacitating chronic health conditions. Present treatment strategies fail to recognize heterogeneity within patients despite wide divergence in individual responses. The persistent mortality rates and serious side effects of non-targeted cytotoxic therapies indicate a need for more refined therapeutic approaches. Advanced genomic research has led to the accumulation of an enormous amount of genetic information and resulted in a consensus distinguishing four molecular subgroups, WNT-activated, SHH-activated, and Group 3 and 4 medulloblastomas. These have distinct origin, demographics, molecular alterations, and clinical outcomes. Although subgroup affiliation does not predict response to therapy, new subgroup-specific markers of prognosis can enable a more layered risk stratification with additional subtypes within each primary subgroup. Here, we summarize subgroup-specific genetic alterations and their utility in current treatment strategies. The transition toward molecularly targeted interventions for newly diagnosed MBs remains slow, and prospective trials are needed to confirm stratifications based on molecular alterations. At the same time, numerous studies focus at fine-tuning the intensity of invasive radio- and chemotherapies to reduce intervention-related long-term morbidity. There are an increasing number of immunotherapy-based treatment strategies including immune checkpoint-inhibitors, oncolytic viruses, CAR-T therapy, and NK cells in recurrent and refractory MBs. Although most trials are in early phase, there is hope for therapeutic breakthroughs for advanced MBs within the next decade.

• Clinical trial
• Group 3
• Group 4
• Immunotherapy
• Prognostic biomarker
• Risk stratification
• SHH
• WNT

Disease relapse occurs in around 30% of children with medulloblastoma, and is almost universally fatal. We aimed to establish whether the clinical and molecular characteristics of the disease at diagnosis are associated with the nature of relapse and subsequent disease course, and whether these associations could inform clinical management.

In this multicentre cohort study we comprehensively surveyed the clinical features of medulloblastoma relapse (time to relapse, pattern of relapse, time from relapse to death, and overall outcome) in centrally reviewed patients who relapsed following standard upfront therapies, from 16 UK Children's Cancer and Leukaemia Group institutions and four collaborating centres. We compared these relapse-associated features with clinical and molecular features at diagnosis, including established and recently described molecular features, prognostic factors, and treatment at diagnosis and relapse.

247 patients (175 [71%] boys and 72 [29%] girls) with medulloblastoma relapse (median year of diagnosis 2000 [IQR 1995–2006]) were included in this study. 17 patients were later excluded from further analyses because they did not meet the age and treatment criteria for inclusion. Patients who received upfront craniospinal irradiation (irradiated group; 178 [72%] patients) had a more prolonged time to relapse compared with patients who did not receive upfront craniospinal irradiation (non-irradiated group; 52 [21%] patients; p<0·0001). In the non-irradiated group, craniospinal irradiation at relapse (hazard ratio [HR] 0·27, 95% CI 0·11–0·68) and desmoplastic/nodular histology (0·23, 0·07–0·77) were associated with prolonged time to death after relapse, MYC amplification was associated with a reduced overall survival (23·52, 4·85–114·05), and re-resection at relapse was associated with longer overall survival (0·17, 0·05–0·57). In the irradiated group, patients with MB_Group3 tumours relapsed significantly more quickly than did patients with MB_Group4 tumours (median 1·34 [0·99–1·89] years vs 2·04 [1·39–3·42 years; p=0·0043). Distant disease was prevalent in patients with MB_Group3 (23 [92%] of 25 patients) and MB_Group4 (56 [90%] of 62 patients) tumour relapses. Patients with distantly-relapsed MB_Group3 and MB_Group4 displayed both nodular and diffuse patterns of disease whereas isolated nodular relapses were rare in distantly-relapsed MB_SHH (1 [8%] of 12 distantly-relapsed MB_SHH were nodular alone compared with 26 [34%] of 77 distantly-relapsed MB_Group3 and MB_Group4). In MB_Group3 and MB_Group4, nodular disease was associated with a prolonged survival after relapse (HR 0·42, 0·21–0·81). Investigation of second-generation MB_Group3 and MB_Group4 molecular subtypes refined our understanding of heterogeneous relapse characteristics. Subtype VIII had prolonged time to relapse and subtype II had a rapid time from relapse to death. Subtypes II, III, and VIII developed a significantly higher incidence of distant disease at relapse whereas subtypes V and VII did not (equivalent rates to diagnosis).

This study suggests that the nature and outcome of medulloblastoma relapse are biology and therapy-dependent, providing translational opportunities for improved disease management through biology-directed disease surveillance, post-relapse prognostication, and risk-stratified selection of second-line treatment strategies.

Cancer Research UK, Action Medical Research, The Tom Grahame Trust, The JGW Patterson Foundation, Star for Harris, The Institute of Child Health - Newcastle University - Institute of Child Health High-Risk Childhood Brain Tumour Network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).

Objective

Medulloblastoma is the most common malignant brain tumor in children younger than four years of age. Children diagnosed with desmoplastic nodular medulloblastoma (DNMB) have more favorable survival outcomes when compared to other subtypes of this disease and, to date, the demographics of DNMB have only been characterized by a few small clinical case series. Additionally, the current effort is being made at reducing radiotherapeutic modalities in this patient population to avoid the adverse effects associated with radiotherapy in children. Therefore, the goal of this study was to characterize the demographics, treatments, and survival outcomes of patients with DNMB using a large federal database.

Methods

The Surveillance, Epidemiology, and End Results database was queried to retrieve demographical, treatment, and survival data for patients diagnosed with DNMB. Statistical testing was performed with the R software stats package (R Foundation for Statistical Computing, Vienna, Austria). Student’s t tests and analysis of variance tests were used to measure differences among survival rates.

Results

Data from 360 patients with DNMB were retrieved from 1975-2016. There was a higher prevalence of DNMB in children younger than four years of age (33% of all cases). Males had a higher prevalence than females (57%). There was a preponderance of diagnoses in white individuals (82% of all cases) and more diagnoses in the Pacific Coast region (49% of all cases). Distant metastases were present at initial diagnosis in 8.7%. Surgery was performed in almost all patients, and gross total resection was achieved in 77%. The overall rate of survival was 77.8% at five years; age, sex, race, and geographical region of diagnosis were not associated with differences in survival outcomes. Patients with no radiotherapy had a lower rate of survival compared to patients with postoperative radiotherapy (mean difference = 19.7%; [95% CI 1.4%-38.0%], p = 0.0314). However, radiotherapy did not improve survival outcomes in patients undergoing chemotherapeutic treatment to a degree with any statistical significance. There was no statistically significant improvement in survival for patients undergoing radiotherapy prior to procedure when compared to patients with no radiotherapy.

Conclusions

In patients undergoing chemotherapeutic treatment for the DNMB subtype of medulloblastoma specifically, additional radiotherapy may offer only minimal benefit to the survival outcome. It is essential continued clinical trials be performed for the purpose of devising alternate treatments to radiotherapy.

• chemotherapy
• desmoplastic nodular medulloblastoma
• epidemiology
• medulloblastoma
• radiotherapy
• seer
• survival

• atypical teratoid/rhabdoid tumor (ATRT)
• ependymoma
• high-grade glioma
• low-grade glioma
• medulloblastoma
• primitive neuro-ectodermal tumor (PNET)

• Medulloblastoma
• PFKP
• STXBP1
• bioinformatic analysis
• prognostic model

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.

• Brain Neoplasms/pathology
• Brain Neoplasms/physiopathology
• Brain Neoplasms/therapy
• Child
• Child, Preschool
• Cohort Studies
• Combined Modality Therapy
• Craniospinal Irradiation/adverse effects
• Cross-Sectional Studies
• Ependymoma/pathology
• Ependymoma/physiopathology
• Ependymoma/therapy
• Female
• Follow-Up Studies
• Germany
• Humans
• Infant
• Intelligence
• Male
• Medulloblastoma/physiopathology
• Medulloblastoma/psychology
• Medulloblastoma/therapy
• Motor Skills
• Multivariate Analysis
• Neuropsychological Tests
• Treatment Outcome

• Elternverein für Leukämie- und Tumorkranker Kinder Würzburg e.v.
• Deutsche Kinderkrebsstiftung

• brain tumor
• chemotherapy
• congenital tumor
• glioblastoma
• newborn

Medical images such as magnetic resonance (MR) imaging provide valuable information for cancer detection, diagnosis, and prognosis. In addition to the anatomical information these images provide, machine learning can identify texture features from these images to further personalize treatment. This study aims to evaluate the use of texture features derived from T₁-weighted post contrast scans to classify different types of brain tumors and predict tumor growth rate in a preclinical mouse model. To optimize prediction models this study uses varying gray-level co-occurrence matrix (GLCM) sizes, tumor region selection and different machine learning models. Using a random forest classification model with a GLCM of size 512 resulted in 92%, 91%, and 92% specificity, and 89%, 85%, and 73% sensitivity for GL261 (mouse glioma), U87 (human glioma) and Daoy (human medulloblastoma), respectively. A tenfold cross-validation of the classifier resulted in 84% accuracy when using the entire tumor volume for feature extraction and 74% accuracy for the central tumor region. A two-layer feedforward neural network using the same features is able to predict tumor growth with 16% mean squared error. Broadly applicable, these predictive models can use standard medical images to classify tumor type and predict tumor growth, with model performance, varying as a function of GLCM size, tumor region, and tumor type.

Childhood medulloblastomas (MB) are heterogeneous and are divided into four molecular subgroups. The provisional non-wingless-activated (WNT)/non-sonic hedgehog-activated (SHH) category combining group 3 and group 4 represents over two thirds of all MBs, coupled with the highest rates of metastases and least understood pathology. The molecular era expanded our knowledge about molecular aberrations involved in MB tumorigenesis, and here, we review processes leading to non-WNT/non-SHH MB formations.

The heterogeneous group 3 and group 4 MBs frequently harbor rare individual genetic alterations, yet the emerging profiles suggest that infrequent events converge on common, potentially targetable signaling pathways. A mutual theme is the altered epigenetic regulation, and in vitro approaches targeting epigenetic machinery are promising. Growing evidence indicates the presence of an intermediate, mixed signature group along group 3 and group 4, and future clarifications are imperative for concordant classification, as misidentifying patient samples has serious implications for therapy and clinical trials.

To subdue the high MB mortality, we need to discern mechanisms of disease spread and recurrence. Current preclinical models do not represent the full scale of group 3 and group 4 heterogeneity: all of existing group 3 cell lines are MYC-amplified and most mouse models resemble MYC-activated MBs. Clinical samples provide a wealth of information about the genetic divergence between primary tumors and metastatic clones, but recurrent MBs are rarely resected. Molecularly stratified treatment options are limited, and targeted therapies are still in preclinical development. Attacking these aggressive tumors at multiple frontiers will be needed to improve stagnant survival rates.

• Group 3
• Group 4
• Medulloblastoma
• Non-WNT/non-SHH
• Prognostic biomarker
• Risk stratification
• Survival

• Medulloblastoma
• Neuroblastoma
• Precision medicine
• Primitive neuroectodermal tumors
• Tumor suppressor protein p53