OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press2910.17650/1818-8346-2013-8-2-8-21HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯContemporary conceptions of etiology, pathogenesis, management and treatment of primary diffuse large b-cell central nervous system lymphomaсовременные представления об этиологии, патогенезе, диагностике и методах лечения первичной диффузной в-клеточной крупноклеточной лимфомы центральной нервной системыVoloshinS. V.ВолошинC. В.
Russian Federation
KrivolapovYu. A.КриволаповЮ. А.
Russian Federation
ShmidtA. V.ШмидтА. В.
Russian Federation
ShuvaevV. A.ШуваевВ. А.
Russian Federation
FominykhM. S.ФоминыхМ. С.
Russian Federation
m.s.fominyh@gmail.comAbdulkadyrovK. M.АбдулкадыровК. М.
Russian Federation
Russian Research Institute of Hematology and Transfusiology, Russian Federal Medico‑Biological AgencyФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии» ФМБА РоссииI.I. Mechnikov North-Western State Medical University, Ministry of Health of RussiaГБОУ ВПО «Северо-Западный государственный медицинский университет им. И.И. Мечникова» Минздрава России220520138282121072014210720142013https://oncohematology.abvpress.ru/ongm/article/view/29

In this article we present the most up-to-date information about etiology, pathogenesis, diagnostic and treatment principles of primary central nervous system diffuse large B-cell lymphoma. We propose algorithm of diagnosis and treatment based on literature review and own experience. The main methods for diagnosis verification are magneto-resonance tomography and stereotactic biopsy of mass with subsequent histological examination including immune staining. The common first-line therapy regimen is high-dose methotrexate therapy. However long-term prognosis still remains poor. Adverse prognostic factors for therapy response are age > 60 years, multifocal lesions, neurologic symptoms,previous treated disease. Considerable part of patient have contraindications or high-risk of adverse events for high-dose chemotherapy treatment. Anti-CD20 monoclonal antibody has no neurological toxicity with intravenous and intrathecal administrations. Combination therapy with reduced dose methotrexate and monoclonal antibody can be a reasonable treatment alternative for old and disable persons. The further survival improvement would be achieved by patient stratification and using of risk-adapted treatment algorithm. 

primary central nervous system diffuse large B-cell lymphomarisk-adapted treatmentrituximabmethotrexateintrathecal administrationпервичная диффузная В-клеточная крупноклеточная лимфома центральной нервной системыриск-адаптированная терапияритуксимабметотрексатинтратекальное введение1. Henry J.M., Heffner R.R.J., Drillard S.H. et al. Primary malignant lymphomas of the central nervous ystem. Cancer 1974;34:1293–302.Henry J.M., Heffner R.R.J., Drillard S.H. et al. Primary malignant lymphomas of the central nervous ystem. Cancer 1974;34:1293–302.2. Hochberg F.H., Miller D.C. Primary central nervous system lymphoma. J Neurosurg 1988;68:835–53.Hochberg F.H., Miller D.C. Primary central nervous system lymphoma. J Neurosurg 1988;68:835–53.3. Fine H.A., Mayer R.J. Primary central nervous system lymphoma. Ann Intern Med 1993;119:1093–104.Fine H.A., Mayer R.J. Primary central nervous system lymphoma. Ann Intern Med 1993;119:1093–104.4. Blay J.Y., Conroy T., Chevreau C. et al. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J ClinBlay J.Y., Conroy T., Chevreau C. et al. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J ClinOncol 1998;16(3):864–71.5. Ahsan H., Neugut Al., Bruce J.N. Trends in incidence of primary malignant brain tumors in USA, 1981–1990. Int J Epidemiol 1995;24:1078–85.Ahsan H., Neugut Al., Bruce J.N. Trends in incidence of primary malignant brain tumors in USA, 1981–1990. Int J Epidemiol 1995;24:1078–85.6. Lutz J.M., Coleman M.P. Trends in primary cerebral lymphoma. Brit J Cancer 1994;7(16):70.Lutz J.M., Coleman M.P. Trends in primary cerebral lymphoma. Brit J Cancer 1994;7(16):70.7. Penn I. Development of cancers as a complication of clinical transplantation. Transplantation Proc 1977;19:1121.Penn I. Development of cancers as a complication of clinical transplantation. Transplantation Proc 1977;19:1121.8. Weintraub J., Warnke R.A. Lymphoma in cardiac allotransplant recipients: clinical and histological features and immunological phenotype. Transplantation 1982;33:347.Weintraub J., Warnke R.A. Lymphoma in cardiac allotransplant recipients: clinical and histological features and immunological phenotype. Transplantation 1982;33:347.9. Hansen P.B., Penkowa M., Kirk O. et al. Human immunodeficiency virus-associated malignant lymphoma in eastern Denmark diagnosed from 1990–1996: clinical features, histopathology, and association with Epstein–Barr virus and human herpes virus. Eur J Haematol 2000;64:68–75.Hansen P.B., Penkowa M., Kirk O. et al. Human immunodeficiency virus-associated malignant lymphoma in eastern Denmark diagnosed from 1990–1996: clinical features, histopathology, and association with Epstein–Barr virus and human herpes virus. Eur J Haematol 2000;64:68–75.10. Bignon Y.J., Clavelou P., Ramos F. et al. Detection of Epstein–Barr virus sequences in primary brain lymphoma without immunodeficiency. Neurol 1991;41:1152–3.Bignon Y.J., Clavelou P., Ramos F. et al. Detection of Epstein–Barr virus sequences in primary brain lymphoma without immunodeficiency. Neurol 1991;41:1152–3.11. Camilleri-Broet S., Criniere E., Broet P. et al. Auniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 2006;107:190–6.Camilleri-Broet S., Criniere E., Broet P. et al. Auniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 2006;107:190–6.12. Balmaceda C., Gaynor J.J., Sun M. et al. Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 1995;38:202–6.Balmaceda C., Gaynor J.J., Sun M. et al. Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 1995;38:202–6.13. Brant Zawadzki M., Enzmann D.R. Computed tomographic brain scanning in patients with lymphoma. Radiology 1978;129:67–71.Brant Zawadzki M., Enzmann D.R. Computed tomographic brain scanning in patients with lymphoma. Radiology 1978;129:67–71.14. Herrlinger U., Weller M., Kuker W. Primary CNS lymphoma in the spinal cord: clinical manifеstation may precede MRI detectability. Neuroradiology 2002;44(3):239–44.Herrlinger U., Weller M., Kuker W. Primary CNS lymphoma in the spinal cord: clinical manifеstation may precede MRI detectability. Neuroradiology 2002;44(3):239–44.15. Pagani J.J., Libshitz H.I., Wallace S., Hayman L.A. Central nervous system leukemia and lymphoma: computed tomographic manifestations. Am J Roentgenol 1981;137(6):1195–201.Pagani J.J., Libshitz H.I., Wallace S., Hayman L.A. Central nervous system leukemia and lymphoma: computed tomographic manifestations. Am J Roentgenol 1981;137(6):1195–201.16. Spillane J.A., Kendall B.E., Moseley I.F. Cerebral lymphoma: clinical radiological correlation. J eurosurg Psichiatry 1982;45:199–208.Spillane J.A., Kendall B.E., Moseley I.F. Cerebral lymphoma: clinical radiological correlation. J eurosurg Psichiatry 1982;45:199–208.17. Whelan M.A., Kricheff I.I. Intracranial lymphoma. Semin Roentgenol 1984; 19:91–9.Whelan M.A., Kricheff I.I. Intracranial lymphoma. Semin Roentgenol 1984; 19:91–9.18. Jellinger K.A., Paulus W. Primary central nervous system lymphomas – an update. J Cancer Res Clin Oncol 1992;119:7–27.Jellinger K.A., Paulus W. Primary central nervous system lymphomas – an update. J Cancer Res Clin Oncol 1992;119:7–27.19. Murray K., Kun L., Cox J. Primary malignant lymphoma of the central nervous system. Results of treatment of 11 cases and review of the literature. J Neurosurg 1986;65:600–7.Murray K., Kun L., Cox J. Primary malignant lymphoma of the central nervous system. Results of treatment of 11 cases and review of the literature. J Neurosurg 1986;65:600–7.20. Bellinzona M., Roser F., Ostertag H. et al. Surgical removal of primary central nervous system lymphoma (PCNSL) presenting as space occupying lesions: a series of 33 cases. Eur J Surg OncolBellinzona M., Roser F., Ostertag H. et al. Surgical removal of primary central nervous system lymphoma (PCNSL) presenting as space occupying lesions: a series of 33 cases. Eur J Surg Oncol2005;31:100–5.;31:100–5.21. Abrey L.E., Yahalom J., DeAngelis L.M. Treatment for Primary CNS Lymphoma: The Next Step. J Clin Oncol 2000;12(17):3144–50.Abrey L.E., Yahalom J., DeAngelis L.M. Treatment for Primary CNS Lymphoma: The Next Step. J Clin Oncol 2000;12(17):3144–50.22. Bashir R., Chamberlain M., Ruby E. et al. T-cell infiltration of primary CNS lymphoma. Neurology 1996;46:440.Bashir R., Chamberlain M., Ruby E. et al. T-cell infiltration of primary CNS lymphoma. Neurology 1996;46:440.23. Miller D.C., Hochberg F.H., Harris N.L. et al. Pathology with clinical correlations of primary central nervous system non-Hodgkin’s lymphoma. The Massachusetts General Hospital experience 1958–1998. Cancer 1998;74:1383–97.Miller D.C., Hochberg F.H., Harris N.L. et al. Pathology with clinical correlations of primary central nervous system non-Hodgkin’s lymphoma. The Massachusetts General Hospital experience 1958–1998. Cancer 1998;74:1383–97.24. Braaten K.M., Betensky R.A., de Leval L. et al. BCL-6 expression predicts improved survival in patients with primary central nervous system lymphoma. Clin Cancer Res 2003;9:1063–9.Braaten K.M., Betensky R.A., de Leval L. et al. BCL-6 expression predicts improved survival in patients with primary central nervous system lymphoma. Clin Cancer Res 2003;9:1063–9.25. Ferreri A.J., Reni M., Zoldan M.C. et al. Importance of complete staging in non-Hodgkin’s lymphoma presenting as a cerebral mass lesion. Cancer 1996;77:827–33.Ferreri A.J., Reni M., Zoldan M.C. et al. Importance of complete staging in non-Hodgkin’s lymphoma presenting as a cerebral mass lesion. Cancer 1996;77:827–33.26. Gerstner E., Batchelor T. Primary central ervous system lymphoma. Arch NeurolGerstner E., Batchelor T. Primary central ervous system lymphoma. Arch Neurol2010;67(3):291–7.;67(3):291–7.27. Marcus R., Hodson D., Coupland S. et al. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). BritishMarcus R., Hodson D., Coupland S. et al. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). BritishCommittee for Standards in Haematology, 2009. Pp. 1–33.28. Ferreri A.J., Blay J.Y., Reni M. et al. Prognostic scoring system for primary CNS lymphoma: The International Extranodal Lymphoma Study Group Experience. J Clin Oncol 2003;21:266–72.Ferreri A.J., Blay J.Y., Reni M. et al. Prognostic scoring system for primary CNS lymphoma: The International Extranodal Lymphoma Study Group Experience. J Clin Oncol 2003;21:266–72.29. Hodson D.J., Bowles K.M., Cooke L.J. et al. Primary central nervous system lymphoma: a single centre experience of 55 unselected cases. Clin Oncol 2005;17:185–91.Hodson D.J., Bowles K.M., Cooke L.J. et al. Primary central nervous system lymphoma: a single centre experience of 55 unselected cases. Clin Oncol 2005;17:185–91.30. DeAngelis L.M. Primary central nervous system lymphomas. Curr Treat Options Oncol 2001;2(4):309–18.DeAngelis L.M. Primary central nervous system lymphomas. Curr Treat Options Oncol 2001;2(4):309–18.31. Reni M., Ferreri A.J.M., Garancini M.P. Therapeutic management of primary central nervous system lymphoma in immunocompetent patients: results of a critical review of the literature. Ann OncolReni M., Ferreri A.J.M., Garancini M.P. Therapeutic management of primary central nervous system lymphoma in immunocompetent patients: results of a critical review of the literature. Ann Oncol1997;8:227–34.;8:227–34.32. Bessell E.M., Graus F., Lopez-Guillermo A. et al. Primary non-Hodgkins lymphoma of the CNS treated with CHOD/BVAM or BVAM chemotherapy before radiotherapy: longterm survival and prognostic factors. Int J Radiat Oncol Biol Phys 2004;59(2):501–8.Bessell E.M., Graus F., Lopez-Guillermo A. et al. Primary non-Hodgkins lymphoma of the CNS treated with CHOD/BVAM or BVAM chemotherapy before radiotherapy: longterm survival and prognostic factors. Int J Radiat Oncol Biol Phys 2004;59(2):501–8.33. Abrey L.E., Ben-Porat L., Panageas K.S. et al. Primary central nervous system lymphoma: the Memorial Sloan–Kettering Cancer Center prognostic model. J Clin Oncol 2006;24(36):5711–15.Abrey L.E., Ben-Porat L., Panageas K.S. et al. Primary central nervous system lymphoma: the Memorial Sloan–Kettering Cancer Center prognostic model. J Clin Oncol 2006;24(36):5711–15.34. Nelson D.F., Martz K.L., Bonner H. et al. Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation TherapyNelson D.F., Martz K.L., Bonner H. et al. Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation TherapyOncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 1992;23:9–17.35. Shibamoto Y., Ogino H., Hasegawa M. et al. Results of radiation monotherapy for primary central nervous system lymphoma in the 1990s. Int J Radiat Oncol Biol Phys 2005;62:809–13.Shibamoto Y., Ogino H., Hasegawa M. et al. Results of radiation monotherapy for primary central nervous system lymphoma in the 1990s. Int J Radiat Oncol Biol Phys 2005;62:809–13.36. Schultz C., Scott C., Sherman W. et al. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiationSchultz C., Scott C., Sherman W. et al. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiationtherapy oncology group protocol 88–06. J Clin Oncol 1996;14:556–64.37. Ferreri A.J., Reni M., Dell’Oro S. et al. Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. OncologyFerreri A.J., Reni M., Dell’Oro S. et al. Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. Oncology2001;60:134–40.;60:134–40.38. DeAngelis L.M., Seiferheld W., Schold S.C. et al. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10.DeAngelis L.M., Seiferheld W., Schold S.C. et al. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10.J Clin Oncol 2002;20:4643–8.39. Poortmans P.M., Kluin-Nelemans H.C., Haaxma-Reiche H. et al. High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDSrelated primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group phase II trial 20962. J Clin Oncol 2003;21:4483–8.Poortmans P.M., Kluin-Nelemans H.C., Haaxma-Reiche H. et al. High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDSrelated primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group phase II trial 20962. J Clin Oncol 2003;21:4483–8.40. Moreton P., Morgan G.J., Gilson D. et al. The development of targeted chemotherapy for CNS lymphoma – a pilot of the IDARAM regimen. Cancer Chemother Pharmacol 2004;53(4):324–8.Moreton P., Morgan G.J., Gilson D. et al. The development of targeted chemotherapy for CNS lymphoma – a pilot of the IDARAM regimen. Cancer Chemother Pharmacol 2004;53(4):324–8.41. Omuro A.M., DeAngelis L.M., Yahalom J. et al. Chemoradiotherapy for primary CNS lymphoma: an intent to treat analysis with complete follow-up. Neurology 2005;64:69–74.Omuro A.M., DeAngelis L.M., Yahalom J. et al. Chemoradiotherapy for primary CNS lymphoma: an intent to treat analysis with complete follow-up. Neurology 2005;64:69–74.42. Shah G.D., Yahalom J., Correa D.D. et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 2007;25(30):4730–35.Shah G.D., Yahalom J., Correa D.D. et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 2007;25(30):4730–35.43. Ferreri A.J., Reni M., Foppoli M. et al. International Extranodal Lymphoma Study Group. High-dose cytarabine plus high-dose methotrexate vs high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 2009;374(9700):1512–20.Ferreri A.J., Reni M., Foppoli M. et al. International Extranodal Lymphoma Study Group. High-dose cytarabine plus high-dose methotrexate vs high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 2009;374(9700):1512–20.44. Pels H., Schmidt-Wolf I.G., Glasmacher A. et al. Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferredPels H., Schmidt-Wolf I.G., Glasmacher A. et al. Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferredradiotherapy. J Clin Oncol 2003;21:4489–95.45. Hoang-Xuan K., Taillandier L., Chinot O. et al. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the EuropeanHoang-Xuan K., Taillandier L., Chinot O. et al. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the EuropeanOrganization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 2003;21:2726–31.46. Batchelor T., Carson K., O’Neill A. et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96–07. J Clin Oncol 2003;21:1044–9.Batchelor T., Carson K., O’Neill A. et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96–07. J Clin Oncol 2003;21:1044–9.47. Herrlinger U., Schabet M., Brugger W. et al. German Cancer Society Neuro- Oncology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary central nervousHerrlinger U., Schabet M., Brugger W. et al. German Cancer Society Neuro- Oncology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary central nervoussystem lymphoma. Ann Neurol 2002;51:247–52.48. Herrlinger U., Kuker W., Uhl M. et al. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 2005;57:843–7.Herrlinger U., Kuker W., Uhl M. et al. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 2005;57:843–7.49. Angelov L., Doolittle N.D., Kraemer D.F. et al. Blood-brain barrier disruption and intraarterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol 2009;27(21):3503–9.Angelov L., Doolittle N.D., Kraemer D.F. et al. Blood-brain barrier disruption and intraarterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol 2009;27(21):3503–9.50. Colombat Ph., Lemevel A., Bertrand P. t al. High-dose chemotherapy with autologous stem cell transplantation as firstline therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Mar Transpl 2006;38:417–20.Colombat Ph., Lemevel A., Bertrand P. t al. High-dose chemotherapy with autologous stem cell transplantation as firstline therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Mar Transpl 2006;38:417–20.51. Montemurro M., Kiefer T., Schuler F. et al. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation andMontemurro M., Kiefer T., Schuler F. et al. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation andresponse-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study. Ann Oncol 2007;18:665–71.52. Abrey L.E., Batchelor T.T., Ferreri A.J. et al. International Primary CNS Lymphoma Collaborative Group. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005;23(22):5034–43.Abrey L.E., Batchelor T.T., Ferreri A.J. et al. International Primary CNS Lymphoma Collaborative Group. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005;23(22):5034–43.53. Fitzsimmons A., Upchurch K., Batchelor T. Clinical features and diagnosis of primary central nervous system lymphoma. Hematol Oncol Clin North Am 2005;19:689–703.Fitzsimmons A., Upchurch K., Batchelor T. Clinical features and diagnosis of primary central nervous system lymphoma. Hematol Oncol Clin North Am 2005;19:689–703.54. Batchelor T., Loeffler J.S. Primary CNS lymphoma. J Clin Oncol 2006;24:1281–8.Batchelor T., Loeffler J.S. Primary CNS lymphoma. J Clin Oncol 2006;24:1281–8.55. Weller M. Glucocorticoid treatment of primary CNS lymphoma. J Neurooncol 1999;43(3):237–9.Weller M. Glucocorticoid treatment of primary CNS lymphoma. J Neurooncol 1999;43(3):237–9.56. Kikuchi K., Watanabe K., Miura S. et al. Steroid-induced regression of primary malignant lymphoma of the brain. Surg Neurol 1996;26:291–6.Kikuchi K., Watanabe K., Miura S. et al. Steroid-induced regression of primary malignant lymphoma of the brain. Surg Neurol 1996;26:291–6.57. Hiraga S., Arita N., Ohnishi T. et al. Rapid infusion of high dose methotrexate resulting in enhanced penetration into CSF and intensified tumour response in PCNSL. J Neurosurg 1999;91:221–30.Hiraga S., Arita N., Ohnishi T. et al. Rapid infusion of high dose methotrexate resulting in enhanced penetration into CSF and intensified tumour response in PCNSL. J Neurosurg 1999;91:221–30.58. Glass J., Gruber M.L., Cher L. et al. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg 1994;81(2):188–95.Glass J., Gruber M.L., Cher L. et al. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg 1994;81(2):188–95.59. Jahnke K., Korfel A., Martus P. et al.; on the behalf of the German Primary Central Nervous System Lymphoma Study Group (G–PCNSL–SG). High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma. Ann Oncol 2005;16:445–9.Jahnke K., Korfel A., Martus P. et al.; on the behalf of the German Primary Central Nervous System Lymphoma Study Group (G–PCNSL–SG). High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma. Ann Oncol 2005;16:445–9.60. Abrey L.E., Moskowitz C.H., Mason W.P. et al. Intensive methotrexate and cytarabine followed by high dose chemotherapy with autologous stem cell rescue in patients with newly diagnosedAbrey L.E., Moskowitz C.H., Mason W.P. et al. Intensive methotrexate and cytarabine followed by high dose chemotherapy with autologous stem cell rescue in patients with newly diagnosedprimary CNS lymphoma: An intent to treat analysis. J Clin Oncol 2003;21:4151–6.61. Doolittle N.D., Miner M.E., Hall W.A. et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 2000;88(3):637–47.Doolittle N.D., Miner M.E., Hall W.A. et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 2000;88(3):637–47.62. Schulz H., Pels H., Schmidt-Wolf I. et al. Intraventricular treatment of relapsed central nervous system lymphoma with the anti-CD20 antibody rituximab. Haematologica 2004 Jun;89:753–4.Schulz H., Pels H., Schmidt-Wolf I. et al. Intraventricular treatment of relapsed central nervous system lymphoma with the anti-CD20 antibody rituximab. Haematologica 2004 Jun;89:753–4.63. Rubenstein J.L., Fridlyand J., Abrey L. et al. Phase i study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007;25:1350–6.Rubenstein J.L., Fridlyand J., Abrey L. et al. Phase i study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007;25:1350–6.