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Childhood Astrocytomas Treatment (PDQ®)
- General Information
- Stage Information
- Treatment Option Overview
- Treatment of Childhood Low-Grade Astrocytomas
- Treatment of Recurrent Childhood Low-Grade Astrocytomas
- Treatment of Childhood High-Grade Astrocytomas
- Treatment of Recurrent Childhood High-Grade Astrocytomas
- Changes to this Summary (04/02/2013)
- About This PDQ Summary
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General Information
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization classification of nervous system tumors.[1][2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.
Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin
The pathologic classification of pediatric brain tumors is a specialized area that is undergoing evolution; review of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.
Childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are histologically graded from grade I to IV according to the World Health Organization's (WHO) histologic typing of central nervous system (CNS) tumors.[1] Tumor types are based on the glial cell type of origin: astrocytomas (astrocytes), oligodendroglial tumors (oligodendrocytes), mixed gliomas (cell types of origin include oligodendrocytes, astrocytes, and ependymal cells) and neuronal tumors (with or without an astrocytic component).
WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (see Table 1).Table 1. World Health Organization (WHO) Histologic Grade and Corresponding Classification for Tumors of the Central Nervous SystemWHO Histologic GradeGrade ClassificationILow grade IILow grade IIIHigh grade IVHigh grade
In 2007, the WHO further categorized astrocytomas, oligodendroglial tumors, and mixed gliomas according to histopathologic features and biologic behavior. It was determined that the pilomyxoid variant of pilocytic astrocytoma may be a more aggressive variant and may be more likely to disseminate, and it was reclassified by the WHO as a grade II tumor (see Table 2).[1][2][4]Table 2. Histologic Grade of Childhood Astrocytomas and Other Tumors of Glial OriginTypeWHO Histologic GradeAstrocytic Tumors: Pilocytic astrocytomaIPilomyxoid astrocytomaIIPleomorphic xanthoastrocytoma IISubependymal giant cell astrocytomaIDiffuse astrocytoma: Gemistocytic astrocytoma IIProtoplasmic astrocytomaIIFibrillary astrocytomaIIAnaplastic astrocytoma IIIGlioblastomaIVOligodendroglial Tumors:OligodendrogliomaIIAnaplastic oligodendrogliomaIIIMixed Gliomas: OligoastrocytomaII Anaplastic oligoastrocytomaIII
Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have preferential CNS locations (see Table 3).Table 3. Childhood Astrocytomas and Other Tumors of Glial Origin and Preferential Central Nervous System (CNS) LocationTumor TypePreferential CNS locationPilocytic astrocytomaOptic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, brain stem, and spinal cord (rare)Pleomorphic xanthoastrocytomaSuperficial location in cerebrum (temporal lobe preferentially)Diffuse astrocytoma (including fibrillary)Cerebrum (frontal and temporal lobes), brain stem, spinal cord, optic nerve, optic chiasm, optic pathway, hypothalamus, and thalamusAnaplastic astrocytoma, glioblastoma Cerebrum; occasionally cerebellum, brain stem, and spinal cordOligodendrogliomasCerebrum (frontal lobe preferentially followed by temporal, parietal, and occipital lobes), cerebellum, brain stem, and spinal cordOligoastrocytomaCerebral hemispheres (frontal lobe preferentially followed by the temporal lobe)Gliomatosis cerebriCerebrum with or without brain stem involvement, cerebellum, and spinal cord
More than 80% of astrocytomas located in the cerebellum are low-grade (pilocytic grade I) and often cystic; most of the remainder are diffuse grade II astrocytomas. Malignant astrocytomas in the cerebellum are rare.[1][2] The presence of certain histologic features has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location.[5][6][7]
Astrocytomas arising in the brain stem may be either high-grade or low-grade, with the frequency of either type being highly dependent on the location of the tumor within the brain stem.[8][9] Tumors not involving the pons are overwhelmingly low-grade gliomas (e.g., tectal gliomas of the midbrain), whereas tumors located exclusively in the pons without exophytic components are largely high-grade gliomas (e.g., diffuse intrinsic pontine gliomas).[8][9]
Children with neurofibromatosis type 1 (NF1) have an increased propensity to develop WHO grade I and II astrocytomas in the visual pathway; approximately 20% of all patients with NF1 will develop a visual pathway glioma. In these patients, the tumor may be found on screening evaluations when the child is asymptomatic or has apparent static neurologic and/or visual deficits. Pathologic confirmation is frequently not obtained in asymptomatic patients, and when biopsies have been performed, these tumors have been found to be predominantly pilocytic (grade I) rather than fibrillary (grade II) astrocytomas.[2][4][10][11][12] In general, treatment is not required for incidental tumors found with surveillance scans. Symptomatic lesions or those that have radiographically progressed may require treatment.[13]
Genomic alterations involving BRAF are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the ERK/MAPK pathway. BRAF activation in pilocytic astrocytoma occurs most commonly through a gene fusion between KIAA1549 and BRAF, producing a fusion protein that lacks the BRAF regulatory domain.[14][15][16][17][18] This fusion is seen in the majority of infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[14][15][19][20][21][22][23] Other genomic alterations in pilocytic astrocytomas that can also activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[15][17][18][24] As expected, given the role of NF1 deficiency in activating the ERK/MAPK pathway, activating BRAF genomic alterations are uncommon in pilocytic astrocytoma associated with NF1.[21] Presence of the BRAF-KIAA1549 fusion predicted for better clinical outcome (progression-free survival [PFS] and overall survival) in one report that described children with incompletely resected low-grade gliomas.[23] However, other factors such as p16 deletion and tumor location may modify the impact of BRAF mutation on outcome.[25] BRAF activation through the KIAA1549-BRAF fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[22][23] BRAF point mutations (V600E) are observed in nonpilocytic pediatric low-grade gliomas as well, including approximately two-thirds of pleomorphic xanthoastrocytoma cases and in ganglioglioma and desmoplastic infantile ganglioglioma.[26][27][28]
Molecular features of pediatric high-grade astrocytomas show some similarities to the genetic aberrations seen in adult glioblastomas that arise from pre-existing lower-grade gliomas (so-called secondary glioblastoma).[29][30][31] These include a high incidence of TP53 mutations, a low incidence of PTEN and P16INK4A mutations, and the presence of PDGF/PDGFR overexpression. However, the IDH1 mutations that have been identified in a high proportion of adults with secondary glioblastoma are rarely seen in pediatric glioblastoma.[32][33] While the incidence of IDH1 mutations is low in children, it increases with age in the adolescent and young adult population.[32] Mutations in histone H3.3 (H3F3A) are present in approximately one-third of non–brain stem pediatric high-grade astrocytomas,[33][34] and most of these cases also have TP53 mutations.[33] Pediatric high-grade astrocytomas with H3F3A mutations often additionally have somatic mutations in ATRX, a gene coding for a protein involved in chromatin remodeling.[33] Diffuse intrinsic pontine gliomas show an even higher frequency of H3F3A mutations than do non–brain stem pediatric high-grade astrocytomas, with approximately three-fourths of cases showing mutations.[34][35] Diffuse intrinsic pontine gliomas show a comparably high frequency of TP53 mutations, but IDH1 and IDH2 mutations are rare.[35] These findings suggest that a substantial proportion of pediatric high-grade astrocytomas are associated with processes required for establishing normal chromatin architecture.
The molecular profile of pediatric patients with oligodendroglioma does not demonstrate deletions of 1p or 19q, as found in 40% to 80% of adult cases. Pediatric oligodendroglioma harbors MGMT gene promoter methylation in the majority of tumors.[36]
Gliomatosis cerebri is a diffuse glioma that involves widespread involvement of the cerebral hemispheres in which it may be confined, but it often extends caudally to affect the brain stem, cerebellum, and/or spinal cord.[1] It rarely arises in the cerebellum and spreads rostrally.[37] The neoplastic cells are most commonly astrocytes, but in some cases, they are oligodendroglia. They may respond to treatment initially, but overall have a poor prognosis.[38]
Low-grade astrocytomas
Low-grade astrocytomas (grade I [pilocytic] and grade II) have a relatively favorable prognosis, particularly for circumscribed, grade I lesions where complete excision may be possible.[39][40][41][42][43][44] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[45][46] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with NF1.
Unfavorable prognostic features include young age, fibrillary histology, and inability to obtain a complete resection.[47] Elevated MIB-1 labeling index, a marker of cellular proliferative activity, is associated with shortened PFS in patients with pilocytic astrocytoma.[7] A BRAF-KIAA fusion, found in pilocytic tumors, confers a better clinical outcome.[23]
Oligodendrogliomas are rare in children and have a relatively favorable prognosis, with the exception of children younger than 3 years who have less than a gross total resection.[48]
High-grade astrocytomas
High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium.[39][42] Spread via the subarachnoid space may occur. Metastasis outside of the CNS has been reported but is extremely infrequent until multiple local relapses have occurred. Biologic markers, such as p53 overexpression and mutation status, may be useful predictors of outcome in patients with high-grade gliomas.[4][49][50] MIB-1 labeling index is predictive of outcome in childhood malignant brain tumors. Both histologic classification and proliferative activity evaluation have been shown to be independently associated with survival.[51] Although high-grade astrocytoma carries a generally poor prognosis in younger patients, those with anaplastic astrocytoma and those in whom a gross total resection is possible may fare better.[43][52][53]
Disease Presentation
Presenting symptoms for childhood astrocytomas depend not only on CNS location, but also size of tumor, rate of growth, and chronologic and developmental age of the child.1Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.2Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007.3Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.4Komotar RJ, Burger PC, Carson BS, et al.: Pilocytic and pilomyxoid hypothalamic/chiasmatic astrocytomas. Neurosurgery 54 (1): 72-9; discussion 79-80, 2004.5Tibbetts KM, Emnett RJ, Gao F, et al.: Histopathologic predictors of pilocytic astrocytoma event-free survival. Acta Neuropathol 117 (6): 657-65, 2009.6Rodriguez FJ, Scheithauer BW, Burger PC, et al.: Anaplasia in pilocytic astrocytoma predicts aggressive behavior. Am J Surg Pathol 34 (2): 147-60, 2010.7Margraf LR, Gargan L, Butt Y, et al.: Proliferative and metabolic markers in incompletely excised pediatric pilocytic astrocytomas--an assessment of 3 new variables in predicting clinical outcome. Neuro Oncol 13 (7): 767-74, 2011.8Fried I, Hawkins C, Scheinemann K, et al.: Favorable outcome with conservative treatment for children with low grade brainstem tumors. Pediatr Blood Cancer 58 (4): 556-60, 2012.9Fisher PG, Breiter SN, Carson BS, et al.: A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer 89 (7): 1569-76, 2000.10Listernick R, Darling C, Greenwald M, et al.: Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history. J Pediatr 127 (5): 718-22, 1995.11Rosai J, Sobin LH, eds.: Dysgenetic syndromes. In: Rosai J, Sobin LH, eds.: Atlas of Tumor Pathology. Third Series. Washington, DC : Armed Forces Institute of Pathology, 1994., pp 379-90.12Allen JC: Initial management of children with hypothalamic and thalamic tumors and the modifying role of neurofibromatosis-1. Pediatr Neurosurg 32 (3): 154-62, 2000.13Molloy PT, Bilaniuk LT, Vaughan SN, et al.: Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology 45 (10): 1897-902, 1995.14Bar EE, Lin A, Tihan T, et al.: Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 67 (9): 878-87, 2008.15Forshew T, Tatevossian RG, Lawson AR, et al.: Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 218 (2): 172-81, 2009.16Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008.17Jones DT, Kocialkowski S, Liu L, et al.: Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28 (20): 2119-23, 2009.18Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008.19Korshunov A, Meyer J, Capper D, et al.: Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 118 (3): 401-5, 2009.20Horbinski C, Hamilton RL, Nikiforov Y, et al.: Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol 119 (5): 641-9, 2010.21Yu J, Deshmukh H, Gutmann RJ, et al.: Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 73 (19): 1526-31, 2009.22Lin A, Rodriguez FJ, Karajannis MA, et al.: BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J Neuropathol Exp Neurol 71 (1): 66-72, 2012.23Hawkins C, Walker E, Mohamed N, et al.: BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 17 (14): 4790-8, 2011.24Janzarik WG, Kratz CP, Loges NT, et al.: Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics 38 (2): 61-3, 2007.25Horbinski C, Nikiforova MN, Hagenkord JM, et al.: Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol 14 (6): 777-89, 2012.26Dougherty MJ, Santi M, Brose MS, et al.: Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol 12 (7): 621-30, 2010.27Dias-Santagata D, Lam Q, Vernovsky K, et al.: BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One 6 (3): e17948, 2011.28Schindler G, Capper D, Meyer J, et al.: Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121 (3): 397-405, 2011.29Paugh BS, Qu C, Jones C, et al.: Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28 (18): 3061-8, 2010.30Bax DA, Mackay A, Little SE, et al.: A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res 16 (13): 3368-77, 2010.31Ward SJ, Karakoula K, Phipps KP, et al.: Cytogenetic analysis of paediatric astrocytoma using comparative genomic hybridisation and fluorescence in-situ hybridisation. J Neurooncol 98 (3): 305-18, 2010.32Pollack IF, Hamilton RL, Sobol RW, et al.: IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst 27 (1): 87-94, 2011.33Schwartzentruber J, Korshunov A, Liu XY, et al.: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482 (7384): 226-31, 2012.34Wu G, Broniscer A, McEachron TA, et al.: Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44 (3): 251-3, 2012.35Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al.: K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124 (3): 439-47, 2012.36Suri V, Jha P, Agarwal S, et al.: Molecular profile of oligodendrogliomas in young patients. Neuro Oncol 13 (10): 1099-106, 2011.37Rorke-Adams LB, Portnoy H: Long-term survival of an infant with gliomatosis cerebelli. J Neurosurg Pediatr 2 (5): 346-50, 2008.38Armstrong GT, Phillips PC, Rorke-Adams LB, et al.: Gliomatosis cerebri: 20 years of experience at the Children's Hospital of Philadelphia. Cancer 107 (7): 1597-606, 2006.39Pollack IF: Brain tumors in children. N Engl J Med 331 (22): 1500-7, 1994.40Hoffman HJ, Berger MS, Becker LE: Cerebellar astrocytomas. In: Deutsch M, ed.: Management of Childhood Brain Tumors. Boston: Kluwer Academic Publishers, 1990, pp 441-56.41Fisher PG, Tihan T, Goldthwaite PT, et al.: Outcome analysis of childhood low-grade astrocytomas. Pediatr Blood Cancer 51 (2): 245-50, 2008.42Pfister S, Witt O: Pediatric gliomas. Recent Results Cancer Res 171: 67-81, 2009.43Qaddoumi I, Sultan I, Gajjar A: Outcome and prognostic features in pediatric gliomas: a review of 6212 cases from the Surveillance, Epidemiology, and End Results database. Cancer 115 (24): 5761-70, 2009.44Wisoff JH, Sanford RA, Heier LA, et al.: Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children's Oncology Group. Neurosurgery 68 (6): 1548-54; discussion 1554-5, 2011.45von Hornstein S, Kortmann RD, Pietsch T, et al.: Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. Pediatr Blood Cancer 56 (7): 1046-54, 2011.46Mazloom A, Hodges JC, Teh BS, et al.: Outcome of patients with pilocytic astrocytoma and leptomeningeal dissemination. Int J Radiat Oncol Biol Phys 84 (2): 350-4, 2012.47Stokland T, Liu JF, Ironside JW, et al.: A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702). Neuro Oncol 12 (12): 1257-68, 2010.48Creach KM, Rubin JB, Leonard JR, et al.: Oligodendrogliomas in children. J Neurooncol 106 (2): 377-82, 2012.49Pollack IF, Finkelstein SD, Woods J, et al.: Expression of p53 and prognosis in children with malignant gliomas. N Engl J Med 346 (6): 420-7, 2002.50Rood BR, MacDonald TJ: Pediatric high-grade glioma: molecular genetic clues for innovative therapeutic approaches. J Neurooncol 75 (3): 267-72, 2005.51Pollack IF, Hamilton RL, Burnham J, et al.: Impact of proliferation index on outcome in childhood malignant gliomas: results in a multi-institutional cohort. Neurosurgery 50 (6): 1238-44; discussion 1244-5, 2002.52Finlay JL, Boyett JM, Yates AJ, et al.: Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group. J Clin Oncol 13 (1): 112-23, 1995.53Villano JL, Seery TE, Bressler LR: Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother Pharmacol 64 (4): 647-55, 2009.
Stage Information
There is no generally recognized staging system for childhood astrocytomas. For the purposes of this summary, childhood astrocytomas will be described as low-grade astrocytoma (pilocytic astrocytomas and diffuse fibrillary astrocytomas) or high-grade astrocytoma (anaplastic astrocytomas and glioblastoma) and as untreated or recurrent.
Treatment Option Overview
Many of the improvements in survival in childhood cancer have been made as a result of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare new therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those that were previously obtained with existing therapy.
Because of the relative rarity of cancer in children, all patients with brain tumors should be considered for entry into a clinical trial. To determine and implement optimum treatment, treatment planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Radiation therapy of pediatric brain tumors is technically very demanding and should be carried out in centers that have experience in that area in order to ensure optimal results.
Debilitating effects on growth and neurologic development have frequently been observed following radiation therapy, especially in younger children.[1][2][3] There are also other less-common complications of radiation therapy, including cerebrovascular accidents.[4] For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy is under study, and preliminary results suggest that chemotherapy can be used to delay, and sometimes obviate, the need for radiation therapy in children with benign and malignant lesions.[5] Long-term management of these patients is complex and requires a multidisciplinary approach.1Packer RJ, Sutton LN, Atkins TE, et al.: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70 (5): 707-13, 1989.2Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80 (6): 1004-10, 1994.3Packer RJ, Sutton LN, Goldwein JW, et al.: Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 74 (3): 433-40, 1991.4Bowers DC, Mulne AF, Reisch JS, et al.: Nonperioperative strokes in children with central nervous system tumors. Cancer 94 (4): 1094-101, 2002.5Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993.
Treatment of Childhood Low-Grade Astrocytomas
To determine and implement optimum management, treatment is often guided by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors.
In infants and young children, low-grade astrocytomas presenting in the hypothalamus may result in the diencephalic syndrome, which is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurologic findings, but can have macrocephaly, intermittent lethargy, and visual impairment.[1] Because the location of these tumors makes a surgical approach difficult, biopsies are not always done. This is especially true in patients with neurofibromatosis type 1 (NF1).[2] When associated with NF1, tumors may be of multifocal origin.
For children with low-grade optic pathway astrocytomas, treatment options should be considered not only to improve survival but also to stabilize visual function.[3][4] Children with isolated optic nerve tumors have a better prognosis than those with lesions that involve the chiasm or that extend along the visual pathway.[1][2][5][6]; [7][Level of evidence: 3iiC] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening.[5][8] Observation is an option for patients with NF1 or nonprogressive masses.[1][5][9][10] Spontaneous regressions of optic pathway gliomas have been reported in children with and without NF1.[11][12][13]
Surgical resection is the primary treatment for childhood low-grade astrocytoma [1][2][5][14] and surgical feasibility is determined by tumor location. For example, complete or near complete removal can be obtained in 90% to 95% of patients with pilocytic tumors that occur in the cerebellum. Similarly, circumscribed, grade I hemispheric tumors are often amenable to complete surgical resection.[14][15][16] For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection or local radiation therapy may result in prolonged progression-free survival (PFS).[17]
Factors related to outcome for children with low-grade gliomas treated with surgery followed by observation were identified in a Children's Oncology Group study that included 518 evaluable patients.[14] Overall outcome for the entire group was 78% PFS at 8 years and 96% overall survival (OS) at 8 years. The following factors were related to prognosis:[14]
- Histology: Approximately three-fourths of patients had pilocytic astrocytoma, and PFS and OS for these patients was superior to that of children with nonpilocytic tumors.
- Extent of resection: Patients with gross total resection had 8-year PFS exceeding 90% and OS of 99%. By comparison, approximately one-half of patients with any degree of residual tumor (as assessed by operative report and by postoperative imaging) showed disease progression by 8 years, although OS exceeded 90%.
- Age: Younger children (age <5 years) showed higher rates of tumor progression but there was no significant age effect for OS in multivariate analysis.
- Tumor location: Cerebellar and cerebral tumors showed higher PFS at 8 years compared with patients with midline and chiasmatic tumors (84% ± 1.9% versus 51% ± 5.9%).
Diffuse astrocytomas may be less amenable to total resection, and this may account for the poorer outcome. The extent of resection necessary for cure, as noted above, is unknown because patients with microscopic and even gross residual tumor after surgery may experience long-term PFS without postoperative therapy.[2][9][14] The long-term functional outcome of cerebellar pilocytic astrocytomas is relatively favorable. Full-scale mean IQs of patients with low-grade gliomas treated with surgery alone are close to the normative population. However, long-term medical, psychological, and educational deficits may be present in these patients.[18][19][Level of evidence: 3iiiC]
Low-grade astrocytomas that occur in midline structures (e.g., hypothalamus, thalamus, brain stem, and spinal cord) can also be aggressively resected, with resultant long-term disease control;[11][12][20]; [21][Level of evidence: 3iiiA] however, such resection may result in significant neurologic sequelae, especially in children younger than 2 years at diagnosis.[11]; [22][Level of evidence: 3iC] Because of the infiltrative nature of some deep-seated lesions, extensive surgical resection may not be appropriate and biopsy only should be considered.[23][Level of evidence: 3iiiDiii] Treatment options for patients with incompletely resected tumor must be individualized and may include observation, a second resection, chemotherapy, and/or radiation. A shunt or other cerebrospinal fluid diversion procedure may be needed.
Following resection, immediate (within 48 hours of resection per Children's Oncology Group [COG] criteria) postoperative magnetic resonance imaging is obtained. Surveillance scans are then obtained periodically for completely resected tumors, although the value following the initial 3- to 6-month postoperative period is uncertain.[24]; [25][Level of evidence: 3iiDiii] In selected patients in whom a portion of the tumor has been resected, the patient may also be observed without further disease-directed treatment, particularly if the pace of tumor regrowth is anticipated to be very slow. Approximately 50% of patients with less-than-gross total resection may have disease that remains progression-free at 5 to 8 years, supporting the observation strategy in selected patients.[14]
Radiation Therapy
Radiation therapy is usually reserved until progressive disease is documented,[16][26] and its use may be further delayed through the use of chemotherapy, a strategy that is commonly employed in young children.[27][28] Radiation therapy results in long-term disease control for most children with chiasmatic and posterior pathway chiasmatic gliomas, but may also result in substantial intellectual and endocrinologic sequelae, cerebrovascular damage, and possibly an increased risk of secondary tumors.[11][17][29][30]; [31][Level of evidence: 2C] An alternative to immediate radiation therapy is subtotal surgical resection, but it is unclear how many patients will have stable disease and for how long.[11] Radiation therapy and alkylating agents are used as a last resort for patients with NF1, given the theoretically heightened risk of inducing neurologic toxic effects and second malignancy in this population.[32] Children with NF1 may be at higher risk for radiation-associated secondary tumors and morbidity due to vascular changes.
For children with low-grade glioma for whom radiation therapy is indicated, conformal radiation therapy or stereotactic radiosurgery approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality. Care must be taken in separating radiation-induced imaging changes from disease progression during the first year after radiation, especially in patients with pilocytic astrocytomas.[33][34][35]; [36][Level of evidence: 2A]; [31][Level of evidence: 2C]; [37][Level of evidence: 3iiiDi]; [38][Level of evidence: 3iiiDii]; [23][39][Level of evidence: 3iiiDiii]
Given the side effects associated with radiation therapy, chemotherapy may be particularly appropriate for patients with NF1 and for younger children.
Chemotherapy may result in objective tumor shrinkage and will delay the need for radiation therapy in most patients.[27][28][40][41] Chemotherapy has been shown to shrink tumors in children with hypothalamic gliomas and the diencephalic syndrome, resulting in weight gain in those who respond to treatment.[42]
The most widely used regimens to treat progression or symptomatic nonresectable, low-grade gliomas are carboplatin with or without vincristine [27][28][43] or a combination of thioguanine, procarbazine, lomustine, and vincristine (TPCV).[41]; [44][Level of evidence: 1iiA] The COG reported the results of a randomized phase III trial (COG-A9952) that treated children younger than 10 years with low-grade chiasmatic/hypothalamic gliomas using one of two regimens: carboplatin and vincristine (CV) or TPCV. The 5-year event-free survival rate was 39% ± 4% for the CV regimen and 52% ± 5% for the TPCV regimen.[44] Other chemotherapy approaches have been employed to treat children with progressive low-grade astrocytomas, including multiagent platinum-based regimens [28][40][45]; [46][Level of evidence: 2Diii] and temozolomide.[47][48]
Reported 5-year PFS rates have ranged from approximately 35% to 60% for children receiving platinum-based chemotherapy for optic pathway gliomas,[28][40] but most patients ultimately require further treatment. This is particularly true for children who initially present with hypothalamic/chiasmatic gliomas that have neuraxis dissemination.[49][Level of evidence: 3iiiDiii]
Among children receiving chemotherapy for optic pathway gliomas, those without NF1 have higher rates of disease progression than those with NF1, and infants have higher rates of disease progression than do children older than 1 year.[28][40][45] Whether vision is improved with chemotherapy is unclear.[50][51][Level of evidence: 3iiiC]
Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in an overexpression of the mTOR complex 1. These children are at risk for the development of subependymal giant cell astrocytomas (SEGA), in addition to cortical tubers and subependymal nodules. For children with symptomatic SEGAs, agents that inhibit mTOR (e.g., everolimus and sirolimus) have been shown in small series to cause significant reductions in the size of these tumors, often eliminating the need for surgery.[52][Level of evidence: 2C]; [53][Level of evidence: 3iiiC] Whether reduction in size of the mass is durable, obviating the need for future surgery, is currently unknown.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via Children's Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium, or other entities. Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood low-grade untreated astrocytoma or other tumor of glial origin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Schneider JH Jr, Raffel C, McComb JG: Benign cerebellar astrocytomas of childhood. Neurosurgery 30 (1): 58-62; discussion 62-3, 1992.2Due-Tønnessen BJ, Helseth E, Scheie D, et al.: Long-term outcome after resection of benign cerebellar astrocytomas in children and young adults (0-19 years): report of 110 consecutive cases. Pediatr Neurosurg 37 (2): 71-80, 2002.3Nicolin G, Parkin P, Mabbott D, et al.: Natural history and outcome of optic pathway gliomas in children. Pediatr Blood Cancer 53 (7): 1231-7, 2009.4Kramm CM, Butenhoff S, Rausche U, et al.: Thalamic high-grade gliomas in children: a distinct clinical subset? Neuro Oncol 13 (6): 680-9, 2011.5Campbell JW, Pollack IF: Cerebellar astrocytomas in children. J Neurooncol 28 (2-3): 223-31, 1996 May-Jun.6Massimi L, Tufo T, Di Rocco C: Management of optic-hypothalamic gliomas in children: still a challenging problem. Expert Rev Anticancer Ther 7 (11): 1591-610, 2007.7Campagna M, Opocher E, Viscardi E, et al.: Optic pathway glioma: long-term visual outcome in children without neurofibromatosis type-1. Pediatr Blood Cancer 55 (6): 1083-8, 2010.8Hernáiz Driever P, von Hornstein S, Pietsch T, et al.: Natural history and management of low-grade glioma in NF-1 children. J Neurooncol 100 (2): 199-207, 2010.9Hayostek CJ, Shaw EG, Scheithauer B, et al.: Astrocytomas of the cerebellum. A comparative clinicopathologic study of pilocytic and diffuse astrocytomas. Cancer 72 (3): 856-69, 1993.10Listernick R, Ferner RE, Liu GT, et al.: Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 61 (3): 189-98, 2007.11Wisoff JH, Abbott R, Epstein F: Surgical management of exophytic chiasmatic-hypothalamic tumors of childhood. J Neurosurg 73 (5): 661-7, 1990.12Albright AL: Feasibility and advisability of resections of thalamic tumors in pediatric patients. J Neurosurg 100 (5 Suppl Pediatrics): 468-72, 2004.13Piccirilli M, Lenzi J, Delfinis C, et al.: Spontaneous regression of optic pathways gliomas in three patients with neurofibromatosis type I and critical review of the literature. Childs Nerv Syst 22 (10): 1332-7, 2006.14Wisoff JH, Sanford RA, Heier LA, et al.: Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children's Oncology Group. Neurosurgery 68 (6): 1548-54; discussion 1554-5, 2011.15Berger MS, Ghatan S, Haglund MM, et al.: Low-grade gliomas associated with intractable epilepsy: seizure outcome utilizing electrocorticography during tumor resection. J Neurosurg 79 (1): 62-9, 1993.16Pollack IF, Claassen D, al-Shboul Q, et al.: Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases. J Neurosurg 82 (4): 536-47, 1995.17Jenkin D, Angyalfi S, Becker L, et al.: Optic glioma in children: surveillance, resection, or irradiation? Int J Radiat Oncol Biol Phys 25 (2): 215-25, 1993.18Turner CD, Chordas CA, Liptak CC, et al.: Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only. Pediatr Blood Cancer 53 (3): 417-23, 2009.19Daszkiewicz P, Maryniak A, Roszkowski M, et al.: Long-term functional outcome of surgical treatment of juvenile pilocytic astrocytoma of the cerebellum in children. Childs Nerv Syst 25 (7): 855-60, 2009.20Tseng JH, Tseng MY: Survival analysis of 81 children with primary spinal gliomas: a population-based study. Pediatr Neurosurg 42 (6): 347-53, 2006.21Milano MT, Johnson MD, Sul J, et al.: Primary spinal cord glioma: a Surveillance, Epidemiology, and End Results database study. J Neurooncol 98 (1): 83-92, 2010.22Scheinemann K, Bartels U, Huang A, et al.: Survival and functional outcome of childhood spinal cord low-grade gliomas. Clinical article. J Neurosurg Pediatr 4 (3): 254-61, 2009.23Sawamura Y, Kamada K, Kamoshima Y, et al.: Role of surgery for optic pathway/hypothalamic astrocytomas in children. Neuro Oncol 10 (5): 725-33, 2008.24Sutton LN, Cnaan A, Klatt L, et al.: Postoperative surveillance imaging in children with cerebellar astrocytomas. J Neurosurg 84 (5): 721-5, 1996.25Dorward IG, Luo J, Perry A, et al.: Postoperative imaging surveillance in pediatric pilocytic astrocytomas. J Neurosurg Pediatr 6 (4): 346-52, 2010.26Fisher BJ, Leighton CC, Vujovic O, et al.: Results of a policy of surveillance alone after surgical management of pediatric low grade gliomas. Int J Radiat Oncol Biol Phys 51 (3): 704-10, 2001.27Packer RJ, Ater J, Allen J, et al.: Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86 (5): 747-54, 1997.28Gnekow AK, Kortmann RD, Pietsch T, et al.: Low grade chiasmatic-hypothalamic glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy -- report from the multicenter treatment study for children and adolescents with a low grade glioma -- HIT-LGG 1996 -- of the Society of Pediatric Oncology and Hematology (GPOH). Klin Padiatr 216 (6): 331-42, 2004 Nov-Dec.29Tao ML, Barnes PD, Billett AL, et al.: Childhood optic chiasm gliomas: radiographic response following radiotherapy and long-term clinical outcome. Int J Radiat Oncol Biol Phys 39 (3): 579-87, 1997.30Khafaga Y, Hassounah M, Kandil A, et al.: Optic gliomas: a retrospective analysis of 50 cases. Int J Radiat Oncol Biol Phys 56 (3): 807-12, 2003.31Merchant TE, Conklin HM, Wu S, et al.: Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27 (22): 3691-7, 2009.32Grill J, Couanet D, Cappelli C, et al.: Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 45 (3): 393-6, 1999.33Chawla S, Korones DN, Milano MT, et al.: Spurious progression in pediatric brain tumors. J Neurooncol 107 (3): 651-7, 2012.34Marcus KJ, Goumnerova L, Billett AL, et al.: Stereotactic radiotherapy for localized low-grade gliomas in children: final results of a prospective trial. Int J Radiat Oncol Biol Phys 61 (2): 374-9, 2005.35Combs SE, Schulz-Ertner D, Moschos D, et al.: Fractionated stereotactic radiotherapy of optic pathway gliomas: tolerance and long-term outcome. Int J Radiat Oncol Biol Phys 62 (3): 814-9, 2005.36Merchant TE, Kun LE, Wu S, et al.: Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 27 (22): 3598-604, 2009.37Kano H, Niranjan A, Kondziolka D, et al.: Stereotactic radiosurgery for pilocytic astrocytomas part 2: outcomes in pediatric patients. J Neurooncol 95 (2): 219-29, 2009.38Hallemeier CL, Pollock BE, Schomberg PJ, et al.: Stereotactic radiosurgery for recurrent or unresectable pilocytic astrocytoma. Int J Radiat Oncol Biol Phys 83 (1): 107-12, 2012.39Mansur DB, Rubin JB, Kidd EA, et al.: Radiation therapy for pilocytic astrocytomas of childhood. Int J Radiat Oncol Biol Phys 79 (3): 829-34, 2011.40Laithier V, Grill J, Le Deley MC, et al.: Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results of the first French prospective study for the French Society of Pediatric Oncology. J Clin Oncol 21 (24): 4572-8, 2003.41Prados MD, Edwards MS, Rabbitt J, et al.: Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen. J Neurooncol 32 (3): 235-41, 1997.42Gropman AL, Packer RJ, Nicholson HS, et al.: Treatment of diencephalic syndrome with chemotherapy: growth, tumor response, and long term control. Cancer 83 (1): 166-72, 1998.43Gururangan S, Cavazos CM, Ashley D, et al.: Phase II study of carboplatin in children with progressive low-grade gliomas. J Clin Oncol 20 (13): 2951-8, 2002.44Ater JL, Zhou T, Holmes E, et al.: Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol 30 (21): 2641-7, 2012.45Massimino M, Spreafico F, Cefalo G, et al.: High response rate to cisplatin/etoposide regimen in childhood low-grade glioma. J Clin Oncol 20 (20): 4209-16, 2002.46Massimino M, Spreafico F, Riva D, et al.: A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma. J Neurooncol 100 (1): 65-71, 2010.47Gururangan S, Fisher MJ, Allen JC, et al.: Temozolomide in children with progressive low-grade glioma. Neuro Oncol 9 (2): 161-8, 2007.48Khaw SL, Coleman LT, Downie PA, et al.: Temozolomide in pediatric low-grade glioma. Pediatr Blood Cancer 49 (6): 808-11, 2007.49von Hornstein S, Kortmann RD, Pietsch T, et al.: Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. Pediatr Blood Cancer 56 (7): 1046-54, 2011.50Moreno L, Bautista F, Ashley S, et al.: Does chemotherapy affect the visual outcome in children with optic pathway glioma? A systematic review of the evidence. Eur J Cancer 46 (12): 2253-9, 2010.51Shofty B, Ben-Sira L, Freedman S, et al.: Visual outcome following chemotherapy for progressive optic pathway gliomas. Pediatr Blood Cancer 57 (3): 481-5, 2011.52Krueger DA, Care MM, Holland K, et al.: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363 (19): 1801-11, 2010.53Franz DN, Leonard J, Tudor C, et al.: Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59 (3): 490-8, 2006.
Treatment of Recurrent Childhood Low-Grade Astrocytomas
Childhood low-grade astrocytomas may recur many years after initial treatment. Recurrent disease is usually at the primary tumor site, although multifocal or widely disseminated disease to other intracranial sites and to the spinal leptomeninges has been documented.[1][2] Most children whose low-grade fibrillary astrocytomas recur will harbor low-grade lesions; however, malignant transformation is possible.[3]
At the time of recurrence, a complete evaluation to determine the extent of the relapse is indicated. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence. The need for surgical intervention must be individualized on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the mass lesion, and the clinical picture.
An individual plan needs to be tailored based on patient age, tumor location, and prior treatment. If patients have not received radiation therapy, local radiation therapy is the usual treatment,[4] although further chemotherapy in lieu of radiation may be considered, depending on the child's age and the extent and location of the tumor.[5][Level of evidence: 3iA]; [6][Level of evidence: 3iiiDi] For children with low-grade glioma for whom radiation therapy is indicated, conformal radiation therapy approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality.[7][8] In patients treated with surgery alone whose disease progresses, chemotherapy and/or radiation therapy are options. If recurrence takes place after irradiation, chemotherapy should be considered. Chemotherapy may result in relatively long-term disease control.[9][10] Vinblastine alone, temozolomide alone, or temozolomide in combination with carboplatin and vincristine may be useful at the time of recurrence for children with low-grade gliomas.[9][10][11]; [12][Level of evidence: 3iiDi]
Patients with low-grade astrocytomas who relapse after being treated with surgery alone should be considered for another surgical resection.[13] If this is not feasible, local radiation therapy is the usual treatment.[14] If there is recurrence in an unresectable site after irradiation, chemotherapy should be considered.[14]
Entry into studies of novel therapeutic approaches should be considered for patients with recurrent brain tumors.[15][16] Information about ongoing clinical trials is available from the NCI Web site.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via Children's Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium, or other entities. Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood astrocytoma or other tumor of glial origin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Perilongo G, Carollo C, Salviati L, et al.: Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region. Cancer 80 (1): 142-6, 1997.2Leibel SA, Sheline GE, Wara WM, et al.: The role of radiation therapy in the treatment of astrocytomas. Cancer 35 (6): 1551-7, 1975.3Giannini C, Scheithauer BW: Classification and grading of low-grade astrocytic tumors in children. Brain Pathol 7 (2): 785-98, 1997.4Jenkin D, Angyalfi S, Becker L, et al.: Optic glioma in children: surveillance, resection, or irradiation? Int J Radiat Oncol Biol Phys 25 (2): 215-25, 1993.5Scheinemann K, Bartels U, Tsangaris E, et al.: Feasibility and efficacy of repeated chemotherapy for progressive pediatric low-grade gliomas. Pediatr Blood Cancer 57 (1): 84-8, 2011.6de Haas V, Grill J, Raquin MA, et al.: Relapses of optic pathway tumors after first-line chemotherapy. Pediatr Blood Cancer 52 (5): 575-80, 2009.7Merchant TE, Conklin HM, Wu S, et al.: Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27 (22): 3691-7, 2009.8Marcus KJ, Goumnerova L, Billett AL, et al.: Stereotactic radiotherapy for localized low-grade gliomas in children: final results of a prospective trial. Int J Radiat Oncol Biol Phys 61 (2): 374-9, 2005.9Packer RJ, Lange B, Ater J, et al.: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol 11 (5): 850-6, 1993.10Gnekow AK, Kortmann RD, Pietsch T, et al.: Low grade chiasmatic-hypothalamic glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy -- report from the multicenter treatment study for children and adolescents with a low grade glioma -- HIT-LGG 1996 -- of the Society of Pediatric Oncology and Hematology (GPOH). Klin Padiatr 216 (6): 331-42, 2004 Nov-Dec.11Gururangan S, Fisher MJ, Allen JC, et al.: Temozolomide in children with progressive low-grade glioma. Neuro Oncol 9 (2): 161-8, 2007.12Bouffet E, Jakacki R, Goldman S, et al.: Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol 30 (12): 1358-63, 2012.13Austin EJ, Alvord EC Jr: Recurrences of cerebellar astrocytomas: a violation of Collins' law. J Neurosurg 68 (1): 41-7, 1988.14Garcia DM, Marks JE, Latifi HR, et al.: Childhood cerebellar astrocytomas: is there a role for postoperative irradiation? Int J Radiat Oncol Biol Phys 18 (4): 815-8, 1990.15Chamberlain MC, Grafe MR: Recurrent chiasmatic-hypothalamic glioma treated with oral etoposide. J Clin Oncol 13 (8): 2072-6, 1995.16Gaynon PS, Ettinger LJ, Baum ES, et al.: Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial. Cancer 66 (12): 2465-9, 1990.
Treatment of Childhood High-Grade Astrocytomas
To determine and implement optimum management, treatment is often guided by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors.
The therapy for both children and adults with supratentorial high-grade astrocytoma includes surgery, radiation therapy, and chemotherapy. Outcome in high-grade gliomas occurring in childhood may be more favorable than that in adults, but it is not clear if this difference is caused by biologic variations in tumor characteristics, therapies used, tumor resectability, or other factors that are presently not understood.[1] The ability to obtain a complete resection is associated with a better prognosis.[2] Radiation therapy is administered to a field that widely encompasses the entire tumor. The radiation therapy dose to the tumor bed is usually at least 54 Gy. Despite such therapy, overall survival rates remain poor. Similarly poor survival is seen in children with spinal cord primaries and children with thalamic high-grade gliomas.[3][4]; [5][Level of evidence: 3iiiA] In one trial, children with glioblastoma who were treated on a prospective randomized trial with adjuvant lomustine, vincristine, and prednisone fared better than children treated with radiation therapy alone.[6] Among patients treated with surgery, radiation therapy, and nitrosourea (lomustine)-based chemotherapy, 5-year progression-free survival was 19% ± 3%; survival was 40% in those who had total resections.[7] Similarly, in a trial of multiagent chemoradiotherapy and adjuvant chemotherapy in addition to valproic acid, 5-year event-free survival (EFS) was 13%, but for children with a complete resection of their tumor, the EFS was 48%.[8][Level of evidence: 2A] In adults, the addition of temozolomide during and after radiation therapy resulted in improved 2-year EFS as compared with treatment with radiation therapy alone. Adult patients with glioblastoma with a methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not benefit from temozolomide.[9][10] The role of temozolomide given concurrently with radiation therapy for children with supratentorial high-grade glioma appears comparable to the outcome seen in children treated with nitrosourea-based therapy [11] and again demonstrated a survival advantage for those children with a methylated MGMT promoter. Younger children may benefit from chemotherapy to delay, modify, or, in selected cases, obviate the need for radiation therapy.[12][13][14] Clinical trials that evaluate chemotherapy with or without radiation therapy are ongoing. Information about ongoing clinical trials is available from the NCI Web site.
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted or is under analysis. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ACNS0822 (Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma): The Children's Oncology Group is conducting a randomized phase II/III study of vorinostat and local radiation therapy or temozolomide and local radiation therapy or bevacizumab and radiation therapy followed by maintenance bevacizumab and temozolomide in newly diagnosed high-grade glioma.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood high-grade untreated astrocytoma or other tumor of glial origin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Rasheed BK, McLendon RE, Herndon JE, et al.: Alterations of the TP53 gene in human gliomas. Cancer Res 54 (5): 1324-30, 1994.2Wisoff JH, Boyett JM, Berger MS, et al.: Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children's Cancer Group trial no. CCG-945. J Neurosurg 89 (1): 52-9, 1998.3Kramm CM, Butenhoff S, Rausche U, et al.: Thalamic high-grade gliomas in children: a distinct clinical subset? Neuro Oncol 13 (6): 680-9, 2011.4Tendulkar RD, Pai Panandiker AS, Wu S, et al.: Irradiation of pediatric high-grade spinal cord tumors. Int J Radiat Oncol Biol Phys 78 (5): 1451-6, 2010.5Wolff B, Ng A, Roth D, et al.: Pediatric high grade glioma of the spinal cord: results of the HIT-GBM database. J Neurooncol 107 (1): 139-46, 2012.6Sposto R, Ertel IJ, Jenkin RD, et al.: The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. J Neurooncol 7 (2): 165-77, 1989.7Fouladi M, Hunt DL, Pollack IF, et al.: Outcome of children with centrally reviewed low-grade gliomas treated with chemotherapy with or without radiotherapy on Children's Cancer Group high-grade glioma study CCG-945. Cancer 98 (6): 1243-52, 2003.8Wolff JE, Driever PH, Erdlenbruch B, et al.: Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol. Cancer 116 (3): 705-12, 2010.9Stupp R, Mason WP, van den Bent MJ, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10): 987-96, 2005.10Hegi ME, Diserens AC, Gorlia T, et al.: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352 (10): 997-1003, 2005.11Cohen KJ, Pollack IF, Zhou T, et al.: Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group. Neuro Oncol 13 (3): 317-23, 2011.12Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993.13Duffner PK, Krischer JP, Burger PC, et al.: Treatment of infants with malignant gliomas: the Pediatric Oncology Group experience. J Neurooncol 28 (2-3): 245-56, 1996 May-Jun.14Dufour C, Grill J, Lellouch-Tubiana A, et al.: High-grade glioma in children under 5 years of age: a chemotherapy only approach with the BBSFOP protocol. Eur J Cancer 42 (17): 2939-45, 2006.
Treatment of Recurrent Childhood High-Grade Astrocytomas
Most patients with high-grade astrocytomas or gliomas will eventually have tumor recurrence, usually within 3 years of original diagnosis but perhaps many years after initial treatment. Disease may recur at the primary tumor site, at the margin of the resection/radiation bed, or at noncontiguous central nervous system sites. Systemic relapse is rare but may occur. At the time of recurrence, a complete evaluation for extent of relapse is indicated for all malignant tumors. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence. The need for surgical intervention must be individualized on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the mass lesion, and the clinical picture.
Patients for whom initial treatment fails may benefit from additional treatment.[1] High-dose, marrow-ablative chemotherapy with hematopoietic stem cell transplant may be effective in a subset of patients with minimal residual disease at time of treatment.[2]; [3][Level of evidence: 3iiiA] Such patients should also be considered for entry into trials of novel therapeutic approaches. Information about ongoing clinical trials is available from the NCI Web site.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via Children's Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium, or other entities. Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood astrocytoma or other tumor of glial origin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.1Warren KE, Gururangan S, Geyer JR, et al.: A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study. J Neurooncol 106 (3): 643-9, 2012.2McCowage GB, Friedman HS, Moghrabi A, et al.: Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas. Med Pediatr Oncol 30 (2): 75-80, 1998.3Finlay JL, Dhall G, Boyett JM, et al.: Myeloablative chemotherapy with autologous bone marrow rescue in children and adolescents with recurrent malignant astrocytoma: outcome compared with conventional chemotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 806-11, 2008.
Changes to this Summary (04/02/2013)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information
Added Mazloom et al. as reference 46.
Treatment of Childhood Low-Grade Astrocytomas
Added text about the results of a randomized phase III trial (COG-A9952) that treated children younger than 10 years with low-grade chiasmatic/hypothalamic gliomas using one of two regimens: carboplatin and vincristine (CV) or TPCV; the 5-year event-free survival rate for CV was 39% ± 4% and for TPCV was 52% ± 5%.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood astrocytomas. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Astrocytomas Treatment are:
- Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
- Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
- Karen Jean Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Roger J. Packer, MD (Children's National Medical Center)
- Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Childhood Astrocytomas Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/child-astrocytomas/HealthProfessional. Accessed <MM/DD/YYYY>.
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This information was last updated on 2013-04-02


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About Walk MS
Join us in celebrating 25 years of Walk MS!
The Seattle Walk MS will be at the University of Washington E18 Parking Lot on Sunday, April 12, 2015. All members of the community are invited to join in the festivities at our "Walker Village" as we gather together to move closer to a world free of MS.
Walk MS Seattle Logistics
- The walk begins at 10:00 a.m. rain or shine!
- Accessible parking is available.
- Snacks and water available at Walker Village and rest stops.
- Check out Walk MS vendors and sponsors at the event.
- For the safety of other walkers, please leave your pets at home.
- Wear your best orange outfit to support the MS Movement!
Participation Options
- Volunteer at Walk MS! Contact Cara Chamberlin at email@example.com or 206-515-4554 for more information, or register online.
- You can start or join an existing Walk MS team. If you have already registered, please contact us at email@example.com and your teams coach will help you out.
The Route
- The walk begins and ends at the University of Washington.
- The 4.6-mile route is along the Burke Gilman Trail to Gas Works Park and back.
- The route is on paved, mostly flat walkways and is accessible.
- View the route map.
- There are three rest stops with snack and water along the way, including entertainment at the Gas Works turn around.
- Registration is free, but we ask each participant to reach the $100 fundraising minimum (which gets you a Walk MS T-shirt!).
- How to turn in donations:
- Mail to: National MS Society, Greater Northwest Chapter, 192 Nickerson St., Ste. 100, Seattle, WA 98109 (include your name or name of Walk MS participant)
- Online with debit or credit card at walkMS.org.
- In person at Walk MS.
- The 2014 Seattle Walk MS raised over $800,000, an average of $276 per participant, which helps to support MS research, local programs, and services and support for people affected by MS. Thank you!
- Learn more about fundraising.
- Download or order fundraising materials.
Questions? Contact us at firstname.lastname@example.com or 1-800-344-4867, ext. 40307.
Join us for the 1st Annual Run MS Seattle 5K at 8:00 a.m. on Sunday, April 12, 2015, the same day as Walk MS! All runners in the community, regardless of physical level or ability, are welcomed to sign up. Join us in this new tradition that will kick off the Walk MS event and move us closer to a world free of multiple sclerosis!
About Run MS Seattle 5K
- The run begins and ends at the University of Washington.
- Shotgun start is at 8:00 a.m.
- The route is along the Burke Gilman Trail.
- The run will be professionally timed and we encourage you to wear your best orange outfit to support the MS Movement!
- The $35 pre-registration/$40 day-of event fee includes a performance running shirt and timing chip.
- Runners can join a Walk MS Team or start their own Walk MS/Run MS team by registering here.
- Walkers are not permitted on the course for the Run MS Seattle 5K. The Walk MS event, utilizing a similar course, will be a non-timed event beginning at 10:00 a.m.
- Runners are welcome to stay for Walk MS and enjoy the festivities!
Questions? Check the 5K FAQ page or contact us at firstname.lastname@example.com or 206-284-4236, press 4.
Packet Pick-up details and route map coming soon!
Sample 5K training plans
- Hal Higdon Training Plan: http://www.halhigdon.com/training/50932/5K-Training-The-Most-Popular-Racing-Distance
- Couch-to-5K Training Plan: http://www.coolrunning.com/engine/2/2_3/181.shtml
"My biggest reason for walking for the cure for MS is the love of my life, my fiance Mike! MS is one of those things that not too many people know too much about and I think that needs to change! I truly believe there is a cure out there somewhere and I hope and pray it is found soon so no one else has to suffer. Thank you for creating the National MS Society and putting on these events so we can all make a difference!"

subset: commoncrawl


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Guide to the diagnosis, treatment and prevention of conditions from A to Z.
Facts About the Spine, Shoulder, and Pelvis
Doctors and Specialists
Chronic Pain
Common Disorders of the Spine, Shoulder, and Pelvis
The skeletal trunk, that part of the body made up of the spine (back and neck), shoulders, and pelvis, acts as the major support system for the rest of the body.
Sometimes called the trunk or the torso, this area of the body is home to weight-bearing bones and joints, muscles, tendons, ligaments, and nerve centers that make movement, stability, and flexibility for the rest of the body possible.
Because of the complexity of its many tasks, the skeletal trunk is vulnerable to many traumatic, degenerative, and overuse disorders. Problems such as degenerative arthritis, nerve impingement, fractures, tendonitis, muscle sprains, and tumors — disorders that can also cause pain and disability in other parts of the body — are common to the skeletal trunk.
Find a physician at another Johns Hopkins Member Hospital:
Find Additional Treatment Centers at:
Whether you're crossing the country or the globe, we make it easy to access world-class care at Johns Hopkins.
U.S. (toll free) 1-410-464-6713 International +1-410-502-7683
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Legal Disclaimer


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View All:
BKE Carter Pant
SALE $39.97 was $49.95 Item #3603026908AM
- Regular fit bootcut pant
- Low rise, 19" bottom opening
- Back besom pockets
- Zip fly
- 100% Cotton.
- Machine wash in cold water with like colors. Use only non-chlorine bleach when needed. Tumble dry low, remove promptly. Cool iron if necessary.
- Made in China.
Have a Question?
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Men's Pants
Men's BKE Pants
We changed our page. Tell us what you think.
- Model Info: Height: 5'10" | Chest: 38" | Waist: 33" | Hip: 39" | Wearing Size: 31x32


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Super Monday Night Combat
Super Monday Night Combat Overview
Super Monday Night Combat is a third person MOBA that puts players in the role of gladiators/fighters in a futuristic televised combat game, in which the objective is to destroy the other team's moneyball. It takes inspiration from many games and genres, from DOTA, Team Fortress 2, to tower defense, and mashes those genres together in a humoristic cocktail that will have you laughing as you gun down your opponent. The variety of characters and classes leads to different play styles and team roles that are all as important in the making of a balanced, victorious team. Each character progresses through matches by improving their abilities, recruiting new minions and buying power-ups. Once the match ends, you're left with some coins to purchase products & endorsements, or you can always save up for a new character. The classes are;
Commandos – This high difficulty, high reward close range class has you surging through enemy lines with movement powers in order to dispatch specific foes with melee abilities. Warning; about as solid as wet tissue!
Strikers – Generalists with a leaning towards ranged combat, but the ability to play many roles well. Essential for a team, they fill the gaps that specialists cannot fill.
Enforcers – Strong, tanky pros with some solid damage and utility abilities. These are the characters you want to initiate, and take the brunt of enemy punishment.
Defenders – Support and defense specialists, efficient at holding positions, buffing their team mates, and keeping them healed. Absolutely necessary; they are the glue that binds the team.
Sniper – Long-range damage dealers meant to support other classes with accurate fire support. Player skill makes or breaks this class.
Super Monday Night Combat Screenshots
Super Monday Night Combat Featured Video
Super Monday Night Combat Full Review
Super Monday Night Combat is back, a definite upgrade from the Xbox Live's Monday Night Combat, this time in free-to-play flavor, and with a whole lot more content (though perhaps still not quite enough). If you pick your game by style or flair, then folks, let me tell you this is one you will not want to miss. It includes a meager, but interesting cast of characters, some solid potential for team play oriented action, and enough challenge to go around. It's also very closely inspired from Team Fortress 2, while also picking from other genres such as MOBAs and tower defenses, mixing various elements into an entertaining mix that blurs the lines of different genres. That being said, does Super Monday Night Combat hit the gold mine with this new mish-mash of a gameplay, or does it fall flat?
Well, for a starter, it hasn't been said enough how bloody hilarious this game is; this is exactly the kind of flair that attracts and "Wows" new players, but that's not exactly so important for the long term appeal, though more on that later. Graphics are definitely one of this game's strong points, and the rocking soundtrack isn't bad either, complementing well the characters/maps. When you start up the game, you'll most likely not be entirely sure what to expect, after all this isn't exactly a straightforward FPS. Well, unfortunately, there's not much interaction in the tutorials as they are actually written guides complemented by YouTube videos. Is that a bad thing? Well, while this makes the size of the game smaller, it seems a bit lacking as far as tutorials go, though there is thankfully a training mode you should most definitely try before playing a real game. Once that's done, you should nonetheless still have an acceptable understanding of game mechanics, enough to get you started in your first game.
Giant Robot Chickens
So how does it all work? Similarly to other MOBA's, you get on a localized matchmaking queue, get matched up, pick a character, and there you go. Games are fairly straightforward; two teams are fighting to take each other's moneyball down, and to do so, you must push towards it with the help of friendly "bots", weaker minions that are released constantly, wave after wave. You will have to take down enemy defenses and pros in order to do so, with the help of a variety of bonuses and super minions you can yourself purchase. The action itself is smooth, the performance is generally good, and winning a game feels very rewarding. Throughout every match, you progress in levels through kills, gaining points you can either put in one of your character's 3 spells, or his offense/defense stats. Matches are filled with bonuses you can grab, ranging from bacon to neutral "creeps" you can take attack for gold/experience, notably Chickey Cantor, a giant robot chicken with its very own soundtrack (YouTube it, it's hilarious). The main issue on this level doesn't actually come from the gameplay; it's simply that leavers are absolutely rampant. There has seldom been a match during the reviewing of this game where there has not been someone absent from one of the two teams.
Cool Guys + Explosions
The character designs are excellent, ranging from floating inventors to a gangster gorilla (complete with Thompson machinegun), and each has a complete set of voice acting, some fairly intricate taunts, and a complete set of role-oriented abilities, dividing characters between damage dealers, tanks, support, long-range damage, and sometimes a few wild mixes thrown in. This leads to a very firmly team oriented gameplay, and lone wolves will often suffer, and make their team suffer in turn. Characters in SMNC are on a rotation, which means that you'll get access to a different number of them every week unless you've bought them from the money store, and that you're very likely to see the same characters over and over again. Thankfully, most of them are a blast to play with, and each has a solid variety of spells or supportive abilities to throw around. They can also all be customized in a variety of ways, for one with endorsements, a sort of items that give you a bonus while, while giving you a disadvantage for the sake of balance. The other way is products, that are basically special effects you can add to your arsenal, with an example being a bomb being dropped upon your death, or a speed boost upon spawning. Both of these types can be purchased with money won in-game, with real money from the cash store, or can be randomly won after a match. You can also add taunts and change the skins of your character or weapon, if the entire experience just isn't crazy and bubbly enough for you.
Bacon Galore
Most of the humor found here is not only contributed in great part by the two announcers, constantly cracking jokes as the match goes, but also by the very iconic character cast. You'll often hear other "pros" yelling out one-liners, and added to the already crowded background, this makes the entire experience very flashy, intense and bright. In fact, playing Super Monday Night Combat often feels like one big sugar rush and it's undeniably very hectic fun. Like a sugar rush however, it can be a short experience as there are currently few characters and maps to enjoy, which definitely blocks what could be a much more fulfilling, prolonged experience. The issue is compounded by the fact that the money store is not at all cheap, and that it takes a LOT of in-game points to purchase a single character. The announcers, while funny, will end up sounding very familiar with time; there's only so fun that can be obtained from repeated humor. As mentioned previously, the money store is not cheap, and taunts can cost upwards of 6$ a piece. The only thing that can be bought with in-game combat credits are endorsements, products and characters, if you want anything more, you'll need to dish out some serious money.
Final Verdict: Great
Super Monday Night Combat is a rewarding strike out in a new direction, bringing humor and third-person action to MOBAs, while keeping intact the tactical play known to the genre. While it lacks a certain amount of content, the foundations are there for an excellent and competitive game with a hefty dose of humor, including such pop culture favorites as bacon, chicken robots and rocket launcher-wielding teenage girls. If you enjoy shooters/RPGs, and can stand the occasional leaver, you'd be shooting yourself in the foot by missing this gem. Well, what are you waiting for? Go get it while it's hot!
Super Monday Night Combat Links
Super Monday Night Combat System Requirements
(estimates based on Monday Night Combat)
Minimum Requirements:
OS: XP(SP3)/Vista/Windows 7
CPU: 2 GHz Processor
RAM: 1GB of RAM
HDD: 2 GB Free
Graphics Card: DirectX 9.0c/Shader3.0 compatible, VRAM 512 MB (NVIDIA GeForce 7800 series or ATI Radeon X1900
Super Monday Night Combat Articles
- Super MNC Now Available On GamersFirst - Posted on March 1, 2013
The free-to-play arena combat game of the century hits GamersFirst.com for the first time.


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Will the Vivaldi be using the Lima driver or using the proprietary X11 2D driver from ARM?
Phoronix: Open-Source ARM Mali Driver Update (Lima)
This weekend at LinuxTag 2012, an update was shared concerning the state of the Lima driver project -- the initiative to create a reverse-engineered, open-source ARM Mali driver...
Will the Vivaldi be using the Lima driver or using the proprietary X11 2D driver from ARM?
were they going to ever focus on making a gallium driver for the mali 400? thats what im most interesdet in, mesa not too long ago gained support for android so it would be able to provide a very capable modile gl implementation
About the timing, it depends, mostly on how much time i get to work on the project. We are doing this job in a structured way, and complete the tasks in a logical and efficient order. There is no point throwing halfarsed stuff into a mesa framework from afar while fundamental REing work is still ongoing. That's just stupid timewasting, and is simply a big and meaningless statement. I am personally quite sick of people who take huge shortcuts, leave tons of blanks, just to be able to pee against the tree, shout "I've done it!!!!!" and then run off to the next tree. That's sort of behaviour is just damaging free software.
And please, look at the timeframe for this project, and then remember that this is all reverse engineering. Where were we 6 months ago? Where are we today?
oh, so this is still in the initial RE phase, i thought this effort was to actualy create a finished product, at least thats what the phoronix articles have been billing it as.
My work/time on the shader reverse engineering and tools has been sponsored by CodeThink.With no company officially financing the work
I saw your recent YouTube video driver demo: Lima Video Driver in Action
Totally awesome work guys!
Best regards,
Rick C. Hodgin
Just ... plain ... awesome!
Best regards,
Rick C. Hodgin


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Dont know who Samantha Saint is? She's a pretty damn hot porn star thats who.
miss howard stern
...now browsing by tag
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Religion & Ethics Newsweekly
CATHOLIC CHURCH AND LABOR/KATHLEEN NORRIS/GARRISONSeries Website »
Episode Guide »
The Diocese of Scranton's severs its 30-year relationship with the city's Catholic teacher's union.
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Jim and Jill Kelly; Who Is My Neighbor?; Atul GawandeSelma March 50th Anniversary; Average MohamedRecruiting Radical Muslims; B Corp Business EthicsMuslim Initiatives Against Extremism; India's Sacred CowsSummit on Extremism; Rabbi Jonathan Sacks; Churches in PubsChurch Economics Prize; Rabbi Jonathan Sacks; LosarVaccination Debate; Homeless Female VeteransScience for Seminaries; India's Slum Dwellers; Thomas MertonState of the Union; Halki Seminary; Bruce CockburnMuslims and Paris Attacks; Restoring Community in FergusonSocial Media Ethics; Raising Children in Two FaithsLook Ahead 2015Look Back 2014Syrian Refugees in Turkey; Pictures of Mary; MessiahChurches and Race; War in Colombia; Pilgrimages; HanukkahHeroin and the Faith Community; Drugs of Last ResortCamden Priest; Inoculation EthicsPope Trip to Turkey; Recruiting Radicals; Our Lady GuadalupeMuslims Against Extremism; Church Move; Judaism & HomelessPhysician-Assisted Death; B Corp Ethics; Kent NerburnMigrant Minors in Court; Buddhism & Nature; Church Rebuilds
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DMCV Sharks Soccer Jerseys, Equipment & Uniforms
Del Mar Carmel Valley Sharks players, coaches & families, welcome to soccerloco! As your club's official uniform supplier and partner, this is the place to get your Del Mar Carmel Valley Sharks uniforms, training gear, fan gear and more.
Del Mar Carmel Valley Sharks Uniforms & Kit Builder
In order to ensure you receive your correct club pricing, we require that you login before shopping DMCV Sharks equipment, uniforms & jerseys. If you need directions on how to create an account and assign it to your club, please click here.


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$15.99 List Price.
You Save $2$13.99Goal Club Members
$13.0942Goal Club Points
Customization adds additional time to the shipping time of your order, regardless of which shipping method you choose.
Click here for Estimated Ship Date. No returns are accepted for customized items.
Represent Oklahoma Arsenal!
Classic adidas, classic soccer. Crew neck tee with adidas logo screened on back. 100% cotton. Imported. NOTE: Gray is 90/10 cotton/polyester.
Lamentamos que todavia no hay descripción en español para este producto.


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Kanye West will be U2's opening act
Kanye West will be U2's opening act
by Celebrity
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Kanye West will be U2's opening act
Now that's sounds like an amazing show!!!
Read More PS...
Link Love
- Zendaya on her many hairstyles: "It's called a wig, people" — Us Weekly
- Dating tips straight from a Game of Thrones actress — HuffPost Celebrity
- Henry Cavill pops up at a London award show — Lainey Gossip
- Jon Hamm reveals the big role he had to turn down — Dlisted
- Jenny McCarthy thinks The View is a sinking ship — ET
- Paula Patton talks about life after splitting from Robin Thicke — JustJared
- This Victoria's Secret model's new shoot is so "en pointe" — Hollywood Tuna
- The Heroes remake signs on another series original! — Pink Is the New Blog
- Bill Cosby isn't doing himself any favors — The Superficial
- This star just had a strain of marijuana named after him — The Blemish


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View by: Most Popular | Alphabetical A to Z | Map
Sheikh Zayed Grand Mosque Center
The Sheikh Zayed Grand Mosque, the largest in the United Arab Emirates and eighth largest in the world, rises majestically from Abu Dhabi and serves as the central place of worship for citizens of ... Read more
Abu Dhabi Corniche
The Abu Dhabi Corniche stretches along the northwestern shore of the island city, a popular spot for beachside recreation. The 5-mile (8-kilometer) stretch of attractive waterfront includes walking ... Read more
Abu Dhabi Heritage Village
Located on the Corniche Breakwater, the Emirates Heritage Club runs a reconstructed traditional village demonstrating the lifestyles and traditions of the cultures native to the Arabian Peninsula. If ... Read more
Emirates Palace
Not to be outdone by Dubai's Burj Al Arab, Abu Dhabi opened its own seven-star hotel in 2005. The Emirates Palace, managed by the Kempinski Group, sits just outside the city on its own private ... Read more
Saadiyat Island
The residential, commercial and leisure area known as Saadiyat Island sits just off the coast of Abu Dhabi. While the project is still under development and set to be completed in 2020, visitors can ... Read more
Ferrari World Abu Dhabi
It's only fitting that a city as extravagant as Abu Dhabi has a theme park to match its extravagance, and in this case, that theme park is Ferrari World Abu Dhabi. The race car-themed park features ... Read more
Abu Dhabi Cruise Port
Towering skyscrapers, modern high rises and brilliant flashing lights greet travelers who dock at this urban port. Abu Dhabi, the largest and wealthiest of the emirates, is ripe with ornate royal ... Read more
Abu Dhabi Falcon Hospital
Usually, it's bad news when your vacation includes a trip to the hospital, but that's not always the case in Abu Dhabi. The Abu Dhabi Falcon Hospital is one of the city's more bizarre yet fascinating ... Read more
Al Ain Oasis
In the heart of Al Ain, a garden-filled city located 100 miles (160 kilometers) east of Abu Dhabi, you'll find the Al Ain Oasis. The largest green space in the emirate of Abu Dhabi offers a welcome ... Read more
Cultural Foundation
Housed in a beautiful contemporary Islamic-style building, the Cultural Foundation serves as the hub for Abu Dhabi's events—with art exhibitions, concerts, theatrical performances, workshops and ... Read more
Jebel Hafeet
Just outside the city of Al Ain, straddling the border of the United Arab Emirates and Oman, Jebel Hafeet rises 4,068 feet (1,240 meters) above the desert landscape. It's the highest peak in the ... Read more
Yas Waterworld
With 45 rides and slides Yas Waterworld is the ideal destination for thrill-seeking adrenaline junkies, active families and daredevil day-trippers. Adventurous visitors can navigate the high-speed ... Read more


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Students: The planet needs you to get involved!
Join Greenpeace's Activist Network to protect the Arctic, get your campus to adopt sustainable seafood policies, protect our national forests, and take down dirty energy.
The Greenpeace Semester has closed. However, please join us through the link above to find out about future trainings and other opportunities!
Want to learn more about tax-deductible giving, donating stock and estate planning? Visit Greenpeace Fund, a nonprofit, 501(c)(3) charitable entity created to increase public awareness and understanding of environmental issues through research, the media and educational programs.


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48 hours until kickoff!
The day before, the day before...
USC kicker Andre Heidari was a Freshman All-American before a knee injury slowed down his sophomore campaign. He is healthy now and booming the ball in anticipation of a big 2013. #AudiDrive2Kickoff
This season marks the 125th anniversary of USC Football. Just 82 days until kickoff... #AudiDrive2Kickoff
Thanks to @TonyBoselli, an all-time great Trojan, for dropping by USC spring practice. #TrojanFamily
Epic photo of @USCDFLO10 by @JohnMcGillen from USC Spring Practice at the Coliseum. #CelebrateAllVictories