Nanoparticles for Diagnosis and Target Therapy in Pediatric Brain Cancers

Pediatric brain tumors represent the most common types of childhood cancer and novel diagnostic and therapeutic solutions are urgently needed. The gold standard treatment option for brain cancers in children, as in adults, is tumor resection followed by radio- and chemotherapy, but with discouraging therapeutic results. In particular, the last two treatments are often associated to significant neurotoxicity in the developing brain of a child, with resulting disabilities such as cognitive problems, neuroendocrine, and neurosensory dysfunctions/deficits. Nanoparticles have been increasingly and thoroughly investigated as they show great promises as diagnostic tools and vectors for gene/drug therapy for pediatric brain cancer due to their ability to cross the blood–brain barrier. In this review we will discuss the developments of nanoparticle-based strategies as novel precision nanomedicine tools for diagnosis and therapy in pediatric brain cancers, with a particular focus on targeting strategies to overcome the main physiological obstacles that are represented by blood–brain barrier.

Central Role of C2H2-Type Zinc Finger-Containing Genes in Pediatric Brain Tumors

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.

Gamma Knife Radiosurgery in the Management of Hypothalamic Glioma: A Case Report with Long-term Follow-up

Background Optic pathway/hypothalamic gliomas are rare pediatric brain tumors. The management paradigm for these challenging tumors includes chemotherapy, radiotherapy, or surgical resection, but the optimal management strategy remains elusive. Gamma Knife radiosurgery (GKRS) has emerged as a promising treatment for such lesions as documented by a small number of cases in the literature. Case Presentation Herein, we present a rare case of hypothalamic glioma in a 13-year-old girl who was referred to our service due to growth of a an incidentally diagnosed hypothalamic lesion following head injury at the age of 8 years. The lesion demonstrated hypointensity on T1 and hyperintensity on T2 without enhancement. Given the growth of the lesion on serial imaging, a stereotactic biopsy was performed demonstrating low-grade glioma. The patient underwent GKRS treatment with a marginal dose of 15 Gy at 50% isodose line for a tumor volume of 2.2 ml. Annual radiological surveillance over the next 17 years demonstrated a gradual shrinkage of the lesion until it completely disappeared. The patient is currently a healthy 31-year-old female without any visual, endocrine, or neurocognitive complaints. Conclusion The outcome obtained after extended follow-up in our patient highlights the safety and efficacy of GKRS in the management of hypothalamic gliomas in pediatrics, which in turn can avoid potentially serious complications of surgery in this vulnerable patient population in this sensitive location.

Cancer Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan

Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients’ peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies <0.1% in the general population and variants suspected to be pathogenic were extracted and analyzed. Pathogenic variants were found in 7 patients (18%): 2 nonsense variants of CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.

Mapping pediatric brain tumors to their origins in the developing cerebellum

Understanding the cellular origins of childhood brain tumors is key for discovering novel tumor-specific therapeutic targets. Previous strategies mapping cellular origins typically involved comparing human tumors to murine embryonal tissues, a potentially imperfect approach due to spatio-temporal gene expression differences between species. Here we use an unprecedented single-nucleus atlas of the developing human cerebellum (Sepp, Leiss, et al) and extensive bulk and single-cell transcriptome tumor data to map their cellular origins with focus on three most common pediatric brain tumors - pilocytic astrocytoma, ependymoma, and medulloblastoma. Using custom bioinformatics approaches, we postulate the astroglial and glial lineages as the origins for posterior fossa ependymomas and radiation-induced gliomas (secondary tumors after medulloblastoma treatment), respectively. Moreover, we confirm that SHH, Group3 and Group4 medulloblastomas stem from granule cell/unipolar brush cell lineages, whereas we propose pilocytic astrocytoma to originate from the oligodendrocyte lineage. We also identify genes shared between the cerebellar lineage of origin and corresponding tumors, and genes that are tumor specific; both gene sets represent promising therapeutic targets. As a common feature among most cerebellar tumors, we observed compositional heterogeneity in terms of similarity to normal cells, suggesting that tumors arise from or differentiate into multiple points along the cerebellar "lineage of origin".

Childhood Malignant Brain Tumors: Balancing the Bench and Bedside

Brain tumors are the leading cause of childhood cancer deaths in developed countries. They also represent the most common solid tumor in this age group, accounting for approximately one-quarter of all pediatric cancers. Developments in neuro-imaging, neurosurgical techniques, adjuvant therapy and supportive care have improved survival rates for certain tumors, allowing a future focus on optimizing cure, whilst minimizing long-term adverse effects. Recent times have witnessed a rapid evolution in the molecular characterization of several of the common pediatric brain tumors, allowing unique clinical and biological patient subgroups to be identified. However, a resulting paradigm shift in both translational therapy and subsequent survival for many of these tumors remains elusive, while recurrence remains a great clinical challenge. This review will provide an insight into the key molecular developments and global co-operative trial results for the most common malignant pediatric brain tumors (medulloblastoma, high-grade gliomas and ependymoma), highlighting potential future directions for management, including novel therapeutic options, and critical challenges that remain unsolved.

A Prospective Study of Social Competence in Survivors of Pediatric Brain Tumors

BACKGROUND/OBJECTIVES: Survivors of pediatric brain tumors (BT) are at increased risk for difficulties with social competence, including poor social information processing (SIP) and peer relationships. Due to improved survival rates among BT, there is a need to better understand these challenges and if they are specific to BT versus other survivors of childhood cancer. METHODS: 51 BT and 34 survivors of pediatric solid tumors (ST) completed evaluations of SIP and peer relationship quality within 6 months of completing treatment and at one year follow-up. Caregivers also completed a measure of social skills. Linear mixed models evaluated (1) differences between BT and ST on SIP and social skills and (2) how indices of SIP were associated with peer relationships over time for ST and BT. RESULTS: BT did not differ from ST on indices of SIP or social skills over time. There was a three-way interaction between measures of SIP, group, and time to predict peer relationships. ST showed a positive association between baseline social skills and theory of mind and peer relationships over time, whereas BT showed an inverse association between baseline social skills and theory of mind and peer relationships over time. CONCLUSION: Baseline SIP and social skills affected the trajectory of BT peer relationships. BT social functioning should be monitored regularly after the completion of treatment to determine if and when intervention services would be beneficial.