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Treatment of Pediatric Low-Grade Gliomas

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Abstract

Purpose of Review

Pediatric low-grade gliomas and glioneuronal tumors (pLGG) account for approximately 30% of pediatric CNS neoplasms, encompassing a heterogeneous group of tumors of primarily glial or mixed neuronal-glial histology. This article reviews the treatment of pLGG with emphasis on an individualized approach incorporating multidisciplinary input from surgery, radiation oncology, neuroradiology, neuropathology, and pediatric oncology to carefully weigh the risks and benefits of specific interventions against tumor-related morbidity. Complete surgical resection can be curative for cerebellar and hemispheric lesions, while use of radiotherapy is restricted to older patients or those refractory to medical therapy. Chemotherapy remains the preferred first-line therapy for adjuvant treatment of the majority of recurrent or progressive pLGG.

Recent Findings

Technologic advances offer the potential to limit volume of normal brain exposed to low doses of radiation when treating pLGG with either conformal photon or proton RT. Recent neurosurgical techniques such as laser interstitial thermal therapy offer a “dual” diagnostic and therapeutic treatment modality for pLGG in specific surgically inaccessible anatomical locations. The emergence of novel molecular diagnostic tools has enabled scientific discoveries elucidating driver alterations in mitogen-activated protein kinase (MAPK) pathway components and enhanced our understanding of the natural history (oncogenic senescence). Molecular characterization strongly supplements the clinical risk stratification (age, extent of resection, histological grade) to improve diagnostic precision and accuracy, prognostication, and can lead to the identification of patients who stand to benefit from precision medicine treatment approaches.

Summary

The success of molecular targeted therapy (BRAF inhibitors and/or MEK inhibitors) in the recurrent setting has led to a gradual and yet significant paradigm shift in the treatment of pLGG. Ongoing randomized trials comparing targeted therapy to standard of care chemotherapy are anticipated to further inform the approach to upfront management of pLGG patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231–51. https://doi.org/10.1093/neuonc/noab106. (The updated 2021 CNS WHO classification introduced a revised classification system for adult and pediatric-type gliomas.•)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wisoff JH, Sanford RA, Heier LA, Sposto R, Burger PC, Yates AJ, et al. Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children’s Oncology Group. Neurosurgery. 2011;68(6):1548–54. https://doi.org/10.1227/NEU.0b013e318214a66e. (discussion 54-5).

    Article  PubMed  Google Scholar 

  3. Bandopadhayay P, Bergthold G, London WB, Goumnerova LC, Morales La Madrid A, Marcus KJ, 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):1173–9. https://doi.org/10.1002/pbc.24958.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Packer RJ, Pfister S, Bouffet E, Avery R, Bandopadhayay P, Bornhorst M, et al. Pediatric low-grade gliomas: implications of the biologic era. Neuro Oncol. 2017;19(6):750–61. https://doi.org/10.1093/neuonc/now209.

    Article  CAS  PubMed  Google Scholar 

  5. Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 2008;118(5):1739–49. https://doi.org/10.1172/JCI33656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet. 2013;45(6):602–12. https://doi.org/10.1038/ng.2611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. • Ryall S, Zapotocky M, Fukuoka K, Nobre L, Guerreiro Stucklin A, Bennett J, et al. Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas. Cancer Cell. 2020;37(4):569-83.e5. https://doi.org/10.1016/j.ccell.2020.03.011. (International collaborative report representing the largest cohort of clinically and molecularly annotated cohort of pLGGs that sheds light on the pLGG molecular landscape and proposes a novel risk stratification system with the potential to improve prognostication and impact treatment.•)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gajjar A, Bowers DC, Karajannis MA, Leary S, Witt H, Gottardo NG. Pediatric brain tumors: innovative genomic information is transforming the diagnostic and clinical landscape. J Clin Oncol. 2015;33(27):2986–98. https://doi.org/10.1200/JCO.2014.59.9217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hwang EI, Kool M, Burger PC, Capper D, Chavez L, Brabetz S, et al. Extensive molecular and clinical heterogeneity in patients with histologically diagnosed CNS-PNET treated as a single entity: a report from the Children’s Oncology Group Randomized ACNS0332 Trial. J Clin Oncol. 2018;36(34):JCO2017764720. https://doi.org/10.1200/JCO.2017.76.4720.

    Article  PubMed  Google Scholar 

  10. Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 2015;129(5):669–78. https://doi.org/10.1007/s00401-015-1405-4.

    Article  CAS  PubMed  Google Scholar 

  11. •• Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20(7):1011–22. https://doi.org/10.1016/S1470-2045(19)30277-3. (First prospective phase II study consortium-based study demonstrating promising efficacy of MEK inhibition in recurrent/refractory pediatric low-grade gliomas with and without NF1. These results led the COG to launch 2 prospective randomized phase III clinical trials for patients with newly diagnosed pediatric low-grade gliomas comparing targeted therapy versus standard of care chemotherapy in patients with and without NF1.••)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jacob K, Quang-Khuong D-A, Jones DTW, Witt H, Lambert S, Albrecht S, et al. Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res. 2011;17(14):4650–60. https://doi.org/10.1158/1078-0432.Ccr-11-0127.

    Article  CAS  PubMed  Google Scholar 

  13. Bale TA, Rosenblum MK. The 2021 WHO classification of tumors of the central nervous system: an update on pediatric low-grade gliomas and glioneuronal tumors. Brain Pathology. 2022;32(4):e13060. https://doi.org/10.1111/bpa.13060.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Packer RJ, Lange B, Ater J, Nicholson HS, Allen J, Walker R, et al. Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol. 1993;11(5):850–6. https://doi.org/10.1200/JCO.1993.11.5.850.

    Article  CAS  PubMed  Google Scholar 

  15. Jones DTW, Kieran MW, Bouffet E, Alexandrescu S, Bandopadhayay P, Bornhorst M, et al. Pediatric low-grade gliomas: next biologically driven steps. Neuro Oncol. 2018;20(2):160–73. https://doi.org/10.1093/neuonc/nox141.

    Article  CAS  PubMed  Google Scholar 

  16. Giantini-Larsen AM, Pannullo S, Juthani RG. Challenges in the diagnosis and management of low-grade gliomas. World Neurosurg. 2022.

  17. 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. https://doi.org/10.1097/MPH.0b013e3182678bf8.

    Article  PubMed  Google Scholar 

  18. Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009;24(11):1397–408. https://doi.org/10.1177/0883073809342005.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gajjar A, Sanford RA, Heideman R, Jenkins JJ, Walter A, Li Y, et al. Low-grade astrocytoma: a decade of experience at St. Jude Children’s Research Hospital. J Clin Oncol. 1997;15(8):2792–9. https://doi.org/10.1200/JCO.1997.15.8.2792.

    Article  CAS  PubMed  Google Scholar 

  20. Fisher PG, Tihan T, Goldthwaite PT, Wharam MD, Carson BS, Weingart JD, et al. Outcome analysis of childhood low-grade astrocytomas. Pediatr Blood Cancer. 2008;51(2):245–50. https://doi.org/10.1002/pbc.21563.

    Article  PubMed  Google Scholar 

  21. Broniscer A, Baker SJ, West AN, Fraser MM, Proko E, Kocak M, et al. Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. J Clin Oncol. 2007;25(6):682–9. https://doi.org/10.1200/jco.2006.06.8213.

    Article  CAS  PubMed  Google Scholar 

  22. Tovar-Spinoza Z, Choi H. MRI-guided laser interstitial thermal therapy for the treatment of low-grade gliomas in children: a case-series review, description of the current technologies and perspectives. Childs Nerv Syst. 2016;32(10):1947–56. https://doi.org/10.1007/s00381-016-3193-0.

    Article  PubMed  Google Scholar 

  23. Easwaran TP, Lion A, Vortmeyer AO, Kingery K, Bc M, Raskin JS. Seizure freedom from recurrent insular low-grade glioma following laser interstitial thermal therapy. Childs Nerv Syst. 2020;36(5):1055–9. https://doi.org/10.1007/s00381-019-04493-6.

    Article  CAS  PubMed  Google Scholar 

  24. Karajannis MA, Souweidane MM, Dunkel IJ. Letter to the Editor regarding clinical debate concerning treatment of pediatric LGG by Cooney et al. Neurooncol Pract. 2020;7(5):569–70. https://doi.org/10.1093/nop/npaa019.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Revere KE, Katowitz WR, Katowitz JA, Rorke-Adams L, Fisher MJ, Liu GT. Childhood optic nerve glioma: vision loss due to biopsy. Ophthalmic Plast Reconstr Surg. 2017;33(3S Suppl 1):S107–9. https://doi.org/10.1097/IOP.0000000000000687.

    Article  PubMed  Google Scholar 

  26. Taveras JM, Mount LA, Wood EH. The value of radiation therapy in the management of glioma of the optic nerves and chiasm. Radiology. 1956;66(4):518–28. https://doi.org/10.1148/66.4.518.

    Article  CAS  PubMed  Google Scholar 

  27. Erkal HS, Serin M, Cakmak A. Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy. Radiother Oncol. 1997;45(1):11–5. https://doi.org/10.1016/s0167-8140(97)00102-3.

    Article  CAS  PubMed  Google Scholar 

  28. Cappelli C, Grill J, Raquin M, Pierre-Kahn A, Lellouch-Tubiana A, Terrier-Lacombe MJ, et al. Long-term follow up of 69 patients treated for optic pathway tumours before the chemotherapy era. Arch Dis Child. 1998;79(4):334–8. https://doi.org/10.1136/adc.79.4.334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jahraus CD, Tarbell NJ. Optic pathway gliomas. Pediatr Blood Cancer. 2006;46(5):586–96. https://doi.org/10.1002/pbc.20655.

    Article  PubMed  Google Scholar 

  30. Armstrong GT, Conklin HM, Huang S, Srivastava D, Sanford R, Ellison DW, et al. Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol. 2011;13(2):223–34. https://doi.org/10.1093/neuonc/noq178.

    Article  PubMed  Google Scholar 

  31. Oh KS, Hung J, Robertson PL, Garton HJ, Muraszko KM, Sandler HM, et al. Outcomes of multidisciplinary management in pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2011;81(4):e481–8. https://doi.org/10.1016/j.ijrobp.2011.01.019.

    Article  PubMed  Google Scholar 

  32. Mishra KK, Puri DR, Missett BT, Lamborn KR, Prados MD, Berger MS, et al. The role of up-front radiation therapy for incompletely resected pediatric WHO grade II low-grade gliomas. Neuro Oncol. 2006;8(2):166–74. https://doi.org/10.1215/15228517-2005-011.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Watson GA, Kadota RP, Wisoff JH. Multidisciplinary management of pediatric low-grade gliomas. Semin Radiat Oncol. 2001;11(2):152–62. https://doi.org/10.1053/srao.2001.21421.

    Article  CAS  PubMed  Google Scholar 

  34. Pollack IF, Claassen D, al-Shboul Q, Janosky JE, Deutsch M. Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases. J Neurosurg. 1995;82(4):536–47. https://doi.org/10.3171/jns.1995.82.4.0536.

    Article  CAS  PubMed  Google Scholar 

  35. Raikar SS, Halloran DR, Elliot M, McHugh M, Patel S, Gauvain KM. Outcomes of pediatric low-grade gliomas treated with radiation therapy: a single-institution study. J Pediatr Hematol Oncol. 2014;36(6):e366–70. https://doi.org/10.1097/MPH.0000000000000142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tsang DS, Murphy ES, Merchant TE. Radiation therapy for optic pathway and hypothalamic low-grade gliomas in children. Int J Radiat Oncol Biol Phys. 2017;99(3):642–51. https://doi.org/10.1016/j.ijrobp.2017.07.023.

    Article  PubMed  Google Scholar 

  37. Packer RJ, Sutton LN, Atkins TE, Radcliffe J, Bunin GR, D’Angio G, et al. A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg. 1989;70(5):707–13. https://doi.org/10.3171/jns.1989.70.5.0707.

    Article  CAS  PubMed  Google Scholar 

  38. 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 Off J Am Soc Clin Oncol. 2009;27(22):3691–7. https://doi.org/10.1200/JCO.2008.21.2738.

    Article  Google Scholar 

  39. Brauner R, Malandry F, Rappaport R, Zucker JM, Kalifa C, Pierre-Kahn A, et al. Growth and endocrine disorders in optic glioma. Eur J Pediatr. 1990;149(12):825–8. https://doi.org/10.1007/BF02072067.

    Article  CAS  PubMed  Google Scholar 

  40. Bowers DC, Mulne AF, Reisch JS, Elterman RD, Munoz L, Booth T, et al. Nonperioperative strokes in children with central nervous system tumors. Cancer. 2002;94(4):1094–101.

    Article  PubMed  Google Scholar 

  41. Armstrong GT, Liu Q, Yasui Y, Huang S, Ness KK, Leisenring W, 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):946–58. https://doi.org/10.1093/jnci/djp148.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Harrabi SB, Bougatf N, Mohr A, Haberer T, Herfarth K, Combs SE, et al. Dosimetric advantages of proton therapy over conventional radiotherapy with photons in young patients and adults with low-grade glioma. Strahlenther Onkol. 2016;192(11):759–69. https://doi.org/10.1007/s00066-016-1005-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Takizawa D, Mizumoto M, Yamamoto T, Oshiro Y, Fukushima H, Fukushima T, et al. A comparative study of dose distribution of PBT, 3D-CRT and IMRT for pediatric brain tumors. Radiat Oncol. 2017;12(1):40. https://doi.org/10.1186/s13014-017-0775-2.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Yock TI, Bhat S, Szymonifka J, Yeap BY, Delahaye J, Donaldson SS, et al. Quality of life outcomes in proton and photon treated pediatric brain tumor survivors. Radiother Oncol. 2014;113(1):89–94. https://doi.org/10.1016/j.radonc.2014.08.017.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer. 2016;122(10):1483–501. https://doi.org/10.1002/cncr.29882.

    Article  PubMed  Google Scholar 

  46. Greenberger BA, Pulsifer MB, Ebb DH, MacDonald SM, Jones RM, Butler WE, et al. Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2014;89(5):1060–8. https://doi.org/10.1016/j.ijrobp.2014.04.053.

    Article  PubMed  Google Scholar 

  47. Indelicato DJ, Bates JE, Mailhot Vega RB, Rotondo RL, Hoppe BS, Morris CG, et al. Second tumor risk in children treated with proton therapy. Pediatr Blood Cancer. 2021;68(7):e28941. https://doi.org/10.1002/pbc.28941.

    Article  CAS  PubMed  Google Scholar 

  48. Indelicato D, Tringale K, Bradley J, Vega RM, Morris C, Casey D, et al. RONC-03. Secondary neoplasms in children with central nervous system (CNS) tumors following radiotherapy in the modern era. Neuro-Oncol. 2022;24(Suppl 1):i176.

    Article  PubMed Central  Google Scholar 

  49. Indelicato DJ, Rotondo RL, Uezono H, Sandler ES, Aldana PR, Ranalli NJ, et al. Outcomes following proton therapy for pediatric low-grade glioma. Int J Radiat Oncol Biol Phys. 2019;104(1):149–56. https://doi.org/10.1016/j.ijrobp.2019.01.078.

    Article  PubMed  Google Scholar 

  50. Bitterman DS, MacDonald SM, Yock TI, Tarbell NJ, Wright KD, Chi SN, et al. Revisiting the role of radiation therapy for pediatric low-grade glioma. J Clin Oncol Off J Am Soc Clin Oncol. 2019;37(35):3335–9. https://doi.org/10.1200/JCO.19.01270.

    Article  Google Scholar 

  51. Marcus KJ, Goumnerova L, Billett AL, Lavally B, Scott RM, Bishop K, 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):374–9. https://doi.org/10.1016/j.ijrobp.2004.06.012.

    Article  PubMed  Google Scholar 

  52. Cherlow JM, Shaw DWW, Margraf LR, Bowers DC, Huang J, Fouladi M, et al. Conformal radiation therapy for pediatric patients with low-grade glioma: results from the Children’s Oncology Group Phase 2 Study ACNS0221. Int J Radiat Oncol Biol Phys. 2019;103(4):861–8. https://doi.org/10.1016/j.ijrobp.2018.11.004.

    Article  PubMed  Google Scholar 

  53. Ater JL, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR, 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):2641–7. https://doi.org/10.1200/JCO.2011.36.6054.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ryall S, Tabori U, Hawkins C. Pediatric low-grade glioma in the era of molecular diagnostics. Acta Neuropathol Commun. 2020;8(1):30. https://doi.org/10.1186/s40478-020-00902-z.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Hargrave DR, Bouffet E, Tabori U, Broniscer A, Cohen KJ, Hansford JR, et al. Efficacy and safety of dabrafenib in pediatric patients with BRAF V600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I/IIa study. Clin Cancer Res. 2019;25(24):7303–11. https://doi.org/10.1158/1078-0432.Ccr-19-2177.

    Article  CAS  PubMed  Google Scholar 

  56. Gutmann DH, Donahoe J, Brown T, James CD, Perry A. Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas. Neuropathol Appl Neurobiol. 2000;26(4):361–7.

    Article  CAS  PubMed  Google Scholar 

  57. D’Angelo F, Ceccarelli M, Tala Garofano L, Zhang J, Frattini V, et al. The molecular landscape of glioma in patients with neurofibromatosis 1. Nat Med. 2019;25(1):176–87. https://doi.org/10.1038/s41591-018-0263-8.

    Article  CAS  PubMed  Google Scholar 

  58. Evans DGR, Salvador H, Chang VY, Erez A, Voss SD, Schneider KW, et al. Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 1. Clin Cancer Res. 2017;23(12):e46–53. https://doi.org/10.1158/1078-0432.Ccr-17-0589.

    Article  PubMed  Google Scholar 

  59. Bhatia S, Chen Y, Wong FL, Hageman L, Smith K, Korf B, et al. Subsequent neoplasms after a primary tumor in individuals with neurofibromatosis type 1. J Clin Oncol Off J Am Soc Clin Oncol. 2019;37(32):3050–8. https://doi.org/10.1200/jco.19.00114.

    Article  CAS  Google Scholar 

  60. Ullrich NJ, Robertson R, Kinnamon DD, Scott RM, Kieran MW, Turner CD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology. 2007;68(12):932–8. https://doi.org/10.1212/01.wnl.0000257095.33125.48.

    Article  CAS  PubMed  Google Scholar 

  61. Sampson JR, Scahill SJ, Stephenson JB, Mann L, Connor JM. Genetic aspects of tuberous sclerosis in the west of Scotland. J Med Genet. 1989;26(1):28–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125–7.

    Article  CAS  PubMed  Google Scholar 

  63. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):243–54. https://doi.org/10.1016/j.pediatrneurol.2013.08.001.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Northrup H, Koenig MK, Pearson DA, Au KS. Tuberous sclerosis complex. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA): University of Washington, Seattle

  65. Crino PB. Molecular pathogenesis of tuber formation in tuberous sclerosis complex. J Child Neurol. 2004;19(9):716–25. https://doi.org/10.1177/08830738040190091301.

    Article  PubMed  Google Scholar 

  66. Grajkowska W, Kotulska K, Jurkiewicz E, Matyja E. Brain lesions in tuberous sclerosis complex. Review Folia neuropathologica. 2010;48(3):139–49.

    PubMed  Google Scholar 

  67. van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science (New York NY). 1997;277(5327):805–8.

    Article  Google Scholar 

  68. Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, Delgado MR, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med Off J Am Coll Med Genet. 2007;9(2):88–100. https://doi.org/10.1097/GIM.0b013e31803068c7.

    Article  CAS  Google Scholar 

  69. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729–34. https://doi.org/10.1038/nrc1974.

    Article  CAS  PubMed  Google Scholar 

  70. Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A. 2002;99(21):13571–6. https://doi.org/10.1073/pnas.202476899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998;13(12):624–8. https://doi.org/10.1177/088307389801301206.

    Article  CAS  PubMed  Google Scholar 

  72. Krueger DA. Management of CNS-related disease manifestations in patients with tuberous sclerosis complex. Curr Treat Options Neurol. 2013;15(5):618–33. https://doi.org/10.1007/s11940-013-0249-2.

    Article  PubMed  Google Scholar 

  73. Goh S, Butler W, Thiele EA. Subependymal giant cell tumors in tuberous sclerosis complex. Neurology. 2004;63(8):1457–61.

    Article  PubMed  Google Scholar 

  74. Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006;59(3):490–8. https://doi.org/10.1002/ana.20784.

    Article  CAS  PubMed  Google Scholar 

  75. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801–11. https://doi.org/10.1056/NEJMoa1001671.

    Article  CAS  PubMed  Google Scholar 

  76. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381(9861):125–32. https://doi.org/10.1016/S0140-6736(12)61134-9.

    Article  CAS  PubMed  Google Scholar 

  77. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, et al. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat Med. 2008;14(8):843–8. https://doi.org/10.1038/nm1788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wiegand G, May TW, Ostertag P, Boor R, Stephani U, Franz DN. Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol. 2013;17(6):631–8. https://doi.org/10.1016/j.ejpn.2013.06.002.

    Article  PubMed  Google Scholar 

  79. Krueger DA, Care MM, Agricola K, Tudor C, Mays M, Franz DN. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology. 2013;80(6):574–80. https://doi.org/10.1212/WNL.0b013e3182815428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008;68(21):8673–7. https://doi.org/10.1158/0008-5472.CAN-08-2097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ryall S, Arnoldo A, Krishnatry R, Mistry M, Khor K, Sheth J, et al. Multiplex detection of pediatric low-grade glioma signature fusion transcripts and duplications using the NanoString nCounter System. J Neuropathol Exp Neurol. 2017;76(7):562–70. https://doi.org/10.1093/jnen/nlx042.

    Article  CAS  PubMed  Google Scholar 

  82. Becker AP, Scapulatempo-Neto C, Carloni AC, Paulino A, Sheren J, Aisner DL, et al. KIAA1549: BRAF gene fusion and FGFR1 hotspot mutations are prognostic factors in pilocytic astrocytomas. J Neuropathol Exp Neurol. 2015;74(7):743–54. https://doi.org/10.1097/nen.0000000000000213.

    Article  CAS  PubMed  Google Scholar 

  83. Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF. Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol. 2010;119(5):641–9. https://doi.org/10.1007/s00401-009-0634-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lassaletta A, Zapotocky M, Mistry M, Ramaswamy V, Honnorat M, Krishnatry R, et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol. 2017;35(25):2934–41. https://doi.org/10.1200/jco.2016.71.8726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cin H, Meyer C, Herr R, Janzarik WG, Lambert S, Jones DTW, 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):763–74. https://doi.org/10.1007/s00401-011-0817-z.

    Article  CAS  PubMed  Google Scholar 

  86. Helgager J, Lidov HG, Mahadevan NR, Kieran MW, Ligon KL, Alexandrescu S. A novel GIT2-BRAF fusion in pilocytic astrocytoma. Diagn Pathol. 2017;12(1):82. https://doi.org/10.1186/s13000-017-0669-5.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Jones DT, Hutter B, Jager N, Korshunov A, Kool M, Warnatz HJ, et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013;45(8):927–32. https://doi.org/10.1038/ng.2682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Fangusaro J, Onar-Thomas A, Poussaint TY, Lensing S, Wu S, Ligon AH, et al. LGG-06. Selumetinib in pediatric patients with non-neurofibromatosis type 1-associated, non-optic pathway (OPG) and non-pilocytic recurrent/progressive low-grade glioma harboring BRAFV600E mutation or BRAF-KIAA1549 fusion: a multicenter prospective Pediatric Brain Tumor Consortium (PBTC) Phase 2 trial. Neuro-Oncol. 2022;24(Supplement_1):i88-i. https://doi.org/10.1093/neuonc/noac079.322.

    Article  PubMed Central  Google Scholar 

  89. Fangusaro J, Onar-Thomas A, Poussaint TY, Wu S, Ligon AH, Lindeman N, et al. LGG-02. A phase II Prospective Trial Of Selumetinib In Children With Recurrent/Progressive pediatric low-grade glioma (pLGG) with a focus upon optic pathway/hypothalamic tumors and visual acuity outcomes: a pediatric brain tumor consortium (PBTC) study, PBTC-029B. Neuro-Oncol. 2019;21(Supplement_2):ii98–9. https://doi.org/10.1093/neuonc/noz036.145.

    Article  PubMed Central  Google Scholar 

  90. Robison N, Pauly J, Malvar J, Gardner S, Allen J, Margol A, et al. LTBK-04. LATE BREAKING ABSTRACT: MEK162 (binimetinib) in children with progressive or recurrent low-grade glioma: a multi-institutional phase II and target validation study. Neuro-Oncol. 2022;24(Supplement_1):i191–2. https://doi.org/10.1093/neuonc/noac079.716.

    Article  PubMed Central  Google Scholar 

  91. Perreault S, Sadat Kiaei D, Dehaes M, Larouche V, Tabori U, Hawkin C, et al. A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway. J Clin Oncol. 2022;40(16_suppl):2042. https://doi.org/10.1200/JCO.2022.40.16_suppl.2042.

    Article  Google Scholar 

  92. Trippett T, Toledano H, Campbell Hewson Q, Verschuur A, Langevin AM, Aerts I, et al. Cobimetinib in pediatric and young adult patients with relapsed or refractory solid tumors (iMATRIX-cobi): a multicenter, phase I/II study. Target Oncol. 2022;17(3):283–93. https://doi.org/10.1007/s11523-022-00888-9.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Fangusaro J, Onar-Thomas A, Wu S, Poussaint TY, Packer R, Kilburn L, et al. LGG-04. A phase II re-treatment study of selumetinib for recurrent or progressive pediatric low-grade glioma (pLGG): a pediatric brain tumor consortium (PBTC) study. Neuro-Oncol. 2020;22(Supplement_3):iii367-iii. https://doi.org/10.1093/neuonc/noaa222.389.

    Article  PubMed Central  Google Scholar 

  94. Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10(3):385–94. https://doi.org/10.1158/1535-7163.Mct-10-0799.

    Article  CAS  PubMed  Google Scholar 

  95. Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell. 2015;28(3):370–83. https://doi.org/10.1016/j.ccell.2015.08.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gierke M, Sperveslage J, Schwab D, Beschorner R, Ebinger M, Schuhmann MU, et al. Analysis of IDH1-R132 mutation, BRAF V600 mutation and KIAA1549–BRAF fusion transcript status in central nervous system tumors supports pediatric tumor classification. J Cancer Res Clin Oncol. 2016;142(1):89–100. https://doi.org/10.1007/s00432-015-2006-2.

    Article  CAS  PubMed  Google Scholar 

  97. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, 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. https://doi.org/10.1007/s00401-011-0802-6.

    Article  CAS  PubMed  Google Scholar 

  98. Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, Polley M-YC, Yu M, et al. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 2010;70(2):512–9. https://doi.org/10.1158/0008-5472.CAN-09-1851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lassaletta A, Zapotocky M, Mistry M, Ramaswamy V, Honnorat M, Krishnatry R, et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol. 2017;35(25):2934–41. https://doi.org/10.1200/JCO.2016.71.8726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Dahiya S, Haydon DH, Alvarado D, Gurnett CA, Gutmann DH, Leonard JR. BRAFV600E mutation is a negative prognosticator in pediatric ganglioglioma. Acta Neuropathol. 2013;125(6):901–10. https://doi.org/10.1007/s00401-013-1120-y.

    Article  CAS  PubMed  Google Scholar 

  101. Mistry M, Zhukova N, Merico D, Rakopoulos P, Krishnatry R, Shago M, et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol. 2015;33(9):1015–22. https://doi.org/10.1200/jco.2014.58.3922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tanaka S, Nakada M, Nobusawa S, Suzuki SO, Sabit H, Miyashita K, et al. Epithelioid glioblastoma arising from pleomorphic xanthoastrocytoma with the BRAF V600E mutation. Brain Tumor Pathol. 2014;31(3):172–6. https://doi.org/10.1007/s10014-014-0192-2.

    Article  PubMed  Google Scholar 

  103. Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 2015;129(5):669–78. https://doi.org/10.1007/s00401-015-1405-4.

    Article  CAS  PubMed  Google Scholar 

  104. Wen PY, Stein A, van den Bent M, De Greve J, Wick A, de Vos FYFL, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. 2022;23(1):53–64. https://doi.org/10.1016/S1470-2045(21)00578-7.

    Article  CAS  PubMed  Google Scholar 

  105. • Salama AKS, Li S, Macrae ER, Park JI, Mitchell EP, Zwiebel JA, et al. Dabrafenib and Trametinib in Patients With Tumors With BRAF(V600E) Mutations: Results of the NCI-MATCH trial subprotocol H. J Clin Oncol Off J Am Soc Clin Oncol. 2020;38(33):3895–904. https://doi.org/10.1200/jco.20.00762. (Subprotocol H (EAY131-H) of the NCI-MATCH platform trial was a single-arm phase II histology agnostic trial investigating the combination of BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in a biomarker-selected cohort of patients with recurrent/refractory solid tumors harboring a BRAFV600 mutation. Dabrafenib and trametinib therapy resulted in responses in 38% of patients and showed a high rate of disease control across a variety of disease histologies eventually culminating in the recent FDA approval of dabrafenib and trametinib for patients with BRAFV600E-mutant solid tumors.•)

    Article  CAS  Google Scholar 

  106. •• Bouffet E, Geoerger B, Moertel C, Whitlock JA, Aerts I, Hargrave D, et al. Efficacy and safety of trametinib monotherapy or in combination with dabrafenib in pediatric BRAF V600-mutant low-grade glioma. J Clin Oncol. 2023;41(3):664–74. https://doi.org/10.1200/JCO.22.01000. (This randomized phase 2 trial tested dabrafenib with trametinib versus standard-of-care chemotherapy (carboplatin/vincristine) and demonstrated improved overall response rate (ORR) and prolonged progression-free survival (PFS) with targeted therapy compared with standard chemotherapy. Dabrafenib with trametinib represents a new standard of care for pediatric patients with newly diagnosed BRAFV600-mutant low-grade glioma.•)

    Article  CAS  PubMed  Google Scholar 

  107. Karajannis MA, Legault G, Fisher MJ, Milla SS, Cohen KJ, Wisoff JH, et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. 2014;16(10):1408–16. https://doi.org/10.1093/neuonc/nou059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sievert AJ, Lang SS, Boucher KL, Madsen PJ, Slaunwhite E, Choudhari N, 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):5957–62. https://doi.org/10.1073/pnas.1219232110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Clarke M, Mackay A, Ismer B, Pickles JC, Tatevossian RG, Newman S, et al. Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes. Cancer Discov. 2020;10(7):942–63. https://doi.org/10.1158/2159-8290.CD-19-1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gessi M, Moneim YA, Hammes J, Goschzik T, Scholz M, Denkhaus D, et al. FGFR1 mutations in Rosette-forming glioneuronal tumors of the fourth ventricle. J Neuropathol Exp Neurol. 2014;73(6):580–4. https://doi.org/10.1097/nen.0000000000000080.

    Article  CAS  PubMed  Google Scholar 

  111. Sievers P, Appay R, Schrimpf D, Stichel D, Reuss DE, Wefers AK, et al. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol. 2019;138(3):497–504. https://doi.org/10.1007/s00401-019-02038-4.

    Article  CAS  PubMed  Google Scholar 

  112. Lasorella A, Sanson M, Iavarone A. FGFR-TACC gene fusions in human glioma. Neuro Oncol. 2017;19(4):475–83. https://doi.org/10.1093/neuonc/now240.

    Article  CAS  PubMed  Google Scholar 

  113. Huse JT, Snuderl M, Jones DT, Brathwaite CD, Altman N, Lavi E, et al. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol. 2017;133(3):417–29. https://doi.org/10.1007/s00401-016-1639-9.

    Article  CAS  PubMed  Google Scholar 

  114. Qaddoumi I, Orisme W, Wen J, Santiago T, Gupta K, Dalton JD, et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol. 2016;131(6):833–45. https://doi.org/10.1007/s00401-016-1539-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Farouk Sait S, Gilheeney SW, Bale TA, Haque S, Dinkin MJ, Vitolano S, et al. Debio1347, an oral FGFR inhibitor: results from a single-center study in pediatric patients with recurrent or refractory FGFR-altered gliomas. JCO Precis Oncol. 2021;5. https://doi.org/10.1200/po.20.00444.

  116. Bandopadhayay P, Ramkissoon LA, Jain P, Bergthold G, Wala J, Zeid R, et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet. 2016;48(3):273–82. https://doi.org/10.1038/ng.3500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ramkissoon LA, Horowitz PM, Craig JM, Ramkissoon SH, Rich BE, Schumacher SE, et al. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A. 2013;110(20):8188–93. https://doi.org/10.1073/pnas.1300252110.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Cicirò Y, Sala A. MYB oncoproteins: emerging players and potential therapeutic targets in human cancer. Oncogenesis. 2021;10(2):19. https://doi.org/10.1038/s41389-021-00309-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chan E, Bollen AW, Sirohi D, Van Ziffle J, Grenert JP, Kline CN, et al. Angiocentric glioma with MYB-QKI fusion located in the brainstem, rather than cerebral cortex. Acta Neuropathol. 2017;134(4):671–3. https://doi.org/10.1007/s00401-017-1759-x.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Chiang J, Harreld JH, Tinkle CL, Moreira DC, Li X, Acharya S, et al. A single-center study of the clinicopathologic correlates of gliomas with a MYB or MYBL1 alteration. Acta Neuropathol. 2019;138(6):1091–2. https://doi.org/10.1007/s00401-019-02081-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. D’Aronco L, Rouleau C, Gayden T, Crevier L, Décarie J-C, Perreault S, et al. Brainstem angiocentric gliomas with MYB–QKI rearrangements. Acta Neuropathol. 2017;134(4):667–9. https://doi.org/10.1007/s00401-017-1763-1.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Li KW, Roonprapunt C, Lawson HC, Abbott IR, Wisoff J, Epstein F, et al. Endoscopic third ventriculostomy for hydrocephalus associated with tectal gliomas. Neurosurg Focus. 2005;18(6a):E2.

    PubMed  Google Scholar 

  123. Epstein F, Constantini S. Practical decisions in the treatment of pediatric brain stem tumors. Pediatr Neurosurg. 1996;24(1):24–34. https://doi.org/10.1159/000121011.

    Article  CAS  PubMed  Google Scholar 

  124. Liu APY, Harreld JH, Jacola LM, Gero M, Acharya S, Ghazwani Y, et al. Tectal glioma as a distinct diagnostic entity: a comprehensive clinical, imaging, histologic and molecular analysis. Acta Neuropathol Commun. 2018;6(1):101. https://doi.org/10.1186/s40478-018-0602-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lapras C, Bognar L, Turjman F, Villanyi E, Mottolese C, Fischer C, et al. Tectal plate gliomas. Part I: microsurgery of the tectal plate gliomas. Acta Neurochir (Wien). 1994;126(2–4):76–83. https://doi.org/10.1007/bf01476414.

    Article  CAS  PubMed  Google Scholar 

  126. May PL, Blaser SI, Hoffman HJ, Humphreys RP, Harwood-Nash DC. Benign intrinsic tectal “tumors” in children. J Neurosurg. 1991;74(6):867–71. https://doi.org/10.3171/jns.1991.74.6.0867.

    Article  CAS  PubMed  Google Scholar 

  127. Chiang J, Li X, Liu APY, Qaddoumi I, Acharya S, Ellison DW. Tectal glioma harbors high rates of KRAS G12R and concomitant KRAS and BRAF alterations. Acta Neuropathol. 2020;139(3):601–2. https://doi.org/10.1007/s00401-019-02112-x.

    Article  CAS  PubMed  Google Scholar 

  128. Dağlioğlu E, Cataltepe O, Akalan N. Tectal gliomas in children: the implications for natural history and management strategy. Pediatr Neurosurg. 2003;38(5):223–31. https://doi.org/10.1159/000069823.

    Article  PubMed  Google Scholar 

  129. Disabato JA, Handler MH, Strain JD, Fleitz JM, Foreman NK. Successful use of intracavitary bleomycin for low-grade astrocytoma tumor cyst. Pediatr Neurosurg. 1999;31(5):246–50. https://doi.org/10.1159/000028871.

    Article  CAS  PubMed  Google Scholar 

  130. Giovanini MA, Mickle JP. Long-term access to cystic brain stem lesions using the Ommaya reservoir: technical case report. Neurosurg. 1996;39(2):404–7. https://doi.org/10.1097/00006123-199608000-00039. (discussion 7-8).

    Article  CAS  Google Scholar 

  131. Perwein T, Benesch M, Kandels D, Pietsch T, Schmidt R, Quehenberger F, et al. High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group. Neuro Oncol. 2021;23(7):1148–62. https://doi.org/10.1093/neuonc/noaa296.

    Article  CAS  PubMed  Google Scholar 

  132. Packer RJ, Ater J, Allen J, Phillips P, Geyer R, Nicholson HS, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86(5):747–54. https://doi.org/10.3171/jns.1997.86.5.0747.

    Article  CAS  PubMed  Google Scholar 

  133. Mahoney DH Jr, Cohen ME, Friedman HS, Kepner JL, Gemer L, Langston JW, et al. Carboplatin is effective therapy for young children with progressive optic pathway tumors: a Pediatric Oncology Group phase II study. Neuro Oncol. 2000;2(4):213–20. https://doi.org/10.1093/neuonc/2.4.213.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Laithier V, Grill J, Le Deley MC, Ruchoux MM, Couanet D, Doz F, 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 Off J Am Soc Clin Oncol. 2003;21(24):4572–8. https://doi.org/10.1200/jco.2003.03.043.

    Article  CAS  Google Scholar 

  135. Gnekow AK, Falkenstein F, von Hornstein S, Zwiener I, Berkefeld S, Bison B, 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):1265–84. https://doi.org/10.1093/neuonc/nos202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Chintagumpala M, Eckel SP, Krailo M, Morris M, Adesina A, Packer R, et al. A pilot study using carboplatin, vincristine, and temozolomide in children with progressive/symptomatic low-grade glioma: a Children’s Oncology Group study†. Neuro Oncol. 2015;17(8):1132–8. https://doi.org/10.1093/neuonc/nov057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Gnekow AK, Walker DA, Kandels D, Picton S, Giorgio P, Grill J, et al. A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma - a final report. Eur J Cancer. 2017;81:206–25. https://doi.org/10.1016/j.ejca.2017.04.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lassaletta A, Scheinemann K, Zelcer SM, Hukin J, Wilson BA, Jabado N, et al. Phase II weekly vinblastine for chemotherapy-naïve children with progressive low-grade glioma: a Canadian Pediatric Brain Tumor Consortium Study. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(29):3537–43. https://doi.org/10.1200/jco.2016.68.1585.

    Article  CAS  Google Scholar 

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This work has been supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center.

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  1. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Sameer Farouk Sait & Matthias A. Karajannis

  2. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA

    Alexandra M. Giantini-Larsen & Mark M. Souweidane

  3. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Kathryn R. Tringale

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Dr. Karajannis reports grants from Y-mAbs Therapeutics (research support) and personal fees from Bayer, AstraZeneca, QED Therapeutics, CereXis, Recursion, Alexion, Cardinal Health, and Medscape (medical advisory board and/or consultant). Dr. Tringale reports grants from Hopper Belmont Foundation and RSNA Resident Grant, as well as honoraria from GT Medical Technologies. Drs. Farouk Sait and Souweidane report no relationships, conditions, or circumstances that present a potential conflict of interest.

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Sait, S.F., Giantini-Larsen, A.M., Tringale, K.R. et al. Treatment of Pediatric Low-Grade Gliomas. Curr Neurol Neurosci Rep 23, 185–199 (2023). https://doi.org/10.1007/s11910-023-01257-3

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