H. Kostron

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 arrest--specific gene 6 (Gas6) in human gliomas is still unknown. EXPERIMENTAL DESIGN: Axl and Gas6 expression was studied in 42 fresh-frozen and 79 paraffin-embedded 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 grades WHO 2 to 4. Moderate to high Axl mRNA expression was found in 61%, Axl protein in 55%, Gas6 mRNA in 81%, and Gas6 protein in 74% of GBM samples, respectively. GBM patients with high 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.

UNLABELLED: 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 = 0.025, and 7.9 vs. 2.3 mo, P = 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.

Photodynamic techniques such as photodynamic diagnosis (PDD), fluorescence-guided tumour resection (FGR) and photodynamic therapy (PDT) are currently undergoing intensive clinical investigations as adjuvant treatment for malignant brain tumours. The following chapter provides an overview on the current clinical data and trials of PDT as well as photosensitizers, technical developments and indications for photodynamic application in neurosurgery. Besides many clinical phase I/II trials for PDT for malignant brain tumours, there are only few controlled clinical trials following tumour resection. Variations in treatment protocols, variation of photosensitizers and light dose make the evaluation scientifically difficult; however there is a clear trend towards prolonging median survival after one single photodynamic treatment as compared to standard therapeutic regimens. According to the meta analysis the median survival after PDT for primary glioblastoma multiforme (WHO grade IV) was 22 months and for recurrent GBM was 9 months as compared to standard conventional treatment, in which it is 15 and 3 months, respectively. Fluorescence-guided resection of the tumour demonstrated significant greater reduction of tumour burden. The combination of PDD/ FGR and intraoperative PDT ("to see and to treat") offers an exciting approach to the treatment of malignant brain tumours. PDT was generally well tolerated and side effects consisted of occasionally increased intracranial pressure and prolonged skin sensitivity against direct sunlight.