Editorial

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Open AccessEditorial

Introduction to the Special Issue on Pediatric Neuro-Oncology

by Natasha Pillay Smiley and Soumen Khatua

Bioengineering 2018, 5(4), 109; https://doi.org/10.3390/bioengineering5040109 - 11 Dec 2018

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Pediatric Neuro-Oncology is a highly specialized field encompassing molecular biology, clinical acumen, evidence based medicine, cancer genetics and neuropsychological care for the diagnosis and treatment of children with central nervous system (CNS) tumors. [...] Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

Research

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12 pages, 1359 KiB

Open AccessCommunication

Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)

by Anders W. Bailey, Amreena Suri, Pauline M. Chou, Tatiana Pundy, Samantha Gadd, Stacey L. Raimondi, Tadanori Tomita and Simone Treiger Sredni

Bioengineering 2018, 5(4), 96; https://doi.org/10.3390/bioengineering5040096 - 04 Nov 2018

Cited by 19 | Viewed by 6233

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also [...] Read more.

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB. Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

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Review

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15 pages, 3551 KiB

Open AccessReview

The Emerging Role of Amino Acid PET in Neuro-Oncology

by Amer M. Najjar, Jason M. Johnson and Dawid Schellingerhout

Bioengineering 2018, 5(4), 104; https://doi.org/10.3390/bioengineering5040104 - 28 Nov 2018

Cited by 23 | Viewed by 5265

Abstract

Imaging plays a critical role in the management of the highly complex and widely diverse central nervous system (CNS) malignancies in providing an accurate diagnosis, treatment planning, response assessment, prognosis, and surveillance. Contrast-enhanced magnetic resonance imaging (MRI) is the primary modality for CNS [...] Read more.

Imaging plays a critical role in the management of the highly complex and widely diverse central nervous system (CNS) malignancies in providing an accurate diagnosis, treatment planning, response assessment, prognosis, and surveillance. Contrast-enhanced magnetic resonance imaging (MRI) is the primary modality for CNS disease management due to its high contrast resolution, reasonable spatial resolution, and relatively low cost and risk. However, defining tumor response to radiation treatment and chemotherapy by contrast-enhanced MRI is often difficult due to various factors that can influence contrast agent distribution and perfusion, such as edema, necrosis, vascular alterations, and inflammation, leading to pseudoprogression and pseudoresponse assessments. Amino acid positron emission tomography (PET) is emerging as the method of resolving such equivocal lesion interpretations. Amino acid radiotracers can more specifically differentiate true tumor boundaries from equivocal lesions based on their specific and active uptake by the highly metabolic cellular component of CNS tumors. These therapy-induced metabolic changes detected by amino acid PET facilitate early treatment response assessments. Integrating amino acid PET in the management of CNS malignancies to complement MRI will significantly improve early therapy response assessment, treatment planning, and clinical trial design. Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

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16 pages, 997 KiB

Open AccessReview

Radiotherapy Advances in Pediatric Neuro-Oncology

by Ethan B. Ludmir, David R. Grosshans and Kristina D. Woodhouse

Bioengineering 2018, 5(4), 97; https://doi.org/10.3390/bioengineering5040097 - 04 Nov 2018

Cited by 15 | Viewed by 6710

Abstract

Radiation therapy (RT) represents an integral component in the treatment of many pediatric brain tumors. Multiple advances have emerged within pediatric radiation oncology that aim to optimize the therapeutic ratio—improving disease control while limiting RT-related toxicity. These include innovations in treatment planning with [...] Read more.

Radiation therapy (RT) represents an integral component in the treatment of many pediatric brain tumors. Multiple advances have emerged within pediatric radiation oncology that aim to optimize the therapeutic ratio—improving disease control while limiting RT-related toxicity. These include innovations in treatment planning with magnetic resonance imaging (MRI) simulation, as well as increasingly sophisticated radiation delivery techniques. Advanced RT techniques, including photon-based RT such as intensity-modulated RT (IMRT) and volumetric-modulated arc therapy (VMAT), as well as particle beam therapy and stereotactic RT, have afforded an array of options to dramatically reduce radiation exposure of uninvolved normal tissues while treating target volumes. Along with advances in image guidance of radiation treatments, novel RT approaches are being implemented in ongoing and future prospective clinical trials. As the era of molecular risk stratification unfolds, personalization of radiation dose, target, and technique holds the promise to meaningfully improve outcomes for pediatric neuro-oncology patients. Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

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16 pages, 1531 KiB

Open AccessReview

Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG)

by Cavan P. Bailey, Mary Figueroa, Sana Mohiuddin, Wafik Zaky and Joya Chandra

Bioengineering 2018, 5(4), 88; https://doi.org/10.3390/bioengineering5040088 - 18 Oct 2018

Cited by 13 | Viewed by 8293

Abstract

Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole [...] Read more.

Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole remains surgery and radiation combined with chemotherapy, while radiation alone is standard treatment for DIPG. Unfortunately, these therapies lack specificity for malignant glioma cells and have few to no reliable biomarkers of efficacy. Recent discoveries have revealed that epigenetic disruption by highly conserved mutations in DNA-packaging histone proteins in pHGG, especially DIPG, contribute to the aggressive nature of these cancers. In this review we pose unanswered questions and address unexplored mechanisms in pre-clinical models and clinical trial data from pHGG patients. Particular focus will be paid towards therapeutics targeting chromatin modifiers and other epigenetic vulnerabilities that can be exploited for pHGG therapy. Further delineation of rational therapeutic combinations has strong potential to drive development of safe and efficacious treatments for pHGG patients. Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

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18 pages, 234 KiB

Open AccessReview

Palliative Care for Children with Central Nervous System Malignancies

by Peter H. Baenziger and Karen Moody

Bioengineering 2018, 5(4), 85; https://doi.org/10.3390/bioengineering5040085 - 13 Oct 2018

Cited by 3 | Viewed by 6367

Abstract

Children with central nervous system (CNS) malignancies often suffer from high symptom burden and risk of death. Pediatric palliative care is a medical specialty, provided by an interdisciplinary team, which focuses on enhancing quality of life and minimizing suffering for children with life-threatening [...] Read more.

Children with central nervous system (CNS) malignancies often suffer from high symptom burden and risk of death. Pediatric palliative care is a medical specialty, provided by an interdisciplinary team, which focuses on enhancing quality of life and minimizing suffering for children with life-threatening or life-limiting disease, and their families. Primary palliative care skills, which include basic symptom management, facilitation of goals-of-care discussions, and transition to hospice, can and should be developed by all providers of neuro-oncology care. This chapter will review the fundamentals of providing primary pediatric palliative care. Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

13 pages, 999 KiB

Open AccessReview

Preclinical Models of Pediatric Brain Tumors—Forging Ahead

by Tara H.W. Dobson and Vidya Gopalakrishnan

Bioengineering 2018, 5(4), 81; https://doi.org/10.3390/bioengineering5040081 - 02 Oct 2018

Cited by 17 | Viewed by 5663

Abstract

Approximately five out of 100,000 children from 0 to 19 years old are diagnosed with a brain tumor. These children are treated with medication designed for adults that are highly toxic to a developing brain. Those that survive are at high risk for [...] Read more.

Approximately five out of 100,000 children from 0 to 19 years old are diagnosed with a brain tumor. These children are treated with medication designed for adults that are highly toxic to a developing brain. Those that survive are at high risk for a lifetime of limited physical, psychological, and cognitive abilities. Despite much effort, not one drug exists that was designed specifically for pediatric patients. Stagnant government funding and the lack of economic incentives for the pharmaceutical industry greatly limits preclinical research and the development of clinically applicable pediatric brain tumor models. As more data are collected, the recognition of disease sub-groups based on molecular heterogeneity increases the need for designing specific models suitable for predictive drug screening. To overcome these challenges, preclinical approaches will need continual enhancement. In this review, we examine the advantages and shortcomings of in vitro and in vivo preclinical pediatric brain tumor models and explore potential solutions based on past, present, and future strategies for improving their clinical relevancy. Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

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16 pages, 1190 KiB

Open AccessReview

Embryonal Tumors of the Central Nervous System in Children: The Era of Targeted Therapeutics

by David E. Kram, Jacob J. Henderson, Muhammad Baig, Diya Chakraborty, Morgan A. Gardner, Subhasree Biswas and Soumen Khatua

Bioengineering 2018, 5(4), 78; https://doi.org/10.3390/bioengineering5040078 - 23 Sep 2018

Cited by 26 | Viewed by 9487

Abstract

Embryonal tumors (ET) of the central nervous system (CNS) in children encompass a wide clinical spectrum of aggressive malignancies. Until recently, the overlapping morphological features of these lesions posed a diagnostic challenge and undermined discovery of optimal treatment strategies. However, with the advances [...] Read more.

Embryonal tumors (ET) of the central nervous system (CNS) in children encompass a wide clinical spectrum of aggressive malignancies. Until recently, the overlapping morphological features of these lesions posed a diagnostic challenge and undermined discovery of optimal treatment strategies. However, with the advances in genomic technology and the outpouring of biological data over the last decade, clear insights into the molecular heterogeneity of these tumors are now well delineated. The major subtypes of ETs of the CNS in children include medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and embryonal tumors with multilayered rosettes (ETMR), which are now biologically and clinically characterized as different entities. These important developments have paved the way for treatments guided by risk stratification as well as novel targeted therapies in efforts to improve survival and reduce treatment burden. Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

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Graphical abstract

15 pages, 1142 KiB

Open AccessReview

Neurocognitive and Psychosocial Outcomes in Pediatric Brain Tumor Survivors

by Peter L. Stavinoha, Martha A. Askins, Stephanie K. Powell, Natasha Pillay Smiley and Rhonda S. Robert

Bioengineering 2018, 5(3), 73; https://doi.org/10.3390/bioengineering5030073 - 11 Sep 2018

Cited by 81 | Viewed by 11356

Abstract

The late neurocognitive and psychosocial effects of treatment for pediatric brain tumor (PBT) represent important areas of clinical focus and ongoing research. Neurocognitive sequelae and associated problems with learning and socioemotional development negatively impact PBT survivors’ overall health-related quality of life, educational attainment [...] Read more.

The late neurocognitive and psychosocial effects of treatment for pediatric brain tumor (PBT) represent important areas of clinical focus and ongoing research. Neurocognitive sequelae and associated problems with learning and socioemotional development negatively impact PBT survivors’ overall health-related quality of life, educational attainment and employment rates. Multiple factors including tumor features and associated complications, treatment methods, individual protective and vulnerability factors and accessibility of environmental supports contribute to the neurocognitive and psychosocial outcomes in PBT survivors. Declines in overall measured intelligence are common and may persist years after treatment. Core deficits in attention, processing speed and working memory are postulated to underlie problems with overall intellectual development, academic achievement and career attainment. Additionally, psychological problems after PBT can include depression, anxiety and psychosocial adjustment issues. Several intervention paradigms are briefly described, though to date research on innovative, specific and effective interventions for neurocognitive late effects is still in its early stages. This article reviews the existing research for understanding PBT late effects and highlights the need for innovative research to enhance neurocognitive and psychosocial outcomes in PBT survivors. Full article

(This article belongs to the Special Issue Update in Pediatric Neuro-Oncology)

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