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Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma

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Abstract

Central nervous system lymphoma (CNSL) is diagnostically challenging. The identification of reliable and easy to measure biomarkers is desirable to facilitate diagnosis. Here, we evaluated the value of cerebrospinal fluid (CSF) osteopontin (OPN) as a diagnostic biomarker for CNSL. OPN concentrations in CSF from 37 patients with CNSL (29 with primary CNSL and 8 with secondary CNS involvement of systemic lymphoma) and 36 controls [6 patients with inflammatory CNS disease other than multiple sclerosis (MS), 8 with MS, 9 with glioblastoma (GBM) and 13 healthy controls] were determined using an enzyme-linked immunosorbent assay. Non-parametric tests and receiver operating characteristic (ROC) curves were performed for determination of diagnostic accuracy. Median CSF OPN level in all CNSL patients was 620 ng/mL and higher than in patients with inflammatory CNS disease (356 ng/mL); P < .05, MS (163 ng/mL); P < .01, GBM (41 ng/mL); P < .01, or healthy controls (319 ng/mL); P < .01. The area under the ROC curve was 0.865 [95 % confidence interval (CI) 0.745–0.985] for differentiating CNSL and patients with inflammatory CNS disease; 0.956 (95 % CI 0.898–1.000) for CNSL and MS patients; 0.988 (95 % CI 0.964–1.000) for CNSL and GBM patients, and 0.915 (95 % CI 0.834–0.996) for CNSL patients and healthy controls. In multivariate analysis, high CSF OPN level was associated with shorter progression-free (HR 1.61, 95 % CI 1.13–2.31; P = .009) and overall survival (HR 1.52, 95 % CI 1.04–2.21; P = .029). CSF OPN is a potential biomarker in CNSL.

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References

  1. Deckert M, Engert A, Bruck W, Ferreri AJ, Finke J, Illerhaus G, Klapper W, Korfel A, Kuppers R, Maarouf M, Montesinos-Rongen M, Paulus W, Schlegel U, Lassmann H, Wiestler OD, Siebert R, DeAngelis LM (2011) Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma. Leukemia 25:1797–1807

    Article  CAS  PubMed  Google Scholar 

  2. Boehme V, Zeynalova S, Kloess M, Loeffler M, Kaiser U, Pfreundschuh M, Schmitz N (2007) Incidence and risk factors of central nervous system recurrence in aggressive lymphoma––a survey of 1693 patients treated in protocols of the German high-grade non-hodgkin’s lymphoma study group (DSHNHL). Ann Oncol 18:149–157

    Article  CAS  PubMed  Google Scholar 

  3. Korfel A, Schlegel U (2013) Diagnosis and treatment of primary CNS lymphoma. Nat Rev Neurol 9:317–327

    Article  CAS  PubMed  Google Scholar 

  4. Baraniskin A, Deckert M, Schulte-Altedorneburg G, Schlegel U, Schroers R (2012) Current strategies in the diagnosis of diffuse large B-cell lymphoma of the central nervous system. Br J Haematol 156:421–432

    Article  PubMed  Google Scholar 

  5. Schroers R, Baraniskin A, Heute C, Vorgerd M, Brunn A, Kuhnhenn J, Kowoll A, Alekseyev A, Schmiegel W, Schlegel U, Deckert M, Pels H (2010) Diagnosis of leptomeningeal disease in diffuse large B-cell lymphomas of the central nervous system by flow cytometry and cytopathology. Eur J Haematol 85:520–528

    Article  PubMed  Google Scholar 

  6. Gleissner B, Siehl J, Korfel A, Reinhardt R, Thiel E (2002) CSF evaluation in primary CNS lymphoma patients by PCR of the CDR III IgH genes. Neurology 58:390–396

    Article  CAS  PubMed  Google Scholar 

  7. Bromberg JE, Doorduijn JK, Illerhaus G, Jahnke K, Korfel A, Fischer L, Fritsch K, Kuittinen O, Issa S, van Montfort C, van den Bent MJ (2013) Central nervous system recurrence of systemic lymphoma in the era of stem cell transplantation–an international primary central nervous system lymphoma study group project. Haematologica 98:808–813

    Article  PubMed  PubMed Central  Google Scholar 

  8. Korfel A, Weller M, Martus P, Roth P, Klasen HA, Roeth A, Rauch M, Hertenstein B, Fischer T, Hundsberger T, Leithauser M, Birnbaum T, Kirchen H, Mergenthaler HG, Schubert J, Berdel W, Birkmann J, Hummel M, Thiel E, Fischer L (2012) Prognostic impact of meningeal dissemination in primary CNS lymphoma (PCNSL): experience from the G-PCNSL-SG1 trial. Ann Oncol 23:2374–2380

    Article  CAS  PubMed  Google Scholar 

  9. Baraniskin A, Kuhnhenn J, Schlegel U, Chan A, Deckert M, Gold R, Maghnouj A, Zollner H, Reinacher-Schick A, Schmiegel W, Hahn SA, Schroers R (2011) Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system. Blood 117:3140–3146

    Article  CAS  PubMed  Google Scholar 

  10. Roth P, Keller A, Hoheisel JD, Codo P, Bauer AS, Backes C, Leidinger P, Meese E, Thiel E, Korfel A, Weller M (2015) Differentially regulated miRNAs as prognostic biomarkers in the blood of primary CNS lymphoma patients. Eur J Cancer 51:382–390

    Article  CAS  PubMed  Google Scholar 

  11. Baraniskin A, Kuhnhenn J, Schlegel U, Schmiegel W, Hahn S, Schroers R (2012) MicroRNAs in cerebrospinal fluid as biomarker for disease course monitoring in primary central nervous system lymphoma. J Neuro Oncol 109:239–244

    Article  CAS  Google Scholar 

  12. Sasayama T, Nakamizo S, Nishihara M, Kawamura A, Tanaka H, Mizukawa K, Miyake S, Taniguchi M, Hosoda K, Kohmura E (2012) Cerebrospinal fluid interleukin-10 is a potentially useful biomarker in immunocompetent primary central nervous system lymphoma (PCNSL). Neuro Oncol 14:368–380

    Article  CAS  PubMed  Google Scholar 

  13. Fischer L, Korfel A, Pfeiffer S, Kiewe P, Volk HD, Cakiroglu H, Widmann T, Thiel E (2009) CXCL13 and CXCL12 in central nervous system lymphoma patients. Clin Cancer Res 15:5968–5973

    Article  CAS  PubMed  Google Scholar 

  14. Rubenstein JL, Wong VS, Kadoch C, Gao HX, Barajas R, Chen L, Josephson SA, Scott B, Douglas V, Maiti M, Kaplan LD, Treseler PA, Cha S, Hwang JH, Cinque P, Cyster JG, Lowell C (2013) CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 121:4740–4748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Viaccoz A, Ducray F, Tholance Y, Barcelos GK, Thomas-Maisonneuve L, Ghesquieres H, Meyronet D, Quadrio I, Cartalat-Carel S, Louis-Tisserand G, Jouanneau E, Guyotat J, Honnorat J, Perret-Liaudet A (2015) CSF neopterin level as a diagnostic marker in primary central nervous system lymphoma. Neuro Oncol 17:1497–1503

    Article  PubMed  Google Scholar 

  16. Shevde LA, Samant RS (2014) Role of osteopontin in the pathophysiology of cancer. Matrix Biol 37:131–141

    Article  CAS  PubMed  Google Scholar 

  17. Brown A (2012) Osteopontin: a key link between immunity, inflammation and the central nervous system. Transl Neurosci 3:288–293

    Article  PubMed  PubMed Central  Google Scholar 

  18. Han SS, Lee SJ, Kim WJ, Ryu DR, Won JY, Park S, Cheon MJ (2013) Plasma osteopontin is a useful diagnostic biomarker for advanced non-small cell lung cancer. Tuberc Respir Dis (Seoul) 75:104–110

    Article  Google Scholar 

  19. Incesoy-Ozdemir S, Sahin G, Bozkurt C, Oren AC, Balkaya E, Ertem U (2013) The relationship between cerebrospinal fluid osteopontin level and central nervous system involvement in childhood acute leukemia. Turk J Pediatr 55:42–49

    PubMed  Google Scholar 

  20. Rud AK, Boye K, Oijordsbakken M, Lund-Iversen M, Halvorsen AR, Solberg SK, Berge G, Helland A, Brustugun OT, Maelandsmo GM (2013) Osteopontin is a prognostic biomarker in non-small cell lung cancer. BMC Cancer 13:540

    Article  PubMed  PubMed Central  Google Scholar 

  21. Poruk KE, Firpo MA, Scaife CL, Adler DG, Emerson LL, Boucher KM, Mulvihill SJ (2013) Serum osteopontin and tissue inhibitor of metalloproteinase 1 as diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. Pancreas 42:193–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li Y, Li L, Wang JT, Kan X, Lu JG (2012) Elevated content of osteopontin in plasma and tumor tissues of patients with laryngeal and hypopharyngeal carcinoma associated with metastasis and prognosis. Med Oncol 29:1429–1434

    Article  CAS  PubMed  Google Scholar 

  23. Zhou C, Zhou HJ, Zhang XF, Lou LL, Ye QH, Zheng Y, Wang J, Zhu HT, Dong QZ, Jia HL, Zhu WW, Guo L, Zhao Y, Gao DM, Qin LX (2013) Postoperative serum osteopontin level is a novel monitor for treatment response and tumor recurrence after resection of hepatitis B-related hepatocellular carcinoma. Ann Surg Oncol 20:929–937

    Article  PubMed  Google Scholar 

  24. Han YP, Ma CK, Wang SQ, Enomoto A, Zhao Y, Takahashi M, Ma J (2014) Evaluation of osteopontin as a potential biomarker for central nervous system embryonal tumors. J Neurooncol 119:343–351

    Article  CAS  PubMed  Google Scholar 

  25. Yuan J, Gu K, He J, Sharma S (2013) Preferential up-regulation of osteopontin in primary central nervous system lymphoma does not correlate with putative receptor CD44v6 or CD44H expression. Hum Pathol 44:606–611

    Article  CAS  PubMed  Google Scholar 

  26. Tun HW, Personett D, Baskerville KA, Menke DM, Jaeckle KA, Kreinest P, Edenfield B, Zubair AC, O’Neill BP, Lai WR, Park PJ, McKinney M (2008) Pathway analysis of primary central nervous system lymphoma. Blood 111:3200–3210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rubenstein JL, Shen A, Batchelor TT, Kadoch C, Treseler P, Shuman MA (2009) Differential gene expression in central nervous system lymphoma. Blood 113:266–267; author reply 267–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiang L, Marlow LA, Cooper SJ, Roemeling CV, Menke DM, Copland JA, Tun HW (2010) Selective central nervous system tropism of primary central nervous system lymphoma. Int J Clin Exp Pathol 3:763–767

    PubMed  PubMed Central  Google Scholar 

  29. Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H (2002) Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol 13:1099–1107

    Article  CAS  PubMed  Google Scholar 

  30. Chowdhury SA, Lin J, Sadiq SA (2008) Specificity and correlation with disease activity of cerebrospinal fluid osteopontin levels in patients with multiple sclerosis. Arch Neurol 65:232–235

    Article  PubMed  Google Scholar 

  31. Wen SR, Liu GJ, Feng RN, Gong FC, Zhong H, Duan SR, Bi S (2012) Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 244:94–96

    Article  CAS  PubMed  Google Scholar 

  32. Braitch M, Nunan R, Niepel G, Edwards LJ, Constantinescu CS (2008) Increased osteopontin levels in the cerebrospinal fluid of patients with multiple sclerosis. Arch Neurol 65:633–635

    Article  PubMed  Google Scholar 

  33. Bornsen L, Khademi M, Olsson T, Sorensen PS, Sellebjerg F (2011) Osteopontin concentrations are increased in cerebrospinal fluid during attacks of multiple sclerosis. Mult Scler 17:32–42

    Article  PubMed  Google Scholar 

  34. Yamaguchi Y, Shao Z, Sharif S, Du XY, Myles T, Merchant M, Harsh G, Glantz M, Recht L, Morser J, Leung LL (2013) Thrombin-cleaved fragments of osteopontin are overexpressed in malignant glial tumors and provide a molecular niche with survival advantage. J Biol Chem 288:3097–3111

    Article  CAS  PubMed  Google Scholar 

  35. Edwards LJ, Sharrack B, Ismail A, Tench CR, Gran B, Dhungana S, Brettschneider J, Tumani H, Constantinescu CS (2013) Increased levels of interleukins 2 and 17 in the cerebrospinal fluid of patients with idiopathic intracranial hypertension. Am J Clin Exp Immunol 2:234–244

    PubMed  PubMed Central  Google Scholar 

  36. Szalardy L, Zadori D, Simu M, Bencsik K, Vecsei L, Klivenyi P (2013) Evaluating biomarkers of neuronal degeneration and neuroinflammation in CSF of patients with multiple sclerosis-osteopontin as a potential marker of clinical severity. J Neurol Sci 331:38–42

    Article  CAS  PubMed  Google Scholar 

  37. Weller M, Martus P, Roth P, Thiel E, Korfel A (2012) Surgery for primary CNS lymphoma? challenging a paradigm. Neuro Oncol 14:1481–1484

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bessell EM, Graus F, Punt JA, Firth JL, Hope DT, Moloney AJ, Lopez-Guillermo A, Villa S (1996) Primary non-Hodgkin’s lymphoma of the CNS treated with BVAM or CHOD/BVAM chemotherapy before radiotherapy. J Clin Oncol 14:945–954

    CAS  PubMed  Google Scholar 

  39. Dai J, Li B, Shi J, Peng L, Zhang D, Qian W, Hou S, Zhao L, Gao J, Cao Z, Zhao J, Wang H, Guo Y (2010) A humanized anti-osteopontin antibody inhibits breast cancer growth and metastasis in vivo. Cancer Immunol Immunother 59:355–366

    Article  CAS  PubMed  Google Scholar 

  40. Megaptche AP, Erb U, Buchler MW, Zoller M (2014) CD44v10, osteopontin and lymphoma growth retardation by a CD44v10-specific antibody. Immunol Cell Biol 92:709–720

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Stephan Kreher.

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SK and AK were the principal investigators; CS and SB did the ELISA analyses; PM and FS did the statistical analyses; FS, SK, MW, PR, US, and SS collected patient data; FS, SK, and AK analysed patient data; FS, SK, and AK wrote the report and all authors approved the report. The authors report no potential conflicts of interest.

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Strehlow, F., Bauer, S., Martus, P. et al. Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma. J Neurooncol 129, 165–171 (2016). https://doi.org/10.1007/s11060-016-2162-5

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  • DOI: https://doi.org/10.1007/s11060-016-2162-5

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