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      Atypical Teratoid Rhabdoid Tumor: Current Therapy and Future Directions


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          Atypical teratoid rhabdoid tumors (ATRTs) are rare central nervous system tumors that comprise approximately 1–2% of all pediatric brain tumors; however, in patients less than 3 years of age this tumor accounts for up to 20% of cases. ATRT is characterized by loss of the long arm of chromosome 22 which results in loss of the hSNF5/INI-1 gene. INI1, a member of the SWI/SNF chromatin remodeling complex, is important in maintenance of the mitotic spindle and cell cycle control. Overall survival in ATRT is poor with median survival around 17 months. Radiation is an effective component of therapy but is avoided in patients younger than 3 years of age due to long term neurocognitive sequelae. Most long term survivors undergo radiation therapy as a part of their upfront or salvage therapy, and there is a suggestion that sequencing the radiation earlier in therapy may improve outcome. There is no standard curative chemotherapeutic regimen, but anecdotal reports advocate the use of intensive therapy with alkylating agents, high-dose methotrexate, or therapy that includes high-dose chemotherapy with stem cell rescue. Due to the rarity of this tumor and the lack of randomized controlled trials it has been challenging to define optimal therapy and advance treatment. Recent laboratory investigations have identified aberrant function and/or regulation of cyclin D1, aurora kinase, and insulin-like growth factor pathways in ATRT. There has been significant interest in identifying and testing therapeutic agents that target these pathways.

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          Most cited references64

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          Histopathology and prognosis of Wilms tumors: results from the First National Wilms' Tumor Study.

          Detailed histological analysis of 427 cases entered on the first National Wilms' Tumor Study revealed that lesions with foci of marked cytological atypism (anaplasia), and those composed predominantly of sarcomatous stroma, were associated with unfavorable outcome. Twenty-five patients had anaplasia, and 24 had sarcomatous lesions of which a total of 28 (57.1%) died of tumor. Three hundred and seventy-eight patients had tumors which showed neither of these features, and only 26 (6.9%) died of tumor. Seven of ten deaths due to tumor in patients diagnosed before two years of age were associated with sarcomatous lesions. Three sarcomatous patterns were recognized, of which one, designated "clear cell" sarcoma, had a predilection for bony metastases. Using criteria defined and illustrated in this paper it is possible to identify in advance those patients likely to do poorly using current therapeutic approaches.
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            Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity.

            Clinical and pathological features of 52 infants and children with atypical teratoid/rhabdoid tumor (ATT/RhT) of the central nervous system are defined. This tumor is typically misdiagnosed as a primitive neuroectodermal tumor (PNET) primarily because 70% of ATT/RhTs contain fields indistinguishable from classic PNETs. Separation of these two tumor types is crucial because the prognosis for ATT/RhT is given even when treatment includes surgery with or without radio and/or chemotherapy. These tumors are most common in infants less than 2 years of age. The cases described in this study arose in intracranially in all but one instance, although one-third had already spread throughout the subarachnoid space at presentation. Clinical signs and symptoms and radiological features do not distinguish ATT/RhTs from PNETs. The tumors are composed entirely (13%) or partly (77%) or rhabdoid cells. Seventy percent contains fields of typical PNET alone or in combinations with mesenchymal and/r epithelial elements. The immunohistochemical profile is unique: epithelial membrane antigen, vimentin, and smooth-muscle actin are positive in the majority of tumors and markers for germ-cell tumors are consistently negative. Abnormalities of chromosome 22 distinguish ATT/RhTs from PNETs, which typically display an i(17q) abnormality.
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              Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF.

              We present evidence that Rb forms a repressor containing histone deacetylase (HDAC) and the hSWI/SNF nucleosome remodeling complex, which inhibits transcription of genes for cyclins E and A and arrests cells in the G1 phase of the cell cycle. Phosphorylation of Rb by cyclin D/cdk4 disrupts association with HDAC, relieving repression of the cyclin E gene and G1 arrest. However, the Rb-hSWI/SNF complex persists and is sufficient to maintain repression of the cyclin A and cdc2 genes, inhibiting exit from S phase. HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF then appear to maintain the order of cyclin E and A expression during the cell cycle, which in turn regulates exit from G1 and from S phase, respectively.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Research Foundation
                12 September 2012
                : 2
                : 114
                [1] 1simpleDivision of Neuro-Oncology, St. Jude Children’s Research Hospital Memphis, TN, USA
                Author notes

                Edited by: Crystal Mackall, National Cancer Institute, USA

                Reviewed by: Crystal Mackall, National Cancer Institute, USA; David Loeb, Johns Hopkins University, USA

                *Correspondence: Amar Gajjar, Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS260 Memphis, TN 38105, USA. e-mail: amar.gajjar@ 123456stjude.org

                This article was submitted to Frontiers in Pediatric Oncology, a specialty of Frontiers in Oncology.

                Copyright © 2012 Ginn and Gajjar.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                : 30 May 2012
                : 22 August 2012
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 66, Pages: 13, Words: 10838
                Review Article

                Oncology & Radiotherapy
                pediatric brain tumors,cyclin d1,tyrosine kinase inhibitors,insulin-like growth factor,aurora kinase,atrt


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