Diagnosis, prognosis and treatment of primary central nervous system lymphoma in the elderly population (Review)

Liu,Yanxia; Yao,Qingmin; Zhang,Feng

doi:10.3892/ijo.2021.5180

Diagnosis, prognosis and treatment of primary central nervous system lymphoma in the elderly population (Review)

Authors:
- Yanxia Liu
- Qingmin Yao
- Feng Zhang
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Affiliations: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
Published online on: February 1, 2021 https://doi.org/10.3892/ijo.2021.5180
Pages: 371-387

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Abstract

Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non‑Hodgkin lymphoma that is unique and different from systemic diffuse large B‑cell lymphomas. The median age at diagnosis of PCNSL is 65 years and its incidence is rising rapidly in the elderly population. A total of ≥20% of all patients with PCNSL are ≥80 years old. Notably, age has been identified as an independent poor prognostic factor for PCNSL. Elderly patients have an inferior prognosis to that of younger patients and are more severely affected by iatrogenic toxicity; therefore, elderly patients represent a unique and vulnerable treatment subgroup. The present review summarized the available literature to provide an improved understanding of the epidemiology, clinical characteristics, diagnosis, prognosis and management of PCNSL in the elderly population. Notably, the incidence of PCNSL in immunocompetent elderly patients, predominantly in men, is increasing. For the diagnosis of CNSL, imaging‑guided stereotactic biopsy is considered the gold standard. When stereotactic biopsy is not possible or conclusive, certain biomarkers have been described that can help establish a diagnosis. PCNSL has a very poor prognosis in the elderly, even though several prognostic scoring systems exist and several prognostic markers have been reported in patients with PCNSL. Furthermore, the treatment of elderly patients remains challenging; it is unlikely that a novel agent could be used as a curative monotherapy; however, a combination of novel agents with polychemotherapy or its combination with other novel drugs may have therapeutic potential.

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1	Bailey P: Intracranial sarcomatous tumors of leptomeingeal origin. Arch Surg. 18:1359–1402. 1929. View Article : Google Scholar
2	Siegal T and Bairey O: Primary CNS lymphoma in the elderly: The challenge. Acta Haematol. 141:138–145. 2019. View Article : Google Scholar : PubMed/NCBI
3	Mulazzani M, Huber M, Borchard S, Langer S, Angele B, Schuh E, Meinl E, Dreyling M, Birnbaum T, Straube A, et al: APRIL and BAFF: Novel biomarkers for central nervous system lymphoma. J Hematol Oncol. 12:1022019. View Article : Google Scholar : PubMed/NCBI
4	Braggio E, Van Wier S, Ojha J, McPhail E, Asmann YW, Egan J, da Silva JA, Schiff D, Lopes MB, Decker PA, et al: Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas. Clin Cancer Res. 21:3986–3994. 2015. View Article : Google Scholar : PubMed/NCBI
5	Chapuy B, Roemer MG, Stewart C, Tan Y, Abo RP, Zhang L, Dunford AJ, Meredith DM, Thorner AR, Jordanova ES, et al: Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 27:869–881. 2016. View Article : Google Scholar
6	Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H and Jaffe ES: The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications. Blood. 117:5019–5032. 2011. View Article : Google Scholar : PubMed/NCBI
7	Villano JL, Koshy M, Shaikh H, Dolecek TA and McCarthy BJ: Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer. 105:1414–1418. 2011. View Article : Google Scholar : PubMed/NCBI
8	O'Neill BP, Decker PA, Tieu C and Cerhan JR: The changing incidence of primary central nervous system lymphoma is driven primarily by the changing incidence in young and middle-aged men and differs from time trends in systemic diffuse large B-cell non-Hodgkin's lymphoma. Am J Hematol. 88:997–1000. 2013. View Article : Google Scholar : PubMed/NCBI
9	Deangelis LM and Iwamoto FM: An update on therapy of primary central nervous system lymphoma. Hematol Am Soc Hematol Educ Program. 2006:311–316. 2006. View Article : Google Scholar
10	Omuro AM, Taillandier L, Chinot O, Carnin C, Barrie M and Hoang-Xuan K: Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly. J Neuro Oncol. 85:207–211. 2007. View Article : Google Scholar
11	Roth P and Hoang-Xuan K: Challenges in the treatment of elderly patients with primary central nervous system lymphoma. Curr Opin Neurol. 27:697–701. 2014. View Article : Google Scholar : PubMed/NCBI
12	Grommes C and DeAngelis LM: Primary CNS lymphoma. J Clin Oncol. 35:2410–2418. 2017. View Article : Google Scholar : PubMed/NCBI
13	Schabet M: Epidemiology of primary CNS lymphoma. J Neurooncol. 43:199–201. 1999. View Article : Google Scholar : PubMed/NCBI
14	Enblad G, Martinsson G, Baecklund E, Hesselager G, Sundström C, Amini RM and Hagberg H: Population-based experience on primary central nervous system lymphoma 2000-2012: The incidence is increasing. Acta Onco. 156:599–607. 2017. View Article : Google Scholar
15	Reni M, Ferreri AJ, Guha-Thakurta N, Blay JY, Dell'Oro S, Biron P and Hochberg FH: Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate. Int J Radiat Oncol Biol Phys. 51:419–425. 2001. View Article : Google Scholar : PubMed/NCBI
16	Chan SM, Hutnik CM, Heathcote JG, Orton RB and Banerjee D: Iris lymphoma in a pediatric cardiac transplant recipient: Clinicopathologic findings. Ophthalmology. 107:1479–1482. 2000. View Article : Google Scholar : PubMed/NCBI
17	Matinella A, Lanzafame M, Bonometti MA, Gajofatto A, Concia E, Vento S, Monaco S and Ferrari S: Neurological complications of HIV infection in pre-HAART and HAART era: A retrospective study. J Neurol. 262:1317–1327. 2015. View Article : Google Scholar : PubMed/NCBI
18	Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A, Finch JL, Grigg R, Hylton T, Pawlish KS, McNeel TS and Goedert JJ: Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 123:187–194. 2008. View Article : Google Scholar : PubMed/NCBI
19	Shiels MS, Pfeiffer RM, Besson C, Clarke CA, Morton LM, Nogueira L, Pawlish K, Yanik EL, Suneja G and Engels EA: Trends in primary central nervous system lymphoma incidence and survival in the U.S. Br J Haematol. 174:417–424. 2016. View Article : Google Scholar : PubMed/NCBI
20	Bathla G and Hegde A: Lymphomatous involvement of the central nervous system. Clin Radiol. 71:602–609. 2016. View Article : Google Scholar : PubMed/NCBI
21	Morell AA, Shah AH, Cavallo C, Eichberg DG, Sarkiss CA, Benveniste R, Ivan ME and Komotar RJ: Diagnosis of primary central nervous system lymphoma: A systematic review of the utility of CSF screening and the role of early brain biopsy. Neurooncol Pract. 6:415–423. 2019.PubMed/NCBI
22	Miller B, Sirotkin I and Martinez C: Review of radiologic considerations in an immunocompetent patient with primary central nervous system lymphoma. Fed Pract. 36(Suppl 5): S51–S53. 2019.PubMed/NCBI
23	Lin X, Khan IRA, Seet YHC, Lee HY and Yu WY: Atypical radiological findings of primary central nervous system lymphoma. Neuroradiology. 62:669–676. 2020. View Article : Google Scholar : PubMed/NCBI
24	Scott BJ, Douglas VC, Tihan T, Rubenstein JL and Josephson SA: A systematic approach to the diagnosis of suspected central nervous system lymphoma. JAMA Neurol. 70:311–319. 2013. View Article : Google Scholar : PubMed/NCBI
25	Ferreri AJM: Therapy of primary CNS lymphoma: Role of intensity, radiation, and novel agents. Hematology Am Soc Hematol Educ Program. 2017:565–577. 2017. View Article : Google Scholar : PubMed/NCBI
26	Malikova H, Burghardtova M, Koubska E, Mandys V, Kozak T and Weichet J: Secondary central nervous system lymphoma: Spectrum of morphological MRI appearances. Neuropsychiatr Dis Treat. 14:733–740. 2018. View Article : Google Scholar : PubMed/NCBI
27	Green K and Hogg JP: Central Nervous System Lymphoma. StatPearls. StatPearls Publishing; Treasure Island, FL: 2020
28	Blay JY, Ongolo-Zogo P, Sebban C, Carrie C, Thiesse P and Biron P: Primary cerebral lymphomas: Unsolved issues regarding first-line treatment, follow-up, late neurological toxicity and treatment of relapses. The FNCLCC. French Fédération Nationale des Centres de Lutte contre le Cancer. Ann Oncol. 11(Suppl 1): S39–S44. 2000. View Article : Google Scholar
29	Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, et al: Distinct types of diffuse large B-cell lymphoma identifified by gene expression profiling. Nature. 403:503–511. 2000. View Article : Google Scholar : PubMed/NCBI
30	Pasqualucci L and Dalla-Favera R: The genetic landscape of diffuse large B-cell lymphoma. Semin Hematol. 52:67–76. 2015. View Article : Google Scholar : PubMed/NCBI
31	Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Müller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, et al: Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 103:275–282. 2004. View Article : Google Scholar
32	Hoang-Xuan K, Bessell E, Bromberg J, Hottinger AF, Preusser M, Rudà R, Schlegel U, Siegal T, Soussain C, Abacioglu U, et al: Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: Guidelines from the European Association for Neuro-Oncology. Lancet Oncol. 16:e322–e332. 2015. View Article : Google Scholar : PubMed/NCBI
33	von Baumgarten L, Illerhaus G, Korfel A, Schlegel U, Deckert M and Dreyling M: The diagnosis and treatment of primary CNS LYmphoma. Dtsch Arztebl Int. 115:419–426. 2018.PubMed/NCBI
34	Antinori A, De Rossi G, Ammassari A, Cingolani A, Murri R, Di Giuda D, De Luca A, Pierconti F, Tartaglione T, Scerrati M, et al: Value of combined approach with thallium-201 single-photon emission computed tomography and Epstein-Barr virus DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol. 17:554–560. 1999. View Article : Google Scholar : PubMed/NCBI
35	Sasagawa Y, Akai T, Tachibana O and Iizuka H: Diagnostic value of interleukin-10 in cerebrospinal fluid for diffuse large B-cell lymphoma of the central nervous system. J Neurooncol. 121:177–183. 2015. View Article : Google Scholar
36	Song Y, Zhang W, Zhang L, Wu W, Zhang Y, Han X, Yang C, Zhang L and Zhou D: Cerebrospinal fluid IL-10 and IL-10/IL-6 as accurate diagnostic biomarkers for primary central nervous system large B-cell lymphoma. Sci Rep. 6:386712016. View Article : Google Scholar : PubMed/NCBI
37	Rubenstein JL, Wong VS, Kadoch C, Gao HX, Barajas R, Chen L, Josephson SA, Scott B, Douglas V, Maiti M, et al: CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood. 121:4740–4748. 2013. View Article : Google Scholar : PubMed/NCBI
38	Viaccoz A, Ducray F, Tholance Y, Barcelos GK, Thomas-Maisonneuve L, Ghesquières H, Meyronet D, Quadrio I, Cartalat-Carel S, Louis-Tisserand G, et al: CSF neopterin level as a diagnostic marker in primary central nervous system lymphoma. Neuro Oncol. 17:1497–1503. 2015. View Article : Google Scholar : PubMed/NCBI
39	Caudie C, Bancel J, Dupont M, Matanza D, Poitevin F and Honnorat J: CSF levels and diagnostic utility of cerebrospinal fluid beta2-microglobulin. Ann Biol Clin (Paris). 63:631–637. 2005.
40	Strehlow F, Bauer S, Martus P, Weller M, Roth P, Schlegel U, Seidel S, Scheibenbogen C, Korfel A and Kreher S: Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma. J Neurooncol. 129:165–171. 2016. View Article : Google Scholar : PubMed/NCBI
41	Kersten MJ, Evers LM, Dellemijn PL, van den Berg H, Portegies P, Hintzen RQ, van Lier RA, von dem Borne AE and van Oers RH: Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies. Blood. 87:1985–1989. 1996. View Article : Google Scholar : PubMed/NCBI
42	Baraniskin A, Kuhnhenn J, Schlegel U, Chan A, Deckert M, Gold R, Maghnouj A, Zöllner H, Reinacher-Schick A, Schmiegel W, et al: Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central system. Blood. 117:3140–3146. 2011. View Article : Google Scholar : PubMed/NCBI
43	Zheng J, Xu J, Ma S, Sun X, Geng M and Wang L: Clinicopathological study of gene rearrangement and microRNA expression of primary central nervous system diffuse large B-cell lymphomas. Int J Clin Exp Pathol. 6:2048–2055. 2013.PubMed/NCBI
44	Yu X, Li Z, Shen J, Chan MT and Wu WK: Role of microRNAs in primary central nervous system lymphomas. Cell Prolif. 49:147–153. 2016. View Article : Google Scholar : PubMed/NCBI
45	Rimelen V, Ahle G, Pencreach E, Zinniger N, Debliquis A, Zalmaï L, Harzallah I, Hurstel R, Alamome I, Lamy F, et al: Tumor cell-free DNA detection in CSF for primary CNS lymphoma diagnosis. Acta Neuropathol Commun. 7:432019. View Article : Google Scholar : PubMed/NCBI
46	Thaler FS, Laurent SA, Huber M, Mulazzani M, Dreyling M, Ködel U, Kümpfel T, Straube A, Meinl E and von Baumgarten L: Soluble TACI and soluble BCMA as biomarkers in primary central nervous system lymphoma. Neuro Oncol. 19:1618–1627. 2017. View Article : Google Scholar : PubMed/NCBI
47	Ho KG and Grommes C: Molecular profiling of primary central nervous system lymphomas-predictive and prognostic value? Curr Opin Neurol. 32:886–894. 2019. View Article : Google Scholar : PubMed/NCBI
48	Deguchi S, Nakashima K, Muramatsu K, Mitsuya K, Oishi T, Shirata K, Hayashi N, Sugino T, Endo M and Nakasu Y: Pretreatment intratumoral susceptibility signals correlate with response to high-dose methotrexate and progression-free survival in primary central nervous system lymphoma. J Clin Neurosci. 69:43–50. 2019. View Article : Google Scholar : PubMed/NCBI
49	Phillips EH, Fox CP and Cwynarski K: Primary CNS lymphoma. Curr Hematol Malig Rep. 9:243–253. 2014. View Article : Google Scholar : PubMed/NCBI
50	Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, Guy G and Lapierre F: Primary intracerebral malignant lymphoma: Report of 248 cases. J Neurosurg. 92:261–266. 2000. View Article : Google Scholar : PubMed/NCBI
51	Lim T, Kim SJ, Kim K, Lee JI, Lim DH, Lee DJ, Baek KK, Lee HY, Han B, Uhm JE, et al: Primary CNS lymphoma other than DLBCL: A descriptive analysis of clinical features and treatment outcomes. Ann Hematol. 90:1391–1398. 2011. View Article : Google Scholar : PubMed/NCBI
52	Van Der Meulen M, Dinmohamed AG, Visser O, Doorduijn JK and Bromberg JEC: Improved survival in primary central nervous system lymphoma up to age 70 only: A population-based study on incidence, primary treatment and survival in the Netherlands, 1989-2015. Leukemia. 31:1822–1825. 2017. View Article : Google Scholar : PubMed/NCBI
53	Fallah J, Qunaj L and Olszewski AJ: Therapy and outcomes of primary central nervous system lymphoma in the United States: Analysis of the national cancer database. Blood Adv. 1:112–121. 2016. View Article : Google Scholar : PubMed/NCBI
54	Graham MS and DeAngelis LM: Improving outcomes in primary CNS lymphoma. Best Pract Res Clin Haematol. 31:262–269. 2018. View Article : Google Scholar : PubMed/NCBI
55	Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, et al: Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227. J Clin Oncol. 34:1620–1625. 2016. View Article : Google Scholar : PubMed/NCBI
56	Royer-Perron L and Hoang-Xuan K: Management of primary central nervous system lymphoma. Presse Med. 47:e213–e244. 2018. View Article : Google Scholar : PubMed/NCBI
57	Kasenda B, Ferreri AJ, Marturano E, Forst D, Bromberg J, Ghesquieres H, Ferlay C, Blay JY, Hoang-Xuan K, Pulczynski EJ, et al: First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)-a systematic review and individual patient data meta-analysis. Ann Oncol. 26:1305–1313. 2015. View Article : Google Scholar : PubMed/NCBI
58	Houillier C, Ghesquières H, Chabrot C, Soussain C, Ahle G, Choquet S, Nicolas-Virelizier E, Bay JO, Vargaftig J, Gaultier C, et al: Rituximab, methotrexate, procarbazine, vincristine and intensifified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: A LOC network study. J Neurooncol. 133:315–320. 2017. View Article : Google Scholar : PubMed/NCBI
59	Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Möhle R, Löw S, Binder M, Atta J, Keller U, et al: High-dose methotrexate-based immune-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 31:846–852. 2017. View Article : Google Scholar
60	Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY and Baron B; European Organization for Research and Treatment of Cancer Brain Tumor Group: Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: A multicenter phase II study (26952) of the European organization for research and treatment of cancer brain tumor group. J Clin Oncol. 21:2726–2731. 2003. View Article : Google Scholar : PubMed/NCBI
61	Illerhaus G, Marks R, Müller F, Ihorst G, Feuerhake F, Deckert M, Ostertag C and Finke J: High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: Results of a prospective pilot and phase II study. Ann Oncol. 20:319–325. 2009. View Article : Google Scholar
62	Roth P, Martus P, Kiewe P, Möhle R, Klasen H, Rauch M, Röth A, Kaun S, Thiel E, Korfel A and Weller M: Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial. Neurology. 79:890–896. 2012. View Article : Google Scholar : PubMed/NCBI
63	Olivier G, Clavert A, Lacotte-Thierry L, Gardembas M, Escoffre-Barbe M, Brion A, Cumin I, Legouffe E, Solal-Celigny P, Chabin M, et al: A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial. Am J Hematol. 89:1024–1029. 2014. View Article : Google Scholar : PubMed/NCBI
64	Omuro A, Chinot O, Taillandier L, Ghesquieres H, Soussain C, Delwail V, Lamy T, Gressin R, Choquet S, Soubeyran P, et al: Methotrexate and temozolomide vs. methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: An intergroup ANOCEF-GOELAMS randomized phase 2 trial. Lancet Haematol. 2:e251–e259. 2015. View Article : Google Scholar : PubMed/NCBI
65	Pulczynski EJ, Kuittinen O, Erlanso M, Hagberg H, Fosså A, Eriksson M, Nordstrøm M, Østenstad B, Fluge Ø, Leppä S, et al: Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-escalating induction and introducing temozolomide maintenance: Results from a phase II study by the Nordic Lymphoma Group. Haematologica. 100:534–540. 2015. View Article : Google Scholar :
66	Mendez JS, Ostrom QT, Gittleman H, Kruchko C, DeAngelis LM, Barnholtz-Sloan JS and Grommes C: The elderly left behind-changes in survival trends of primary central nervous system lymphoma over the past 4 decades. Neuro Oncol. 20:687–694. 2018. View Article : Google Scholar
67	Langner-Lemercier S, Houillier C, Soussain C, Ghesquières H, Chinot O, Taillandier L, Soubeyran P, Lamy T, Morschhauser F, Benouaich-Amiel A, et al: Primary CNS lymphoma at first relapse/progression: Characteristics, management, and outcome of 256 patients from The French LOC network. Neuro Oncol. 18:1297–1303. 2016. View Article : Google Scholar : PubMed/NCBI
68	Jahnke K, Thiel E, Martus P, Herrlinger U, Weller M, Fischer L and Korfel A; German Primary Central Nervous System Lymphoma Study Group: Relapse of primary central nervous system lymphoma: Clinical features, outcome and prognostic factors. J Neurooncol. 80:159–165. 2006. View Article : Google Scholar : PubMed/NCBI
69	Nayak L, Hedvat C, Rosenblum MK, Abrey LE and DeAngelis LM: Late relapse in primary central nervous system lymphoma: Clonal persistence. Neuro Oncol. 13:525–529. 2011. View Article : Google Scholar : PubMed/NCBI
70	Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, Schultz C, Leibel S, Nelson D, Mehta M and DeAngelis LM: Primary central nervous system lymphoma: The memorial Sloankettering cancer Center prognostic model. J Clin Oncol. 24:5711–5715. 2006. View Article : Google Scholar : PubMed/NCBI
71	Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, Calderoni A, Rossi A, Vavassori V, Conconi A, et al: Prognostic scoring system for primary CNS lymphomas: The International extranodal lymphoma study group experience. J Clin Oncol. 21:266–272. 2003. View Article : Google Scholar : PubMed/NCBI
72	Weller M, Martus P, Roth P, Thiel E and Korfel A; German PCNSL Study Group: Surgery for primary CNS lymphoma? Challenging a paradigm. Neuro Oncol. 14:1481–1484. 2012. View Article : Google Scholar : PubMed/NCBI
73	Makino K, Nakamura H, Hide T, Kuroda J, Yano S and Kuratsu J: Prognostic impact of completion of initial high-dose methotrexate therapy on primary central nervous system lymphoma: A single institution experience. Int J Clin Oncol. 20:29–34. 2015. View Article : Google Scholar
74	Nakasu Y, Mitsuya K, Hayashi N, Okamura I, Mori K, Enami T, Tatara R, Nakasu S and Ikeda T: Response-adapted treatment with upfront high-dose chemotherapy followed by autologous stem-cell transplantation rescue or consolidation phase high-dose methotrexate for primary central nervous system lymphoma: A long-term mono-center study. Springerplus. 5:3072016. View Article : Google Scholar : PubMed/NCBI
75	Kondo E, Ikeda T, Izutsu K, Chihara D, Shimizu-Koresawa R, Fujii N, Sakai T, Kondo T, Kubo K, Kato Y, et al: High dose chemotherapy with autologous stem cell transplantation in primary central nervous system lymphoma: Data from the Japan Society for Hematopoietic Cell Transplantation (JSHCT) registry. Biol Blood Marrow Transplant. 25:899–905. 2019. View Article : Google Scholar : PubMed/NCBI
76	Levy O, DeAngelis LM, Filippa DA, Panageas KS and Abrey LE: Bcl-6 predicts improved prognosis in primary central nervous system lymphoma. Cancer. 112:151–156. 2008. View Article : Google Scholar
77	Preusser M, Woehrer A, Koperek O, Rottenfusser A, Dieckmann K, Gatterbauer B, Roessler K, Slavc I, Jaeger U, Streubel B, et al: Primary central nervous system lymphoma: A clinicopathological study of 75 cases. Pathology. 42:547–552. 2010. View Article : Google Scholar : PubMed/NCBI
78	Niparuck P, Boonsakan P, Sutthippingkiat T, Pukiat S, Chantrathammachart P, Phusanti S, Boonyawat K, Puavilai T, Angchaisuksiri P, Ungkanont A, et al: Treatment outcome and prognostic factors in PCNSL. Diagn Pathol. 14:562019. View Article : Google Scholar : PubMed/NCBI
79	Chen C, Zhuo H, Wei X and Ma X: Contrast-enhanced MRI texture parameters as potential prognostic factors for primary central nervous system lymphoma patients receiving high-dose methotrexate-based chemotherapy. Contrast Media Mol Imaging. 2019:54814912019. View Article : Google Scholar : PubMed/NCBI
80	Alame M, Pirel M, Costes-Martineau V, Bauchet L, Fabbro M, Tourneret A, De Oliveira L, Durand L, Roger P, Gonzalez S, et al: Characterisation of tumour microenvironment and immune checkpoints in primary central nervous system diffuse large B cell lymphomas. Virchows Arch. 476:891–902. 2020. View Article : Google Scholar
81	Cho I, Lee H, Yoon SE, Ryu KJ, Ko YH, Kim WS and Kim SJ: Serum levels of soluble programmed death-ligand 1 (sPD-L1) in patients with primary central nervous system diffuse large B-cell lymphoma. BMC Cancer. 20:1202020. View Article : Google Scholar : PubMed/NCBI
82	Cambruzzi E: Primary intra-axial diffuse large b-cell lymphoma in immunocompetent patients: Clinical impact of molecular analysis and histogenetic evaluation. World Neurosurg. 134:215–220. 2020. View Article : Google Scholar
83	Yuan XG, Huang YR, Yu T, Xu Y, Liang Y, Zhang XH, Sun CR and Zhao XY: Primary central nervous system lymphoma in China: A single-center retrospective analysis of 167 cases. Ann Hematol. 99:93–104. 2020. View Article : Google Scholar
84	Tabouret E, Houillier C, Martin-Duverneuil N, Blonski M, Soussain C, Ghesquières H, Houot R, Larrieu D, Soubeyran P, Gressin R, et al: Patterns of response and relapse in primary CNS lymphomas after first-line chemotherapy: Imaging analysis of the ANOCEF-GOELAMS prospective randomized trial. Neuro Oncol. 19:422–429. 2017.
85	Chunsong H, Yuling H, Li W, Jie X, Gang Z, Qiuping Z, Qingping G, Kejian Z, Li Q, Chang AE, et al: CXC chemokine ligand 13 and CC chemokine ligand 19 cooperatively render resistance to apoptosis in B cell lineage acute and chronic lymphocytic leukemia CD23+CD5+ B cells. J Immunol. 177:6713–6722. 2006. View Article : Google Scholar : PubMed/NCBI
86	Le M, Garcilazo Y, Ibáñez-Juliá MJ, Younan N, Royer-Perron L, Benazra M, Mokhtari K, Houillier C, Hoang-Xuan K and Alentorn A: Pretreatment hemoglobin as an independent prognostic factor in primary central nervous system lymphomas. Hematologic malignancies. Oncologist. 24:e898–e904. 2019. View Article : Google Scholar
87	Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y, Morishima Y, Takeuchi K, Izumo T, Mori S, et al: Age-related EBV associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: A study of 96 patients. Clin Cancer Res. 13:5124–5132. 2007. View Article : Google Scholar : PubMed/NCBI
88	Wu T, Kang H, Zhuang D, Ma Y, Lin Z, Suolitiken D, Chen B and Xu X: The role of ABCB1 polymorphism as a prognostic marker for primary central nervous system lymphoma. Ann Hematol. 98:923–930. 2019. View Article : Google Scholar : PubMed/NCBI
89	Yang X, Wang Y, Sun X, Bai X, Cui Q, Zhu H, Qian J, Chen Y, Sun S, Ji N, et al: STAT3 activation is associated with IL-10 expression and survival in primary central nervous system lymphoma. World Neurosurg. 134:e1077–e1084. 2020. View Article : Google Scholar
90	Hatzl S, Posch F, Deutsch A, Beham-Schmid C, Stöger H, Greinix H, Pichler M, Neumeister P and Prochazka KT: Immunohistochemistry for c-myc and bcl-2 overexpression improves risk stratification in primary central nervous system lymphoma (PCNSL). Hematol Oncol. 38:277–283. 2020. View Article : Google Scholar : PubMed/NCBI
91	Yin W, Xia X, Wu M, Yang H, Zhu X, Sun W and Ge M: The impact of BCL-2/MYC protein expression and gene abnor-mality on primary central nervous system diffuse large B-cell lymphoma. Int J Clin Exp Pathol. 12:2215–2223. 2019.
92	Villa D, Tan KL, Steidl C, Ben-Neriah S, Al Moosawi M, Shenkier TN, Connors JM, Sehn LH, Savage KJ, Scott DW, et al: Molecular features of a large cohort of primary central nervous system lymphoma using tissue microarray. Blood Adv. 3:3953–3961. 2019. View Article : Google Scholar : PubMed/NCBI
93	Takano S, Hattori K, Ishikawa E, Narita Y, Iwadate Y, Yamaguchi F, Nagane M, Akimoto J, Oka H, Tanaka S, et al: MyD88 mutation in elderly predicts poor prognosis in primary central nervous system lymphoma: Multi-institutional analysis. World Neurosurg. 112:e69–e73. 2018. View Article : Google Scholar
94	Nayyar N, White MD, Gill CM, Lastrapes M, Bertalan M, Kaplan A, D'Andrea MR, Bihun I, Kaneb A, Dietrich J, et al: MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas. Blood Adv. 3:375–383. 2019. View Article : Google Scholar : PubMed/NCBI
95	Mondello P, Cuzzocrea S, Arrigo C, Pitini V, Mian M and Bertoni F: STAT6 activation correlates with cerebrospinal fluid IL-4 and IL-10 and poor prognosis in Primary Central Nervous System Lymphoma. Hematol Oncol. 38:106–110. 2020. View Article : Google Scholar
96	Hyung J, Hong JY, Kim S, Ryu JS, Huh J and Suh C: Beta-2 microglobulin as a prognostic factor of primary central nervous system lymphoma. Blood Res. 54:285–288. 2019. View Article : Google Scholar
97	Kim S, Nam SJ, Park C, Kwon D, Yim J, Song SG, Ock CY, Kim YA, Park SH, Kim TM, et al: High tumoral PD-L1 expression and low PD-1 + or CD8 + tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system. Oncoimmunology. 8:e16266532019. View Article : Google Scholar
98	Gopal S, Martin KE, Richards KL and Eron JJ: Clinical presentation, treatment, and outcomes among 65 patients with HIV-associated lymphoma treated at the University of North Carolina 2000-2010. AIDS Res Hum Retroviruses. 28:798–805. 2012. View Article : Google Scholar :
99	Han CH and Batchelor TT: Diagnosis and management of primary central nervous system lymphoma. Cancer. 123:4314–4324. 2017. View Article : Google Scholar : PubMed/NCBI
100	Corry J, Smith JG, Wirth A, Quong G and Liew KH: Primary central nervous system lymphoma: Age and performance status are more important than treatment modality. Int J Radiat Oncol Biol Phys. 41:615–620. 1998. View Article : Google Scholar : PubMed/NCBI
101	Mohile SG, Dale W, Somerfield MR, Schonberg MA, Boyd CM, Burhenn PS, Canin B, Cohen HJ, Holmes HM, Hopkins JO, et al: Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology. J Clin Oncol. 36:2326–2347. 2018. View Article : Google Scholar : PubMed/NCBI
102	Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, DeFelice J, Levine RM, Lubiner ET, Reyes P, Schreiber FJ III and Balducci L: Predicting the risk of chemotherapy toxicity in older patients: The chemotherapy risk assessment scale for high-age patients (CRASH) score. Cancer. 118:3377–3386. 2012. View Article : Google Scholar
103	Hiraga S, Arita N, Ohnishi T, Kohmura E, Yamamoto K, Oku Y, Taki T, Sato M, Aozasa K and Yoshimine T: Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas. J Neurosurg. 91:221–230. 1999. View Article : Google Scholar : PubMed/NCBI
104	Glass J, Shustik C, Hochberg FH, Cher L and Gruber ML: Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). J Neurooncol. 30:257–265. 1996. View Article : Google Scholar : PubMed/NCBI
105	Binnahil M, Au K, Lu JQ, Wheatley BM and Sankar T: The influence of Cortico-steroids on diagnostic accuracy of biopsy for primary central nervous system lymphoma. Can J Neurol Sci. 43:721–725. 2016. View Article : Google Scholar : PubMed/NCBI
106	Porter AB, Giannini C, Kaufmann T, Lucchinetti CF, Wu W, Decker PA, Atkinson JL and O'Neill BP: Primary central nervous system lymphoma can be histologically diagnosed after previous corticosteroid use: A pilot study to determine whether corticosteroids prevent the diagnosis of primary central nervous system lymphoma. Ann Neurol. 63:662–667. 2008. View Article : Google Scholar : PubMed/NCBI
107	Mathew BS, Carson KA and Grossman SA: Initial response to glucocorticoids: A potentially important prognostic factor in patients with primary CNS lymphoma. Cancer. 106:383–387. 2006. View Article : Google Scholar
108	Batchelor TT: Primary central nervous system lymphoma: A curable disease. Hematol Oncol. 37(Suppl 1): S15–S18. 2019. View Article : Google Scholar
109	Nabors LB, Portnow J, Baehring J, Brem H, Butowski N, Forsyth P, Hattangadi-Gluth J, Holdhoff M, Horbinski C, Howard S, et al: NCCN Clinical Practice Guidelines in Oncology. Central Nervous System Cancers. 1:32–35. 2018.
110	Rushworth D, Mathews A, Alpert A and Cooper LJ: Dihydrofolate reductase and thymidylate synthase transgenes resistant to methotrexate interact to permit novel transgene regulation. J Biol Chem. 290:22970–22976. 2015. View Article : Google Scholar : PubMed/NCBI
111	Goecke IA, Alvarez C, Henríquez J, Salas K, Molina ML, Ferreira A and Gatica H: Methotrexate regulates the expres-sion of glucocorticoid receptor alpha and beta isoforms in normal human peripheral mononuclear cells and human lymphocyte cell lines in vitro. Mol Immunol. 44:2115–2123. 2007. View Article : Google Scholar
112	Madle M, Krämer I, Lehners N, Schwarzbich M, Wuchter P, Herfarth K, Egerer G, Ho AD and Witzens-Harig M: The influence of rituximab, high-dose therapy followed by autologous stem cell transplantation, and age in patients with primary CNS lymphoma. Ann Hematol. 94:1853–1857. 2015. View Article : Google Scholar : PubMed/NCBI
113	Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD and Kaplan LD: Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 31:3061–3068. 2013. View Article : Google Scholar : PubMed/NCBI
114	Jahnke K, Korfel A, Martus P, Weller M, Herrlinger U, Schmittel A, Fischer L and Thiel E; 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. 16:445–449. 2005. View Article : Google Scholar : PubMed/NCBI
115	Welch MR, Omuro A and Deangelis LM: Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center. Neuro Oncol. 14:1304–1311. 2012. View Article : Google Scholar : PubMed/NCBI
116	Illerhaus G, Schorb E and Kasenda B: Novel agents for primary central nervous system lymphoma: Evidence and perspectives. Blood. 132:681–688. 2018. View Article : Google Scholar : PubMed/NCBI
117	Faivre G, Butler MJ, Le I and Brenner A: Temozolomide as a single agent maintenance therapy in elderly patients with primary CNS lymphoma. Clin Lymphoma Myeloma Leuk. 19:665–669. 2019. View Article : Google Scholar : PubMed/NCBI
118	Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, et al: LY231514, a pyrrolo[2,3-d] pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 57:1116–1123. 1997.PubMed/NCBI
119	Raizer JJ, Rademaker A, Evens AM, Rice L, Schwartz M, Chandler JP, Getch CC, Tellez C and Grimm SA: Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer. 118:3743–3748. 2012. View Article : Google Scholar
120	Han S, Wang M, Liu B and Yu J: Pemetrexed for primary central nervous system lymphoma in the elderly. Clin Transl Oncol. 18:138–143. 2016. View Article : Google Scholar
121	Pardridge WM: BBB-genomics: Creating new openings for brain-drug targeting. Drug Discovery Today. 6:381–383. 2001. View Article : Google Scholar : PubMed/NCBI
122	Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, et al: High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): A phase 3, randomised, non-inferiority trial. Lancet Oncol. 11:1036–1047. 2010. View Article : Google Scholar : PubMed/NCBI
123	Birnbaum T, Stadler EA, von Baumgarten L and Straube A: Rituximab significantly improves complete response rate in patients with primary CNS lymphoma. J Neurooncol. 109:285–291. 2012. View Article : Google Scholar : PubMed/NCBI
124	Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, Grossman SA and Ye X: High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology. 83:235–239. 2014. View Article : Google Scholar : PubMed/NCBI
125	Miyakita Y, Ohno M, Takahashi M, Muragaki Y, Katai H and Narita Y: Immunochemotherapy using rituximab (RTX) and high-dose methotrexate (HD-MTX): An evaluation of the addition of RTX to HD-MTX in recurrent primary central nervous system lymphoma (PCNSL). Jpn J Clin Oncol. 47:919–924. 2017. View Article : Google Scholar : PubMed/NCBI
126	Fritsch K, Kasenda B, Hader C, Nikkhah G, Prinz M, Haug V, Haug S, Ihorst G, Finke J and Illerhaus G: Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly. Ann Oncol. 22:2080–2085. 2011. View Article : Google Scholar : PubMed/NCBI
127	Iwamoto FM, Schwartz J, Pandit-Taskar N, Peak S, Divgi CR, Zelenetz AD, Humm J and Abrey LE: Study of radiolabeled indium-111 and yttrium-90 ibritumomab tiuxetan in primary central nervous system lymphoma. Cancer. 110:2528–2534. 2007. View Article : Google Scholar : PubMed/NCBI
128	Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, et al: Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: Results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 3:e217–e227. 2016. View Article : Google Scholar : PubMed/NCBI
129	Schmitt AM, Herbrand AK, Fox CP, Bakunina K, Bromberg JEC, Cwynarski K, Doorduijn JK, Ferreri AJM, Illerhaus G, Issa S, et al: Rituximab in primary central nervous system lymphoma-a systematic review and Meta-analysis. Hematol Oncol. 37:548–557. 2019. View Article : Google Scholar : PubMed/NCBI
130	Bromberg JEC, Issa S, Bakunina K, Minnema MC, Seute T, Durian M, Cull G, Schouten HC, Stevens WBC, Zijlstra JM, et al: Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): A randomised, open-label, phase 3 inter-group Study. Lancet Oncol. 20:216–228. 2019. View Article : Google Scholar : PubMed/NCBI
131	Han X, Ji Y, Ouyang M, Zhu T and Zhou D: Efficacy and safety of HD-MTX based systemic chemotherapy regimens: Retrospective study of induction therapy for primary central nervous system lymphoma in Chinese. Sci Rep. 7:170532017. View Article : Google Scholar : PubMed/NCBI
132	Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, Van't Veer M, Hansen M, Soubeyran P, Taphoorn M, Thomas J, Van den Bent M, Fickers M, et al: High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European organization for research and treatment of cancer lymphoma group phase II trial 20962. J Clin Oncol. 21:4483–4488. 2003. View Article : Google Scholar : PubMed/NCBI
133	van Tellingen O, Boogerd W, Nooijen WJ and Beijnen JH: The vascular compartment hampers accurate determination of teniposide penetration into braintumor tissue. Cancer Chemother Pharmacol. 40:330–334. 1997. View Article : Google Scholar
134	Wu J, Duan L, Zhang L, Sun Z, Fu X, Li X, Li L, Wang X, Zhang X, Li Z, et al: Fotemustine, teniposide and dexametha-sone versus high-dose methotrexate plus cytarabine in newly diagnosed primary CNS lymphoma: A randomised phase 2 trial. J Neurooncol. 140:427–434. 2018. View Article : Google Scholar : PubMed/NCBI
135	Wang YX, Huang Y, Xu XP, Chen BB, Lin ZG, Ma Y, Ding TL and Wang Q: Curative effect of methotrexate combined with teniposide in the treatment of primary central nervous system lymphoma. Oncol Lett. 19:2097–2106. 2020.PubMed/NCBI
136	Deng X, Xu X, Lin D, Zhang X, Yu L, Sheng H, Yin B, Zhang N and Lin J: Real-world impact of surgical excision on overall survival in primary central nervous system lymphoma. Front Oncol. 10:1312020. View Article : Google Scholar : PubMed/NCBI
137	Kinslow CJ, Rae AI, Neugut AI, Adams CM, Cheng SK, Sheth SA, McKhann GM, Sisti MB, Bruce JN, Iwamoto FM, et al: Surgery plus adjuvant radiotherapy for primary central nervous system lymphoma. Br J Neurosurg. 34:690–696. 2020. View Article : Google Scholar : PubMed/NCBI
138	Korfel A and Schlegel U: Diagnosis and treatment of primary CNS lymphoma. Nat Rev Neurol. 9:317–327. 2013. View Article : Google Scholar : PubMed/NCBI
139	Schlegel U and Korfel A: Is whole-brain radiotherapy still a standard treatment for primary central nervous system lymphomas? Curr Opin Neurol. 31:733–739. 2018. View Article : Google Scholar : PubMed/NCBI
140	Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM and Abrey LE: Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 25:4730–4735. 2007. View Article : Google Scholar : PubMed/NCBI
141	Lee TH, Lee JH, Chang JH, Ye SJ, Kim TM, Park CK, Kim IH, Kim BH and Wee CW: Reduced-dose whole-brain radiotherapy with tumor bed boost after upfront high-dose methotrexate for primary central nervous system lymphoma. Radiat Oncol J. 38:35–43. 2020. View Article : Google Scholar : PubMed/NCBI
142	Gaut D and Schiller GJ: Hematopoietic stem cell transplantation in primary central nervous system lymphoma: A review of the literature. Int J Hematol. 109:260–277. 2019. View Article : Google Scholar : PubMed/NCBI
143	Schorb E, Fox CP, Fritsch K, Isbell L, Neubauer A, Tzalavras A, Witherall R, Choquet S, Kuittinen O, De-Silva D, et al: High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: A European retrospective study. Bone Marrow Transplant. 52:1113–1119. 2017. View Article : Google Scholar : PubMed/NCBI
144	Vu K, Mannis G, Hwang J, Geng H and Rubenstein JL: Low-dose lenalidomide maintenance after induction therapy in older patients with primary central nervous system lymphoma. Br J Haematol. 186:180–183. 2019. View Article : Google Scholar : PubMed/NCBI
145	Bairey O and Siegal T: The possible role of maintenance treatment for primary central nervous system lymphoma. Blood Rev. 32:378–386. 2018. View Article : Google Scholar : PubMed/NCBI
146	Reni M and Ferreri AJ: Therapeutic management of refractory or relapsed primary central nervous system lymphomas. Ann Hematol. 80(Suppl 3): B113–B117. 2001.
147	Otani R, Yamada R, Kushihara Y, Inazuka M and Shinoura N: Continuous intrathecal injection therapy of methotrexate is a therapeutic option in primary CNS lymphoma. J Clin Neurosci. 69:26–30. 2019. View Article : Google Scholar : PubMed/NCBI
148	Soussain C, Suzan F, Hoang-Xuan K, Cassoux N, Levy V, Azar N, Belanger C, Achour E, Ribrag V, Gerber S, et al: Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol. 19:742–749. 2001. View Article : Google Scholar : PubMed/NCBI
149	Correa DD, Braun E, Kryza-Lacombe M, Ho KW, Reiner AS, Panageas KS, Yahalom J, Sauter CS, Abrey LE, DeAngelis LM, et al: Longitudinal cognitive assessment in patients with primary CNS lymphoma treated with induction chemotherapy followed by reduced-dose whole-brain radiotherapy or autologous stem cell transplantation. J Neurooncol. 144:553–562. 2019. View Article : Google Scholar : PubMed/NCBI
150	Atilla E, Sahin U, Atilla PA, Merter M, Ozyurek E, Ceyhan K and Bozdag SC: Allogeneic stem cell transplantation for relapsed primary central nervous system lymphoma: Is it feasible? Hematol Oncol Stem Cell Ther. 12:220–225. 2019. View Article : Google Scholar
151	Varadi G, Or R, Kapelushnik J, Naparstek E, Nagler A, Brautbar C, Amar A, Kirschbaum M, Samuel S, Slavin S and Siegal T: Graft-versus-lymphoma effect after allogeneic peripheral blood stem cell transplantation for primary central nervous system lymphoma. Leuk Lymphoma. 34:185–190. 1999. View Article : Google Scholar : PubMed/NCBI
152	Tu S, Zhou X, Guo Z, Huang R, Yue C, He Y, Li M, Chen Y, Liu Y, Chang LJ and Li Y: CD19 and CD70 Dual-target chimeric antigen receptor T-cell therapy for the treatment of relapsed and refractory primary central nervous system diffuse large B-cell lymphoma. Front Oncol. 9:13502019. View Article : Google Scholar : PubMed/NCBI
153	Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, Schmitz R, Yang Y, Cole DE, Melani C, Higham CS, et al: Inhibition of B cell receptor signaling by Ibrutinib in primary CNS lymphoma. Cancer Cell. 31:833–843.e5. 2017. View Article : Google Scholar : PubMed/NCBI
154	Narita Y, Nagane M, Mishima K, Terui Y, Arakawa Y, Yonezawa H, Asai K, Fukuhara N, Sugiyama K, Shinojima N, et al: Phase 1/2 study of tirabrutinib, a second-generation Bruton's tyro-sine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma. Neuro Oncol. noaa1452020. View Article : Google Scholar : Epub ahead of print.
155	Tun HW, Johnston PB, DeAngelis LM, Atherton PJ, Pederson LD, Koenig PA, Reeder CB, Omuro AMP, Schiff D, O'Neill B, et al: Phase I study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma. Blood. 132:2240–2248. 2018. View Article : Google Scholar : PubMed/NCBI
156	Nayak L, Iwamoto FM, LaCasce A, Mukundan S, Roemer MGM, Chapuy B, Armand P, Rodig SJ and Shipp MA: PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood. 129:3071–3073. 2017. View Article : Google Scholar : PubMed/NCBI
157	Ferry JA: The diversity of diffuse large B-cell lymphoma in extranodal sites: Overview and update. J Hematopathol. 7:57–70. 2014. View Article : Google Scholar
158	Chamoun K, Choquet S, Boyle E, Houillier C, Larrieu-Ciron D, Al Jijakli A, Delrieu V, Delwail V, Morschhauser F, Hoang-Xuan K and Soussain C: Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: A retrospective case series. Neurology. 88:101–102. 2017. View Article : Google Scholar
159	Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D, Codega P, Nichol D, Clark O, Hsieh WY, et al: IbrutInib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov. 7:1018–1029. 2017. View Article : Google Scholar : PubMed/NCBI
160	Soussain C, Choquet S, Blonski M, Leclercq D, Houillier C, Rezai K, Bijou F, Houot R, Boyle E, Gressin R, et al: Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II 'proof-of-concept' iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network. Eur J Cancer. 117:121–130. 2019. View Article : Google Scholar : PubMed/NCBI
161	Yang Y, Shaffer AL III, Emre NC, Ceribelli M, Zhang M, Wright G, Xiao W, Powell J, Platig J, Kohlhammer H, et al: Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 21:723–737. 2012. View Article : Google Scholar : PubMed/NCBI
162	Houillier C, Choquet S, Touitou V, Martin-Duverneuil N, Navarro S, Mokhtari K, Soussain C and Hoang-Xuan K: Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma. Neurology. 84:325–326. 2015. View Article : Google Scholar
163	Rubenstein JL, Geng H, Fraser EJ, Formaker P, Chen L, Sharma J, Killea P, Choi K, Ventura J, Kurhanewicz J, et al: Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. Blood Adv. 2:1595–1607. 2018. View Article : Google Scholar : PubMed/NCBI
164	Ghesquieres H, Chevrier M, Laadhari M, Chinot O, Choquet S, Moluçon-Chabrot C, Beauchesne P, Gressin R, Morschhauser F, Schmitt A, et al: Lenalidomide in combination with intrave-nous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: A multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA). Ann Oncol. 30:621–628. 2019. View Article : Google Scholar : PubMed/NCBI
165	Takashima Y, Sasaki Y, Hayano A, Homma J, Fukai J, Iwadate Y, Kajiwara K, Ishizawa S, Hondoh H, Tokino T and Yamanaka R: Target amplicon exomesequencing identifies promising diagnosis and prognostic markers involved in RTK-RAS and PI3K-AKT signaling as central oncopathways in primary central nervous system lymphoma. Oncotarget. 9:27471–27486. 2018. View Article : Google Scholar : PubMed/NCBI
166	Todorovic Balint M, Jelicic J, Mihaljevic B, Kostic J, Stanic B, Balint B, Pejanovic N, Lucic B, Tosic N, Marjanovic I, et al: Gene mutation profiles in primary diffuse large B cell lymphoma of central nervous system: Next generation sequencing analyses. Int J Mol Sci. 17:6832016. View Article : Google Scholar :
167	Zhang X and Liu Y: Targeting the the PI3K/AKT/mTOR signaling pathway in primary central nervous system lymphoma: Current status and future prospects. CNS Neurol Disord Drug Targets. 19:165–173. 2020. View Article : Google Scholar
168	Korfel A, Schlegel U, Herrlinger U, Dreyling M, Schmidt C, von Baumgarten L, Pezzutto A, Grobosch T, Kebir S, Thiel E, et al: Phase II trial of temsirolimus for Relapsed/Refractory primary CNS lymphoma. J Clin Oncol. 34:1757–1763. 2016. View Article : Google Scholar : PubMed/NCBI
169	Grommes C, Pentsova E, Nolan C, Wolfe J, Mellinghoff IK and Deangelis L: Phase II study of single agent buparlisib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL). Ann Oncol. 27(Suppl 6): vi103–vi113. 2016.
170	Ezell SA, Mayo M, Bihani T, Tepsuporn S, Wang S, Passino M, Grosskurth SE, Collins M, Parmentier J, Reimer C, et al: Synergistic induction of apoptosis by combination of BTK and dual mTORC1/2 inhibitors in diffuse large B cell lymphoma. Oncotarget. 5:4990–5001. 2014. View Article : Google Scholar : PubMed/NCBI
171	Tarantelli C, Gaudio E, Arribas AJ, Kwee I, Hillmann P, Rinaldi A, Cascione L, Spriano F, Bernasconi E, Guidetti F, et al: PQR309 is a novel dual PI3K/mTOR inhibitor with preclinical antitumor activity in lymphomas as a single agent and in combination therapy. Clin Cancer Res. 24:120–129. 2018. View Article : Google Scholar
172	Furuse M, Nonoguchi N, Omura N, Shirahata M, Iwasaki K, Inui T, Kuroiwa T, Kuwabara H and Miyatake SI: Immunotherapy of Nivolumab with dendritic cell vaccination is effective against intractable recurrent primary central nervous system lymphoma: A case report. Neurol Med Chir (Tokyo). 57:191–197. 2017. View Article : Google Scholar
173	Chan TSY, Khong PL, Au-Yeung R, Kwong YL and Tse E: Low-dose nivolumab induced durable complete response in relapsed primary central nervous system diffuse large B cell lymphoma. Ann Hematol. 98:2227–2230. 2019. View Article : Google Scholar : PubMed/NCBI