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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 63022

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Special Issue Editors

Prof. Dr. Tadanori Tomita

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Guest Editor

Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Interests: pediatric neurosurgery; congenital CNS malformations; neuro-oncology; developmental biology; spine and spinal cord tumors; spinal tumors
Special Issues, Collections and Topics in MDPI journals

Dr. Guifa Xi

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Co-Guest Editor

Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Interests: pediatric brain tumor; brain tumor molecular biology; cancer biology; nanomedicine; convection enhanced delivery; radio chemo resistance

Prof. Dr. Stewart Goldman

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Guest Editor

Division of Pediatric Hematology, Onclology, Neuro-oncology & Stem Cell Transplantation, Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Interests: Pediatric Neuro-oncology; DIPG; Developmental Therapeutics; Precision Medicine; Quality of life/Patient Reported Outcomes; CNS tumor late effects

Special Issue Information

Dear Colleagues,

Pediatric brain tumors are the most common solid tumors affecting infants and young children. Among them, high grade gliomas, diffuse intrinsic pontine glioma (DIPG), ependymoma, embryonal tumors including medulloblastoma, and atypical teratoid rhabdoid tumor (ATRT) etc. remain devastating, often refractory to surgical resection and adjuvant radio-chemotherapy, leading to poor patient survival. Advanced research analyses have shown tumor heterogeneity and plasticity, genetic mutations, microenvironment and metabolic alterations, and chromatin remodeling are contributors that challenge current therapeutic strategies which result in unfavorable clinic outcomes.

This special issue will present advanced clinical and research articles and high quality review-papers focusing on the latest advances in the treatment of pediatric malignant brain tumors, which may include targeted therapy and immunotherapy. We request research scientists to submit the results of not only molecular-based but translational investigations of malignant pediatric brain tumors directing for prospective clinical applications. We encourage clinicians to submit their articles describing innovative diagnostic (e.g. liquid biopsy; molecular classification), and therapeutic approaches and protocols with their results. Surgeons are encouraged to submit their experience of minimally invasive surgery and regional therapy such as convection enhanced delivery, radiation therapy and thermo-ablation in order to contribute to the care of prospective pediatric brain tumors. Comprehensive up-to-date reviews to these topics are also encouraged in order to summarize and understand the current status and future directions.

Prof. Dr. Tadanori Tomita
Dr. Guifa Xi
Prof. Dr. Stewart Goldman
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (14 papers)

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16 pages, 3846 KiB

Open AccessArticle

Pediatric Suprasellar Germ Cell Tumors: A Clinical and Radiographic Review of Solitary vs. Bifocal Tumors and Its Therapeutic Implications

by Darian R. Esfahani, Tord Alden, Arthur DiPatri, Guifa Xi, Stewart Goldman and Tadanori Tomita

Cancers 2020, 12(9), 2621; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092621 - 14 Sep 2020

Cited by 20 | Viewed by 3574

Abstract

Suprasellar germ cell tumors (S-GCTs) are rare, presenting in either solitary or multifocal fashion. In this study, we retrospectively examine 22 solitary S-GCTs and 20 bifocal germ cell tumors (GCTs) over a 30-year period and demonstrate clinical, radiographic, and prognostic differences between the two groups with therapeutic implications. Compared to S-GCTs, bifocal tumors were almost exclusively male, exhibited higher rate of metastasis, and had worse rates of progression free and overall survival trending toward significance. We also introduce a novel magnetic resonance (MR) imaging classification of suprasellar GCT into five types: a IIIrd ventricle floor tumor extending dorsally with or without an identifiable pituitary stalk (Type Ia, Ib), ventrally (Type III), in both directions (Type II), small lesions at the IIIrd ventricle floor extending to the stalk (Type IV), and tumor localized in the stalk (Type V). S-GCTs almost uniformly presented as Type I–III, while most bifocal GCTs were Type IV with a larger pineal mass. These differences are significant as bifocal GCTs representing concurrent primaries or subependymal extension may be treated with whole ventricle radiation, while cerebrospinal fluid (CSF)-borne metastases warrant craniospinal irradiation (CSI). Although further study is necessary, we recommend CSI for bifocal GCTs exhibiting high-risk features such as metastasis or non-germinomatous germ cell tumor histology. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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16 pages, 5141 KiB

Open AccessArticle

Nuclear Receptor Binding Protein 2 Is Downregulated in Medulloblastoma, and Reduces Tumor Cell Survival upon Overexpression

by Anqi Xiong, Ananya Roy, Argyris Spyrou, Holger Weishaupt, Voichita D. Marinescu, Tommie Olofsson, Ola Hermanson, Fredrik J. Swartling and Karin Forsberg-Nilsson

Cancers 2020, 12(6), 1483; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061483 - 06 Jun 2020

Cited by 5 | Viewed by 3438

Abstract

Pseudokinases, comprising 10% of the human kinome, are emerging as regulators of canonical kinases and their functions are starting to be defined. We previously identified the pseudokinase Nuclear Receptor Binding Protein 2 (NRBP2) in a screen for genes regulated during neural differentiation. During mouse brain development, NRBP2 is expressed in the cerebellum, and in the adult brain, mainly confined to specific neuronal populations. To study the role of NRBP2 in brain tumors, we stained a brain tumor tissue array for NRPB2, and find its expression to be low, or absent, in a majority of the tumors. This includes medulloblastoma (MB), a pediatric tumor of the cerebellum. Using database mining of published MB data sets, we also find that NRBP2 is expressed at a lower level in MB than in the normal cerebellum. Recent studies indicate that MB exhibits frequent epigenetic alternations and we therefore treated MB cell lines with drugs inhibiting DNA methylation or histone deacetylation, which leads to an upregulation of NRBP2 mRNA expression, showing that it is under epigenetic regulation in cultured MB cells. Furthermore, forced overexpression of NRBP2 in MB cell lines causes a dramatic decrease in cell numbers, increased cell death, impaired cell migration and inhibited cell invasion in vitro. Taken together, our data indicate that downregulation of NRBP2 may be a feature by which MB cells escape growth regulation. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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21 pages, 4667 KiB

Open AccessArticle

Erbb4 Is Required for Cerebellar Development and Malignant Phenotype of Medulloblastoma

by Juncal Aldaregia, Peio Errarte, Ane Olazagoitia-Garmendia, Marian Gimeno, Jose Javier Uriz, Timothy R. Gershon, Idoia Garcia and Ander Matheu

Cancers 2020, 12(4), 997; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040997 - 17 Apr 2020

Cited by 3 | Viewed by 3130

Abstract

Medulloblastoma is the most common and malignant pediatric brain tumor in childhood. It originates from dysregulation of cerebellar development, due to an excessive proliferation of cerebellar granule neuron precursor cells (CGNPs). The underlying molecular mechanisms, except for the role of SHH and WNT pathways, remain largely unknown. ERBB4 is a tyrosine kinase receptor whose activity in cancer is tissue dependent. In this study, we characterized the role of ERBB4 during cerebellum development and medulloblastoma progression paying particular interests to its role in CGNPs and medulloblastoma stem cells (MBSCs). Our results show that ERBB4 is expressed in the CGNPs during cerebellum development where it plays a critical role in migration, apoptosis and differentiation. Similarly, it is enriched in the population of MBSCs, where also controls those critical processes, as well as self-renewal and tumor initiation for medulloblastoma progression. These results are translated to clinical samples where high levels of ERBB4 correlate with poor outcome in Group 4 and all medulloblastomas groups. Transcriptomic analysis identified critical processes and pathways altered in cells with knock-down of ERBB4. These results highlight the impact and underlying mechanisms of ERBB4 in critical processes during cerebellum development and medulloblastoma. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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25 pages, 3566 KiB

Open AccessArticle

Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid

by Mariah M. Hoffman, Jessica S. Zylla, Somshuvra Bhattacharya, Kristin Calar, Timothy W. Hartman, Ratan D. Bhardwaj, W. Keith Miskimins, Pilar de la Puente, Etienne Z. Gnimpieba and Shanta M. Messerli

Cancers 2020, 12(3), 756; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030756 - 23 Mar 2020

Cited by 25 | Viewed by 4705

Abstract

Central nervous system atypical teratoid/rhabdoid tumors (ATRTs) are rare and aggressive tumors with a very poor prognosis. Current treatments for ATRT include resection of the tumor, followed by systemic chemotherapy and radiation therapy, which have toxic side effects for young children. Gene expression analyses of human ATRTs and normal brain samples indicate that ATRTs have aberrant expression of epigenetic markers including class I histone deacetylases (HDAC’s) and lysine demethylase (LSD1). Here, we investigate the effect of a small molecule epigenetic modulator known as Domatinostat (4SC-202), which inhibits both class I HDAC’s and Lysine Demethylase (LSD1), on ATRT cell survival and single cell heterogeneity. Our findings suggest that 4SC-202 is both cytotoxic and cytostatic to ATRT in 2D and 3D scaffold cell culture models and may target cancer stem cells. Single-cell RNA sequencing data from ATRT-06 spheroids treated with 4SC-202 have a reduced population of cells overexpressing stem cell-related genes, including SOX2. Flow cytometry and immunofluorescence on 3D ATRT-06 scaffold models support these results suggesting that 4SC-202 reduces expression of cancer stem cell markers SOX2, CD133, and FOXM1. Drug-induced changes to the systems biology landscape are also explored by multi-omics enrichment analyses. In summary, our data indicate that 4SC-202 has both cytotoxic and cytostatic effects on ATRT, targets specific cell sub-populations, including those with cancer stem-like features, and is an important potential cancer therapeutic to be investigated in vivo. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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20 pages, 3498 KiB

Open AccessArticle

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors

by Huy Minh Tran, Kuo-Sheng Wu, Shian-Ying Sung, Chun Austin Changou, Tsung-Han Hsieh, Yun-Ru Liu, Yen-Lin Liu, Min-Lan Tsai, Hsin-Lun Lee, Kevin Li-Chun Hsieh, Wen-Chang Huang, Muh-Lii Liang, Hsin-Hung Chen, Yi-Yen Lee, Shih-Chieh Lin, Donald Ming-Tak Ho, Feng-Chi Chang, Meng-En Chao, Wan Chen, Shing-Shung Chu, Alice L. Yu, Yun Yen, Che-Chang Chang and Tai-Tong Wong Show full author list Hide full author list

Cancers 2020, 12(3), 752; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030752 - 22 Mar 2020

Cited by 7 | Viewed by 4610

Abstract

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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24 pages, 5297 KiB

Open AccessArticle

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan

by Kuo-Sheng Wu, Donald Ming-Tak Ho, Shiann-Tarng Jou, Alice L. Yu, Huy Minh Tran, Muh-Lii Liang, Hsin-Hung Chen, Yi-Yen Lee, Yi-Wei Chen, Shih-Chieh Lin, Feng-Chi Chang, Min-Lan Tsai, Yen-Lin Liu, Hsin-Lun Lee, Kevin Li-Chun Hsieh, Wen-Chang Huang, Shian-Ying Sung, Che-Chang Chang, Chun Austin Changou, Kung-Hao Liang, Tsung-Han Hsieh, Yun-Ru Liu, Meng-En Chao, Wan Chen, Shing-Shung Chu, Er-Chieh Cho and Tai-Tong Wong Show full author list Hide full author list

Cancers 2020, 12(3), 653; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030653 - 11 Mar 2020

Cited by 9 | Viewed by 4248

Abstract

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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18 pages, 5264 KiB

Open AccessArticle

CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents

by Gianmarco Pallavicini, Giorgia Iegiani, Gaia Elena Berto, Elisa Calamia, Edoardo Trevisiol, Andrea Veltri, Simona Allis and Ferdinando Di Cunto

Cancers 2020, 12(3), 542; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030542 - 26 Feb 2020

Cited by 15 | Viewed by 3742

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children, and it is classified into four biological subgroups: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The current treatment is surgery, followed by irradiation and chemotherapy. Unfortunately, these therapies are only partially effective. Citron kinase protein (CITK) has been proposed as a promising target for SHH MB, whose inactivation leads to DNA damage and apoptosis. D283 and D341 cell lines (Group 3/Group 4 MB) were silenced with established siRNA sequences against CITK, to assess the direct effects of its loss. Next, D283, D341, ONS-76 and DAOY cells were treated with ionizing radiation (IR) or cisplatin in combination with CITK knockdown. CITK depletion impaired proliferation and induced cytokinesis failure and apoptosis of G3/G4 MB cell lines. Furthermore, CITK knockdown produced an accumulation of DNA damage, with reduced RAD51 nuclear levels. Association of IR or cisplatin with CITK depletion strongly impaired the growth potential of all tested MB cells. These results indicate that CITK inactivation could prevent the expansion of G3/G4 MB and increase their sensitivity to DNA-damaging agents, by impairing homologous recombination. We suggest that CITK inhibition could be broadly associated with IR and adjuvant therapy in MB treatment. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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17 pages, 6009 KiB

Open AccessArticle

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

by Anuja Neve, Jessica Migliavacca, Charles Capdeville, Marc Thomas Schönholzer, Alexandre Gries, Min Ma, Karthiga Santhana Kumar, Michael Grotzer and Martin Baumgartner

Cancers 2019, 11(12), 1985; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121985 - 10 Dec 2019

Cited by 7 | Viewed by 3144

Abstract

In the Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB), tumor initiation and progression are in part driven by smoothened (SMO) and fibroblast growth factor (FGF)-receptor (FGFR) signaling, respectively. We investigated the impact of the SMO-FGFR crosstalk on tumor growth and invasiveness in MB. We found that FGFR signaling represses GLI1 expression downstream of activated SMO in the SHH MB line DAOY and induces MKI67, HES1, and BMI1 in DAOY and in the group 3 MB line HD-MBO3. FGFR repression of GLI1 does not affect proliferation or viability, whereas inhibition of FGFR is necessary to release SMO-driven invasiveness. Conversely, SMO activation represses FGFR-driven sustained activation of nuclear ERK. Parallel activation of FGFR and SMO in ex vivo tumor cell-cerebellum slice co-cultures reduced invasion of tumor cells without affecting proliferation. In contrast, treatment of the cells with the SMO antagonist Sonidegib (LDE225) blocked invasion and proliferation in cerebellar slices. Thus, sustained, low-level SMO activation is necessary for proliferation and tissue invasion, whereas acute, pronounced activation of SMO can repress FGFR-driven invasiveness. This suggests that the tumor cell response is dependent on the relative local abundance of the two factors and indicates a paradigm of microenvironmental control of invasion in SHH MB through mutual control of SHH and FGFR signaling. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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13 pages, 1809 KiB

Open AccessArticle

PATZ1 Is Overexpressed in Pediatric Glial Tumors and Correlates with Worse Event-Free Survival in High-grade Gliomas

by Annalisa Passariello, Maria Elena Errico, Vittoria Donofrio, Manuela Maestrini, Alia Zerbato, Laura Cerchia, Maria Capasso, Mario Capasso and Monica Fedele

Cancers 2019, 11(10), 1537; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101537 - 11 Oct 2019

Cited by 8 | Viewed by 2430

Abstract

Glial tumors are the leading cause of cancer-related death and morbidity in children. Their diagnosis, mainly based on clinical and histopathological factors, is particularly challenging because of their high molecular heterogeneity. Thus, tumors with identical histotypes could result in variable biological behaviors and prognoses. The PATZ1 gene has been recently shown to be expressed in adult gliomas, including glioblastomas, where it correlates with the proneural subtype and with a better prognosis. Here, we analyzed the expression of PATZ1 in pediatric gliomas, first at mRNA level in a public database, and then at protein level, by immunohistochemistry, in a cohort of 52 glial brain tumors from young patients aged from 6 months to 16 years. As for adult tumors, we show that PATZ1 is enriched in glial tumors compared to the normal brain, where it correlates positively and negatively with a proneural and mesenchymal signature, respectively. Moreover, we show that PATZ1 is expressed at variable levels in our cohort of tumors. Higher expression was detected in high-grade than low-grade gliomas, suggesting a correlation with the malignancy. Among high-grade gliomas, higher levels of PATZ1 have consistently been found to correlate with worse event-free survival. Therefore, our study may imply new diagnostic opportunities for pediatric gliomas. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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Review

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16 pages, 3520 KiB

Open AccessReview

Modern Radiotherapy for Pediatric Brain Tumors

by Nicholas J. DeNunzio and Torunn I. Yock

Cancers 2020, 12(6), 1533; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061533 - 11 Jun 2020

Cited by 44 | Viewed by 5339

Abstract

Cancer is a leading cause of death in children with tumors of the central nervous system, the most commonly encountered solid malignancies in this population. Radiotherapy (RT) is an integral part of managing brain tumors, with excellent long-term survival overall. The tumor histology will dictate the volume of tissue requiring treatment and the dose. However, radiation in developing children can yield functional deficits and/or cosmetic defects and carries a risk of second tumors. In particular, children receiving RT are at risk for neurocognitive effects, neuroendocrine dysfunction, hearing loss, vascular anomalies and events, and psychosocial dysfunction. The risk of these late effects is directly correlated with the volume of tissue irradiated and dose delivered and is inversely correlated with age. To limit the risk of developing these late effects, improved conformity of radiation to the target volume has come from adopting a volumetric planning process. Radiation beam characteristics have also evolved to achieve this end, as exemplified through development of intensity modulated photons and the use of protons. Understanding dose limits of critical at-risk structures for different RT modalities is evolving. In this review, we discuss the physical basis of the most common RT modalities used to treat pediatric brain tumors (intensity modulated radiation therapy and proton therapy), the RT planning process, survival outcomes for several common pediatric malignant brain tumor histologies, RT-associated toxicities, and steps taken to mitigate the risk of acute and late effects from treatment. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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18 pages, 2398 KiB

Open AccessReview

Pediatric Low-Grade Gliomas

by Kelly L. Collins and Ian F. Pollack

Cancers 2020, 12(5), 1152; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051152 - 04 May 2020

Cited by 24 | Viewed by 9763

Abstract

Brain tumors constitute the largest source of oncologic mortality in children and low-grade gliomas are among most common pediatric central nervous system tumors. Pediatric low-grade gliomas differ from their counterparts in the adult population in their histopathology, genetics, and standard of care. Over the past decade, an increasingly detailed understanding of the molecular and genetic characteristics of pediatric brain tumors led to tailored therapy directed by integrated phenotypic and genotypic parameters and the availability of an increasing array of molecular-directed therapies. Advances in neuroimaging, conformal radiation therapy, and conventional chemotherapy further improved treatment outcomes. This article reviews the current classification of pediatric low-grade gliomas, their histopathologic and radiographic features, state-of-the-art surgical and adjuvant therapies, and emerging therapies currently under study in clinical trials. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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18 pages, 2993 KiB

Open AccessReview

Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma

by Han Zou, Brad Poore, Alberto Broniscer, Ian F. Pollack and Baoli Hu

Cancers 2020, 12(3), 643; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030643 - 10 Mar 2020

Cited by 14 | Viewed by 5037

Abstract

Medulloblastoma, the most common pediatric malignant brain tumor, continues to have a high rate of morbidity and mortality in childhood. Recent advances in cancer genomics, single-cell sequencing, and sophisticated tumor models have revolutionized the characterization and stratification of medulloblastoma. In this review, we discuss heterogeneity associated with four major subgroups of medulloblastoma (WNT, SHH, Group 3, and Group 4) on the molecular and cellular levels, including histological features, genetic and epigenetic alterations, proteomic landscape, cell-of-origin, tumor microenvironment, and therapeutic approaches. The intratumoral molecular heterogeneity and intertumoral cellular diversity clearly underlie the divergent biology and clinical behavior of these lesions and highlight the future role of precision treatment in this devastating brain tumor in children. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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13 pages, 1680 KiB

Open AccessReview

Bone Morphogenetic Protein 4 Targeting Glioma Stem-Like Cells for Malignant Glioma Treatment: Latest Advances and Implications for Clinical Application

by Sonali Nayak, Ashorne Mahenthiran, Yongyong Yang, Mark McClendon, Barbara Mania-Farnell, Charles David James, John A. Kessler, Tadanori Tomita, Shi-Yuan Cheng, Samuel I. Stupp and Guifa Xi

Cancers 2020, 12(2), 516; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020516 - 24 Feb 2020

Cited by 13 | Viewed by 4761

Abstract

Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicates its potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, with an emphasis on pediatric malignant gliomas. We also summarize BMP4 delivery strategies, highlighting biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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24 pages, 2185 KiB

Open AccessReview

Molecular Imaging in Pediatric Brain Tumors

by Agostino Chiaravalloti, Luca Filippi, Maria Ricci, Andrea Cimini and Orazio Schillaci

Cancers 2019, 11(12), 1853; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121853 - 23 Nov 2019

Cited by 12 | Viewed by 3914

Abstract

In the last decade, several radiopharmaceuticals have been developed and investigated for imaging in vivo of pediatric brain tumors with the aim of exploring peculiar metabolic processes as glucose consumption, amino-acid metabolism, and protein synthesis with nuclear medicine techniques. Although the clinical shreds of evidence are limited, preliminary results are encouraging. In this review, we performed web-based and desktop research summarizing the most relevant findings of the literature published to date on this topic. Particular attention was given to the wide spectrum of nuclear medicine advances and trends in pediatric neurooncology and neurosurgery. Furthermore, the role of somatostatin receptor imaging through single-photon emission computed tomography (SPECT) and positron emission tomography (PET) probes, with reference to their potential therapeutic implications, was examined in the peculiar context. Preliminary results show that functional imaging in pediatric brain tumors might lead to significant improvements in terms of diagnostic accuracy and it could be of help in the management of the disease. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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