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10.09.2014 admin
Find a doctor at The Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center or Johns Hopkins Community Physicians.
Types of Brain and Spinal Cord Tumors in ChildrenHow serious a brain or spinal cord tumor is in a child depends on its grade. Glioblastoma multiforme (GBM) is an incurable brain cancer with median survival of just 14 months; it results in more years of life lost, per patient, than any other type of cancer.
Paediatric CNS tumours are challenging to treat; complete surgical resections are limited by the safety of operating within critical brain locations, radiotherapy can significantly damage the fragile developing brain and several tumours respond poorly to current available chemotherapeutics. Until recently, pHGG was considered to be the same disease entity as its adult counterpart. Thus pHGG is clearly distinct from the adult disease and novel therapeutic strategies should be evaluated using paediatric preclinical models where possible, rather than simply extrapolating data from adult based models.
The limbic system responds to olfatory stimulation by initiating responses necessary for survival, such as hunger and thirst. Within the center of the brain lies the thalamus, which is the brain's information relay station.
The olfactory innervation of the limbic system is exceptional in that it represents the only sensory system that directly innervates areas of cortex.
Despite GBM tumours being notoriously heterogeneous, with a wide range of phenotypes, treatment is universal: surgery, radiotherapy and alkylating chemotherapy with temozolomide. Other cancers have benefitted from the elucidation of molecular subtypes, and subsequent development of novel therapeutics to specifically target the genetic defects that distinguish them.


Whereas the majority of tumours result from sporadic mutations, genetic cancer predisposition syndromes account for a small percentage of cases. Over the last decade surgical advancements have helped improve safety and feasibility during resections, radiotherapy has advanced through the use of conformal techniques and proton therapy and chemotherapy protocols and delivery methods have been optimized. The World Health Organization classification system for brain tumours uses a histological grading scale for gliomas which categorizes tumours of grade III (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma) and IV (glioblastoma, gliosarcoma) as high grade, associated with malignant behaviour. However, over the past decade, exome and whole genome sequencing alongside molecular and clinical data gathered from pHGG clinical trials, have confirmed that paediatric and adult HGGs are biologically and clinically distinct.  Adult and paediatric gliomas differ in preferential tumour location and whereas HGGs are the most common brain tumour in adults, low grade gliomas (LGG) are the most common in children. Lesions in the limbic system may result in voracious appetite, increased (often perverse) sexual activity, and docitlity (including loss of normal fear and anger responses). Surrounding the thalamus is a group of structures, the limbic system, which is involved in survival behavior and emotions such as rage and fright. The activation of eating behavior is carried out by a motivational area of the brain called the hypothalamus.
Applying the same approach to GBM resulted in the identification of four potential expression-derived subtypes, though only one displays a significantly different response to treatment compared with the others.
Overall, the 5-year survival for paediatric CNS tumours is around 73%, however this statistic represents an extremely heterogeneous group of tumours (Table 1) with prognosis based on histology, staging, patient age at diagnosis, disease location and specific tumour biology. Improved understanding of tumourigenesis and molecular pathways has led to the development of biologically targeted therapeutics, which are currently being explored in early phase trials. Despite aggressive management consisting of maximal surgical resection, chemotherapy and radiotherapy, pHGGs usually recur and are associated with five-year survival outcomes between 15-35%.


Interestingly, malignant transformation of LGG to HGG in adults is approximately 50%, whereas for pLGG such transformation is rare, with rates around 7%. Closely linked with the limbic system is the hypothalamus, which has overall control of the body's automatic processes. These fibers directly innervate areas of cortex known as the limbic system, and the orbitofrontal cortex indirectly via thalamus.
However, since then more detailed profiling of cancer genomes has highlighted the prevalence of within-tumour heterogeneity, which provides additional barriers and opportunities for understanding cancer and identifying targeted treatments.
However, in spite of this, survival statistics over the past two decades have not significantly improved and there still remains a group of tumours associated with poor prognosis.
Biologically, there are distinct differences in DNA copy number, gene expression profiles and genetic mutations between adult and paediatric HGGs, summarised in Table 2. Novel therapeutic strategies are clearly needed and here at LICAP we are working towards this goal. Two significant key genomic differences appear to define the paediatric disease;  first platelet-derived growth factor receptor alpha (PDGFRA) is a predominant target of focal amplification (in adult HGG, epidermal growth factor receptor (EGFR) is the common target) and second, mutations in histone H3 and ATRX-DAXX genes  are a mark of paediatric versus adult disease.




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