Brain Tumor Research Research Articles

Making the Case for Pediatric Metastatic and Non-Malignant Brain Tumor Surveillance and Research

To identify pediatric primary and metastatic brain tumors in Ontario, Canada.

Canine brain tumours: a model for the human disease?

Canine brain tumours are becoming established as naturally occurring models of disease to advance diagnostic and therapeutic understanding successfully. The size and structure of the dog's brain, histopathology and molecular characteristics of canine brain tumours, as well as the presence of an intact immune system, all support the potential success of this model. The limited success of current therapeutic regimens such as surgery and radiation for dogs with intracranial tumours means that there can be tremendous mutual benefit from collaboration with our human counterparts resulting in the development of new treatments. The similarities and differences between the canine and human diseases are described in this article, emphasizing both the importance and limitations of canines in brain tumour research. Recent clinical veterinary therapeutic trials are also described to demonstrate the areas of research in which canines have already been utilized and to highlight the important potential benefits of translational research to companion dogs.

GE-11 * THE FLORIDA CENTER FOR BRAIN TUMOR RESEARCH (FCBTR): BUILDING INFRASTRUCTURE TO FIND A CURE

INTRODUCTION: High quality tumor samples and DNA, coupled with annotated clinical data are the building blocks of basic, translational, and clinical research but are often difficult to obtain in a high-quality and standardized format and are expensive to maintain. In 2006, the legislature of the State of Florida appropriated funding for the Florida Center for Brain Tumor Research (FCBTR) to establish a coordinated biorepository and annotated clinical database among the state's public and private universities, hospitals, and biomedical industries. METHODS: Infrastructure for the collection, storage, and distribution of tumor and normal tissues and DNA is maintained by the FCBTR. Central coordination and annotated clinical database management is facilitated at the University of Florida. Samples are collected and distributed under institutional IRB approval. Participating member institutions (n = 8) are represented on the FCBTR Scientific Advisory Council through gubernatorial or state legislature appointed representatives that provide governing oversight of FCBTR operations. In collaboration with ABC2, peer-reviewed FCBTR pilot grants have been awarded to investigators throughout the state of Florida to support brain tumor research initiatives. RESULTS: To date, 8506 samples from 1100 patients have been collected under IRB approval by the FCBTR. Eight research awards to neuro-oncology investigators have been funded through the pilot award program. Distribution of FCBTR-maintained tissues has supported over thirty publications, submissions to The Cancer Genome Atlas, and several awarded and pending NIH grants. A NIH R24 (Resource-Related Research Project) grant to establish, characterize, and distribute primary glioma stem cell-like lines (GSCs) has been awarded to UF, with the FCBTR functioning as the coordinating center for deposition and distribution of GSC resources. CONCLUSIONS: State support for multi-institutional biorepositories is a model that should be considered by state legislatures for advancement of brain tumor research and other disease-related research initiatives.

AI-15 * EPIDERMAL GROWTH FACTOR-LIKE MODULE CONTAINING MUCIN-LIKE HORMONE RECEPTOR 2 ROLE IN PREDICTING SURVIVAL IN INVASIVE GLIOMAS

Epidermal growth factor (EGF) module-containing mucin-like receptor 2 (EMR2) is a member of the seven span transmembrane adhesion G-protein coupled receptor subclass. This protein is expressed in a subset of glioblastoma (GBM) cells and associated with an invasive phenotype. The expression pattern and functional significance of EMR2 in low grade or anaplastic astrocytomas is unknown and our goal was to expand and further define EMR2's role in gliomas with an aggressive invasive phenotype. Using the TCGA survival data we describe EMR2 expression patterns across histologic grades of gliomas and demonstrate an association between increased EMR2 expression and poor survival (p < 0.05). We support this data with qPCR of EMR2 expression in 3 separate tumor grades from our own brain tumor research center showing increase in EMR2 expression correlates with tumor grade (p < 0.05). This data supports our prior functional data depicting that EMR2-positive neoplasms possess a greater capacity for infiltrative and metastatic spread. Genomic analysis suggests that EMR2 overexpression is associated with the mesenchy mal GBM subtype(p < 0.0001). We also demonstrate that immunohistorchemistry (IHC) is a feasible method for screening GBM patients for EMR2 expression. Protein and mRNA analysis demonstrated variable expression of all isoforms of EMR2 in all glioma grades, however GBM displayed the most diverse isoforms expression pattern as well as the highest expression of the EGF1-5 isoform of EMR2. Finally, a correlation of an increase in EMR2 expression after bevacizumab treatment in glioma cells lines as well as in an animal model is identified (P < 0.05). This observation should serve as the impetus for future studies to determine if this up-regulation of EMR2 plays a role in the observation of the diffuse and increasingly invasive recurrence patterns witnessed in a subset of GBM patients after bevacizumab treatment.

Health-Related Quality of Life or Quantity of Life: A Difficult Trade-Off in Primary Brain Tumors?

Health-related quality of life (HRQoL) measurements have become increasingly important in brain tumor research, next to traditional outcome measures such as overall and progression-free survival. Several validated questionnaires have been developed to measure HRQoL in clinical trials, as well as in clinical practice. In brain tumor patients, both the tumor and treatment may have an impact on HRQoL, which can be positive and negative. When determining the net clinical benefit of a new treatment strategy, both the quantity and quality of life (QOL) should be considered. Because treatment may benefit or harm both quantity and QOL, a trade-off discussion may arise when these two outcomes are conflicting.

A fast and simple differentiation protocol to study the pro-neurogenic activity of soluble factors in neurospheres

Sphere-forming assays are widely used for the propagation, characterization and manipulation of adult brain-derived stem- and progenitor cells. However despite the broad application of this cell culture system in neural stem cell- and brain tumor research, no standardized protocols exist. Variations in experimental procedures not only concern the use of media components but also cell density, the number of passages the cells are propagated before analysis and, in cases where the neurogenic or gliogenic potential of the cells is investigated, the duration that the cells are allowed to differentiate. The latter deserves consideration because the proportion of differentiated cells obtained at the endpoint of the experiment depends not only on the absolute number of cells that differentiate at a given time, but also on the number of cell divisions prior to differentiation and the rate of cell death in the cultures. In the present study we describe a fast and simple differentiation protocol to investigate the pro-neurogenic potential of soluble factors added to subventricular zone (SVZ)-derived neurospheres. The assay relies on the use of primary neurospheres and very short differentiation times, thereby largely excluding the contribution of cell proliferation and cell death to the results. We use this modified assay to test the consequence of pharmacological inhibition of the EGF receptor-, Erk1/2-, Protein Kinase B/AKT-, and Sonic Hedgehog-pathways on neuronal differentiation of SVZ-neurosphere cultures.

Chemotherapy in Childhood Brain Tumors

Over time, the systematic evaluation of conventional chemotherapy for the treatment of childhood malignant brain tumors has revealed subtype-specific effectiveness. While having a pivotal role in improving survival for medulloblastoma patients, its activity against other tumors, such as pediatric high-grade glioma, remains disappointing. Today’s clinician faces a dilemma when trying to improve patient outcomes further; escalating traditional treatment is likely to produce only additional morbidity without improving cure, particularly for the very young. The current evolution of genetic and molecular brain tumor research brings with it the hope of establishing novel targeted agents that can either supplement or replace standard chemotherapy to improve patient outcome and minimize toxicity. This article reviews literature from the past year evaluating both conventional chemotherapy and molecular agents for the three most common tumor subgroups; medulloblastoma, glioma (low/high-grade) and ependymoma. Future treatment strategies across North America and Europe are also highlighted.

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.

Industry progress report on neuro-oncology: Biotech update 2013

For the second time, The Brain Tumor Center of the Weill Cornell Brain and Spine Center, in collaboration with Voices Against Brain Cancer, hosted The Brain Tumor Biotech Summit in New York City in June 2013. After a very successful first summit in 2012, this innovative event has established a platform for intensive networking between neuro-oncologists, neurosurgeons, neuroscientists, members of the biotechnology and pharmaceutical communities, members of the financial community and leaders of non-profit organizations. This year's summit highlighted dendritic cell vaccines, novel antibody, heat shock protein and targeted therapies as well as exosome technologies, MRI-guided therapies and other novel drug delivery tools. This report presents a short overview of the current progress in brain tumor research and therapy as presented at the 2013 Brain Tumor Biotech Summit.

Abstract 2649: Human adipose tissue-derived mesenchymal stem cells can target brain tumor initiating cells.

Abstract Abstract The discovery of neural stem cells offers paradigm shift in brain tumor research. In neuro-oncology, the biology of neural stem cells has been pursued in two ways: as cancer stem cells to understand the origin and maintenance of brain tumors and as a potential cell-based vehicle for gene therapy. In addition to neural stem cells, mesenchymal stem cells (MSCs) have been reported to possess tumor-tropic migratory capacities. However, there is scanty data on migratory capacity of MSC toward brain tumor initiating cells (BTICs). This study focuses on investigating the ability of human adipose tissue derived MSCs (hAT-MSCs) to target BTICs and their cross-talk in the microenvironment. BTICs were isolated from three different kinds of brain tumors (medulloblastoma, atypical teratoid/rhabdoid tumor (ATRT), glioblastoma). The migration capacities of hAT-MSCs toward BTICs were examined both in vitro transwell assay and in vivo bioluminescence imaging analysis. To investigate the crosstalk between hAT-MSCs and BTICs, various cytokines were analyzed. Using co-culture system of hAT-MSCs and BTICs, we analyzed the mRNA expression patterns of cytokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, XCR1, CXCR1, IL-8R, CXCR4, CX3CR1, IL1R1, IL6R, MET, PDGFRB, KDR, CD44, IFNAR1 and TEK) by qRT-PCR and protein level of their ligand in co-cultured media by Bio-Plex human cytokine ELISA. We confirmed the migratory capacity of t hAT-MSCs toward BTICs in vitro and BTICs-derived xenograft brain tumors in vivo live imaging. mRNA expression of receptors (CCR4, CCR5, CCR10, XCR1, CXCR1, IL-8R, CXCR4, PDGFRB, KDR, CD44, IFNAR1 and TEK) increased two- to eighteen-fold higher levels. The cytokine analysis revealed that the ligand levels of hAT-MSCs (medulloblastoma: VEGF, IL6, IL8, CCL3, CCL2 and TEK; ATRT: VEGF, CCL3 and TEK; glioblastoma: CCL2, PDGF, TEK and IGF1) and the ligand levels BTICs (medulloblastoma: CCL5 and CXCL4; ATRT: IL-8 and CXCL4; glioblastoma: CXCL4 and IGF1) were elevated in the co-cultured media. Our findings demonstrated that hAT-MSCs can target BTICs. Cross-talk between hAT-MSCs cytokine receptor and BTICs ligand (medulloblastoma: CCR5/CCL5 and CXCR4/CXCL4; ATRT: IL-8R/IL-8 and CXCR4/CXCL4; glioblastoma: CXCR4/CXCL4 and IGF1R/IGF1) play cardinal role in this process. Citation Format: Seung Ah Choi, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Jung Won Choi, Hyung Ah Kim, Se Hee Kim, Yong Hwy Kim, Sung Eun Kwon, Young-Hoon Kim, Seung-Ki Kim. Human adipose tissue-derived mesenchymal stem cells can target brain tumor initiating cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2649. doi:10.1158/1538-7445.AM2013-2649

Surgical outcomes in choroid plexus papillomas: an institutional experience

Choroid plexus papillomas (CPPs) are rare, indolent lesions that comprise less than 0.5 % of intracranial tumors. We sought to assess the long-term outcomes and associated surgical complications at our institution. A review of the University of California, San Francisco (UCSF) Brain Tumor Research Center (BTRC) database was performed to identify a cohort of patients treated for CPP from 1997 to 2011. Patients were grouped based on tumor location and extent of resection. Outcomes including progression-free survival and surgical complications were assessed. We identified 24 patients (16 female, 8 male) ranging in age from 6 months to 55 years (median 29 years) treated at our institution. Tumors were found in the following locations: 16 (67 %) fourth ventricle/cerebellopontine angle; 7 (29 %) lateral ventricle; 1 (4 %) third ventricle. Gross total resection (GTR) was achieved in 20 patients (83 %) with subtotal resection (STR) in 4 (17 %). Median follow-up time was 2.8 years with 3 recurrences identified at 1.6, 3.3, and 8.5 years. Extent of resection and tumor location were not associated with recurrence. There was one new permanent neurologic deficit detected after surgery. All patients were alive at most recent follow-up. Attempted gross total resection is the standard treatment for CPPs and generally associated with excellent outcomes. Since recurrences are rare, even among patients who undergo STR, radiation may be reserved for cases of tumor progression. This modern experience at a tertiary care center performed exclusively during the MRI-era demonstrates that CPPs can be safely removed with minimal morbidity and good tumor control.

New take-off to an international journal.

The Journal of Korean Brain Tumor Society was first published on March 30, 2002, and 22 issues have been published until 2012 without delay or interruption. The journal was published twice a year and was a mix of Korean and English languages. When we consider the reality in the field of brain tumor research, it was possible because of a lot of effort and sacrifice of many members of the previous editor-in chiefs. I would like to express our deepest gratitude to the members of the former editor-in chiefs. Through these efforts of the past 10 years, the Journal of Korean Brain Tumor Society was approved as a regular member by Korean Association of Medical Journal Editors (KAMJE) in 2013, and was able to establish a foundation to develop into an international journal in the future. The Korean Society for Neuro-Oncology which was founded in 2011 decided to publish a journal in collaboration with The Korean Brain Tumor Society. Through many discussions, the Journal of Korean Brain Tumor Society was re-launched as an English journal with a new name Brain Tumor Research and Treatment (BTRT). BTRT is the official journal of The Korean Brain Tumor Society and The Korean Society for Neuro-Oncology. BTRT aims to enter the SCI (E) class within five years. To develop into an international journal, we appointed international editors who are very famous in the field of brain tumor research, such as Susan M. Chang (UCSF), Frederick F. Lang (MDACC), Hideyuki Saya (Keio University), Koichi Ichimura (National Cancer Center Japan), Patrick Y. Wen (Harvard Medical School), Michael Lim (Johns Hopkins Hospital), and Isaac Yang (UCLA). We reinforced the review committee as a comprehensive multi-disciplinary team consisting of prestige experts of neurosurgery, radiation oncology, hemato-oncology, pediatric hemato-oncology, radiology, pathology, and basic scientists. The journal homepage and on-line submission system will be completed in the near future with wholehearted help from The Korean Brain Tumor Society and The Korean Society for Neuro-Oncology. The BTRT covers all basic and clinical researches related to brain and spinal cord tumors, and papers from all over the world are welcome. Currently, the representative journals in the field of Neuro-oncology are Neuro-Oncology and the Journal of Neuro-Oncology, which are very high quality journals and which are hard to be accepted for publication. Therefore, BTRT welcomes submissions especially from Asian countries. We hope that BTRT serves as a venue of the academic communication and sharing of information among brain tumor researchers from around the world, as well as from Asia. We had planned to publish twice a year, but within a short period, we aim to publish 4 times a year. So, submissions from many researchers are needed. BTRT just began to prepare to be listed as SCI (E) class. Therefore, all papers that are submitted should comply with all the international research ethics regulations, and peer review will be more stringent than before. We will switch to open access and will try to be listed in KoreaMed, Synapse, Pubmed Central, SCOPUS, etc to be able to be read by many readers from all over the world. Lastly, I want to express my sincere gratitude to Professor Oh-Ryong Kim, the president of Korean Brain Tumor Society, and Doctor Seung-Hoon Lee, the president of Korean Society for Neuro-Oncology for the wholehearted help. And I want to offer words of thanks to the members of editorial board, reviewers that have been participated enthusiastically.

What underlies the diversity of brain tumors?

Glioma and medulloblastoma represent the most commonly occurring malignant brain tumors in adults and in children, respectively. Recent genomic and transcriptional approaches present a complex group of diseases and delineate a number of molecular subgroups within tumors that share a common histopathology. Differences in cells of origin, regional niches, developmental timing, and genetic events all contribute to this heterogeneity. In an attempt to recapitulate the diversity of brain tumors, an increasing array of genetically engineered mouse models (GEMMs) has been developed. These models often utilize promoters and genetic drivers from normal brain development and can provide insight into specific cells from which these tumors originate. GEMMs show promise in both developmental biology and developmental therapeutics. This review describes numerous murine brain tumor models in the context of normal brain development and the potential for these animals to impact brain tumor research.

An Integrated Method for Reproducible and Accurate Image-Guided Stereotactic Cranial Irradiation of Brain Tumors Using the Small Animal Radiation Research Platform

Preclinical studies of cranial radiation therapy (RT) using animal brain tumor models have been hampered by technical limitations in the delivery of clinically relevant RT. We established a bioimageable mouse model of glioblastoma multiforme (GBM) and an image-guided radiation delivery system that facilitated precise tumor localization and treatment and which closely resembled clinical RT. Our novel radiation system makes use of magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) to define tumor volumes, computed tomographic (CT) imaging for accurate treatment planning, a novel mouse immobilization system, and precise treatments delivered with the Small Animal Radiation Research Platform. We demonstrated that, in vivo, BLI correlated well with MRI for defining tumor volumes. Our novel restraint system enhanced setup reproducibility and precision, was atraumatic, and minimized artifacts on CT imaging used for treatment planning. We confirmed precise radiation delivery through immunofluorescent analysis of the phosphorylation of histone H2AX in irradiated brains and brain tumors. Assays with an intravenous near-infrared fluorescent probe confirmed that radiation of orthografts increased disruption of the tumor blood-brain barrier (BBB). This integrated model system, which facilitated delivery of precise, reproducible, stereotactic cranial RT in mice and confirmed RT's resultant histologic and BBB changes, may aid future brain tumor research.

Pediatric neurosurgery at the Hospital for Sick Children, The University of Toronto

The neurosurgery service at the Hospital for Sick Children began with the appointment of Dr. William S. Keith (1902–1987) in 1933 [1]. Dr. Keith had trained in Surgery in Toronto, and had received specialty training with Percival Bailey and Paul Bucy in Chicago, and at the National Hospital for Neurological Disorders at Queen’s Square in London, England. He was the sole appointee and neurosurgeon for children with neurosurgical disorders in Toronto, and Ontario for nearly 21 years. Dr. Keith was joined by Dr. E Bruce Hendrick in 1954 after he had obtained subspecialty training in pediatric neurosurgery in Boston under the tutelage of Dr. Franc Ingraham and Dr. Donald Matson. Dr. Hendrick was Neurosurgeon-in-Chief from 1964 until 1986, and was one of the founders of the International Society of Pediatric Neurosurgery (ISPN). He died in 2001 from complications relating to ruptured diverticulitis. In his name and honor, the annual E. Bruce Hendrick Lectureship has been established at Sick Kids. Dr. Harold J. Hoffman was appointed to the neurosurgical Staff at Sick Kids in 1964. He was a prolific author with over 200 peer-reviewed articles, and an authority on tethered cord, craniopharyngioma, epilepsy surgery, and Chiari malformation. Dr. Hoffman marveled at and acquired many new technologies that kept Sick Kids neurosurgery ahead of the curve for complex neurosurgical procedures. He was quick to use neuronavigation, the cavitron and laser. He also designed theHoffman T-tube shunt for lumboperitoneal shunts, and a “unishunt” designedwith his close colleague and friend, Dr. Fred Epstein. During his career, Dr. Hoffman was President of the American Society of Pediatric Neurosurgery (ASPN), President of the ISPN, and President of the Canadian Neurosurgical Society. He was Neurosurgeon-in-Chief at Sick Kids from 1986 to 1996. In his name and honor, upon retirement in 1998, the Harold J Hoffman/Shoppers Drug Mart Chair in Pediatric Neurosurgery was established at Sick Kids. Dr. Hoffman died in 2004 after fighting a dementing illness for several years. Dr. Robin P. Humphreys joined the neurosurgical staff at Sick Kids in 1970. He initiated the Craniofacial Program at Sick Kids with Dr. Ian Munro, and over the years became a world authority on the management of children with spina bifida and vascular malformations. He was President of the ASPN from 1992 to 1993, and of the ISPN from 1993 to 1994. Dr. Humphreys was Neurosurgeon-in-Chief at Sick Kids from 1996 to 2003. In his name, the Robin and Judith Humphreys lectureship at Sick Kids has been established, and is given by the graduating chief fellow annually. It is difficult to describe the magnitude of the numerous contributions made by Drs. Hendrick, Hoffman, and Humphreys, who were collectively referred to as the “3 H’s”worldwide. They were frequently cited on each other’s written works, and together they wrote many of the seminal textbooks and articles which have helped shape the field of pediatric neurosurgery to the present day. The next generation of pediatric neurosurgeons at Sick Kids began in 1988 with the appointment of James Drake, and in 1990 of James Rutka. The “two Jims” brought an element of research to the neurosurgery service as Jim Drake pursued interests in bioengineering, and Jim Rutka established the first brain tumor research laboratory. They were followed in sequence by Peter Dirks in 1998, Abhaya Kulkarni in 2003, and Michael Taylor in 2004. Paediatric Neurosurgery at SickKids Dr. E. Bruce Hendrick

To implement the “Diagnosis of Brain Tumours in Children” guideline and reduce delays in diagnosis in childhood brain tumours

<h3>Introduction</h3> The RCPCH endorsed Brain Pathways Guideline (www.headsmart.org.uk) for selecting patients for scanning with symptoms of brain tumour has been a sustained collaboration between Children9s Brain Tumour Research Centre (CBTRC), Samantha Dickson Brain Tumour Trust (SDBTT), University of Southampton and the RCPCH. The clinical guideline and the HeadSmart Campaign aim to reduce median symptom interval (SI) for UK children to 5 weeks, by enhancing public and professional awareness and offering web-based support for selection of children for scanning, observation or reassurance. The strategy was developed in response to: ▶delays in diagnosis observed by specialists; ▶media reports of delays; ▶questions in the House of Commons; ▶the All Party Parliamentary Group Manifesto (2010), which placed delays in diagnosis as its top action point. <h3>Aims</h3> The HeadSmart campaign aims to reduce SI to a median of 5 weeks, to equal the best reported worldwide. It is supported by a decision support website, a Clinical Champions9 network recording SI for newly diagnosed patients, and an evaluation programme; a Health Economic model is in development. <h3>Methods</h3> CBTRC developed a research strategy, SDBTT identified funding from Community Fund (2002). A literature review, meta-analysis of reported symptom intervals and a Delphi consensus process generated the Clinical Guideline which was endorsed by RCPCH (2005) and supported by other Colleges, accredited by NHS Evidence and is being considered within NICE Cancer Referral Guidance review. The dissemination strategy included: ▶Survey of healthcare professionals9 awareness of childhood brain tumours and the HeadSmart campaign ▶Survey of public awareness of childhood brain tumours and the HeadSmart campaign ▶Development of the HeadSmart website ▶Presentation of guideline material at regional and national professional meetings ▶Recruitment of clinical champions ▶Media campaign – television, radio and facebook Concurrent government reports have prioritised timely diagnosis and access to treatment and justify prioritisation of children within health service developments. <h3>Conclusions</h3> This approach is enhancing awareness of clinical presentations of a rare but important childhood condition in primary and secondary care. Early results (see linked abstracts) show promising reduction in SI, the campaign will run until 2013. This model of prioritising diagnostics in children may be applicable to other childhood conditions.

Malignant Gliomas

Dr. Butowski is Associate Professor, Department of Neurological Surgery, Division of Neuro-Oncology, and Neuro-Oncologist, Brain Tumor Research Center; and Dr. Berger is Kathleen M. Plant Distinguished Professor and Chairman, Department of Neurological Surgery, and Director, Brain Tumor Research Center, University of California, San Francisco, 400 Parnassus Ave, #0372, San Francisco, CA 94143; E-mail: [email protected]. All faculty and staff in a position to control the content of this CME activity and their spouses/life partners, if any, have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Category: Tumor Lippincott Continuing Medical Education Institute, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Lippincott Continuing Medical Education Institute, Inc. designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed form, answering at least 70% of the quiz questions correctly. This activity expires on April 29, 2013.

Stimulating anti-tumor immune response: the problem of regulatory T-cells

Approaches to stimulating an anti-tumor immune response in glioblastoma patients have been a subject of interest in preclinical and clinical brain tumor research for decades. To this end, substantial effort has been directed towards inhibiting regulatory T cells (Tregs), which promote immune tolerance and limit the effectiveness of therapies that depend on evoking an anti-tumor immune response. In the current issue of Neuro-Oncology, Wainwright et al. (1) investigate the origin of glioblastoma-associated Tregs, specifically whether they are thymus derived vs. induced; this knowledge may be critically important to developing effective approaches to limiting Treg anti-tumor immunosuppression. To achieve their objective, the authors used a murine, syngeneic, immunocompetent, orthotopic engraftment model to evaluate the effect of thymectomy on systemically administered anti-Treg CD25 mAb and found that the thymus is necessary for animal subjects to experience a survival benefit from this Treg-depleting treatment. To establish the relevance of the experimental model observations to glioblastoma in patients, a human tumor tissue microarray was examined for expression of the thymus-derived marker Helios in tumor-resident Tregs; the results showed that the majority of tumor-associated T-cells were Helios positive. In total, the results of this elegant study suggest that attempts to suppress Tregs, in association with therapies for evoking patient anti-tumor immune response, need to be targeted to the periphery, where Treg development and expansion predominates. However, since brain tumor patients present with Tregs already infiltrating their malignancy, it may additionally be necessary to target Tregs in the brain. This, in turn, would require the use of Treg-suppressive therapeutics with favorable biodistribution properties. The featured article emphasizes the increasing interest in exploiting patients' immune responses to combat their disease, while informing us of the complexity of cell types and processes involved in the immune response to cancer. How best to manipulate immune function to achieve improved outcomes in brain tumor patients is certain to remain a subject of keen interest, with innovative approaches such as Treg depletion through antibody administration, providing reason for optimism about the eventual benefits of immunotherapy in neuro-oncology practice.

Abstract 878: DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma

Abstract Although much is known about molecular and chromosomal characteristics that distinguish glioma histologic subtypes, DNA methylation patterns of gliomas and their association with mutation of isocitrate dehydrogenase (IDH) genes has only recently begun to be investigated. We measured DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at UCSF, as well as non-tumor brain tissues (n = 7), with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Next, differential DNA methylation between tumor and non-tumor was assessed. RPMM was again used to model methylation data for tumors with IDH mutation data (n = 95). Associations between IDH mutation and survival were also examined. Among all gliomas (n = 131), RPMM resulted in eleven methylation classes, and there was a statistically significant association between methylation class and glioma histologic subtype (P &amp;lt; 2.2 × 10−16). Comparing non-tumor brain tissues to gliomas to investigate differential methylation, glioblastomas showed a low ratio of hyper- to hypomethylated loci (ratio = 1.3) compared with the ratio for astrocytomas, oligoastrocytomas, and oligodendrogliomas (ratios = 3.7, 7.6, and 9.7, respectively). Ependymomas had increased hypomethylation (ratio = 0.3). These ratios were significantly different across glioma subtypes (Permutation P &amp;lt; .0001). Assessing IDH1 and IDH2 mutation (IDH), 59% of gliomas had an IDH mutation. IDH mutation was more common in oligoastrocytomas, oligodendrogliomas, or astrocytomas than in glioblastomas, pilocytic astrocytomas, or ependymomas (P = 6.4 × 10−9); in lower-grade tumors (P = .01); in tumors with TP53 mutation (P = .06); and in younger patients (P = .0009). In addition, patients whose tumors harbored mutant IDH had significantly improved survival (HR = 0.27, 95% CI = 0.10 to 0.72). In tumors with available IDH mutation data, RPMM resulted in nine methylation classes, methylation class was significantly associated with IDH mutation (P = 3.0 × 10−16), and this association remained significant when controlling for patient age and tumor histology (likelihood ratio P &amp;lt; .0001). Only two methylation classes contained tumors with IDH mutation, and they had a homogeneous, hypermethylation-rich character compared to the methylation classes for tumors with wild-type IDH. The homogeneity of methylation classes for gliomas with IDH mutation, despite their histologic diversity, strongly suggests that IDH mutation “drives” the observed hypermethylated phenotype, irrespective of tumor histology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 878. doi:10.1158/1538-7445.AM2011-878

Review of presenting symptoms and time to diagnosis of children with primary brain tumours

AimsTo assess if there was a delay in referral and central nervous system (CNS) imaging in children who have been diagnosed with a primary brain tumour over the last 15...