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BRIEF COMMUNICATIONS: J. C. Reijneveld, D. Brandsma, W. Boogerd, J.G.M. Bonfrer, S. Kalmijn, E. E. Voest, A. Geurts-Moespot, M. C. Visser, and M. J.B. Taphoorn CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases Neurology 2005; 65: 1120-1122 [Abstract] [Full text] [PDF]

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CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases

Morris D. Groves   (31 January 2006)

Reply from the authors

Jaap C. Reijneveld, Dieta Brandsma   (31 January 2006)

CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases 31 January 2006
Morris D. Groves, University of Texas MD Anderson Cancer Center 1400 Holcombe Unit 431, Houston, Texas 77030 Send Correspondence to journal: Re: CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases mgroves{at}mdanderson.org Morris D. Groves	Reijneveld et al report CSF levels of vascular endothelial growth factor (VEGF) and urokinase-type plasminogen activator (uPA) from 53 patients with leptomeningeal metastases (LM) and 43 control patients. [1] This interesting study furthers a line of investigation relating angiogenesis to LM [2,3] and may pave the way for therapeutic trials targeting pro- angiogenic molecules. Besides revealing potential pathophysiologic processes, these molecules may serve as surrogates of CSF tumor burden, biomarkers of disease and response to therapy. The authors found a correlation between elevated CSF levels of total protein with both CSF VEGF and uPA but the presence or absence of hydrocephalus or other CSF flow abnormality was not mentioned. Impaired CSF flow by either mechanism could have caused an elevation of the CSF VEGF and uPA and the typical CSF proteins. CSF flow obstruction which is not alleviated by treatment is a well known marker of poor survival in LM patients [4] and can be accompanied by elevated CSF protein levels. Data on the CSF flow from the LM patients would help place the VEGF and uPA levels in context with the patient outcomes. If slow CSF flow causes elevations in these protein levels in the CSF, their use as biomarkers will need to be considered in conjunction with CSF flow to derive meaning from changes in the levels over time. In future studies, a drop in the CSF angiogenesis biomarker level could simply reflect opening of a CSF block rather than a true response to an anti-angiogenic therapy. Additionally, 19 of 53 patients had positive imaging evidence of LM. It would be useful to know the CSF levels of VEGF and uPA in relation to the presence or absence of visible disease on neuro-imaging. If higher CSF levels are correlated with more extensive visible tumor on imaging (notwithstanding the CSF flow issues mentioned above), a stronger argument can be developed for the use of these as surrogate markers of CSF tumor burden and not just markers of the presence or absence of disease. Lastly, of the 53 patients with LM, all but 5 had solid tumors. VEGF is usually associated with solid tumors [5], and less often with liquid tumors. Providing data on the CSF marker levels as they relate to the specific tumor histologies would be useful. It is foreseeable that some tumor markers will be useful in only limited subsets of LM histologies. References 1. Reijneveld JC, Brandsma D, Boogerd W, et al. CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases. Neurology 2005;65:1120-1122. 2. Stockhammer GF, Poewe WF, Burgstaller SF, et al. Vascular endothelial growth factor in CSF: a biological marker for carcinomatous meningitis. Neurology 2000;54:1670-1676. 3. Herrlinger U, Wiendl H, Renninger M, Forschler H, Dichgans J, Weller M. Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diagnostic and prognostic value. Br J Cancer 2004;91:219-224. 4. Glantz MJ, Hall WA, Cole BF,et al. Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status. Cancer 1995;75:2919-2931. 5. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20:4368-4380. Disclosure: The author reports no conflicts of interest.
Reply from the authors 31 January 2006
Jaap C. Reijneveld, Department of Neurology, VU University Medical Center HP 2A.87, PO Box 7057 1007 MB Amsterdam Holland, Dieta Brandsma Send Correspondence to journal: Re: Reply from the authors JC.Reijneveld{at}vumc.nl Jaap C. Reijneveld, et al.	We thank Dr. Groves for his interesting comments on our recent article regarding CSF levels of angiogenesis-related proteins in leptomeningeal metastases (LM). [1] He comments that we did not mention the presence or absence of hydrocephalus or other CSF flow abnormalities in our study. He argues that an impaired CSF flow may result in increased CSF protein levels, including angiogenesis-related proteins such as urokinase-type plasminogen activator (uPA) and vascular endothelial growth factor (VEGF). This CSF block- related increase might obscure the correlation between uPA- and VEGF- levels on the one hand, and survival on the other. We think that this is a valuable addition to our article, especially when both factors as response markers are used. It might be hazardous to simply extrapolate an increase in CSF protein level in patients with impaired CSF flow, to an increase of uPA- and VEGF-concentrations, as this has never actually been demonstrated. The author also wonders whether higher CSF uPA- and VEGF-levels were correlated with the presence or absence of visible disease on neuroimaging. It is possible that higher CSF-levels would be accompanied by (more) visible tumor load on imaging studies. In our study population of 53 patients with LM, however, uPA- and VEGF-levels were not associated with visible tumor load on imaging studies (n=50; Mann Whitney U test: uPA: p=0,194, VEGF: p=0,712). We think that the lack of significance may be attributed to the relatively low sensitivity of computed tomography (CT; n=10), and even magnetic resonance imaging (MRI; n=40) for detection of leptomeningeal tumor. [2] Furthermore, the author would like to know whether increases in uPA and VEGF were associated with specific tumor types. Although we describe a relatively large group of 53 patients with LM, a subdivision in groups with different primary tumors would result in very small numbers per patient group. We purposely refrained from statistical comparison of CSF VEGF- and uPA-levels in patient groups subdivided by primary tumor type. We agree with the author that further studies regarding the role of these proteins in LM are necessary, and may not only result in the revelation of potential pathophysiologic processes, but also in an better defined role for these molecules as surrogates of CSF tumor burden, biomarkers of disease and response to therapy. Disclosure: The authors report no conflicts of interest.