The Changing Landscape of Pediatric Low-Grade Gliomas: Clinical Challenges and Emerging Therapies

Abstract

Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children. Though histologically benign and associated with excellent outcome, patients with unresectable lesions—mostly young children with midline tumors—experience multiple progressions and are at increased risk for long-term neurological sequelae. PLGGs in children with underlying genetic predisposition syndromes—especially neurofibromatosis type 1 and tuberous sclerosis—have a distinct natural history and biology with important treatment implications. Given the complexity of medical issues, optimal management requires a large network of health care providers; treatment decisions must address both tumor control and potential side effects of the therapy. Current treatment strategies often fail to induce sustained tumor regression and many children require several lines of therapy, highlighting the need for novel therapies. Here, we review the current management of PLGG and discuss how new molecular targets—in particular alterations of the Ras/MAPK pathway—are rapidly changing our approach to PLGG.

Keywords

low-grade glioma - children - Ras/MAPK - NF1 - tuberous sclerosis

• References

• 1 Ostrom QT, Gittleman H, Liao P , et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-oncol 2014; 16 (Suppl. 04) iv1-iv63
• 2 Bandopadhayay P, Bergthold G, London WB , et al. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer 2014; 61 (7) 1173-1179
• 3 Wisoff 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 2011; 68 (6) 1548-1554 , discussion 1554–1555
• 4 Arora RS, Alston RD, Eden TO, Estlin EJ, Moran A, Birch JM. Age-incidence patterns of primary CNS tumors in children, adolescents, and adults in England. Neuro-oncol 2009; 11 (4) 403-413
• 5 Stokland 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 2010; 12 (12) 1257-1268
• 6 Sinson G, Sutton LN, Yachnis AT, Duhaime AC, Schut L. Subependymal giant cell astrocytomas in children. Pediatr Neurosurg 1994; 20 (4) 233-239
• 7 Gajjar A, Sanford RA, Heideman R , et al; Jude Children's Research Hospital. Low-grade astrocytoma: a decade of experience at St. J Clin Oncol 1997; 15 (8) 2792-2799
• 8 Youland RS, Khwaja SS, Schomas DA, Keating GF, Wetjen NM, Laack NN. Prognostic factors and survival patterns in pediatric low-grade gliomas over 4 decades. J Pediatr Hematol Oncol 2013; 35 (3) 197-205
• 9 Benesch M, Lackner H, Sovinz P , et al. Late sequela after treatment of childhood low-grade gliomas: a retrospective analysis of 69 long-term survivors treated between 1983 and 2003. J Neurooncol 2006; 78 (2) 199-205
• 10 Qaddoumi 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 2009; 115 (24) 5761-5770
• 11 Douw L, Klein M, Fagel SS , et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol 2009; 8 (9) 810-818
• 12 Aarsen FK, Paquier PF, Reddingius RE , et al. Functional outcome after low-grade astrocytoma treatment in childhood. Cancer 2006; 106 (2) 396-402
• 13 Johnson BE, Mazor T, Hong C , et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 2014; 343 (6167) 189-193
• 14 Mistry M, Zhukova N, Merico D , et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 2015; 33 (9) 1015-1022
• 15 Broniscer A, Baker SJ, West AN , et al. Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. J Clin Oncol 2007; 25 (6) 682-689
• 16 Ater 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 2012; 30 (21) 2641-2647
• 17 Bouffet E, Jakacki R, Goldman S , et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol 2012; 30 (12) 1358-1363
• 18 Massimino M, Spreafico F, Cefalo G , et al. High response rate to cisplatin/etoposide regimen in childhood low-grade glioma. J Clin Oncol 2002; 20 (20) 4209-4216
• 19 Prados MD, Edwards MS, Rabbitt J, Lamborn K, Davis RL, Levin VA. Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen. J Neurooncol 1997; 32 (3) 235-241
• 20 Laithier V, Grill J, Le Deley MC , et al; French Society of Pediatric Oncology. 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 2003; 21 (24) 4572-4578
• 21 Gururangan S, Fisher MJ, Allen JC , et al. Temozolomide in children with progressive low-grade glioma. Neuro-oncol 2007; 9 (2) 161-168
• 22 Cappellano AM, Petrilli AS, da Silva NS , et al. Single agent vinorelbine in pediatric patients with progressive optic pathway glioma. J Neurooncol 2015; 121 (2) 405-412
• 23 Pfister S, Janzarik WG, Remke M , et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 2008; 118 (5) 1739-1749
• 24 Jones DT, Hutter B, Jäger N , et al; International Cancer Genome Consortium PedBrain Tumor Project. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 2013; 45 (8) 927-932
• 25 Zhang J, Wu G, Miller CP , et al; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013; 45 (6) 602-612
• 26 Louis DN, Ohgaki H, Wiestler OD , et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114 (2) 97-109
• 27 Tihan T, Fisher PG, Kepner JL , et al. Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropathol Exp Neurol 1999; 58 (10) 1061-1068
• 28 Jeon YK, Cheon JE, Kim SK, Wang KC, Cho BK, Park SH. Clinicopathological features and global genomic copy number alterations of pilomyxoid astrocytoma in the hypothalamus/optic pathway: comparative analysis with pilocytic astrocytoma using array-based comparative genomic hybridization. Mod Pathol 2008; 21 (11) 1345-1356
• 29 Kepes JJ, Rubinstein LJ, Eng LF. Pleomorphic xanthoastrocytoma: a distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer 1979; 44 (5) 1839-1852
• 30 Giannini C, Scheithauer BW, Burger PC , et al. Pleomorphic xanthoastrocytoma: what do we really know about it?. Cancer 1999; 85 (9) 2033-2045
• 31 Fouladi M, Jenkins J, Burger P , et al. Pleomorphic xanthoastrocytoma: favorable outcome after complete surgical resection. Neuro-oncol 2001; 3 (3) 184-192
• 32 Lellouch-Tubiana A, Boddaert N, Bourgeois M , et al. Angiocentric neuroepithelial tumor (ANET): a new epilepsy-related clinicopathological entity with distinctive MRI. Brain Pathol 2005; 15 (4) 281-286
• 33 Rodriguez FJ, Lim KS, Bowers D, Eberhart CG. Pathological and molecular advances in pediatric low-grade astrocytoma. Annu Rev Pathol 2013; 8: 361-379
• 34 Tibbetts KM, Emnett RJ, Gao F, Perry A, Gutmann DH, Leonard JR. Histopathologic predictors of pilocytic astrocytoma event-free survival. Acta Neuropathol 2009; 117 (6) 657-665
• 35 Bowers DC, Gargan L, Kapur P , et al. Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents. J Clin Oncol 2003; 21 (15) 2968-2973
• 36 Dirven CM, Koudstaal J, Mooij JJ, Molenaar WM. The proliferative potential of the pilocytic astrocytoma: the relation between MIB-1 labeling and clinical and neuro-radiological follow-up. J Neurooncol 1998; 37 (1) 9-16
• 37 Fisher BJ, Naumova E, Leighton CC , et al. Ki-67: a prognostic factor for low-grade glioma?. Int J Radiat Oncol Biol Phys 2002; 52 (4) 996-1001
• 38 Zülch KJ. Histological Typing of Tumours of the Central Nervous System. Geneva: World Health Organization; 1979
• 39 Kleihues P, Burger PC, Scheithauer BW , et al. Histological Typing of Tumours of the Central Nervous System. 2nd ed. Berlin; New York: Springer-Verlag; 1993
• 40 Dudley RW, Torok MR, Gallegos DR , et al. Pediatric low-grade ganglioglioma: epidemiology, treatments, and outcome analysis on 348 children from the surveillance, epidemiology, and end results database. Neurosurgery 2015; 76 (3) 313-319 , discussion 319, quiz 319–320
• 41 Scheinemann K, Bartels U, Huang A , et al. Survival and functional outcome of childhood spinal cord low-grade gliomas. Clinical article. J Neurosurg Pediatr 2009; 4 (3) 254-261
• 42 Gnekow AK, Falkenstein F, von Hornstein S , et al. Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro-oncol 2012; 14 (10) 1265-1284
• 43 von 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 2011; 56 (7) 1046-1054
• 44 Lewis RA, Gerson LP, Axelson KA, Riccardi VM, Whitford RP. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology 1984; 91 (8) 929-935
• 45 Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372 (9639) 657-668
• 46 Roth J, Roach ES, Bartels U , et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol 2013; 49 (6) 439-444
• 47 Porto L, Kieslich M, Franz K , et al. Spectroscopy of untreated pilocytic astrocytomas: do children and adults share some metabolic features in addition to their morphologic similarities?. Childs Nerv Syst 2010; 26 (6) 801-806
• 48 Strong JA, Hatten Jr HP, Brown MT , et al. Pilocytic astrocytoma: correlation between the initial imaging features and clinical aggressiveness. AJR Am J Roentgenol 1993; 161 (2) 369-372
• 49 Kreth FW, Faist M, Rossner R, Volk B, Ostertag CB. Supratentorial World Health Organization Grade 2 astrocytomas and oligoastrocytomas. A new pattern of prognostic factors. Cancer 1997; 79 (2) 370-379
• 50 Floeth FW, Pauleit D, Sabel M , et al. Prognostic value of O-(2-18F-fluoroethyl)-L-tyrosine PET and MRI in low-grade glioma. J Nucl Med 2007; 48 (4) 519-527
• 51 Wen PY, Macdonald DR, Reardon DA , et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010; 28 (11) 1963-1972
• 52 Gonen O, Wang ZJ, Viswanathan AK, Molloy PT, Zimmerman RA. Three-dimensional multivoxel proton MR spectroscopy of the brain in children with neurofibromatosis type 1. AJNR Am J Neuroradiol 1999; 20 (7) 1333-1341
• 53 Pont MS, Elster AD. Lesions of skin and brain: modern imaging of the neurocutaneous syndromes. AJR Am J Roentgenol 1992; 158 (6) 1193-1203
• 54 Castillo M, Green C, Kwock L , et al. Proton MR spectroscopy in patients with neurofibromatosis type 1: evaluation of hamartomas and clinical correlation. AJNR Am J Neuroradiol 1995; 16 (1) 141-147
• 55 DiPaolo DP, Zimmerman RA, Rorke LB, Zackai EH, Bilaniuk LT, Yachnis AT. Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain. Radiology 1995; 195 (3) 721-724
• 56 Gutmann DH, Aylsworth A, Carey JC , et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997; 278 (1) 51-57
• 57 Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13 (8) 834-843
• 58 Arnautovic A, Billups C, Broniscer A, Gajjar A, Boop F, Qaddoumi I. Delayed diagnosis of childhood low-grade glioma: causes, consequences, and potential solutions. Childs Nerv Syst 2015; 31 (7) 1067-1077
• 59 Suharwardy J, Elston J. The clinical presentation of children with tumours affecting the anterior visual pathways. Eye (Lond) 1997; 11 (Pt 6) 838-844
• 60 Desai KI, Nadkarni TD, Muzumdar DP, Goel A. Prognostic factors for cerebellar astrocytomas in children: a study of 102 cases. Pediatr Neurosurg 2001; 35 (6) 311-317
• 61 Grill J, Laithier V, Rodriguez D, Raquin MA, Pierre-Kahn A, Kalifa C. When do children with optic pathway tumours need treatment? An oncological perspective in 106 patients treated in a single centre. Eur J Pediatr 2000; 159 (9) 692-696
• 62 Gropman AL, Packer RJ, Nicholson HS , et al. Treatment of diencephalic syndrome with chemotherapy: growth, tumor response, and long term control. Cancer 1998; 83 (1) 166-172
• 63 Perilongo G, Carollo C, Salviati L , et al. Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region. Cancer 1997; 80 (1) 142-146
• 64 Poussaint TY, Barnes PD, Nichols K , et al. Diencephalic syndrome: clinical features and imaging findings. AJNR Am J Neuroradiol 1997; 18 (8) 1499-1505
• 65 Griessenauer CJ, Rizk E, Miller JH , et al. Pediatric tectal plate gliomas: clinical and radiological progression, MR imaging characteristics, and management of hydrocephalus. J Neurosurg Pediatr 2014; 13 (1) 13-20
• 66 Pollack IF, Pang D, Albright AL. The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. J Neurosurg 1994; 80 (4) 681-688
• 67 Stark AM, Fritsch MJ, Claviez A, Dörner L, Mehdorn HM. Management of tectal glioma in childhood. Pediatr Neurol 2005; 33 (1) 33-38
• 68 Bleeker FE, Hopman SM, Merks JH, Aalfs CM, Hennekam RC. Brain tumors and syndromes in children. Neuropediatrics 2014; 45 (3) 137-161
• 69 Hagel C, Stemmer-Rachamimov AO, Bornemann A , et al. Clinical presentation, immunohistochemistry and electron microscopy indicate neurofibromatosis type 2-associated gliomas to be spinal ependymomas. Neuropathology 2012; 32 (6) 611-616
• 70 Kleihues P, Schäuble B, zur Hausen A, Estève J, Ohgaki H. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 1997; 150 (1) 1-13
• 71 Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet 2011; 157C (2) 83-89
• 72 Huson SM, Compston DA, Clark P, Harper PS. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J Med Genet 1989; 26 (11) 704-711
• 73 [Anonymous]. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, MD., USA, July 13-15, 1987. Neurofibromatosis 1988; 1 (3) 172-178
• 74 Wallace MR, Marchuk DA, Andersen LB , et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990; 249 (4965) 181-186
• 75 DeClue JE, Papageorge AG, Fletcher JA , et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 1992; 69 (2) 265-273
• 76 Yunoue S, Tokuo H, Fukunaga K , et al. Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras. J Biol Chem 2003; 278 (29) 26958-26969
• 77 von Deimling A, Krone W, Menon AG. Neurofibromatosis type 1: pathology, clinical features and molecular genetics. Brain Pathol 1995; 5 (2) 153-162
• 78 Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol 2009; 145 (8) 883-887
• 79 Wimmer K, Kratz CP, Vasen HF , et al; EU-Consortium Care for CMMRD (C4CMMRD). Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD). J Med Genet 2014; 51 (6) 355-365
• 80 Tan TY, Orme LM, Lynch E , et al. Biallelic PMS2 mutations and a distinctive childhood cancer syndrome. J Pediatr Hematol Oncol 2008; 30 (3) 254-257
• 81 Shlien A, Campbell BB, de Borja R , et al; Biallelic Mismatch Repair Deficiency Consortium. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet 2015; 47 (3) 257-262
• 82 Chan JA, Zhang H, Roberts PS , et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 2004; 63 (12) 1236-1242
• 83 Malmer B, Grönberg H, Bergenheim AT, Lenner P, Henriksson R. Familial aggregation of astrocytoma in northern Sweden: an epidemiological cohort study. Int J Cancer 1999; 81 (3) 366-370
• 84 Sadetzki S, Bruchim R, Oberman B , et al; Gliogene Consortium. Description of selected characteristics of familial glioma patients - results from the Gliogene Consortium. Eur J Cancer 2013; 49 (6) 1335-1345
• 85 Shete S, Lau CC, Houlston RS , et al; Gliogene Consortium. Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium. Cancer Res 2011; 71 (24) 7568-7575
• 86 Jalali A, Amirian ES, Bainbridge MN , et al. Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium. Sci Rep 2015; 5: 8278
• 87 Fried I, Tabori U, Tihan T, Reginald A, Bouffet E. Optic pathway gliomas: a review. CNS Oncol 2013; 2 (2) 143-159
• 88 Walker EJ, Zhang C, Castelo-Branco P , et al. Monoallelic expression determines oncogenic progression and outcome in benign and malignant brain tumors. Cancer Res 2012; 72 (3) 636-644
• 89 Walker DA, Liu J, Kieran M , et al; CPN Paris 2011 Conference Consensus Group. A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neuro-oncol 2013; 15 (4) 462-468
• 90 Leonard JR, Perry A, Rubin JB, King AA, Chicoine MR, Gutmann DH. The role of surgical biopsy in the diagnosis of glioma in individuals with neurofibromatosis-1. Neurology 2006; 67 (8) 1509-1512
• 91 Lam C, Bouffet E, Tabori U, Mabbott D, Taylor M, Bartels U. Rapamycin (sirolimus) in tuberous sclerosis associated pediatric central nervous system tumors. Pediatr Blood Cancer 2010; 54 (3) 476-479
• 92 Krueger DA, Care MM, Holland K , et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363 (19) 1801-1811
• 93 Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 2009; 27 (22) 3691-3697
• 94 Grill J, Couanet D, Cappelli C , et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 1999; 45 (3) 393-396
• 95 Rosenstock JG, Evans AE, Schut L. Response to vincristine of recurrent brain tumors in children. J Neurosurg 1976; 45 (2) 135-140
• 96 Lefkowitz IB, Packer RJ, Sutton LN , et al. Results of the treatment of children with recurrent gliomas with lomustine and vincristine. Cancer 1988; 61 (5) 896-902
• 97 Packer RJ, Sutton LN, Bilaniuk LT , et al. Treatment of chiasmatic/hypothalamic gliomas of childhood with chemotherapy: an update. Ann Neurol 1988; 23 (1) 79-85
• 98 Packer RJ, Ater J, Allen J , et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 1997; 86 (5) 747-754
• 99 Lafay-Cousin L, Holm S, Qaddoumi I , et al. Weekly vinblastine in pediatric low-grade glioma patients with carboplatin allergic reaction. Cancer 2005; 103 (12) 2636-2642
• 100 Bartels U, Hawkins C, Jing M , et al. Vascularity and angiogenesis as predictors of growth in optic pathway/hypothalamic gliomas. J Neurosurg 2006; 104 (5, Suppl): 314-320
• 101 Hatva E, Böhling T, Jääskeläinen J, Persico MG, Haltia M, Alitalo K. Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol 1996; 148 (3) 763-775
• 102 Friedman HS, Petros WP, Friedman AH , et al. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 1999; 17 (5) 1516-1525
• 103 Friedman HS, Prados MD, Wen PY , et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27 (28) 4733-4740
• 104 Fangusaro J, Gururangan S, Poussaint TY , et al. Bevacizumab (BVZ)-associated toxicities in children with recurrent central nervous system tumors treated with BVZ and irinotecan (CPT-11): a Pediatric Brain Tumor Consortium Study (PBTC-022). Cancer 2013; 119 (23) 4180-4187
• 105 Packer RJ, Jakacki R, Horn M , et al. Objective response of multiply recurrent low-grade gliomas to bevacizumab and irinotecan. Pediatr Blood Cancer 2009; 52 (7) 791-795
• 106 Hwang EI, Jakacki RI, Fisher MJ , et al. Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas. Pediatr Blood Cancer 2013; 60 (5) 776-782
• 107 Gururangan S, Fangusaro J, Poussaint TY , et al. Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas—a Pediatric Brain Tumor Consortium study. Neuro-oncol 2014; 16 (2) 310-317
• 108 Avery RA, Hwang EI, Jakacki RI, Packer RJ. Marked recovery of vision in children with optic pathway gliomas treated with bevacizumab. JAMA Ophthalmol 2014; 132 (1) 111-114
• 109 Scheinemann K, Bartels U, Tsangaris E , et al. Feasibility and efficacy of repeated chemotherapy for progressive pediatric low-grade gliomas. Pediatr Blood Cancer 2011; 57 (1) 84-88
• 110 Marcus 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 2005; 61 (2) 374-379
• 111 Merchant TE, Kun LE, Wu S, Xiong X, Sanford RA, Boop FA. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 2009; 27 (22) 3598-3604
• 112 Muller K, Gnekow A, Falkenstein F , et al. Radiotherapy in pediatric pilocytic astrocytomas. A subgroup analysis within the prospective multicenter study HIT-LGG 1996 by the German Society of Pediatric Oncology and Hematology (GPOH). Strahlentherapie und Onkologie. Strahlentherapie und Onkologie 2013; 189: 647-655
• 113 Paulino AC, Mazloom A, Terashima K , et al. Intensity-modulated radiotherapy (IMRT) in pediatric low-grade glioma. Cancer 2013; 119 (14) 2654-2659
• 114 Saran FH, Baumert BG, Khoo VS , et al. Stereotactically guided conformal radiotherapy for progressive low-grade gliomas of childhood. Int J Radiat Oncol Biol Phys 2002; 53 (1) 43-51
• 115 Klein M, Heimans JJ, Aaronson NK , et al. Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet 2002; 360 (9343) 1361-1368
• 116 Sharif S, Ferner R, Birch JM , et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol 2006; 24 (16) 2570-2575
• 117 Nicolin G, Parkin P, Mabbott D , et al. Natural history and outcome of optic pathway gliomas in children. Pediatr Blood Cancer 2009; 53 (7) 1231-1237
• 118 Kalamarides M, Acosta MT, Babovic-Vuksanovic D , et al. Neurofibromatosis 2011: a report of the Children's Tumor Foundation annual meeting. Acta Neuropathol 2012; 123 (3) 369-380
• 119 Armstrong GT, Liu Q, Yasui Y , et al. Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study. J Natl Cancer Inst 2009; 101 (13) 946-958
• 120 Armstrong GT. Long-term survivors of childhood central nervous system malignancies: the experience of the Childhood Cancer Survivor Study. Eur J Paediatr Neurol 2010; 14 (4) 298-303
• 121 Ellenberg L, Liu Q, Gioia G , et al. Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology 2009; 23 (6) 705-717
• 122 Zuzak TJ, Poretti A, Drexel B, Zehnder D, Boltshauser E, Grotzer MA. Outcome of children with low-grade cerebellar astrocytoma: long-term complications and quality of life. Childs Nerv Syst 2008; 24 (12) 1447-1455
• 123 Avery RA, Bouffet E, Packer RJ, Reginald A. Feasibility and comparison of visual acuity testing methods in children with neurofibromatosis type 1 and/or optic pathway gliomas. Invest Ophthalmol Vis Sci 2013; 54 (2) 1034-1038
• 124 Fisher MJ, Avery RA, Allen JC , et al; REiNS International Collaboration. Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology 2013; 81 (21) (Suppl. 01) S15-S24
• 125 Fisher MJ, Loguidice M, Gutmann DH , et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro-oncol 2012; 14 (6) 790-797
• 126 Jacob K, Albrecht S, Sollier C , et al. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 2009; 101 (4) 722-733
• 127 Jones DT, Kocialkowski S, Liu L , et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008; 68 (21) 8673-8677
• 128 Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 2008; 67 (9) 878-887
• 129 Deshmukh H, Yeh TH, Yu J , et al. High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene 2008; 27 (34) 4745-4751
• 130 Cin H, Meyer C, Herr R , et al. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol 2011; 121 (6) 763-774
• 131 Dahiya S, Yu J, Kaul A, Leonard JR, Gutmann DH. Novel BRAF alteration in a sporadic pilocytic astrocytoma. Case Rep Med 2012; 2012: 418672
• 132 Dimitriadis E, Alexiou GA, Tsotsou P , et al. BRAF alterations in pediatric low grade gliomas and mixed neuronal-glial tumors. J Neurooncol 2013; 113 (3) 353-358
• 133 Roth JJ, Santi M, Pollock AN , et al. Chromosome band 7q34 deletions resulting in KIAA1549-BRAF and FAM131B-BRAF fusions in pediatric low-grade Gliomas. Brain Pathol 2015; 25 (2) 182-192
• 134 Lawson AR, Hindley GF, Forshew T , et al. RAF gene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology. Genome Res 2011; 21 (4) 505-514
• 135 Hawkins C, Walker E, Mohamed N , et al. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 2011; 17 (14) 4790-4798
• 136 Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro-oncol 2012; 14 (6) 777-789
• 137 Ida CM, Lambert SR, Rodriguez FJ , et al. BRAF alterations are frequent in cerebellar low-grade astrocytomas with diffuse growth pattern. J Neuropathol Exp Neurol 2012; 71 (7) 631-639
• 138 Jacob K, Quang-Khuong DA, Jones DT , et al. Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 2011; 17 (14) 4650-4660
• 139 Tabori U, Vukovic B, Zielenska M , et al. The role of telomere maintenance in the spontaneous growth arrest of pediatric low-grade gliomas. Neoplasia 2006; 8 (2) 136-142
• 140 Davies H, Bignell GR, Cox C , et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417 (6892) 949-954
• 141 Schindler 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 2011; 121 (3) 397-405
• 142 Dahiya S, Haydon DH, Alvarado D, Gurnett CA, Gutmann DH, Leonard JR. BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma. Acta Neuropathol 2013; 125 (6) 901-910
• 143 Wan PT, Garnett MJ, Roe SM , et al; Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004; 116 (6) 855-867
• 144 Huillard E, Hashizume R, Phillips JJ , et al. Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc Natl Acad Sci U S A 2012; 109 (22) 8710-8715
• 145 Raabe EH, Lim KS, Kim JM , et al. BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res 2011; 17 (11) 3590-3599
• 146 Michaloglou C, Vredeveld LC, Soengas MS , et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005; 436 (7051) 720-724
• 147 Rodriguez EF, Scheithauer BW, Giannini C , et al. PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathol 2011; 121 (3) 407-420
• 148 Arcaro A, Guerreiro AS. The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics 2007; 8 (5) 271-306
• 149 Sepp T, Yates JR, Green AJ. Loss of heterozygosity in tuberous sclerosis hamartomas. J Med Genet 1996; 33 (11) 962-964
• 150 Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH. Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev 2012; 26 (23) 2561-2566
• 151 Chapman PB, Hauschild A, Robert C , et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364 (26) 2507-2516
• 152 Rochet NM, Kottschade LA, Markovic SN. Vemurafenib for melanoma metastases to the brain. N Engl J Med 2011; 365 (25) 2439-2441
• 153 Flaherty KT, Robert C, Hersey P , et al; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367 (2) 107-114
• 154 Robert C, Karaszewska B, Schachter J , et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372 (1) 30-39
• 155 Karajannis MA, Legault G, Fisher MJ , et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro-oncol 2014; 16 (10) 1408-1416
• 156 Sievert AJ, Lang SS, Boucher KL , et al. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci U S A 2013; 110 (15) 5957-5962
• 157 Shih KC, Shastry M, Williams JT , et al. Successful treatment with dabrafenib (GSK2118436) in a patient with ganglioglioma. J Clin Oncol 2014; 32 (29) e98-e100