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BACKGROUND F18-FET PET has an established diagnostic role in adult brain gliomas, here we analyzed image derived static & dynamic parameters with available conventional MRI, histological, clinical & follow up data in assessment of pediatric brain tumor patient at different stages of the disease. METHODS Forty-four pediatric patients with median age 7 years, diagnosed with brain tumors and underwent forty-seven 18F-FET PET scans either initially (20 scans) or post-therapy (27 scans) were enrolled. Standardized analysis of Summed FET PET images early from 10-20 min and late from 30-40 min post-injection were used for static (mean & maximum Tumor to Brain Ratio "TBR" & Biological Tumor Volume "BTV") parameters evaluation as well as the Time Activity Curve "TAC". RESULTS 19 out of 20 initially assessed patients had pathologically &/or clinico-radiologically proven neoplastic lesions and one patient had pathologically proven abscess. Receiver Operator Curve (ROC) marked early TBR max 2.95, early TBR mean 1.76, late TBR max 2.5 and late TBR mean 1.74 as discriminator points with diagnostic accuracy reaching 90% when TBR max was combined with dynamic parameters. Significant association was found between initial FET scans, early & late BTV & Event Free Survival "EFS" (P value =0.042 & 0.005 respectively). In post-therapy assessment, the diagnostic accuracy of conventional MRI was 81.48% when used alone and 96.30% when combined with F18-FET PET scan findings. A cutoff point of 3.2 cm3 for late BTV, in posttherapy scans, was successfully marked as a predictor for therapy response (P-value 0.042) and was significantly associated with EFS (P-value 0.002). In FET-avid / MRI non-enhancing lesions, early TBR max was able to detect highly malignant processes (high-grade tumors in initial scans & residue/recurrence in post-therapy scans) with 80% sensitivity & 100% specificity when cutoff value of 2.25 was used (P-value =0.024). In patients with FET-avid brainstem lesions, whether enhancing or non-enhancing in MRI scans, 81.8% were associated with high risk diagnoses and 68.2% of them were associated with poor therapy outcome. The degree of FET uptake matched tumor-grading, but did not show significant association with OS or EFS (P-value >0.05). CONCLUSIONS F18-FET PET seems to be an evolving pediatric neuroimaging technique with valuable diagnostic & prognostic information at initial and post-therapy evaluation.

The central nervous system (CNS) tumors constitute the most common type of solid tumors in the pediatric population. The cerebral and cerebellar parenchyma are the most common site of pediatric CNS neoplasms. Imaging plays an important role in detection, characterization, staging and prognostication of brain tumors. The focus of the current article is pediatric brain tumor imaging with emphasis on pearls and pitfalls of conventional and advanced imaging in various pediatric brain tumor subtypes. The article also elucidates changes in brain tumor terms and entities as applicable to pediatric patients, updated as per World Health Organization (WHO) 2016 classification of primary CNS tumors. This classification introduced the genetic and/or molecular information of primary CNS neoplasms as part of comprehensive tumor pathology report in the routine clinical workflow. The concepts from 2016 classification have been further refined based on current research, by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) group and published in the form of updates. The updates serve as guidelines in the time interval between WHO updates and expect to be broadly adopted in the subsequent WHO classification. The current review covers most pediatric brain tumors except pituitary tumors, meningeal origin tumors, nerve sheath tumors and CNS lymphoma/leukemia.

Characteristic arterial spin labeling (ASL) perfusion patterns are seen in a wide variety of pediatric brain pathologies, highlighting the potential added value and prognostic role of this magnetic resonance imaging (MRI) perfusion-weighted imaging modality. Our objective is to review the basic clinical physics, technical underpinnings, and artifacts and challenges as we highlight some of the most clinically relevant pathologies to the application of ASL in the pediatric setting.

Zinc fingers consist of one of the most abundant motifs in transcription factors and DNA-binding proteins. Recent studies provide evidence on the pathological implication of zinc finger proteins in various neurodevelopmental disorders and malignancies but their role in pediatric brain tumors is largely unexplored. To this end, we investigated the differential expression of zinc finger-containing genes along with relevant biological processes and pathways among four main brain tumor categories (pilocytic astrocytomas, ependymomas, medulloblastomas and glioblastomas). By employing an extended bioinformatic toolset, we performed a preliminary in silico study in order to identify the expression of zinc finger-containing genes and associated functions in pediatric brain tumors. Our data analysis reveals the prominent role of C2H2-type zinc finger-containing genes in the molecular mechanisms underlying pediatric brain tumors followed by the Ring and PHD finger types. Significant dysregulation of ABLIM2 and UHFR1 genes was detected in all tumor types drawing attention to the dysregulation of cell polarization process and Ubiquitin-Proteasome System (UPS) in the pathogenesis of pediatric brain tumors. Moreover, significant gene clustering was observed in multiple locations with two highly visible clusters revealing a contrast in gene regulation between medulloblastomas and the other three brain tumor types, indicating a promising area of future research.

Magnetic resonance spectroscopy (MRS) is a valuable adjunct to structural brain imaging. State-of-the-art MRS has benefited greatly from recent technical advancements. Neurometabolic alterations in pediatric brain diseases have implications for diagnosis, prognosis, and therapy. Herein, the authors discuss MRS technical considerations and applications in the setting of various pediatric disease processes including tumors, metabolic diseases, hypoxic/ischemic encephalopathy/stroke, epilepsy, demyelinating disease, and infection.

Magnetic resonance (MR) perfusion is a robust imaging technique that assesses the passage of blood through the cerebral vascular network using a variety of techniques. The applications of MR perfusion have been expanded and is well suited to investigate cerebrovascular diseases and cerebral neoplastic processes in pediatric patients. Assessment of brain perfusion can augment the information obtained on conventional MR imaging and provides additional information on the biological and physiologic features of pediatric brain tumors. Similarly, MR perfusion can help guide the management of a variety of pediatric cerebrovascular diseases, including acute ischemic stroke and Moyamoya syndrome.

Pediatric central nervous system tumors are the most common tumors in children, it constitute 15%-20% of all malignancies in children and are the leading cause of cancer related deaths in children. Proteogenomics is an emerging field of biological research that utilizes a combination of proteomics, genomics, and transcriptomics to aid in the discovery and identification of biomarkers for diagnosis and therapeutic purposes. Integrative proteogenomics analysis of pediatric tumors identified underlying biological processes and potential treatments as well as the functional effects of somatic mutations and copy number variation driving tumorigenesis.

PURPOSE OF REVIEW Brain tumors are the most frequent solid cancer in the pediatric population. Owing to the rarity of environmental clues about their origin, it is tempting to consider these neoplasms as developmental processes gone awry. Our review will explore the heuristic power of this hypothesis and the influence of these findings on the clinical management. RECENT FINDING A more accurate description of cancer predisposition syndrome has shown their frequent association with developmental abnormalities. Several genes involved in pediatric brain tumor oncogenesis are involved in developmental processes. Modeling of several pediatric brain tumor in cerebral organoids, mimicking embryonal stage of brain development, indicates that early events during brain development create the conditions necessary for their oncogenesis. SUMMARY The onset of multiple brain tumor types early in life suggests a functional relationship between brain development and oncogenesis. A growing body of evidence seems to support the hypothesis that some of the main developmental steps in the brain can be highjacked by the tumors during their initiation. Collaborations between neuroscientists and oncologists should provide room for improvement in the knowledge for these neoplasms.

SummaryIn recent years, novel insight into molecular mechanisms has allowed the identification of drug targets for various pediatric brain tumors. The aim of this article is to give an overview of new treatment options in neurofibromatosis type 1 (NF1), novel tyrosine kinase inhibitors that target oncogenic gene fusions in pediatric brain tumors, and antiangiogenesis as promising therapy especially in recurrent medulloblastoma.

BACKGROUND Pediatric brain arteriovenous malformations (AVMs) are a significant cause of morbidity but the role of multimodal therapy in the treatment of these lesions is not well understood. OBJECTIVE To compare the outcomes of stereotactic radiosurgery (SRS) with and without prior embolization for pediatric AVMs. METHODS We retrospectively evaluated the International Radiosurgery Research Foundation pediatric AVM database. AVMs were categorized, based on use of pre-embolization (E + SRS) or lack thereof (SRS-only). Outcomes were compared in unadjusted and inverse probability weight (IPW)-adjusted models. Favorable outcome was defined as obliteration without post-SRS hemorrhage or permanent radiation-induced changes (RIC). RESULTS The E + SRS and SRS-only cohorts comprised 91 and 448 patients, respectively. In unadjusted models, the SRS-only cohort had higher rates of obliteration (68.5% vs 43.3%

Background Longitudinal measurement of tumor burden with magnetic resonance imaging (MRI) is an essential component of response assessment in pediatric brain tumors. We developed a fully automated pipeline for the segmentation of tumors in pediatric high-grade gliomas, medulloblastomas, and leptomeningeal seeding tumors. We further developed an algorithm for automatic 2D and volumetric size measurement of tumors. Methods The preoperative and postoperative cohorts were randomly split into training and testing sets in a 4:1 ratio. A 3D U-Net neural network was trained to automatically segment the tumor on T1 contrast-enhanced and T2/FLAIR images. The product of the maximum bidimensional diameters according to the RAPNO (Response Assessment in Pediatric Neuro-Oncology) criteria (AutoRAPNO) was determined. Performance was compared to that of 2 expert human raters who performed assessments independently. Volumetric measurements of predicted and expert segmentations were computationally derived and compared. Results A total of 794 preoperative MRIs from 794 patients and 1003 postoperative MRIs from 122 patients were included. There was excellent agreement of volumes between preoperative and postoperative predicted and manual segmentations, with intraclass correlation coefficients (ICCs) of 0.912 and 0.960 for the 2 preoperative and 0.947 and 0.896 for the 2 postoperative models. There was high agreement between AutoRAPNO scores on predicted segmentations and manually calculated scores based on manual segmentations (Rater 2 ICC = 0.909; Rater 3 ICC = 0.851). Lastly, the performance of AutoRAPNO was superior in repeatability to that of human raters for MRIs with multiple lesions. Conclusions Our automated deep learning pipeline demonstrates potential utility for response assessment in pediatric brain tumors. The tool should be further validated in prospective studies.

Pediatric brain tumors are an incredibly diverse group of neoplasms and neuropathological tumor classification is an essential part of patient care. Classification of pediatric brain tumors has changed considerably in recent years as molecular diagnostics have become incorporated with routine histopathology in the diagnostic process. This article will focus on the fundamental major histologic, immunohistochemical, and molecular features that neuropathologists use to make an integrated diagnosis of pediatric brain tumors. This concise review will focus on tumors that are integral to the central nervous system in pediatric patients including: embryonal tumors, low and high grade gliomas, glioneuronal tumors, ependymomas, and choroid plexus tumors.

Background: Tumors of the thalamic origin represent about 2-5% of pediatric brain tumors. They are considered a challenging subset of brain tumors to both neurosurgeons and radiotherapists due to their critical anatomical position and the proximity of functionally significant structures especially in children. Aim of Study: Is to present the authors' experience in the management of 33 cases of pediatric thalamic brain tumors. Patients and Methods: Medical records of 33 pediatric patients with thalamic brain tumors admitted to CCHE during the period from July, 2007 till December, 2014 have been reviewed as regard surgical inter-ference, chemotherapy and radiation therapy in relevance to different histo-pathological subtypes, tumor size, patients' age and patients' presenting symptoms. Conclusion: Pediatric thalamic brain tumors are highly challenging tumors with significant level of morbidity and mortality that require integrated analysis of further studies to achieve better outcome.

Sluggish Cognitive Tempo (SCT) describes a pattern of under-activity, poor initiation, and slowness. It was first reported within the Attention Deficit Hyperactivity Disorder (ADHD) literature and found to be positively associated with the inattentive symptoms of ADHD and negatively or not significantly associated with the hyperactivity/impulsivity symptoms of ADHD. SCT has since been considered applicable to the pediatric oncology population given the emergence of inattentive, sluggish symptoms secondary to cancer treatment. The present study examined the unique contribution of SCT to various processing speed skills in a clinical sample of pediatric brain tumor (BT) survivors in order to determine the degree to which SCT explained timed “cognitive” processing components. Measures included speeded naming, graphomotor speed, and speeded inhibition. Hierarchical linear regression analyses were used to predict performance-based measures of processing speed. After controlling for verbal ability and inattention, SCT, particularly Daydreamy SCT (β = −0.698, p = 0.023), explained 28% of variance in speeded inhibition. SCT did not add significantly to the prediction of speeded naming or graphomotor speed. Findings suggest that the “daydreamy” aspect of SCT, rather than “sluggishness” per se, may be related to more complex, cognitively-demanding tasks with greater executive functioning burdens in BT survivors. Implications for intervention for oncology survivors as well as future research directions are discussed.

Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs.

Traditional management of newly diagnosed pediatric brain tumors (PBTs) consists of cranial imaging, typically magnetic resonance imaging (MRI), and is frequently followed by tissue diagnosis, through either surgical biopsy or tumor resection. Therapy regimes are typically dependent on histological diagnosis. To date, many treatment regimens are based on molecular biology. The scope of this article is to discuss the role of diagnosis and further treatment of PBTs based solely on MRI features, in light of the latest treatment protocols. Typical MRI findings and indications for surgical biopsy of these lesions are described.

Objective We aim to provide a thorough description of the efforts and outcomes of the Co-Pilot Project in Ukraine, which facilitates neurosurgical collaboration between American and Ukrainian physicians. Methods The Co-Pilot Project, which operates under its parent nonprofit organization, Razom, organized multiple trips for American physicians to Ukraine. Activities included consulting in clinic, assisting with neurosurgical operations, and providing didactic lectures. Further efforts have included coordinating training opportunities for Ukrainian surgeons. We retrospectively reviewed all operations performed by Ukrainian partner physicians alongside American co-pilot physicians across Ukraine since August 2016. Results Teams of Ukrainian and American physicians operated on 78 patients (24 children and 54 adults) for a total of 84 procedures in 5 different cities (Kyiv, Lutsk, Lviv, Odessa, and Stryi) of Ukraine. Operations were classified into the following categories: adult brain tumors (n = 39), adult spine tumors (n = 1), epilepsy (n = 9), pain (n = 2), pediatric brain tumors (n = 11), vascular/endovascular (n = 10), and miscellaneous (n = 12). Four illustrative cases are described in detail. Of the patients with brain tumors, 43.5% (20/46) had giant tumors, and gross total resection or near-total resection was achieved in 78.3% (36/46). Conclusions Profound disparities in neurosurgical care exist globally, which has led to the formation of collaborative relationships between physicians from various countries. We hope that the work of the Co-Pilot Project in Ukraine can serve as a template for effective international neurosurgical collaboration in other low-to-middle-income countries.

Minimal residual disease (MRD) assessment has revolutionized the clinical management of pediatric leukemias but has remained challenging to implement in pediatric brain tumors. In this issue of Cancer Cell, Liu et al. describe an approach to measuring MRD in pediatric medulloblastoma through the use of cell-free DNA in cerebrospinal fluid, with important prognostic implications.

Brain contrast-enhanced ultrasound (CEUS) is an emerging application that can complement gray-scale US and yield additional insights into cerebral flow dynamics. CEUS uses intravenous injection of ultrasound contrast agents (UCAs) to highlight tissue perfusion and thus more clearly delineate cerebral pathologies including stroke, hypoxic-ischemic injury and focal lesions such as tumors and vascular malformations. It can be applied not only in infants with open fontanelles but also in older children and adults via a transtemporal window or surgically created acoustic window. Advancements in CEUS technology and post-processing methods for quantitative analysis of UCA kinetics further elucidate cerebral microcirculation. In this review article we discuss the CEUS examination protocol for brain imaging in children, current clinical applications and future directions for research and clinical uses of brain CEUS.

Medulloblastoma is a frequent high-grade neoplasm among pediatric brain tumours. Its classical imaging features are a midline tumour growing into the fourth ventricle, hyperdense on CT-scan, displaying a hypersignal when using diffusion-weighted imaging, with a variable contrast enhancement. Nevertheless, atypical imaging features have been widely reported, varying according to the age of the patient, and histopathological subtype. In this study, we review the classical and atypical imaging features of medulloblastomas, with emphasis on advanced MRI techniques, histopathological and molecular subtypes and characteristics, and follow-up modalities.

Purpose of review Recent genetic and molecular findings have impacted the diagnosis, prognosis, and in some instances, treatment strategies for children with pediatric central nervous system tumors. Herein, we review the most up-to-date molecular findings and how they have impacted tumor classification and clinical care. Recent findings It is now recognized that aberrations of the mitogen-activated protein kinase pathway are present in the majority of pediatric low-grade glioma. Also, there has been the identification of recurrent histone H3 K27M mutations in diffuse intrinsic pontine and other midline gliomas. Medulloblastoma is now divided into four molecular subgroups with distinct characteristics and prognoses. The classification of other unique embryonal tumors is also highlighted. Finally, we present the newest classification of ependymoma; supratentorial ependymomas comprise two subtypes based on expression of the chromosome 11 Open Reading Frame 95-reticuloendotheliosis Viral Oncogene Homolog A or yes-associated protein 1 fusion, whereas posterior fossa ependymomas are divided into two distinct molecular subgroups, posterior fossa-A and posterior fossa-B. Summary These advances in the molecular classification of pediatric central nervous system tumors have not only assisted in diagnoses, but they have led to a new era of tumor classification and prognostication. They also have served as drivers for the evaluation of new targeted therapies based upon molecular aberrations with the hope for improved survival outcomes for our patients.

Accurate tissue segmentation of large-scale pediatric brain MR images from multiple sites is essential to characterize early brain development. Due to imaging motion/Gibbs artifacts and multi-site issue (or domain shift issue), it remains a challenge to accurately segment brain tissues from multi-site pediatric MR images. In this paper, we present a multi-scale self-supervised learning (M-SSL) framework to accurately segment tissues for multi-site pediatric brain MR images with artifacts. Specifically, we first work on the downsampled images to estimate coarse tissue probabilities and build a global anatomic guidance. We then train another segmentation model based on the original images to estimate fine tissue probabilities, which are further integrated with the global anatomic guidance to refine the segmentation results. In the testing stage, to alleviate the multi-site issue, we propose an iterative self-supervised learning strategy to train a site-specific segmentation model based on a set of reliable training samples automatically generated for a to-be-segmented site. The experimental results on pediatric brain MR images with real artifacts and multi-site subjects from the iSeg-2019 challenge demonstrate that our M-SSL method achieves better performance compared with several state-of-the-art methods.

Conventional radiation therapy (RT) to pediatric brain tumors exposes a large volume of normal brain to unwarranted radiation causing late toxicity. We hypothesized that in well demarcated pediatric tumors lacking microscopic extensions, fractionated stereotactic RT (SRT), without target volume expansions, can reduce high dose normal tissue irradiation without affecting local control.Between 2008 and 2017, 52 pediatric patients with brain tumors were treated using the CyberKnife (CK) with SRT in 180 to 200 cGy per fraction. Thirty representative cases were retrospectively planned for intensity modulated RT (IMRT) with 4-mm PTV expansion. We calculated the volume of normal tissue within the high or intermediate dose region adjacent to the target. Plan quality and radiation dose-volume dosimetry parameters were compared between CK and IMRT plans. We also reported overall survival, progression-free survival (PFS), and local control.Tumors included low-grade gliomas (n = 28), craniopharyngiomas (n = 16), and ependymomas (n = 8). The volumes of normal tissue receiving high (≥80% of prescription dose or ≥40 Gy) or intermediate (80%dose ≥50% of the prescription dose or 40 Gydose ≥25 Gy) dose were significantly smaller with CK versus IMRT plans (P.0001 for all comparisons). With a median follow-up of 3.7 years (range, 0.1-9.0), 3-year local control was 92% for all patients. Eight failures occurred: 1 craniopharyngioma (marginal), 2 ependymomas (both in-field), and 5 low-grade gliomas (2 in-field, 1 marginal, and 2 distant).Fractionated SRT using CK without target volume expansion appears to reduce the volume of irradiated tissue without majorly compromising local control in pediatric demarcated brain tumors. These results are hypothesis generating and should be tested and validated in prospective studies.

OBJECTIVEStereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs.METHODSThe authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared.RESULTSThe overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation.CONCLUSIONSApproximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.

Radiation therapy (RT) is a mainstay for the treatment of pediatric brain tumors. As improvements in and sophistication of this modality continue to increase the survival of patients, the long-term sequelae of RT pose significant challenges in the clinical management of this patient population as they transition into adulthood. In this special edition, we review the short- and long-term effects of RT for the treatment of pediatric brain tumors and the necessary surveillance required for follow-up.

OBJECTIVEBecause caregivers are a crucial part of a child’s medical care, it is important to understand how to best communicate with them during hospitalization. Qualitative research can elucidate the best strategies for effective parent–provider communication. This study aims to reveal communication styles of neurosurgery team members, and to identify areas for improvement in the future.METHODSCaregivers of children with a newly diagnosed brain tumor requiring neurosurgery were enrolled during their child’s hospitalization. During routine follow-up clinic visits within 3 months after diagnosis and tumor resection, caregivers participated in a semistructured interview, which assessed the quality of communication with the neurosurgery and oncology teams during hospitalization. Interviews were audio-recorded, transcribed, and coded for common themes until thematic saturation was reached.RESULTSDuring caregiver interviews (N = 22), several domains were discussed including communicating the diagnosis to the patient and siblings, to the rest of the family/support network, and with the neurosurgery team. Regarding parent–neurosurgeon communication, 82% of caregivers identified at least one positive aspect and 55% identified at least one negative aspect of communication. Caregivers who provided positive feedback appreciated that their neurosurgeon was thorough (73%), direct (27%), or compassionate (14%). They also valued when providers would speak “on my level” (18%) and would speak directly to the patient (27%). In terms of negative feedback, caregivers identified miscommunications (32%), discussing the diagnosis in front of the child before feeling prepared to do so (14%), and a lack of clarity about expectations, medications, or treatment (32%).CONCLUSIONSThese data provide specific ways in which neurosurgery providers have communicated effectively with caregivers and identify areas for improvement. Results have been used to develop a navigator-led intervention geared toward improving parent–provider communication during hospitalization for resection of a brain tumor.

Current standard of care for many CNS tumors involves surgical resection followed by chemotherapy and/or radiation. Some pediatric brain tumor types are infiltrative and diffuse in nature, which reduces the role for surgery. Furthermore, children are extremely vulnerable to neurological sequelae from surgery and radiation therapy, thus alternative approaches are in critical need. As molecular targets underlying various cancers become more clearly defined, there is an increasing push for targeted gene therapies. Viral vectors and nonviral nanoparticles have been thoroughly investigated for gene delivery and show promise as vectors for gene therapy for pediatric brain cancer. Here, we review inorganic and organic materials in development for nanoparticle gene delivery to the brain with a particular focus on safety.

There is no evidence that prolonged pre diagnostic symptomatic intervals (PSI) increases the risk of death in pediatric brain tumors. When investigating the role of time previous research had not controlled for confounding variables or measured the pretreatment interval (PTI). We use the term global delay interval (GDI) to describe the sum of PSI and PTI. The aim of this research was to evaluate whether there was a decrease in the probability of survival in children with brain tumors due to a prolonged PSI, PTI and GDI, using a multivariate survival analysis. We retrospective review 127 clinical records labeled with the diagnosis of CNS tumors attended at a specialized pediatric center in Mexico City from January 2008 to December 2012. Patients with PSI and GDI diagnosed between 3 and 6 months showed statistical lower probability of surviving that those with intervals

Children diagnosed with brain tumors have the lowest overall survival of all pediatric cancers. Recent molecular studies have resulted in the discovery of recurrent driver mutations in many pediatric brain tumors. However, despite these molecular advances, the clinical outcomes of high grade tumors, including H3K27M diffuse midline glioma (H3K27M DMG), remain poor. To address the paucity of tissue for biological studies, we have established a comprehensive protocol for the coordination and processing of donated specimens at postmortem. Since 2010, 60 postmortem pediatric brain tumor donations from 26 institutions were coordinated and collected. Patient derived xenograft models and cell cultures were successfully created (76% and 44% of attempts respectively), irrespective of postmortem processing time. Histological analysis of mid-sagittal whole brain sections revealed evidence of treatment response, immune cell infiltration and the migratory path of infiltrating H3K27M DMG cells into other midline structures and cerebral lobes. Sequencing of primary and disseminated tumors confirmed the presence of oncogenic driver mutations and their obligate partners. Our findings highlight the importance of postmortem tissue donations as an invaluable resource to accelerate research, potentially leading to improved outcomes for children with aggressive brain tumors.

Brain tumors are the most common solid tumor in childhood, and although survival outcomes continue to improve, survival is frequently offset by devastating late effects from tumor and treatment. The long-term effects of brain tumors and the therapy necessary to treat them range from sensory and neuroendocrine abnormalities to neurocognitive deficits leading to inferior quality of life. The multifactorial neurocognitive injury is one of the most broadly impacting and challenging late effects to predict and subsequently treat. Certain treatment modalities, such as intrathecal methotrexate and radiation, have been shown to be associated with poor neurocognition; however, long-term outcomes remain highly variable. There are efforts underway to investigate how to better predict, identify, and manage such neurocognitive injury in survivors of pediatric brain tumors. Herein, we focus on the current knowledge of neurocognitive outcomes and potential treatment strategies for this high-risk group.

This study recruited 2 centers with expertise in treating pediatric brain tumors with robotic radiation delivery system photon therapy and proton therapy, respectively, to study the plan quality and dose deposition characteristics of robotic radiation delivery system photon therapy and intensity modulated proton therapy (IMPT) plans.A total of 18 patients clinically treated with the robotic radiation delivery system were planned with IMPT. Cases were planned per the standard of care of each institution but respected the same planning objectives. The comparison included 3 aspects: plan quality, dose fall-off characteristics around the target volume, and the volume of the high-, intermediate-, and low-dose baths.All robotic radiation delivery system and IMPT plans met the planning objectives. However, IMPT significantly reduced the maximum dose to organs at risk away from the planning target volume (PTV), such as the cochlea and eye (P.05), and the mean dose to the normal brain (P.05). No statistically significant difference was observed in the maximum dose to the optical pathway and brain stem. Robotic radiation delivery system plans demonstrated a sharper dose fall-off within 5 mm around the PTV (P.05), whereas IMPT significantly lowered the dose to the normal tissue beyond 10 mm from the PTV (P.05). The robotic radiation delivery system offers a smaller high-dose bath whereas IMPT offers a smaller low-dose bath (P.05). However, the difference in intermediate dose is not statistically significant.In general, robotic radiation delivery system plans exhibit reduced high-dose exposure to normal tissue, and IMPT plans have considerably smaller volumes of low-dose exposure with differences in medium-range dose baths increasingly favoring protons as tumor size increases.

Congenital brain malformations comprise a spectrum of disorders that result from a variety of causes, including genetic abnormalities, ischemia, infections, and toxic exposures. Although most cases are discovered in infancy or childhood, clinically occult abnormalities may prove to be confounding, especially if first encountered later in life on imaging examinations obtained for other indications or in the context of superimposed pathology. This review article provides an overview of congenital brain malformations because they may be encountered at all ages for general radiologists.

Malignant gliomas constitute a smaller portion of brain tumors in children compared with adults. Nevertheless, they can be devastating tumors with poor prognosis. Recent advances and improved understanding of the genetic and molecular characterization of pediatric brain tumors, including those of malignant gliomas, have led to the reclassification of many pediatric brain tumors and new entities have been defined. In this paper, we will present some of the more recent characterization and pertinent changes in pediatric high-grade gliomas, along with the conventional and advanced imaging features associated with these entities. Implications of the recent changes in pediatric malignant glioma classifications will also be discussed.

Pediatric low-grade gliomas (pLGGs), the most frequent pediatric brain tumors, include different entities harboring distinct histological and molecular features. A major limitation in the development of treatments for these tumors is the absence of reliable in vitro models that would allow a better understanding of the molecular mechanisms that support their growth. Surgical excision is the primary treatment method and the extent of resection represents one of the strongest prognostic factors. pLGGs that cannot be completely resected are prone to recur and associated with relapses and extensive morbidities, thus remaining a major clinical challenge. We established a protocol to successfully derive primary patient-derived pLGG cells and to fully characterize them from a molecular point of view. Primary patients-derived pLGG cells were extensively analyzed in order to confirm their reliability as cellular models. Specifically, we evaluated the growth rate, senescence, and molecular features, such as BRAF mutational status, methylation, and protein expression profile. This study extensively describes pLGG primary cellular models in terms of isolation, culture method, and molecular characterization that can be used to investigate pLGG biology.

PURPOSE Proton radiotherapy (PRT) may lessen the neuropsychological risk traditionally associated with cranial radiotherapy for the treatment of pediatric brain tumors by reducing the dose to normal tissue compared with that of photon radiotherapy (XRT). We examined the change in intellectual scores over time in patients with pediatric medulloblastoma treated with craniospinal PRT versus XRT. METHODS Intelligence test scores were obtained for a sample of pediatric patients treated between 2007 and 2018 on the same medulloblastoma protocols that differed only in radiotherapy modality (PRT v XRT). Growth curve analyses compared change in scores over time since diagnosis between groups. RESULTS Longitudinal intelligence data from 79 patients (37 PRT, 42 XRT) were examined. Groups were similar on most demographic/clinical variables, including sex (67.1% male), age at diagnosis (mean, 8.6 years), craniospinal irradiation dose (median, 23.4 Gy), length of follow-up (mean, 4.3 years), and parental education (mean, 14.3 years). Boost dose ( P < .001) and boost margin ( P = .001) differed between groups. Adjusting for covariates, the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The XRT group exhibited a significant decline in global IQ, working memory, and processing speed (all P < .05). The PRT group exhibited stable scores over time in all domains with the exception of processing speed ( P = .003). CONCLUSION To our knowledge, this is the first study to compare intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT on comparable, contemporary protocols. PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, although processing speed emerged as a vulnerable domain for both groups. This study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

Brain arteriovenous malformations (AVMs) are vascular abnormalities that typically present with spontaneous hemorrhage, seizure, or as a mass lesion. Pediatric brain AVMs are rarely diagnosed but carry a higher rate of rupture. We report a 7-week-old infant with rapid fatal intracranial hemorrhage from an undiagnosed brain. AVM confirmed at autopsy. Literature review on pediatric patients who had acute death caused by previously undiagnosed brain AVM from 1992 to 2018 revealed that cerebellum is the most frequent location of such AVMs, followed by thalamus. All the children had extensive intracranial hemorrhage that led to their deterioration despite surgical intervention.