Serum S100 A Noninvasive Marker of Blood-Brain Barrier Function and Brain Lesions Andrew A. Kanner, M.D. 1–3 Nicola Marchi, Ph.D. 3 Vincent Fazio, M.S. 3 Marc R. Mayberg, M.D. 1–3 Michael T. Koltz, M.S. 3 Vitaly Siomin, M.D. 1 Glen H. J. Stevens, D.O., Ph.D. 1 Thomas Masaryk, M.D. 3,4 Barbara Ayumar, B.S. 1 Michael A. Vogelbaum, M.D., Ph.D. 1 Gene H. Barnett, M.D. 1 Damir Janigro, Ph.D. 1,3–5 1 Brain Tumor Institute, The Cleveland Clinic, Cleveland, Ohio. 2 Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3 Cerebrovascular Research Center, The Cleveland Clinic, Cleveland, Ohio. 4 Department of Neurological Surgery, The Cleve- land Clinic, Cleveland, Ohio. 5 Department of Cell Biology, The Cleveland Clinic, Cleveland, Ohio. Supported by grants HL51614, NS43284, and NS38195 to Damir Janigro. The authors acknowledge the continuous support of Sangtec Medical Inc. (Bromma, Sweden). Address for reprints: Damir Janigro, Ph.D., c/o Martha Tobin, Editorial Services Manager, Depart- ment of Neurosurgery, S-80, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; Fax: (216) 445-1466; E-mail: janigrd@ ccf.org Dr. Janigro is a consultant to Sangtec Medical Inc. Received November 4, 2002; revision received December 31, 2002; accepted February 11, 2003. BACKGROUND. S100 protein is expressed constitutively by brain astrocytes. Ele- vated S100 levels in cerebrospinal fluid and serum reported after head trauma, subarachnoid hemorrhage, and stroke were correlated with the extent of brain damage. Because elevated serum S100 also was shown to indicate blood-brain barrier (BBB) dysfunction in the absence of apparent brain injury, it remains unclear whether elevation of serum levels of S100 reflect BBB dysfunction, pa- renchymal damage, or both. METHODS. The authors conducted a prospective study of serum S100 levels in six patients who underwent hyperosmotic BBB disruption (BBBD) with intraarterial chemotherapy for primary central nervous system lymphoma. In addition, 53 serum S100 samples were measured in 51 patients who had a variety of primary or metastatic brain lesions at the time of neuroimaging. RESULTS. S100 was correlated directly with the degree of clinical and radiologic signs of BBBD in patients who were enrolled in the hyperosmotic study. In patients with neoplastic brain lesions, gadolinium enhancement on a magnetic resonance image was correlated with elevated S100 levels (n = 45 patients; 0.16  0.1 g/L; mean  standard error of the mean) versus nonenhancing scans (n = 8 patients; 0.069  0.04 g/L). Primary brain tumors (n = 8 patients; 0.12  0.08) or central nervous system metastases also presented with elevated serum S100 levels (n = 27 patients; 0.14  0.34). Tumor volume was correlated with serum S100 levels only in patients with vestibular schwannoma (n = 6 patients; 0.13  0.10 g/L) but not in patients with other brain lesions. CONCLUSIONS. S100 was correlated directly with the extent and temporal se- quence of hyperosmotic BBBD, further suggesting that S100 is a marker of BBB function. Elevated S100 levels may indicate the presence of radiologically detect- able BBB leakage. Larger prospective studies may better determine the true spec- ificity of S100 as a marker for BBB function and as an early detection or follow-up marker of brain tumors. Cancer 2003;97:2806 –13. © 2003 American Cancer Society. DOI 10.1002/cncr.11409 KEYWORDS: blood-brain barrier disruption, brain damage, magnetic resonance imaging, metastatic brain tumor. S erum S100 is a low-molecular-weight Ca 2+ -binding protein com- posed of two isomeric subunits and is found predominately in astroglial and Schwann cells. 1–5 S100 normally is low or is not de- tectable in serum; however, elevated serum levels have been detected in a number of neuropathologic conditions. 6 –15 Intraoperative mea- surements have demonstrated temporary elevations in serum S100 levels during cardiac and carotid artery surgery that investigators believed was caused by cerebral emboli. 16,17 Both the time course and the degree of elevation were associated strongly with neuropsychological 2806 © 2003 American Cancer Society