Purpose: The receptor tyrosine kinase Axl has recently been identified as a critical element in the invasive properties of glioma cell lines. However, the effect of Axl and its ligand growth arrestŝ pecific gene 6 (Gas6) in human gliomas is still unknown. Experimental Design: Axl and Gas6 expression was studied in 42 fresh-frozen and 79 paraffinembedded glioma specimens by means of reverse transcription-PCR and immunohistochemistry. The prognostic value of Axl and Gas6 expression was evaluated using a population-based tissue microarray derived from a cohort of 55 glioblastoma multiforme (GBM) patients.Results: Axl and Gas6 were detectable in gliomas of malignancy gradesWHO 2 to 4. Moderate to high Axl mRNA expression was found in 61%, Axl protein in 55%, Gas6 mRNA in 81%, and Gas6 proteinin 74% of GBMsamples, respectively. GBM patients withhigh Axl expression and Axl/Gas6 coexpression showed a significantly shorter time to tumor progression and an association with poorer overall survival. Comparative immunohistochemical studies showed that Axl staining was most pronounced in glioma cells of pseudopalisades and reactive astrocytes. Additionally, Axl/ Gas6 coexpression was observed in glioma cells and tumor vessels. In contrast, Axl staining was not detectable in nonneoplastic brain tissue and Gas6 was strongly expressed in neurons.Conclusions: In human gliomas, Axl and Gas6 are frequently overexpressed in both glioma and vascular cells and predict poor prognosis in GBM patients. Our results indicate that specific targeting of the Axl/Gas6 signaling pathway may represent a potential new approach for glioma treatment.

The objective of this study was to compare MRI response assessment with metabolic O-(2-18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) PET response evaluation during antiangiogenic treatment in patients with recurrent high-grade glioma (rHGG). Methods: Eleven patients with rHGG were treated biweekly with bevacizumab-irinotecan. MR images and 18 F-FET PET scans were obtained at baseline and at follow-up 8-12 wk after treatment onset. MRI treatment response was evaluated by T1/T2 volumetry according to response assessment in neurooncology (RANO) criteria. For 18 F-FET PET evaluation, an uptake reduction of more than 45% calculated with a standardized uptake value of more than 1.6 was defined as a metabolic response (receiver-operating-characteristic curve analysis). MRI and 18 F-FET PET volumetry results and response assessment were compared with each other and in relation to progression-free survival (PFS) and overall survival (OS). Results: At follow-up, MR images showed partial response in 7 of 11 patients (64%), stable disease in 2 of 11 patients (18%), and tumor progression in 2 of 11 patients (18%). In contrast, 18 F-FET PET revealed 5 of 11 metabolic responders (46%) and 6 of 11 nonresponders (54%). MRI and 18 F-FET PET showed that responders survived significantly longer than did nonresponders (10.24 vs. 4.1 mo, P 5 0.025, and 7.9 vs. 2.3 mo, P 5 0.015, respectively). In 4 patients (36.4%), diagnosis according to RANO criteria and 18 F-FET PET was discordant. In these cases, PET was able to detect tumor progression earlier than was MRI. Conclusion: In rHGG patients undergoing antiangiogenic treatment, 18 F-FET PET seems to be predictive for treatment failure in that it contributes important information to response assessment based solely on MRI and RANO criteria.

Background and Purpose: Sneddon's syndrome, characterized by generalized livedo racemosa and

Summary. We report a 53-year-old man with lymphoid blast crisis of Ph + chronic myeloid leukaemia who was treated with STI571, a selective inhibitor of the enzymatic activity of BCR-ABL. He responded excellently to STI571 (600 mg/d), obtaining a complete cytogenetic remission after 3 months of therapy. Although remission in the bone marrow was sustained, the patient developed an isolated central nervous system relapse. Subsequent analyses of STI571 concentrations in the cerebrospinal fluid (CSF) revealed 2-log lower CSF levels of STI571 than corresponding plasma levels. These are the first data demonstrating a low penetration of orally administered STI571 into the CSF in humans.

Leptomeningeal metastasis (LM) is a devastating complication that occurs in 5% of patients with breast cancer. Early diagnosis and initiation of treatment are essential to prevent neurological deterioration. However, early diagnosis of LM remains challenging because 25% of cerebrospinal fluid (CSF) samples produce false-negative results at first cytological examination. We developed a new, MS-based method to investigate the protein expression patterns present in the CSF from patients with breast cancer with and without LM. CSF samples from 106 patients with active breast cancer (54 with LM and 52 without LM) and 45 control subjects were digested with trypsin. The resulting peptides were measured by MALDI-TOF MS. Then, the mass spectra were analyzed and compared between patient groups using newly developed bioinformatics tools. A total of 895 possible peak positions was detected, and 164 of these peaks discriminated between the patient groups (Kruskal-Wallis, p < 0.01). The discriminatory masses were clustered, and a classifier was built to distinguish patients with breast cancer with and without LM. After bootstrap validation, the classifier had a maximum accuracy of 77% with a sensitivity of 79% and a specificity of 76%. Direct MALDI-TOF analysis of tryptic digests of CSF gives reproducible peptide profiles that can assist in diagnosing LM in patients with breast cancer. The same method can be used to develop diagnostic assays for other neurological disorders. One of the tumors most frequently associated with LM is breast cancer. During the course of the disease, ϳ5% of patients with metastatic breast cancer will develop symptoms caused by LM. This debilitating complication's response to therapy depends upon early treatment. However, diagnosis of LM remains challenging because 25% of samples tested are false negative at the first cytological examination of the CSF, probably because of sampling error (1).Protein expression profiling of body fluids from patients with cancer has recently become a valuable tool for obtaining information on the state of protein circuits inside tumor cells and outside the cells at the host-tumor interface (2, 3). In serum and CSF, low molecular weight proteins and peptides that are related to this altered microenvironmental "cancerous" state can be detected.We studied the differential tryptic peptide profiles in the CSF from patients with breast cancer with and without LM and in CSF from control subjects. Studying CSF has several advantages over studying serum. First, tumor cells in LM patients are located in the CSF and in the leptomeninges that are surrounded by CSF. Before their transport into serum, tumor-related proteins will therefore first be shed into the CSF. Second, the normal protein concentration of CSF is 100-to 400-fold lower than in serum (4). This results in a significant over-representation of LM-related proteins in CSF compared From the ‡Laboratory of Neuro-oncology, Department of Neurology, Dr Molewaterplein 40, 3015 GD, and § §Department