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1 Diplomarbeitsthema Histo-morphometric analysis of angioarchitecture in low-grade gliomas on 2D high-resolution digital images Collaborators: Medical University of Vienna: Matthias Preusser, MD Department of Internal Medicine I/Oncology Johannes A. Hainfellner, MD Institute of Neurology Harald Heinzl, PhD Core Unit for Medical Statistics and Informatics, Section of Clinical Biometrics Adelheid Woehrer, MD Medical University of Vienna Institute of Neurology Georg Widhalm, MD Department of Neurosurgery Vienna University of Technology: Wolfgang Wertz Matthias Templ, ... ... Frank Rattay, ... ... Cornelia Wenger, ... ... 2 Background Low-grade gliomas (LGG) including diffuse astrocytoma, oligoastrocytoma and oligodendroglioma are rare brain neoplasms most commonly affecting adults [1]. LGG show diffuse growth in the brain parenchyma and invariably recur or progress to high-grade glioma. Most cases of LGG lead to patient death with survival times ranging from approximately 5-15 years [1]. By definition, at histopathological analysis LGG lack glomeruloid and layered endothelial proliferates typically found in high-grade glioma [1]. However, LGG show considerable variability in vascularization between cases (Figure 1). Little is known about patterns of angioarchitecture and their clinical relevance in LGG. Methods commonly used for assessment of tumor vascularization including analysis of hot-spot microvessel density (MVD) have substantial methodological limitations (low interobserver reproducibility) and seem inadequate to describe the irregular geometry of tumor angioarchitecture [2]. Histo-morphometric analysis of tumor vascularization may more adequately capture the complex architecture by considering the number of vessels, the variability in vessel shapes and sizes and the pattern of vessel distribution within a tumor specimen. Aim of the study The aim of the present study is to develop a reliable algorithm for computer-assisted objective assessment of LGG angioarchitecture. Methods The study will be performed on formalin-fixed and paraffin-embedded tumour tissue specimens from 20 LGG patients treated at the Medical University of Vienna. Of each tissue specimen, immunohistochemical staining for CD34 antigen will be performed to visualize intratumoural microvessels. All immunostained slides will be scanned and the high resolution 2D digital slides will be stored for further data processing. Algorithms that yield objective indicators of tumour vascularization on the 2D images will be defined after critical appraisal of available mathematics and informatics tools, and consensual agreement achieved between the experts in medicine and mathematics/statistics/informatics. 3 Outlook If this project succeeds in development of an algorithm for objective assessment of LGG angioarchitecture on 2D high resolution digital images, the reproducibility and clinical relevance will be tested in EORTC study 22033-26033, a large, multicenter, prospective, randomized clinical phase III trial investigating the effect of primary chemotherapy with temozolomide versus radiotherapy in patients with low grade gliomas. Adult patients with histologically proven supratentorial LGG are eligible and chromosome arm 1p deletion status will be included as stratification factor. Of each patient enrolled in the trial, formalin-fixed and paraffin-embedded (FFPE) tumor tissue specimens are being collected in a central pathology laboratory (Erasmus University Hospital, Rotterdam, the Netherlands). As of August 2009, 354 of 466 required patients have been randomized. Randomization of the last patient is expected for late 2010. 4 References 1. Louis DN, Ohgaki H, Wiestler OD, Cavanee WK: WHO Classification of Tumours of the Central Nervous System. IARC Press, Lyon, 2007 2. Preusser M, Heinzl H, Gelpi E, Schonegger K, Haberler C, Birner P, Marosi C, Hegi M, Gorlia T, Hainfellner JA (2006) Histopathologic assessment of hot-spot microvessel density and vascular patterns in glioblastoma: Poor observer agreement limits clinical utility as prognostic factors: a translational research project of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Cancer 107:162-170. 5 Legend to Figure 1. The vascularization is variable between low-grade-glioma (LGG) cases. A. Exemplary case of LGG showing delicate and evenly distributed microvessels. B. Exemplary case of LGG showing delicate clusters of irregularly shaped microvessels. Glomeruloid and layered endothelial proliferates typical for high grade glioma are lacking. A and B: Anti-CD34 immunohistochemistry; brown signals: endothelial cells, blue signals: tumour cell nuclei.