**1. Introduction**

158 Advances in the Biology, Imaging and Therapies for Glioblastoma

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Noninvasive imaging methods, including positron emission tomography (PET), have become essential for diagnosis and staging of gliomas, and monitoring of treatment response. The utility of these techniques have been found to be highly dependent on tumor grade. According to the World Health Organization (WHO) classification of tumors (Kleihues and Sobin 2000), gliomas are classified into 3 main histological types: astrocytoma, oligodendroglioma and glioblastoma. These histological types are further classified on the basis of anaplasia and degree of malignancy as: grade I, noninvasive glioma (pilocytic astrocytoma); grade II, less-invasive glioma (astrocytomas and oligodendrogliomas); grade III, invasive glioma (analplastic astrocytoma/oligodendrogliomas); and grade IV, highly invasive glioma (glioblastoma, or GBM).

Low-grade gliomas (grade I and II) typically affect younger patients. Grade I glioma is the most common form of glioma in children and is less frequent in adults (Burkhard et al. 2003) while grade II gliomas are common in adults (mean age of onset is 40 years) (Hagerstrand et al. 2008). Median survival for low-grade glioma is varied but prognosis and treatment require regular follow ups. Low-grade gliomas grow slowly or stabilize spontaneously and with surgical resection, median survival can be 20 years or more (Burkhard et al. 2003). For high-grade gliomas, the mean age of onset is 40 years for grade III glioma and 61 years for GBM (Ohgaki and Kleihues 2005). GBM is the most malignant and most common glioma, accounting for 45% - 50% of all adult gliomas. Median survival for grade III glioma is 2-3 years and for GBM is 1 year (Chen 2007). For optimal disease prognosis, treatment and follow up, one should be able to delineate the tumor lesion and most importantly, differentiate benign lesions from neoplastic lesions, low-grade from high grade tumors, and tumor progression from therapy induced necrosis. As will be discussed later, efforts are also being directed toward defining early imaging predictors of response to therapy.

Conventional imaging with magnetic resonance imaging (MRI) provides excellent anatomical definition of brain tumors. MRI is highly sensitive in identifying lesions, mass effect, edema, hemorrhage, necrosis and signs of increased intracranial pressure (Chen 2007). Pathologic changes are characterized on MRI by increased water content (edema) and blood-brain barrier (BBB) disruption, visualized as contrast enhancement (Grosu et al. 2002). Most tumors (low-grade or high-grade) have prolonged T1 and T2 relaxation times and thus

PET Imaging of Gliomas 161

[18F]FDG-PET has also been useful to differentiate hypoglycolytic non-malignant toxoplasmosis common in AIDS patients from hyperglycolytic CNS lymphoma (Hoffman et

Assessment of [18F]FDG uptake in gliomas has high prognostic value (Di Chiro 1987). De Witte et al. (1996) studied 28 patients with histologically proven low-grade gliomas with [18F]FDG–PET and followed progression of disease for a mean of 27 months. All 19 patients with tumors that were hypoglycolytic on PET were alive at the end of the follow-up period, whereas 6 of 9 patients with hyperglycolytic patterns on PET died. The prognostic utility of [18F]FDG–PET has been confirmed in several other studies (Alavi et al. 1988; Barker

Although [18F]FDG-PET is accurate to detect high-grade gliomas, it has limited usefulness in detection of low-grade gliomas and some high-grade gliomas such as post-operative residual and recurrent glioma (Olivero et al. 1995; Ricci et al. 1998). Since glucose is the preferred fuel in normal brain, high [18F]FDG uptake in surrounding normal tissues in brain is unavoidable (Di Chiro et al. 1982). Low grade gliomas tend to have the same or lower [18F]FDG uptake as compared to average [18F]FDG uptake in white matter, thus resulting in false negative readings (Kawai et al. 2005). This is also true for certain high-grade gliomas, especially hypoglycolytic residual (Padma et al. 2003) and recurrent tumors (Chao et al. 2001) that may exhibit less or similar [18F]FDG uptake to average [18F]FDG uptake in grey matter. In addition, in the case of patients with Alzheimer disease and epilepsy, affected regions in brain can show decreased [18F]FDG uptake compared to background (Fazekas et al. 1989; McGeer et al. 1986). On the other hand, brain regions with abscess or acute necrosis occurring hours of weeks after radiotherapy, chemotherapy can show increased [18F]FDG uptake compared to background leading to false positive readings (Floeth et al. 2006). Thus, low tumor-to-normal background radioactivity concentration (T/N) ratios and difficult to interpret contrasts between normal and pathological regions limit the specificity of

[18F]FDG-PET to detect low-grade and residual or relapsed high-grade brain tumors.

Given these concerns, attempts have been made to improve the accuracy of [18F]FDG for imaging of gliomas. In cases where T/N (white or grey matter) ratios for [18F]FDG uptake are not useful for delineating low-grade, residual or relapsed high-grade glioma, two strategies have been reported to help: (1) co-registration of [18F]FDG–PET images with MR images (Chao et al. 2001; Wang et al. 2006) and (2) delayed [18F]FDG–PET imaging (Spence et al. 2004). Co-registration and interpretation of [18F]FDG–PET images with MR images can improve the performance of [18F]FDG–PET **(Figure 1)** for detecting low-grade (Borgwardt et al. 2005; Wong et al. 2004), residual or relapsed high-grade gliomas (Chao et al. 2001; Wang et al. 2006). Low grade gliomas can be identified by similar [18F]FDG uptake to white matter in regions with increased signal on T2-weighted MRI (Borgwardt et al. 2005; Wong et al. 2004), while recurrent high grade gliomas are often indicated as [18F]FDG uptake in regions with contrast enhancement on T1-weighted MRI (Chao et al. 2001; Wang et al. 2006). Delayed PET imaging, as proposed by Spence et al. (2004), is another strategy to improve the contrast between tumor lesion and background. In this study, nineteen patients with gliomas were imaged from 0 to 90 min and once or twice at 3–8 h after injection. In 12 of 19 patients, visual analysis of delayed images up to 8 h afterinjection showed these images to better distinguish relapsed tumors in grey matter (**Figure 2**). Standardized uptake values (SUVs) were also greater in tumors than in normal grey or white matter on delayed imaging. Using kinetic modeling, they demonstrated that the rate constant of

al. 1993).

et al. 1997; Padma et al. 2003; Patronas et al. 1985).

appear hypointense on T1-weighted images but hyperintense on T2-weighted images relative to normal brain (Grosu et al. 2002; Sartor 1999). In low-grade gliomas, peritumoral edema is minimal or absent and no contrast enhancement is seen due to intact BBB. Whereas, in high-grade gliomas, peritumoral edema is frequently seen and the tumor lesions usually show contrast enhancement, correlated with the extent of neovascularization and loss of integrity of the BBB owing to tumor infiltration and production of vascular endothelial growth factor. The anatomical features obtained by MRI are not sufficient to differentiate low-grade from high-grade gliomas with intact BBB, tumor lesions from inflammatory or vascular processes, and post-operative residual/relapse from necrosis (Chen 2007).

In contrast to MRI, positron emission tomography (PET) provides unique functional information of tumors on a range of biological processes such as glucose metabolism, protein/DNA synthesis, cell proliferation, membrane synthesis, angiogenesis and oxygen tension that can reflect the changes in neoplasm (Basu and Alavi 2009). Assessment of the status of these processes in areas of interest in brain has been shown to be helpful in detection and grading of gliomas, delineation of tumor margins, disease prognosis and treatment. PET has also been useful in differentiating post-operative residual tumor from therapy induced necrosis and edema. This review discusses radiopharmaceuticals and progress in the development of PET techniques for imaging of gliomas in the following areas: glucose uptake, amino acid transport, cellular proliferation rate, choline uptake, somatostatin receptor density, angiogenesis and hypoxia.
