Pediatric Neuro-oncology Research Articles

Fatal gastrointestinal hemorrhage in a young boy with newly diagnosed metastatic medulloblastoma on high dose dexamethasone.

A 10-year-old boy with newly diagnosed metastatic medulloblastoma was placed on high dose dexamethasone and ranitidine prior to surgery. The child underwent subtotal resection and was discharged 5 days postoperatively with an uneventful hospital course on a tapering dose of dexamethasone and ranitidine. Over the next 2 days the patient complained of mild abdominal distension with flatulence, without pain, vomiting, or dysmotility. On follow-up in clinic 5 days after discharge, he had normal vital signs when he suddenly became pale and had loss of consciousness. Emergent computerized tomography of the head showed no acute hemorrhage and complete blood count revealed hemoglobin of 4.2 gm/dL. In spite of maximum resuscitation with copious blood products the patient died. Autopsy revealed evidence of duodenal perforation with intraluminal hemorrhage. This case demonstrates a rare fatal complication of high dose dexamethasone therapy even with concurrent gastrointestinal prophylactic therapy. We provide a review of the limited literature on steroid use in pediatric neurooncology with regard to gastrointestinal bleeding.

Metrics and Textural Features of MRI Diffusion to Improve Classification of Pediatric Posterior Fossa Tumors

Qualitative radiologic MR imaging review affords limited differentiation among types of pediatric posterior fossa brain tumors and cannot detect histologic or molecular subtypes, which could help to stratify treatment. This study aimed to improve current posterior fossa discrimination of histologic tumor type by using support vector machine classifiers on quantitative MR imaging features. This retrospective study included preoperative MRI in 40 children with posterior fossa tumors (17 medulloblastomas, 16 pilocytic astrocytomas, and 7 ependymomas). Shape, histogram, and textural features were computed from contrast-enhanced T2WI and T1WI and diffusivity (ADC) maps. Combinations of features were used to train tumor-type-specific classifiers for medulloblastoma, pilocytic astrocytoma, and ependymoma types in separation and as a joint posterior fossa classifier. A tumor-subtype classifier was also produced for classic medulloblastoma. The performance of different classifiers was assessed and compared by using randomly selected subsets of training and test data. ADC histogram features (25th and 75th percentiles and skewness) yielded the best classification of tumor type (on average >95.8% of medulloblastomas, >96.9% of pilocytic astrocytomas, and >94.3% of ependymomas by using 8 training samples). The resulting joint posterior fossa classifier correctly assigned >91.4% of the posterior fossa tumors. For subtype classification, 89.4% of classic medulloblastomas were correctly classified on the basis of ADC texture features extracted from the Gray-Level Co-Occurence Matrix. Support vector machine-based classifiers using ADC histogram features yielded very good discrimination among pediatric posterior fossa tumor types, and ADC textural features show promise for further subtype discrimination. These findings suggest an added diagnostic value of quantitative feature analysis of diffusion MR imaging in pediatric neuro-oncology.

Neuro-Oncology: Past Milestones and the Journey Ahead

Neuro-Oncology will soon reach a new milestone, as Dr. Patrick Wen, Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, assumes the role of editor-in-chief in January 2014. As the journal enters this new era, I find myself reflecting on the milestones it has already reached. The journal has experienced impressive growth and success during its relatively short history, much of which is due to the ambitious vision with which it was founded and the support of numerous individuals and professional societies that are committed to the science and practice of neuro-oncology. In 1996, the newly formed Society for Neuro-Oncology (SNO), headed by its first president, Dr. Victor A. Levin, Director of the Brain Tumor Center at The University of Texas MD Anderson Cancer Center, decided to create a journal dedicated to publishing high-quality, multidisciplinary, international neuro-oncology research. Dr. Darell D. Bigner at Duke University Medical Center graciously agreed to be its first editor-in-chief. Neuro-Oncology was launched, as a quarterly journal, with a 3-year grant of $246,384 from the Pediatric Brain Tumor Foundation in January of 1999. SNO provided a loan of $20,000 a year for 3 years; the two other major international neuro-oncology societies, European Association of Neuro-Oncology (EANO) and Japan Society of Neuro-Oncology (JSNO), also supported the journal. Duke University Publishing was chosen as the journal's publisher. From the beginning, Dr. Bigner placed great value on giving readers access to information as soon as possible and allowing authors to publish as quickly as possible; thus, all articles were published on the Internet. In addition, in further support of the neuro-oncology community, the journal has long published the abstracts of papers presented at major neuro-oncology conferences around the world, including the annual meeting of SNO, the annual meeting of EANO, the International Conference on Brain Tumor Research and Therapy (the Asilomar Conference), and the International Symposium on Pediatric Neuro-Oncology. In 2007, I became the journal's second editor-in-chief. To provide more balanced representation from each of the three major societies, the journal was restructured, with three executive editors: Dr. C. David James (University of California San Francisco), representing SNO; Dr. Michael Weller (University Hospital Zurich), representing EANO; and Dr. Ryo Nishikawa (Saitama Medical University), representing JSNO. The journal was expanded to a bimonthly publication the following year. In 2010, Neuro-Oncology was further expanded to a monthly publication schedule while simultaneously transitioning to a new publisher, Oxford University Press. This history-setting move further broadened its international scope, as Oxford University Press has offices throughout Asia, Africa, Europe, Australia, and North and South America and initiatives that grant developing countries access to publications at a very low cost or for free. In addition, EANO decided to provide the journal electronically to its members as part of their membership, further improving its reach. More importantly, the journal has not grown in volume and reach at the expense of its value and influence. Its impact factor has steadily increased each year, from 2.717 in 2002 (the first year it was calculated) to 5.723 in 2011 and 6.180 in 2012. Neuro-Oncology currently ranks 10th of 192 clinical neurology journals and 24th of 196 oncology journals. Submissions have also increased, almost doubling over the past 4 years to a projected 997 for 2013; we accept approximately 20% of submissions, allowing us to select only the highest quality research for publication. In fact, as described in the October 2013 editorial, the journal's success has inspired the creation of a new clinical practice journal, Neuro-Oncology Practice. I am proud to have served as editor in chief of Neuro-Oncology. It has been a wonderful journey with my executive editors and the distinguished editorial board over the last seven years. I would also like to thank our editorial staff, reviewers, authors, and readers for making this publication such a success. I look forward to seeing the journal excel in the coming years under Dr. Wen's leadership.

Presentation, pathology, and treatment outcome of brain tumors in 172 consecutive children at CURE Children’s Hospital of Uganda. The predominance of the visible diagnosis and the uncertainties of epidemiology in sub-Saharan Africa

This study reviews the first operative series of pediatric brain tumors from Uganda, the largest series from Sub-Saharan Africa, and explores the challenges to progress in pediatric neuro-oncology in the region. This is a retrospective operative series of brain tumors in 172 children at Cure Children's Hospital of Uganda over 10years. Demographics, clinical presentation, lesion location, histopathology, operative management, and outcome were investigated. Survival was assessed using Kaplan-Meier method. Log-rank test and p value with Bonferroni correction were used to determine significance of survival differences. There were 103 males (59.9%) and 69 females (40.1%; mean age at diagnosis 6.5years with 29% < 2years). The most common histologic types were pilocytic astrocytoma (23.2%), ependymoma (16.3%), craniopharyngioma (9.9%), choroid plexus papilloma (9.3%), and medulloblastoma (8.1%). Supratentorial tumors (62.2%) were more common. Symptomatic hydrocephalus predominated at presentation (66.9%). In 71 (41.3%), the presentation was macrocephaly or a visible mass. Estimated 5-year survival was 60%. The majority of pediatric brain tumors in the region likely go unrecognized. Most that do come to attention have a "visible diagnosis." Unlike operative series from developed countries, information about the incidence, prevalence, and overall burden of disease for different tumor types cannot be deduced from the various operative series reported from limited resource countries because of the selection bias that is unique to this context. Delayed presentation and poor access to adjuvant therapies were important contributors to the high mortality. The epidemiology of pediatric brain tumors in sub-Saharan Africa is obscure.

Stroke in patients with active and non-active malignancy

Stroke in patients with active and non-active malignancy

Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells

The stem cell-associated transcription co-factor ZNF521 has been implicated in the control of hematopoietic, osteo-adipogenic and neural progenitor cells. ZNF521 is highly expressed in cerebellum and in particular in the neonatal external granule layer that contains candidate medulloblastoma cells-of-origin, and in the majority of human medulloblastomas. Here we have explored its involvement in the control of human and murine medulloblastoma cells. The effect of ZNF521 on growth and tumorigenic potential of human medulloblastoma cell lines as well as primary Ptc1-/+ mouse medulloblastoma cells was investigated in a variety of in vitro and in vivo assays, by modulating its expression using lentiviral vectors carrying the ZNF521 cDNA, or shRNAs that silence its expression. Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and ability to generate clones in single-cell cultures and semisolid media, and enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells displayed a greatly enhanced tumorigenic potential in nude mice. All these activities required the ZNF521 N-terminal motif that recruits the nucleosome remodeling and histone deacetylase complex, which might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in human UW228 medulloblastoma cells that display high baseline expression decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, Zfp521 silencing in mouse Ptc1-/+ medulloblastoma cells drastically reduced their growth and tumorigenic potential. Our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of medulloblastoma cells.

Myeloablative chemotherapy and autologous stem cell transplantation in patients with relapsed or progressed central nervous system germ cell tumors: results of Korean Society of Pediatric Neuro-Oncology (KSPNO) S-053 study

The present study evaluated the feasibility and effectiveness of myeloablative high-dose chemotherapy and autologous stem cell transplantation in patients with relapsed or progressed central nervous system germ cell tumors (CNS-GCTs). Eleven patients with non-germinomatous germ cell tumors and nine patients with germinomas were enrolled. Patients received between two and eight cycles of conventional chemotherapy prior to HDCT/autoSCT with or without radiotherapy. Overall, 16 patients proceeded to the first HDCT/autoSCT, and nine proceeded to the second HDCT/autoSCT. CTE (carboplatin-thiotepa-etoposide) and cyclophosphamide-melphalan (CM) regimens were used for the first and second HDCT, respectively. Toxicities during HDCT/autoSCT were acceptable, and there were no treatment-related deaths. Twelve patients experienced relapse or progression; however, four patients with germinomas remain alive after subsequent RT. Therefore, a total of 12 patients (four NGGCTs and eight germinomas) remain alive with a median follow-up of 47 months (range 22-90) after relapse or progression. The probability of 3-year overall survival was 59.1 ± 11.2 % (36.4 ± 14.5 % for NGGCTs vs. 88.9 ± 10.5 % for germinomas, P = 0.028). RT, particularly craniospinal RT, was associated with a better tumor response prior to HDCT/autoSCT and a better final outcome. In conclusion, HDCT/autoSCT was feasible, and survival rates were encouraging. Further study with a larger cohort of patients is needed to elucidate the role of HDCT/autoSCT in the treatment of relapsed or progressed CNS-GCTs.

Acute paediatric paraplegia: A case series review

Paediatric paraplegia resulting from spinal cord pathology of any cause is rare; hence prognostic information for children less than 16 years is limited. This case series review aims to ascertain all cases of paediatric paraplegia from 1997 to 2012 in the former Northern Region of England. MethodsChildren presenting with sudden paraplegia before the age of 16 years were multiply ascertained from databases in the regional paediatric neurology, neuroradiology, neuro-oncology and adult spinal injuries units. Data were obtained from retrospective case note review. ResultsA total of 44 cases (24 female) were identified. The incidence is estimated at 0.49 per 100,000 children under 16/year (95% confidence interval 0.41–0.57). Mean age of onset was 8.8 years and the most common aetiology was inflammatory. Twelve months post presentation, mortality was zero and a good outcome (defined as Gross Motor Function Classification System grades I or II) was seen in 66.6%. Motor outcome at 12 months was associated with the presence of bladder/bowel signs at presentation, previous viral illness and initial severity of paraplegia. Bladder signs at presentation were the strongest predictor of prognosis (OR for poor motor outcome 10.3). We were unable to demonstrate a relationship between aetiology and late outcome. ConclusionPaediatric paraplegia is rare. Mortality rates are low and 66.6% have a good outcome with fully or nearly independent walking. Bladder signs are the strongest predictor of prognosis.

Challenges with defining response to antitumor agents in pediatric neuro-oncology: A report from the response assessment in pediatric neuro-oncology (RAPNO) working group

Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations.

Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study

Identification of robust biomarkers of malignancy and methods to establish disease progression is a major goal in paediatric neuro-oncology. We investigated whether methylation of the TERT promoter can be a biomarker for malignancy and patient outcome in paediatric brain tumours. For the discovery cohort, we used samples obtained from patients with paediatric brain tumours and individuals with normal brain tissues stored at the German Cancer Research Center (Heidelberg, Germany). We used methylation arrays for genome-wide assessment of DNA. For the validation cohort, we used samples obtained from several tissues for which full clinical and follow-up data were available from two hospitals in Toronto (ON, Canada). We did methylation analysis using quantitative Sequenom and pyrosequencing of an identified region of the TERT promoter. We assessed TERT expression by real-time PCR. To establish whether the biomarker could be used to assess and predict progression, we analysed methylation in paired samples of tumours that transformed from low to high grade and from localised to metastatic, and in choroid plexus tumours of different grades. Finally, we investigated overall survival in patients with posterior fossa ependymomas in which the identified region was hypermethylated or not. All individuals responsible for assays were masked to the outcome of the patients. Analysis of 280 samples in the discovery cohort identified one CpG site (cg11625005) in which 78 (99%) of 79 samples from normal brain tissues and low-grade tumours were not hypermethylated, but 145 (72%) of 201 samples from malignant tumours were hypermethylated (>15% methylated; p<0.0001). Analysis of 68 samples in the validation cohort identified a subset of five CpG sites (henceforth, upstream of the transcription start site [UTSS]) that was hypermethylated in all malignant paediatric brain tumours that expressed TERT but not in normal tissues that did not express TERT (p<0.0001). UTSS had a positive predictive value of 1.00 (95% CI 0.95-1.00) and a negative predictive value of 0.95 (0.87-0.99). In two paired samples of paediatric gliomas, UTSS methylation increased during transformation from low to high grade; it also increased in two paired samples that progressed from localised to metastatic disease. Two of eight atypical papillomas that had high UTSS methylation progressed to carcinomas, while the other six assessed did not progress or require additional treatment. 5-year overall survival was 51% (95% CI 31-71) for 25 patients with hypermethylated UTSS posterior fossa ependymomas and 95% (86-100) for 20 with non-hypermethylated tumours (p=0.0008). 5-year progression-free survival was 86% (68-100) for the 25 patients with non-hypermethylated UTSS tumours and 30% (10-50) for those with hypermethylated tumours (p=0.0008). Hypermethylation of the UTSS region in the TERT promoter is associated with TERT expression in cancers. In paediatric brain tumours, UTSS hypermethylation is associated with tumour progression and poor prognosis. This region is easy to amplify, and the assay to establish hypermethylation can be done on most tissues in most clinical laboratories. Therefore the UTSS region is a potentially accessible biomarker for various cancers. The Canadian Institute of Health Research and the Terry Fox Foundation.

Molecular markers in pediatric neuro-oncology.

Pediatric molecular neuro-oncology is a fast developing field. A multitude of molecular profiling studies in recent years has unveiled a number of genetic abnormalities unique to pediatric brain tumors. It has now become clear that brain tumors that arise in children have distinct pathogenesis and biology, compared with their adult counterparts, even for those with indistinguishable histopathology. Some of the molecular features are so specific to a particular type of tumors, such as the presence of the KIAA1549-BRAF fusion gene for pilocytic astrocytomas or SMARCB1 mutations for atypical teratoid/rhabdoid tumors, that they could practically serve as a diagnostic marker on their own. Expression profiling has resolved the existence of 4 molecular subgroups in medulloblastomas, which positively translated into improved prognostication for the patients. The currently available molecular markers, however, do not cover all tumors even within a single tumor entity. The molecular pathogenesis of a large number of pediatric brain tumors is still unaccounted for, and the hierarchy of tumors is likely to be more complex and intricate than currently acknowledged. One of the main tasks of future molecular analyses in pediatric neuro-oncology, including the ongoing genome sequencing efforts, is to elucidate the biological basis of those orphan tumors. The ultimate goal of molecular diagnostics is to accurately predict the clinical and biological behavior of any tumor by means of their molecular characteristics, which is hoped to eventually pave the way for individualized treatment.

Visual acuity in children with low grade gliomas of the visual pathway: implications for patient care and clinical research

Low grade gliomas affecting the visual pathway, commonly referred to as optic pathway gliomas (OPGs), have a relatively high survival rate but can cause significant vision loss. While previous treatment outcomes for tumors of the central nervous system have focused primarily on changes in tumor size or patient survival, more recently preservation of vision has also become a primary objective when treating these tumors. Visual acuity (VA) is the most testable and reliable visual parameter in young children with OPGs. Unfortunately, standardized VA assessments have neither been employed to make treatment decisions nor used as primary outcomes in clinical trials. The lack of a standardized VA assessment has also hindered the ability to interpret and compare results between studies. It is essential that all members of the multidisciplinary care team (i.e., pediatric neuro-oncologist, neurologist, neurosurgeon, and ophthalmologist) can accurately interpret VA results and properly use them to guide management decisions. Specifically, determining what constitutes a significant change in VA and the factors that may influence these results should be incorporated into collective team recommendations. This review describes the VA assessment in children with OPGs and proposes a standardized VA testing protocol for future pediatric OPG clinical treatment trials.

Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?

Diffuse intrinsic pontine gliomas (DIPGs), with a median survival of 9 months, represent the biggest therapeutic challenge in pediatric neuro-oncology. Despite many clinical trials, no major improvements in treatment have been made over the past 30 years. In most cases, biopsy is not needed for diagnosis because DIPG diagnosis is based on a typical clinical picture with radiologic evidence on magnetic resonance imaging. Therefore, little data on newly diagnosed DIPG have been published and are confounded by including autopsy (i.e., postradiation therapy) cases. In most cancers, advancing to cure has been linked to the discovery of relevant biomarkers, only found by access to tissue. Therefore, to further understand the biology of DIPG, fresh tissue samples must be obtained at diagnosis. However, most neurosurgical teams are reluctant to perform biopsy in pediatric patients, citing potential risks and lack of direct benefit. Yet, in reviewing 90 patients with and the published data on brainstem biopsy, these procedures have a diagnostic yield and morbidity and mortality rates similar to those reported for other brain locations. In addition, the quality and quantity of the material obtained confirm the diagnosis and inform an extended molecular screen, including biomarker study-information important to designing next-generation trials with targeted agents. Stereotactic biopsies can be considered a safe procedure in well-trained neurosurgical teams and could be incorporated in well-defined protocols for patients with DIPG.

Diffuse intrinsic pontine glioma (DIPG): Time to biopsy again?

Pediatric Blood & CancerVolume 58, Issue 4 p. 487-488 Highlight Diffuse intrinsic pontine glioma (DIPG): Time to biopsy again? Tobey J. MacDonald MD, Corresponding Author Tobey J. MacDonald MD tobey.macdonald@emory.edu Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Atlanta, Georgia Emory Children's Center, Emory University School of Medicine, Atlanta, Georgia Director, Pediatric Neuro-Oncology Program, Aflac Cancer Center and Blood Disorders Service; Associate Professor of Pediatrics, Emory University School of Medicine.Associate Professor of Pediatrics, Emory Children's Center, Emory University School of Medicine, 2015 Uppergate Drive NE, Suite 442, Atlanta, GA 30322.===Search for more papers by this author Tobey J. MacDonald MD, Corresponding Author Tobey J. MacDonald MD tobey.macdonald@emory.edu Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Atlanta, Georgia Emory Children's Center, Emory University School of Medicine, Atlanta, Georgia Director, Pediatric Neuro-Oncology Program, Aflac Cancer Center and Blood Disorders Service; Associate Professor of Pediatrics, Emory University School of Medicine.Associate Professor of Pediatrics, Emory Children's Center, Emory University School of Medicine, 2015 Uppergate Drive NE, Suite 442, Atlanta, GA 30322.===Search for more papers by this author First published: 13 February 2012 https://doi.org/10.1002/pbc.24090Citations: 21 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume58, Issue4April 2012Pages 487-488 RelatedInformation

Promises and challenges of exhausting pediatric neural cancer stem cells

Cancer relapse is one of the major setbacks in pediatric oncology. Cancer stem cells (CSCs) have emerged as a major driving force governing tumor recurrence. CSCs are a small subpopulation of cells capable of regenerating a tumor and are resistant to conventional anticancer therapies. No CSC therapy has been approved by the US Food and Drug Administration. Because CSCs and normal stem cells share many characteristics, CSC-directed therapies have potential detrimental effects on normal stem cells, tissue maintenance, and development. Designing treatments that specifically target neural CSCs while allowing neural tissue stem cells to normally develop the brain is a major challenge in pediatric neuro-oncology. In recent years, better identification and characterization of neural CSCs, together with identifying differences between CSCs and normal neural stem cells, have been key factors in developing tailored therapeutics for these devastating diseases. This review focuses on the promises and challenges of pediatric neural CSC-directed therapies. We delineate the options currently in use to exhaust the ability of neural CSCs to self-renew. Finally, we suggest a comprehensive approach to combine anti-CSC therapies with other therapeutic approaches to prevent tumor recurrence.

Personalized cancer care: Opportunities and challenges in pediatric neuro‐oncology

Personalized cancer care: Opportunities and challenges in pediatric neuro‐oncology

Neuropsychological assessment and intervention in pediatric neuro-oncology

Learning abilities and memory or attentional skills are still underestimated as treatment sequel in case for children and adolescents with brain tumours. As survival rates in pediatric neuro-oncology have risen over the past decades, tumour- and treatment related neurocognitive late effects remain problematic for survivors of pediatric brain tumours. Estimates of neurocognitive late effects range widely, as rates have been documented in 40 to 100% of survivors. Based on clinical experience and observations, (ethical) guiding principles concerning the way neuropsychological assessment is carried out were developed.

Pediatric ependymomas

Ependymomas remain a therapeutic challenge in pediatric neuro-oncology. These tumors are chemoresistant and rather radioresistant and until recently little was known about their biology. Histopathological grading of ependymomas according to the WHO classification is neither reproducible, nor correlated with outcome, especially in young children. Characterization of molecular abnormalities in ependymomas offers now a better understanding of their initiation and progression; different biological subtypes of tumors have been described and would need further validation. The identification of new prognostic biomarkers, such as tenascin-C overexpression or chromosome 1q gain, will considerably help patient stratification in future trials. Finally, the recent discovery of specific pathways involved in ependymomas oncogenesis, such as Notch-1or EPHB2 offers new perspectives for the development of targeted therapies. A comprehensive biological work-out including CGHarray and immunohistochemistry for specific biomarkers should now be recommended for the current management of pediatric ependymoma, especially in young children if radiotherapy has to be omitted in the first line of treatment.

Editorial: Brain tumors

For over a century physicians have tried to use what they see under the microscope to predict the behavior of brain tumors and to determine which treatment strategies would best benefit their patients. This approach has been particularly frustrating in pediatric neurooncology. What appears to be the same tumor in an infant may behave quite differently in an older child. That “same tumor” may have a very different prognosis in one anatomical location compared to another. A commonality in most pediatric brain tumor patients remains that what we accomplish as neurosurgeons in our attempts to remove a child’s tumor is presently the most important factor in that child’s prognosis. For most pediatric brain tumors, the difference between a grosstotal resection and a subtotal resection doubles the child’s chances of survival. As such, advances in neuroimaging and image-guided surgery are among the greatest adjuncts to surgery. The application of frameless stereotactic image guidance, functional neuroimaging, intraoperative MR imaging, early postoperative MR imaging, and second-look surgery has allowed the neurosurgeon to be more aggressive. This is evidenced by the fact that the number of children enrolled in national clinical trials with no or minimal residual tumor on their MR imaging has nearly doubled over the last 2 decades. Another major advance has been the routine banking of tumor tissue. This resource, coupled with more readily available molecular profiling techniques, has allowed us to understand that two ependymomas that look the same histologically are not the same tumor in the spinal cord as in the posterior fossa or the supratentorial space.8 The understanding of the molecular events giving rise to these tumors has allowed us to develop animal and in vitro models that are both histologically and molecularly the same as those in the human condition.4 The same holds true for small round blue-cell tumors. The recognition that molecular alterations in the INI-1 gene are associated with atypical teratoid rhabdoid tumors was a seminal occurrence.7 We now recognize that what we once called a medulloblastoma is one of several tumor subtypes.1 The Wnt-positive tumors, recognized by nuclear staining for b-catenin, are more likely to arise in younger children, are more likely to be located within the fourth ventricle, and in our last treatment trial were associated with 100% progression-free survival.2 Efforts are now underway to reduce the toxic side effects of treatment in this subgroup of children. Medulloblastomas associated with Sonic hedgehog (Shh) signaling abnormalities arise from a different cancer stem cell, are more likely to be located in the cerebellar hemisphere, and are more likely to be noted in infants and older children.3 With the development of GDC-0449, a specific Shh inhibitor, we now have targeted therapy for children with those medulloblastoma subtypes. For children with c-myc amplification or with large-cell anaplastic medulloblastomas, the prognosis remains dismal and we must develop novel targeted therapies for those children.5 In low-grade astrocytomas, similar progress has been made. The identification of BRAF abnormalities in pilocytic astrocytomas, the recognition that subependymal giant cell tumors respond quite nicely to mTOR inhibitors, and that antiangiogenesis agents such as bevacizumab offer specific molecular targets for treatment in these tumors, is further evidence that the understanding of the molecular pathways involved in tumor formation is our future. In this paper6 by Dr. Pollack, a pediatric neurosurgeon who has dedicated his life to better understanding childhood brain tumors, a very clear and readable overview of the progress made in the management of a variety of childhood brain tumors has been provided. A number of truths can be gleaned from the article. First, given the molecular studies that are available for these tumors, it behooves us at surgery not only to provide tissue for histology but also to bank fresh tumor tissue for future reference in each case. Second, children and their families should be offered enrollment in prospective clinical 133 134

Mouse models of medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumor. Despite its prevalence and importance in pediatric neuro-oncology, the genes and pathways responsible for its initiation, maintenance, and progression remain poorly understood. Genetically engineered mouse models are an essential tool for uncovering the molecular and cellular basis of human diseases, including cancer, and serve a valuable role as preclinical models for testing targeted therapies. In this review, we summarize how such models have been successfully applied to the study of medulloblastoma over the past decade and what we might expect in the coming years.