**6. Acknowledgements**

This work was supported in part by grants CTQ2010-20960-C02-02 to P.L.L. and grant SAF2008-01327 to S.C. A.M.M. held an Erasmus Fellowship from Coimbra University and E.C.C. a predoctoral CSIC contract. The valuable contribution of Mr. Javier Perez drafting the illustrations is gratefully acknowledged.

#### **7. References**

246 Advances in the Biology, Imaging and Therapies for Glioblastoma

Fig. 13. Change in perfusion in a pathologically confirmed GMB case before (A) and after (B) the initiation of anti-angiogenic chemotherapy. Left images in both panels show contrast enhanced T1W images used to measure tumor volume (green). Right images depict CA leakage corrected rCBV maps showing tumor perfusion (red arrow) (Sawlani, Raizer et al.)

In summary, we presented an overview of the fundamentals and clinical applications of advanced Magnetic Resonance Imaging protocols providing in situ information on water diffusion and blood perfusion in gliomas. These methodologies have shown considerable ability to provide functional information on the malignancy of these lesions as well as in its response to therapy. Together, they allow for a more adequate patient management based fully in non invasive non destructive examinations. These MRI approaches have been, however, applied independently in most cases. The future use of combinations of these two strategies may offer the possibility to compensate the limitations of one technology with the strengths of the other, still maintaining their non invasive character. In this sense, combined diffusion-perfusion methodologies may provide in the future significant advances, becoming even more effective in clinic for the diagnosis, prognosis and therapy assessment

Reproduced with permission.

of gliomas.

**5. Concludig remarks and future perspectives** 


Lyng, H., O. Haraldseth, et al. (2000). "Measurement of cell density and necrotic fraction in

Moffat, B. A., T. L. Chenevert, et al. (2005). "Functional diffusion map: a noninvasive MRI

Moffat, B. A., T. L. Chenevert, et al. (2006). "The functional diffusion map: an imaging

Mori, S. and P. B. Barker (1999). "Diffusion magnetic resonance imaging: its principle and

Mori, S. and P. C. van Zijl (2002). "Fiber tracking: principles and strategies - a technical

Nucifora, P. G., R. Verma, et al. (2007). "Diffusion-tensor MR imaging and tractography: exploring brain microstructure and connectivity." Radiology 245(2): 367-84. Ostergaard, L. (2005). "Principles of cerebral perfusion imaging by bolus tracking." J Magn

Ostergaard, L., A. G. Sorensen, et al. (1996). "High resolution measurement of cerebral blood

Ostergaard, L., R. M. Weisskoff, et al. (1996). "High resolution measurement of cerebral

Pacheco-Torres, J., D. Calle, et al. "Environmentally sensitive paramagnetic and diamagnetic

Pauliah, M., V. Saxena, et al. (2007). "Improved T(1)-weighted dynamic contrast-enhanced

Petersen, E. T., I. Zimine, et al. (2006). "Non-invasive measurement of perfusion: a critical review of arterial spin labelling techniques." Br J Radiol 79(944): 688-701. Price, S. J., N. G. Burnet, et al. (2003). "Diffusion tensor imaging of brain tumours at 3T: a potential tool for assessing white matter tract invasion?" Clin Radiol 58(6): 455-62. Provenzale, J. M., S. Mukundan, et al. (2006). "Diffusion-weighted and perfusion MR

Provenzale, J. M., G. R. Wang, et al. (2002). "Comparison of permeability in high-grade and

Reardon, D. A., J. N. Rich, et al. (2006). "Recent advances in the treatment of malignant

Roberts, H. C., T. P. Roberts, et al. (2002). "Quantitative estimation of microvascular

MR imaging with histopathologic grading." Acad Radiol 9 Suppl 1: S151-5. Rosen, B. R., J. W. Belliveau, et al. (1990). "Perfusion imaging with NMR contrast agents."

approach and statistical analysis." Magn Reson Med 36(5): 715-25.

and preliminary results." Magn Reson Med 36(5): 726-36.

flow using intravascular tracer bolus passages. Part II: Experimental comparison

blood flow using intravascular tracer bolus passages. Part I: Mathematical

contrast agents for nuclear magnetic resonance imaging and spectroscopy." Curr

MRI to probe microvascularity and heterogeneity of human glioma." Magn Reson

imaging for brain tumor characterization and assessment of treatment response."

low-grade brain tumors using dynamic susceptibility contrast MR imaging." AJR

permeability in human brain tumors: correlation of dynamic Gd-DTPA-enhanced

Magn Reson Med 43(6): 828-36.

applications." Anat Rec 257(3): 102-9.

review." NMR Biomed 15(7-8): 468-80.

Sci U S A 102(15): 5524-9.

Reson Imaging 22(6): 710-7.

Top Med Chem 11(1): 115-30.

Imaging 25(9): 1292-9.

Radiology 239(3): 632-49.

Am J Roentgenol 178(3): 711-6.

Magn Reson Med 14(2): 249-65.

astrocytoma." J Clin Oncol 24(8): 1253-65.

259-67.

human melanoma xenografts by diffusion weighted magnetic resonance imaging."

biomarker for early stratification of clinical brain tumor response." Proc Natl Acad

biomarker for the early prediction of cancer treatment outcome." Neoplasia 8(4):


Gauvain, K. M., R. C. McKinstry, et al. (2001). "Evaluating pediatric brain tumor cellularity with diffusion-tensor imaging." AJR Am J Roentgenol 177(2): 449-54. Gideon, P., C. Thomsen, et al. (1994). "Increased self-diffusion of brain water in hydrocephalus measured by MR imaging." Acta Radiol 35(6): 514-9. Hajnal, J. V., M. Doran, et al. (1991). "MR imaging of anisotropically restricted diffusion of

Hamstra, D. A., C. J. Galban, et al. (2008). "Functional diffusion map as an early imaging

Hamstra, D. A., A. Rehemtulla, et al. (2007). "Diffusion magnetic resonance imaging: a biomarker for treatment response in oncology." J Clin Oncol 25(26): 4104-9. Jackson, A., G. C. Jayson, et al. (2003). "Reproducibility of quantitative dynamic contrastenhanced MRI in newly presenting glioma." Br J Radiol 76(903): 153-62. Jakab, A., P. Molnar, et al. "Glioma grade assessment by using histogram analysis of

Jenkinson, M. D., D. G. Du Plessis, et al. (2007). "Advanced MRI in the management of adult

Kinoshita, M., K. Yamada, et al. (2005). "Fiber-tracking does not accurately estimate size of

Kleiser, R., P. Staempfli, et al. "Impact of fMRI-guided advanced DTI fiber tracking

Kono, K., Y. Inoue, et al. (2001). "The role of diffusion-weighted imaging in patients with

Krabbe, K., P. Gideon, et al. (1997). "MR diffusion imaging of human intracranial tumours."

Larsson, H. B., F. Courivaud, et al. (2009). "Measurement of brain perfusion, blood volume,

Larsson, H. B., C. Thomsen, et al. (1992). "In vivo magnetic resonance diffusion

Law, M., S. Yang, et al. (2003). "Glioma grading: sensitivity, specificity, and predictive values

Le Bihan, D., E. Breton, et al. (1986). "MR imaging of intravoxel incoherent motions:

Lu, S., D. Ahn, et al. (2003). "Peritumoral diffusion tensor imaging of high-grade gliomas and metastatic brain tumors." AJNR Am J Neuroradiol 24(5): 937-41.

conventional MR imaging." AJNR Am J Neuroradiol 24(10): 1989-98. Lazar, M., A. L. Alexander, et al. (2006). "White matter reorganization after surgical resection

fiber bundle in pathological condition: initial neurosurgical experience using neuronavigation and subcortical white matter stimulation." Neuroimage 25(2): 424-9.

techniques on their clinical applications in patients with brain tumors."

and blood-brain barrier permeability, using dynamic contrast-enhanced T(1)-

measurement in the brain of patients with multiple sclerosis." Magn Reson Imaging

of perfusion MR imaging and proton MR spectroscopic imaging compared with

of brain tumors and vascular malformations." AJNR Am J Neuroradiol 27(6): 1258-71.

application to diffusion and perfusion in neurologic disorders." Radiology 161(2):

Comput Assist Tomogr 15(1): 1-18.

gliomas." Br J Neurosurg 21(6): 550-61.

Neuroradiology 52(1): 37-46.

Neuroradiology 39(7): 483-9.

10(1): 7-12.

401-7.

and overall survival." J Clin Oncol 26(20): 3387-94.

diffusion tensor imaging-derived maps." Neuroradiology.

brain tumors." AJNR Am J Neuroradiol 22(6): 1081-8.

weighted MRI at 3 tesla." Magn Reson Med 62(5): 1270-81.

water in the nervous system: technical, anatomic, and pathologic considerations." J

biomarker for high-grade glioma: correlation with conventional radiologic response


**13** 

 *Oklahoma City* 

*U.S.A.* 

**Assessment of Rodent Glioma Models Using** 

There is a strong need to obtain precise surrogate biomarkers to improve the accuracy of diagnosis for gliomas, and to effectively evaluate therapeutic response. Often pre-clinical models of disease are used to develop diagnostic procedures and assess the effectiveness of a potential therapy. For gliomas, there are a variety of rodent models that have been investigated by numerous investigators over the past few decades, ranging from intracranial rodent glioma cell implantation models, intracranial human glioma xenografts, orthotopic implantation of human glioma stem cells, multipotent human glioblastoma stem-like neurosphere lines, transgenic mouse models, to viral-induced progenitor or stem cell derived glioma models. Tumor grades in these models vary from low to high grade tumors, with many of the high-grade glioma models sharing some of the characteristics of human grade IV glioblastoma multiforme (GBM). Many of the characteristic features of gliomas can be assessed diagnostically with *in vivo* imaging techniques such as magnetic resonance imaging (MRI). MRI has the capability of obtaining morphological/anatomical, functional, biophysical, molecular and metabolic information of a disease at various pathological stages of development. Tumor characteristics often associated with aggressive gliomas include an invasive growth pattern, angiogenesis, necrosis, hypoxia, edema, and alterations in major metabolic pathways. Morphological features, such as tumor size and position, infiltrative growth, hemorrhaging, necrotic lesions, edema, mass effect, heterogeneity, and cyst formation, can be followed using standard contrast-enhanced T1-weighted MR imaging or

Although conventional MRI provides us with some indication about the nature of the lesion or tumor, it has limited sensitivity and specificity in determining histological type and grade, delineating margins and differentiating edema, as well as effectively evaluating therapeutic effects or side-effects. Incorporating some advanced MR techniques, such as MR angiography (MRA), perfusion-weighted MR imaging (PWI), diffusion-weighted MR imaging (DWI), MR spectroscopy (MRS), and molecular MRI (mMRI), may help to overcome some of those limitations. Angiogenesis associated with major blood vessels can be assessed using MR angiography, whereas perfusion-weighted imaging can be used to monitor angiogenesis associated with capillary vessels in tumors. Biophysical parameters such as water diffusion, as measured by diffusion-weighted imaging, have also provided

**1. Introduction** 

non-contrast T2-weighted imaging.

**Magnetic Resonance Imaging Techniques** 

Rheal A. Towner, Ting He, Sabrina Doblas and Nataliya Smith *Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation* 

