rentradВестник рентгенологии и радиологииJournal of radiology and nuclear medicine0042-46762619-0478Limited Liability Company "LUCHEVAYA DIAGNOSTIKA", Russian Association of Radiologists10.20862/0042-4676-2015-0-1-1-27rentrad-7Research ArticleОБЗОРЫREVIEWSДиффузно растущие опухоли ствола мозга у детей и подростков: изменила ли результаты изменяющаяся тактика лечения?Diffusely growing brainstem tumors in children and adolescents: Has alternating treatment policy changed results?ЩербенкоО. И.ShcherbenkoO. I.

д. м. н., профессор, вед. науч. сотр. лаборатории комплексных методов лечения онкологических заболеваний у детей

MD, PhD, DSc, Professor, Leading Researcher of Laboratory of Complex Methods of Treating Cancer in Children

ФГБУ «Российский научный центр рентгенорадиологии» Министерства здравоохранения РФРоссияFederal Scientific Center of Roentgenradiology, Ministry of Health of the RFRussian Federation201527022016014351Copyright © Щербенко О.И., 20162016Щербенко О.И.Shcherbenko O.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.russianradiology.ru/jour/article/view/7

Проведен анализ публикаций в Medline за последние 20 лет, посвященных лечению диффузно растущих опухолей ствола мозга у детей и подростков. Основным методом лечения этих  заболеваний остаются лучевая и химиолучевая терапия. Использование различных вариантов фракционирования дозы облучения и разных комбинаций цитотоксических препаратов не привело к существенным изменениям отдаленных результатов. Большинство больных, независимо от варианта примененного лечения, умирают в течение ближайших 1–2 лет от прогрессирования опухоли. Прогноз в основном зависит от биологических свойств опухоли, в течение длительного срока живут, как правило, больные с вариантами глиом низкой злокачественности. Качество жизни длительно живущих после лечения больных в разной степени страдает из-за отдаленных последствий лучевой терапии. Надежды на повышение эффективности лечения связаны с разработкой методов таргетной терапии на основе молекулярно-биологических маркеров.

 

 

 

 

 

 

The authors analyze the MEDLINE publications in the past 20 years on the treatment of diffusely growing brainstem tumors in children and adolescents. Radiation and  chemoradiation are main treatments for these diseases. The use of different radiationdose fractionation modes and different combinations of cytotoxic drugs has caused no significant changes in long-term results. Whatever the used treatment option is, most patients die within the next 1–2 years after tumor progression. Prognosis mainly depends on the biological properties of a tumor and patients with low-grade glioma generally survive longer. The late effects of radiotherapy make quality of life worse in long-term survivorsafter treatment. Hopes to enhance therapeutic effectiveness are placed on the development of targeted therapy options based on molecular biological markers.

детиопухоли ствола мозгалучевая терапияхимиотерапиятаргетная терапияchildrenbrainstemradiotherapychemotherapytargeted therapyReferencesMen’ T.Kh., Polyakov V.G., Aliev M.D. Epidemiology of malignant neoplasms in children in Russia. Onkopediatriya. 2014; 1: 7–13 (in Russian).Men’ T.Kh., Polyakov V.G., Aliev M.D. Epidemiology of malignant neoplasms in children in Russia. Onkopediatriya. 2014; 1: 7–13 (in Russian).Halperin E.C., Constin L.S., Tarbell N.J., Kan L.E. Pediatric radiation oncology. 2nd ed. New York: Raven Press; 1994.Halperin E.C., Constin L.S., Tarbell N.J., Kan L.E. Pediatric radiation oncology. 2nd ed. New York: Raven Press; 1994.Robison N.J., Kieran M.W. Identification of novel biologic targets in the treatment of newly diagnosed diffuse intrinsic pontine glioma. Am. Soc. Clin. Oncol. Educ. Book. 2012; 32: 625–8.Robison N.J., Kieran M.W. Identification of novel biologic targets in the treatment of newly diagnosed diffuse intrinsic pontine glioma. Am. Soc. Clin. Oncol. Educ. Book. 2012; 32: 625–8.Walker D.A., Liu J., Kieran M., Jabado N., Picton S., Packer R., St Rose C. 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): 462–8.Walker D.A., Liu J., Kieran M., Jabado N., Picton S., Packer R., St Rose C. 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): 462–8.Ahmed K.A., Laack N.N., Eckel L.J., Orme N.M., Wetjen N.M. Histologically proven, low-grade brainstem gliomas in children: 30-year experience with long-term followup at Mayo Clinic. Am. J. Clin. Oncol. 2014; 37 (1): 51–6.Ahmed K.A., Laack N.N., Eckel L.J., Orme N.M., Wetjen N.M. Histologically proven, low-grade brainstem gliomas in children: 30-year experience with long-term followup at Mayo Clinic. Am. J. Clin. Oncol. 2014; 37 (1): 51–6.Cage T.A., Samagh S.P., Mueller S., Nicolaides T., Haas-Kogan D., Prados M. et al. Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children. Childs Nerv. Syst. 2013; 29 (8): 1313–9.Cage T.A., Samagh S.P., Mueller S., Nicolaides T., Haas-Kogan D., Prados M. et al. Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children. Childs Nerv. Syst. 2013; 29 (8): 1313–9.Freeman C.R. Hyperfractionated radiotherapy for diffuse intrinsic brain stem tumors in children. Pediatr. Neurosurg. 1996; 24 (2): 103–10.Freeman C.R. Hyperfractionated radiotherapy for diffuse intrinsic brain stem tumors in children. Pediatr. Neurosurg. 1996; 24 (2): 103–10.Lewis J., Lucraft H., Gholkar A. UKCCSG study of accelerated radiotherapy for pediatric brain stemgliomas. United Kingdom Childhood Cancer Study Group. Int. J. Radiat. Oncol. Biol. Phys. 1997; 38 (5): 925–9.Lewis J., Lucraft H., Gholkar A. UKCCSG study of accelerated radiotherapy for pediatric brain stemgliomas. United Kingdom Childhood Cancer Study Group. Int. J. Radiat. Oncol. Biol. Phys. 1997; 38 (5): 925–9.Hebert M.E., Halperin E.C., OakesW.J. Multiple fraction-perday radiotherapy for patients with brain stem tumors. J. Neurooncol. 1993; 17 (2): 131–8. 10. Packer R.J., Boyett J.M., Zimmerman R.A., Albright A.L., Kaplan A.M., Rorke L.B. et al. Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer. 1994; 74 (6): 1827–34.Hebert M.E., Halperin E.C., OakesW.J. Multiple fraction-perday radiotherapy for patients with brain stem tumors. J. Neurooncol. 1993; 17 (2): 131–8. 10. Packer R.J., Boyett J.M., Zimmerman R.A., Albright A.L., Kaplan A.M., Rorke L.B. et al. Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer. 1994; 74 (6): 1827–34.Janssens G.O., Jansen M.H., Lauwers S.J. Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis. J. Radiat. Oncol. Biol. Phys. 2013; 85 (2): 315–20.Janssens G.O., Jansen M.H., Lauwers S.J. Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis. J. Radiat. Oncol. Biol. Phys. 2013; 85 (2): 315–20.Zaghloul M.S., Eldebawy E., Ahmed S., Mousa A.G., Amin A., Refaat A. et al. Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): A randomized controlled trial. Radiother. Oncol. 2014; S0167-8140(14)00029-2.Zaghloul M.S., Eldebawy E., Ahmed S., Mousa A.G., Amin A., Refaat A. et al. Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): A randomized controlled trial. Radiother. Oncol. 2014; S0167-8140(14)00029-2.Negretti L., Bouchireb K., LevyPiedbois C., Habrand J.L., Dhermain F. et al. Hypofractionated radiotherapy in the treatment of diffuse intrinsic pontine glioma in children: a single institution's experience. J. Neurooncol. 2011; 104 (3): 773–7.Negretti L., Bouchireb K., LevyPiedbois C., Habrand J.L., Dhermain F. et al. Hypofractionated radiotherapy in the treatment of diffuse intrinsic pontine glioma in children: a single institution's experience. J. Neurooncol. 2011; 104 (3): 773–7.Sirachainan N., Pakakasama S., Visudithbhan A., Chiamchanya S., Tuntiyatorn L., Dhanachai M. et al. Concurrent radiotherapy with temozolomide followed by adjuvant temozolomide and cis-retinoic acid in children with diffuse intrinsic pontine glioma. Neuro Oncol. 2008; 10 (4): 577–82.Sirachainan N., Pakakasama S., Visudithbhan A., Chiamchanya S., Tuntiyatorn L., Dhanachai M. et al. Concurrent radiotherapy with temozolomide followed by adjuvant temozolomide and cis-retinoic acid in children with diffuse intrinsic pontine glioma. Neuro Oncol. 2008; 10 (4): 577–82.Fang H.H., Nie Q., Kang J.B., Li F.M., Cai C.L. Safety and efficacy of three-dimensional conformal radiotherapy combined with temozolomide in treatment of diffuse brainstem gliomas. Zhonghua Zhong Liu Za Zhi. 2011; 33 (9): 707–9.Fang H.H., Nie Q., Kang J.B., Li F.M., Cai C.L. Safety and efficacy of three-dimensional conformal radiotherapy combined with temozolomide in treatment of diffuse brainstem gliomas. Zhonghua Zhong Liu Za Zhi. 2011; 33 (9): 707–9.Shcherbenko O.I., Zorina E.V., Zelinskaya N.I., Parkhomenko R.A. Diffuse growing tumor of the brain stem as a model to assess the current capabilities of conservative treatment of inoperable glioma of the brain stem. Detskaya onkologiya. 2012; 3: 71–4 (in Russian).Shcherbenko O.I., Zorina E.V., Zelinskaya N.I., Parkhomenko R.A. Diffuse growing tumor of the brain stem as a model to assess the current capabilities of conservative treatment of inoperable glioma of the brain stem. Detskaya onkologiya. 2012; 3: 71–4 (in Russian).Chassot A., Canale S., Varlet P., Puget S., Roujeau T., Negretti L. et al. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. J. Neurooncol. 2012; 106 (2): 399–407.Chassot A., Canale S., Varlet P., Puget S., Roujeau T., Negretti L. et al. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. J. Neurooncol. 2012; 106 (2): 399–407.Chiang K.L., Chang K.P., Lee Y.Y., Huang P.I., Hsu T.R., Chen Y.W. et al. Role of temozolomide in the treatment of newly diagnosed diffuse brainstem glioma in children: experience at a single institution. Childs Nerv. Syst. 2010; 26 (8): 1035–41.Chiang K.L., Chang K.P., Lee Y.Y., Huang P.I., Hsu T.R., Chen Y.W. et al. Role of temozolomide in the treatment of newly diagnosed diffuse brainstem glioma in children: experience at a single institution. Childs Nerv. Syst. 2010; 26 (8): 1035–41.Cohen K.J., Heideman R.L., Zhou T., Holmes E.J., Lavey R.S., Bouffet E. et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group. Neuro Oncol. 2011; 13 (4): 410–6.Cohen K.J., Heideman R.L., Zhou T., Holmes E.J., Lavey R.S., Bouffet E. et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group. Neuro Oncol. 2011; 13 (4): 410–6.Bailey S., Howman A., Wheatley K., Wherton D., Boota N., Pizer B. et al. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy–results of a United Kingdom phase II trial (CNS 2007 04). Eur. J. Cancer. 2013; 49 (18): 3856–62.Bailey S., Howman A., Wheatley K., Wherton D., Boota N., Pizer B. et al. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy–results of a United Kingdom phase II trial (CNS 2007 04). Eur. J. Cancer. 2013; 49 (18): 3856–62.Miller K., Schlamann A., Guckenberger M., Warmuth-Metz M., Glьck A., Pietschmann S. et al. Quality of survival among children treated for brain stem glioma. Pediatr. Neurosurg. 1994; 20 (4): 226–32.Miller K., Schlamann A., Guckenberger M., Warmuth-Metz M., Glьck A., Pietschmann S. et al. Quality of survival among children treated for brain stem glioma. Pediatr. Neurosurg. 1994; 20 (4): 226–32.Shcherbenko O.I., Parkhomenko R.A., Zelinskaya N.I., Antonenko F.F. The effectiveness of re-irradiation therapy in continued growth the diffuse brain stem tumors in children. Rossiyskiy zhurnal detskoy gematologii i onkologii. 2014; 2: 79–80 (in Russian).Shcherbenko O.I., Parkhomenko R.A., Zelinskaya N.I., Antonenko F.F. The effectiveness of re-irradiation therapy in continued growth the diffuse brain stem tumors in children. Rossiyskiy zhurnal detskoy gematologii i onkologii. 2014; 2: 79–80 (in Russian).Kim C.Y., Kim S.K., Phi J.H., Lee M.M., Kim I.A., Kim I.H. et al. A prospective study of temozolomide plus thalidomide during and after radiation therapy for pediatric diffuse pontine gliomas: preliminary results of the Korean Society for Pediatric Neuro-Oncology study. J. Neurooncol. 2010; 100 (2): 193–8.Kim C.Y., Kim S.K., Phi J.H., Lee M.M., Kim I.A., Kim I.H. et al. A prospective study of temozolomide plus thalidomide during and after radiation therapy for pediatric diffuse pontine gliomas: preliminary results of the Korean Society for Pediatric Neuro-Oncology study. J. Neurooncol. 2010; 100 (2): 193–8.Zaky W., Wellner M., Brown R.J., Blьml S., Finlay J.L., Dhall G. Treatment of children with diffuse intrinsic pontine gliomas with chemoradiotherapy followed by a combination of temozolomide, irinotecan, and bevacizumab. Pediatr. Hematol. Oncol. 2013; 30 (7): 623–32.Zaky W., Wellner M., Brown R.J., Blьml S., Finlay J.L., Dhall G. Treatment of children with diffuse intrinsic pontine gliomas with chemoradiotherapy followed by a combination of temozolomide, irinotecan, and bevacizumab. Pediatr. Hematol. Oncol. 2013; 30 (7): 623–32.Bernier-Chastagner V., Grill J., Doz F., Bracard S., Gentet J.C., Marie-Cardine A. et al. Topotecan as a radiosensitizer in the treatment of children with malignant diffuse brainstem gliomas: results of a French Society of Paediatric Oncology Phase II Study. Cancer. 2005; 104 (12): 2792–7.Bernier-Chastagner V., Grill J., Doz F., Bracard S., Gentet J.C., Marie-Cardine A. et al. Topotecan as a radiosensitizer in the treatment of children with malignant diffuse brainstem gliomas: results of a French Society of Paediatric Oncology Phase II Study. Cancer. 2005; 104 (12): 2792–7.Korones D.N., Fisher P.G., Kretschmar C., Zhou T., Chen Z., Kepner J. et al. Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children's Oncology Group phase II study. Pediatr. Blood Cancer. 2008; 50 (2): 227–30.Korones D.N., Fisher P.G., Kretschmar C., Zhou T., Chen Z., Kepner J. et al. Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children's Oncology Group phase II study. Pediatr. Blood Cancer. 2008; 50 (2): 227–30.Michalski A., Bouffet E., Taylor R.E., Hargrave D., Walker D., Picton S. et al. The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma. J. Neurooncol. 2010; 100 (1): 81–8.Michalski A., Bouffet E., Taylor R.E., Hargrave D., Walker D., Picton S. et al. The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma. J. Neurooncol. 2010; 100 (1): 81–8.Haas-Kogan D.A., Banerjee A., Poussaint T.Y., Kocak M., Prados M.D., Geyer J.R. et al. Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas. Neuro Oncol. 2011; 13 (3): 298–306.Haas-Kogan D.A., Banerjee A., Poussaint T.Y., Kocak M., Prados M.D., Geyer J.R. et al. Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas. Neuro Oncol. 2011; 13 (3): 298–306.Bradley K.A., Zhou T., McNallKnapp R.Y. Motexafin-gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a children's oncology group phase 2 study. Int. J. Radiat. Oncol. Biol. Phys. 2013; 85 (1): 55–60.Bradley K.A., Zhou T., McNallKnapp R.Y. Motexafin-gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a children's oncology group phase 2 study. Int. J. Radiat. Oncol. Biol. Phys. 2013; 85 (1): 55–60.Ohno M., Natsume A., Fujii M., Ito M., Wakabayashi T. Interferonbeta, MCNU, and conventional radiotherapy for pediatric patients with brainstem glioma. Pediatr. Blood Cancer. 2009; 53 (1): 37–41.Ohno M., Natsume A., Fujii M., Ito M., Wakabayashi T. Interferonbeta, MCNU, and conventional radiotherapy for pediatric patients with brainstem glioma. Pediatr. Blood Cancer. 2009; 53 (1): 37–41.Wolff J.E., Rytting M., Vats T., Ater J., Mahajan A., Woo S. et al. Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience. J. Neurooncol. 2012; 106 (2): 391–7.Wolff J.E., Rytting M., Vats T., Ater J., Mahajan A., Woo S. et al. Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience. J. Neurooncol. 2012; 106 (2): 391–7.Greenberg M.L., Fisher P.G., Freeman C., Korones D.N., Bernstein M., Friedman H. et al. Etoposide, vincristine, and cyclosporin A with standard-dose radiation therapy in newly diagnosed diffuse intrinsic brainstem gliomas: a pediatric oncology group phase I study. Pediatr. Blood Cancer. 2005; 45 (5): 644–8.Greenberg M.L., Fisher P.G., Freeman C., Korones D.N., Bernstein M., Friedman H. et al. Etoposide, vincristine, and cyclosporin A with standard-dose radiation therapy in newly diagnosed diffuse intrinsic brainstem gliomas: a pediatric oncology group phase I study. Pediatr. Blood Cancer. 2005; 45 (5): 644–8.Massimino M., Spreafico F., Biassoni V., Simonetti F., Riva D., Trecate G. et al. Diffuse pontine gliomas in children: changing strategies, changing results? A mono-institutional 20-year experience. J. Neurooncol. 2008; 87 (3): 355–61.Massimino M., Spreafico F., Biassoni V., Simonetti F., Riva D., Trecate G. et al. Diffuse pontine gliomas in children: changing strategies, changing results? A mono-institutional 20-year experience. J. Neurooncol. 2008; 87 (3): 355–61.Hall W.A., Doolittle N.D., Daman M., Bruns P.K., Muldoon L., Fortin D. et al. Osmotic bloodbrain barrier disruption chemotherapy for diffuse pontine gliomas. J. Neurooncol. 2006; 77 (3): 279–84.Hall W.A., Doolittle N.D., Daman M., Bruns P.K., Muldoon L., Fortin D. et al. Osmotic bloodbrain barrier disruption chemotherapy for diffuse pontine gliomas. J. Neurooncol. 2006; 77 (3): 279–84.Kretschmar C.S., Tarbell N.J., Barnes P.D., Krischer J.P., Burger P.C., Kun L. Pre-irradiation chemotherapy and hyperfractionated radiation therapy 66 Gy for children with brain stem tumors. A phase II study of the Pediatric Oncology Group, Protocol 8833. Cancer. 1993; 72 (4): 1404–13.Kretschmar C.S., Tarbell N.J., Barnes P.D., Krischer J.P., Burger P.C., Kun L. Pre-irradiation chemotherapy and hyperfractionated radiation therapy 66 Gy for children with brain stem tumors. A phase II study of the Pediatric Oncology Group, Protocol 8833. Cancer. 1993; 72 (4): 1404–13.Jennings M.T., Sposto R., Boyett J.M., Vezina L.G., Holmes E., Berger M.S. et al. Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group. J. Clin. Oncol. 2002; 20 (16): 3431–7.Jennings M.T., Sposto R., Boyett J.M., Vezina L.G., Holmes E., Berger M.S. et al. Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group. J. Clin. Oncol. 2002; 20 (16): 3431–7.Broniscer A., Gajjar A., Bhargava R., Langston J.W., Heideman R., Jones D. et al. Brain stem involvement in children with neurofibromatosis type 1: role of magnetic resonance imaging and spectroscopy in the distinction from diffuse pontine glioma. Neurosurgery. 1997; 40(2): 331–7.Broniscer A., Gajjar A., Bhargava R., Langston J.W., Heideman R., Jones D. et al. Brain stem involvement in children with neurofibromatosis type 1: role of magnetic resonance imaging and spectroscopy in the distinction from diffuse pontine glioma. Neurosurgery. 1997; 40(2): 331–7.Bouffet E., Raquin M., Doz F., Gentet J.C., Rodary C., Demeocq F. et al. Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer. 2000; 88 (3): 685–92.Bouffet E., Raquin M., Doz F., Gentet J.C., Rodary C., Demeocq F. et al. Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer. 2000; 88 (3): 685–92.Porkholm M., Valanne L., Lцnnqvist T., Holm S., Lannering B., Riikonen P. et al. Radiation therapy and concurrent topotecan followed by maintenance triple anti-angiogenic therapy with thalidomide, etoposide, and celecoxib for pediatric diffuse intrinsic pontine glioma. Pediatr. Blood Cancer. 2014; 61 (9): 1603–9.Porkholm M., Valanne L., Lцnnqvist T., Holm S., Lannering B., Riikonen P. et al. Radiation therapy and concurrent topotecan followed by maintenance triple anti-angiogenic therapy with thalidomide, etoposide, and celecoxib for pediatric diffuse intrinsic pontine glioma. Pediatr. Blood Cancer. 2014; 61 (9): 1603–9.Felix F.H., de Araujo O.L., da Trindade K.M., Trompieri N.M., Fontenele J.B. Potential role for valproate in the treatment of highrisk brain tumors of childhoodresults from a retrospective observational cohort study. Pediatr. Hematol. Oncol. 2011; 28 (7): 556–70.Felix F.H., de Araujo O.L., da Trindade K.M., Trompieri N.M., Fontenele J.B. Potential role for valproate in the treatment of highrisk brain tumors of childhoodresults from a retrospective observational cohort study. Pediatr. Hematol. Oncol. 2011; 28 (7): 556–70.Chuba P.J., Zamarano L., Hamre M., Bhambhani K., Canady A., Guys M.B. et al. Permanent I-125 brain stem implants in children. Childs Nerv. Syst. 1998; 14 (10): 570–7.Chuba P.J., Zamarano L., Hamre M., Bhambhani K., Canady A., Guys M.B. et al. Permanent I-125 brain stem implants in children. Childs Nerv. Syst. 1998; 14 (10): 570–7.Broniscer A., Laningham F.H., Kocak M., Krasin M.J., Fouladi M., Merchant T.E. et al. Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma. Cancer. 2006; 106 (6): 1364–71.Broniscer A., Laningham F.H., Kocak M., Krasin M.J., Fouladi M., Merchant T.E. et al. Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma. Cancer. 2006; 106 (6): 1364–71.Nelson M.D., Soni D., Baram T.Z. Necrosis in pontine gliomas: radiation induced or natural history? Radiology. 1994; 191 (1): 279–82.Nelson M.D., Soni D., Baram T.Z. Necrosis in pontine gliomas: radiation induced or natural history? Radiology. 1994; 191 (1): 279–82.Griebel M., Friedman H.S., Halperin E.C., Wiener M.D., Marks L., Oakes W.J. et al. Reversible neurotoxicity following hyperfractionated radiation therapy of brain stem glioma. Med. Pediatr. Oncol. 1991; 19 (3): 182–6.Griebel M., Friedman H.S., Halperin E.C., Wiener M.D., Marks L., Oakes W.J. et al. Reversible neurotoxicity following hyperfractionated radiation therapy of brain stem glioma. Med. Pediatr. Oncol. 1991; 19 (3): 182–6.Ko C., Kaushal A., Hammoud D.A., Steffen-Smith E.A., Bent R., Citrin D. et al. Role of early postradiation magnetic resonance imaging scans in children with diffuse intrinsic pontine glioma. Int. J. Radiat. Oncol. Biol. Phys. 2012; 83 (4): 1252–6.Ko C., Kaushal A., Hammoud D.A., Steffen-Smith E.A., Bent R., Citrin D. et al. Role of early postradiation magnetic resonance imaging scans in children with diffuse intrinsic pontine glioma. Int. J. Radiat. Oncol. Biol. Phys. 2012; 83 (4): 1252–6.Combs S.E., Steck I., Schulz-Ertner D., Welzel T., Kulozik A.E., Behnisch W. et al. Long-term outcome of high-precision radiotherapy in patients with brain stem gliomas: results from a difficult-totreat patient population using fractionated stereotactic radiotherapy. Radiother. Oncol. 2009; 91 (1): 60–6.Combs S.E., Steck I., Schulz-Ertner D., Welzel T., Kulozik A.E., Behnisch W. et al. Long-term outcome of high-precision radiotherapy in patients with brain stem gliomas: results from a difficult-totreat patient population using fractionated stereotactic radiotherapy. Radiother. Oncol. 2009; 91 (1): 60–6.Klimo P. Jr, Pai Panandiker A.S., Thompson C.J. Management and outcome of focal low-grade brainstem tumors in pediatric patients: the St. Jude experience. J. Neurosurg. Pediatr. 2013; 11 (3): 274–81.Klimo P. Jr, Pai Panandiker A.S., Thompson C.J. Management and outcome of focal low-grade brainstem tumors in pediatric patients: the St. Jude experience. J. Neurosurg. Pediatr. 2013; 11 (3): 274–81.Jackson S., Patay Z., Howarth R., Pai Panandiker A.S., Onar-Thomas A., Gajjar A. et al. Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma. J. Neurooncol. 2013; 114 (3): 339–44.Jackson S., Patay Z., Howarth R., Pai Panandiker A.S., Onar-Thomas A., Gajjar A. et al. Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma. J. Neurooncol. 2013; 114 (3): 339–44.Fried I., Hawkins C., Scheinemann K., Tsangaris E., Hesselson L., Bartels U. et al. Favorable outcome with conservative treatment for children with low grade brainstem tumors. Pediatr. Blood Cancer. 2012; 58 (4): 556–60.Fried I., Hawkins C., Scheinemann K., Tsangaris E., Hesselson L., Bartels U. et al. Favorable outcome with conservative treatment for children with low grade brainstem tumors. Pediatr. Blood Cancer. 2012; 58 (4): 556–60.Pollack I.F., Shultz B., Mulvihill J.J. The management of brainstem gliomas in patients with neurofibromatosis 1. Neurology. 1996; 46 (6): 1652–60.Pollack I.F., Shultz B., Mulvihill J.J. The management of brainstem gliomas in patients with neurofibromatosis 1. Neurology. 1996; 46 (6): 1652–60.Gururangan S., Chi S.N., Young Poussaint T., Onar-Thomas A., Gilbertson R.J., Vajapeyam S. et al. Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study. J. Clin Oncol. 2010; 28 (18): 3069–75.Gururangan S., Chi S.N., Young Poussaint T., Onar-Thomas A., Gilbertson R.J., Vajapeyam S. et al. Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study. J. Clin Oncol. 2010; 28 (18): 3069–75.Wolff J.E., Rytting M.E., Vats T.S., Zage P.E., Ater J.L., Woo S. et al. Induction treatment for diffuse intrinsic pontine glioma, experience of M.D. Anderson Cancer Center. Anticancer. Res. 2011; 31 (6): 2265–9.Wolff J.E., Rytting M.E., Vats T.S., Zage P.E., Ater J.L., Woo S. et al. Induction treatment for diffuse intrinsic pontine glioma, experience of M.D. Anderson Cancer Center. Anticancer. Res. 2011; 31 (6): 2265–9.Dunkel I.J., O'Malley B., Finlay J.L. Is there a role for high-dose chemotherapy with stem cell rescue forbrain stem tumors of childhood? Pediatr. Neurosurg. 1996; 24 (5): 263–6.Dunkel I.J., O'Malley B., Finlay J.L. Is there a role for high-dose chemotherapy with stem cell rescue forbrain stem tumors of childhood? Pediatr. Neurosurg. 1996; 24 (5): 263–6.Buczkowicz P., Hoeman C., Rakopoulos P., Pajovic S., Letourneau L., Dzamba M. et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat. Genet.2014; 46 (5): 451–6.Buczkowicz P., Hoeman C., Rakopoulos P., Pajovic S., Letourneau L., Dzamba M. et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat. Genet.2014; 46 (5): 451–6.Ballester L.Y., Wang Z., Shandilya S., Miettinen M., Burger P.C., Eberhart C.G. et al. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am. J. Surg. Pathol. 2013; 37 (9): 1357–64.Ballester L.Y., Wang Z., Shandilya S., Miettinen M., Burger P.C., Eberhart C.G. et al. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am. J. Surg. Pathol. 2013; 37 (9): 1357–64.

The authors declare that there are no conflicts of interest present.