Introduction Lymphomatous meningitis is a common complication of central nervous system (CNS) lymphomas at initial diagnosis or at recurrence. Although a positive result is highly specific, cerebrospinal fluid (CSF) cytology for lymphoma cells has low sensitivity, and up to one third of patients with active leptomeningeal disease have cytologically false- negative results. 1-3 This lack of sensitivity is probably due to insufficient CSF, cellular disintegration during processing, lymphoma cells adherent to the leptomeninges, and sampling error when CSF is taken far from the site of active disease in the neuraxis. 4,5 A diagnosis of lymphomatous meningitis could still be made if there is overwhelming evidence suggested by neuroimaging and pattern of neurologic deficits. 6 The presence of monoclonal immunoglobulins in CSF protein electrophoresis and demonstration of monoclonality of lymphoid cells by flow cytometry, as well as positive CSF biomarkers like β 2 -microglobulin and lactate dehydrogenase (LDH), could help to corroborate the neuroimaging and clinical findings for lymphomatous meningitis. However, in our experience, oligoclonal immunoglobulin bands appear more frequently than monoclonal bands in the CSF, and these oligoclonal bands can be produced by reactive B lymphocytes. Flow cytometry is often limited by insufficient cells in the CSF. Furthermore, β 2 -microglobulin and LDH are not specific for lymphoma, because they are increased in CNS infections and other inflammatory conditions. As a result, new biomarkers for lymphomatous meningitis with a better specificity than those currently available are needed. Matrix metalloproteinases (MMPs), a family of zinc-dependent proteases, play an important role in the metastasis of tumor cells and in angiogenesis. 7 Most of the MMPs are secreted by tumor cells in the proenzyme form, with the Zn 2+ -binding catalytic site covered by the protein’s quaternary structure. When it is cleaved by MMPs or other proteases, the Zn 2+ -binding catalytic site is exposed, making it enzymatically active. Matrix metalloproteinase–2, MMP-9, and membrane-type-1 MMP are important for glioma migration. 8,9 Matrix metalloproteinases are also implicated in the remodeling of blood vessels, and it can allow the migration of endothelial cells to form new blood vessels during angiogenesis. 7 We hypothesize that MMPs would be important in lymphomatous meningitis, Matrix Metalloprotease–9 in Cerebrospinal Fluid Correlates with Disease Activity in Lymphomatous Meningitis Eric T. Wong, 1,2 Diana Lee, 1,2 Angela Tam, 1,2 Shiva Gautam, 3 Julian K. Wu 1,4 Purpose: The detection of lymphoma cells in cerebrospinal fluid (CSF) as a means to diagnose lymphomatous meningitis is problematic due to its low sensitivity. We hypothesize that matrix metalloproteases (MMPs) would be important in lymphomatous meningitis because lymphoma cells may produce MMPs for brain invasion and angiogenesis. Patients and Methods: Twenty- nine samples of CSF collected longitudinally from 5 patients receiving treatments for primary or metastatic CNS lymphomas were retrospectively analyzed by zymography. Cerebrospinal fluid cytology was correlated with levels of total protein, glucose, MMP-2, MMP-9, activated MMP-9, and 130 kDa MMP. Results: Increased CSF white blood cells (65 ± 32 cells/μL vs. 9 ± 8 cells/μL; P = 0.03) and MMP-9 (12.108 ± 2.675 vs. 9.359 ± 1.936; P = 0.02) had a strong correlation with abnormal CSF cytology. In addition, we observed that activated MMP-9 would appear and disappear depending on disease activity. Although there was nearly a 4-fold increase of mean activated MMP-9 in CSF samples with abnormal cytology findings when compared with negative cytology findings, the correlation did not reach statistical significance (1.382 ± 0.76 vs. 0.389 ± 0.155; P = 0.17). Conclusion: Matrix metalloprotease–9 correlated strongly with lymphomatous meningitis, but MMP-2, activated MMP-2, activated MMP-9, and 130-kDa MMP did not. Clinical Lymphoma & Myeloma, Vol. 7, No. 4, 305-308, 2007 Key words: Brain, Central nervous system, Neoplastic meningitis Abstract Original Contribution Submitted: Mar 26, 2006; Revised: Sep 12, 2006; Accepted: Oct 10, 2006 Address for correspondence: Eric T. Wong, MD, Brain Tumor Center & Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 Fax: 617-667-1664; e-mail: ewong@bidmc.harvard.edu 1 Brain Tumor Center & Neuro-Oncology Unit 2 Department of Neurology 3 Biostatistics Program 4 Division of Neurosurgery Harvard Medical School & Beth Israel Deaconess Medical Center, Boston, MA Electronic forwarding or copying is a violation of US and International Copyright Laws. 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