Spatially Quantifying Microscopic Tumor Invasion and Proliferation Using a Voxel-Wise Analytical Solution to a Glioma Growth Model and Serial Diffusion MRI
Benjamin M. Ellingson^1,2, Scott D. Rand^1,2, Mark G. Malkin^1,3, Robert Prost², Jennifer M. Connelly^1,4, Pete S. LaViolette^1,5, Devyani P. Bedekar^1,2, Kathleen M. Schmainda^1,2
1Translational Brain Tumor Program, Medical College of Wisconsin, Milwaukee, WI, United States; ²Dept. of Radiology, Medical College of Wisconsin, Milwaukee, WI, United States; ³Dept. of Neurology and Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, United States; ⁴Dept. of Neurology, Medical College of Wisconsin, Milwaukee, WI, United States; ⁵Dept. of Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States

The objective of the current study was to develop a voxel-wise analytical solution to a glioma growth model using serial diffusion MRI in order to spatially map and quantify regions of microscopic tumor invasion and proliferation. Results demonstrate a strong correlation between proliferation rate and MR spectroscopic measurements of choline-to-N-acetylaspartate ratio. Proliferation rate and cell motility rates were shown to increase with increasing malignancy, as well as easily distinguish between radiation necrosis and recurrent tumor. This technique may be valuable for assessing tumor dynamics and predicting response to treatment in all types of cancers.

DCE MRI Derived Kep Is a Surrogate Marker of MMP-9 Expression in Patients with Glioblastoma Multiforme
Rishi Awasthi¹, Nuzhat Husain², Priyanka Soni², Prativa Sahoo³, Sanjay Behari⁴, Shaleen Kumar⁵, Rakesh Pandey⁶, Ram Kishore Singh Rathore³, Rakesh Kumar Gupta^1
1Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India; ²Pathology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, UP, India, Lucknow, Uttar Pradesh, India; ³Mathematics and Statistics, Indian Institute of technology Kanpur, Kanpur, Uttar Pradesh, India; ⁴Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India; ⁵Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India; ⁶Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

DCE-MRI was performed on 17 patients with Glioblastoma multiforme (GBM). Various perfusion metrics were analyzed and correlated with immunohistochemically obtained MMP-9 expression. Among the perfusion metrics, Kep was found to have the best correlation with MMP-9 expression suggesting that it can be used as a surrogate for MMP-9 expression. A total of 8 patients were also followed up clinically to observe the duration of survival. The MMP-9 expression and quantified perfusion metrics were also correlated with the duration of survival. MMP-9 expression showed a significant negative correlation with the duration of survival indicating the possible role of MMP-9 in tumor progression as one of the factors. The Kep, Ktrans, Ve, rCBV and rCBF also correlated significantly with the duration of survival proving the utility of DCE MRI in forecasting tumor progression in malignant glioma. We suggest that Kep holds promise as a surrogate for MMP9 expression in GBM.

Metabolic Characterization of Recurrent Grade 2 Glioma Using Proton HR-MAS Spectroscopy
Llewellyn Jalbert¹, Adam Elkhaled¹, Radhika Srinivasan¹, Hikari Yoshihara¹, Colleen Cloyd^1,2, Gabriela Bourne¹, Susan M. Chang³, Soonmee Cha¹, John Kurhanewicz^1,4, Sarah J. Nelson^1,4
1Department of Radiology & Biomedical Imaging, University of California - San Francisco, San Francisco, CA, United States; ²School of Pharmacy, University of California - San Francisco, San Francisco, CA, United States; ³Department of Neurological Surgery, University of California - San Francisco, San Francisco, CA, United States; ⁴Department of Bioengineering & Therapeutic Sciences , University of California - San Francisco, San Francisco, CA, United States

Proton High Resolution Magic Angle Spectroscopy (¹H HR-MAS) has offered new insight into tumor physiology that may be valuable in understanding the process of glial tumorigenesis.  Fifty-four patients w/ pathologically confirmed WHO Grade 2 recurrent glioma underwent pre-surgical MRI / 3D MRSI, image guided biopsy excision, and ¹H HR-MAS analysis.  Patients whose tumors had histologically upgraded to WHO Grade 3 exhibited greater concentrations of PC (p=.008), GPC (p=.049), glucose (p=.002), and total choline (p=.01). Our ¹H HR-MAS results may contribute in identifying low-grade glioma patients whose tumors have become more aggressive and assist in treatment planning and selection.

Correlation of Metabolic Characteristics with Diffusion Tensor Imaging in Human Gliomas
Greg A. Fellows¹, Alan J. Wright², Tom R. Barrick³, Dominick J. O. McIntyre⁴, Chris A. Clark⁵, B. Anthony Bell⁶, Franklyn A. Howe^7
1Department of Neurosurgery, King's College Hospital London NHS Trust, London, United Kingdom; ²Radiology, UMC st. Radboud University Hospital, Nijmegen, Netherlands; ³Clinical Neuroscience, St George's, University of London, London, United Kingdom; ⁴CRUK Cambridge Research Institute, Cambridge, United Kingdom; ⁵Radiology and Physics Unit, UCL Institute of Child Health, London, United Kingdom; ⁶Academic Neurosurgery, St George's, University of London, London, United Kingdom; ⁷Cardiac & Vascular Sciences, St George's, University of London, London, United Kingdom

Gliomas are the most common primary brain tumour, and in their most aggressive form, glioblastoma multiforme, are associated with a mean survival of 9-12 months.  Despite maximal therapy, nearly all gliomas eventually recur.  The majority of this recurrence is at the limits of previous resection / radiotherapy margins.  We have combined 1H spectroscopy metabolite maps and DTI structural metrics of 30 histologically confirmed glioma patients to increase our understanding of the tissue changes that occur within the tumour and at the tumour-brain interface.  We identify metabolite correlations with DTI metrics as a surrogate marker for tumour infiltration.

An Image Similarity-Guided Correspondence Correction for Voxel-Wise Analysis Applied to MR Imaging of Glioblastoma Multiforme Acquired Pre- And Post-Chemoradiotherapy
Jeremy David Hoisak^1,2, Eng-Siew Koh^1,3, Eugene Yu⁴, Andrea Kassner⁴, Normand J. Laperriere^1,3, Cynthia Ménard^1,3, David A. Jaffray^1,2
1Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada; ²Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; ³Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; ⁴Medical Imaging, University of Toronto, Toronto, Ontario, Canada

Response assessment with a voxel-wise analysis of serial image change has advantages over conventional tumor measurements, but is susceptible to uncertainties from inconsistent voxel correspondences between scans arising from a dynamic tumor morphology. A correspondence correction method based on a metric of voxel similarity was applied to a functional diffusion map (fDM) analysis of co-registered T1-weighted and diffusion-weighted images of glioblastoma multiforme acquired pre- and post-chemoradiotherapy. The correction resulted in a statistically significant alteration in the quantification of apparent diffusion coefficient (ADC) change pre- and post-therapy, and has the potential to improve the accuracy of subsequent determinations of therapy outcome.

Glycerolphosphocholine Is the Predominant Choline-Containing Compound and Is Correlated with Proliferation in Non-Enhancing Astrocytoma
Tracy Richmond McKnight¹, Kenneth James Smith¹, Susan Chang², Mitchel Berger^2
1Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States; ²Neurological Surgery, University of California San Francisco, San Francisco, CA, United States

We performed 1D HRMAS and 2D TOCSY MR spectroscopy on a cohort of biopsies from high and low grade non-contrast-enhancing astrocytoma. We quantified PC, GPC, free Cho, and the GPC:PC concentration ratio as well as cell proliferation and cell density. Our results show that GPC is the predominant choline-containing compound in non-enhancing astrocytoma irrespective of grade and that there is a positive association between Ki-67, tCho, and GPC, but not PC. These results suggest that the presence of contrast-enhancement influences choline metabolism in astrocytoma.

Correlation of DTI Metrics with Proliferation Index and Survival Analysis in Glioblastomas
Sona Saksena¹, Rajan Jain¹, Jayant Narang¹, Lonni Schultz², David Hearshen¹, Lisa Scarpace³, Norman Lehman⁴, Tom Mikkelsen^3
1Radiology, Henry Ford Hospital, Detroit, MI, United States; ²Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, United States; ³Neurosurgery, Henry Ford Hospital, Detroit, MI, United States; ⁴Pathology, Henry Ford Hospital, Detroit, MI, United States

DTI data were acquired from thirty-four patients with glioblastomas with an aim to retrospectively correlate the changes in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) with degree of proliferation index determined histologically and patient survival analysis. We found that patients with ADCmin (¡Ü0.6) and FAmean (¡Ü0.2) had lower progression free survival rate or poorer prognosis. In conclusion, DTI can be used as a clinical prognostic biomarker for disease free survival in patients with glioblastomas and might be useful for planning initial treatment strategy in these patients.

Effects of Bevacizumab on the Tumor Vascularity Assessed with DCE-MRI in Recurrent Anaplastic Astrocytomas
Weiting Zhang¹, Teri N. Kreisl¹, Jeffrey Solomon², Richard C. Reynolds¹, Daniel R. Glen¹, Robert W. Cox¹, Howard A. Fine¹, John A. Butman^1
1National Institutes of Health, Bethesda, MD, United States; ²Medical Numerics, Inc., Germantown, MD, United States

DCE-MRI was used to monitor the effects of bevacizumab on physiologic measures of tumor vascularity, such as blood brain barrier permeability, represented as Ktrans , and vascular perfusion represented as fpv, in patients with recurrent anaplastic astrocytoma. Bevacizumab dramatically reduces Ktrans, fpv, and enhancing tumor volume as early as 4 days and this effect persisted at least for 4 weeks. Tumors with larger baseline enhancing tumor volume and greater baseline Ktrans were related to poorer prognosis.

Assessing the Effects of Radiation Therapy on Normal Brain Tissue in Patients with Glioma Using Susceptibility-Weighted Imaging at 7 Tesla
Janine M. Lupo¹, Cynthia Chuang², Bert Jimenez¹, Susan M. Chang³, Igor J. Barani², Christopher P. Hess¹, Sarah J. Nelson^1,4
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States; ²Department of Radiation Oncology, University of California, San Francisco, United States; ³Department of Neurosurgery, University of California, San Francisco, United States; ⁴Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States

The potential effects of radiotherapy on neurocognitive ability and quality of life has recently become of great importance as new treatments extend survival in less malignant grade brain tumors.  We used Susceptibility-Weighted Imaging at 7T to evaluate the long-term effects of radiation therapy on normal-appearing brain tissue in 20 glioma patients. Microbleeds appeared in irradiated patients after 2 years from receiving therapy, but not in patients treated with only chemotherapy. The prevalence of these lesions increased over time since receiving radiation therapy.  The majority of these microbleeds resided within tissue that received 98% of the maximum dose.

Functional Diffusion Maps (FDMs) Applied to FLAIR Abnormal Regions Can Detect Pseudoprogression from Recurrent Tumor in Malignant Glioma
Benjamin M. Ellingson^1,2, Mark G. Malkin^1,3, Scott D. Rand^1,2, Jennifer M. Connelly^1,4, Pete S. LaViolette^1,5, Devyani P. Bedakar^1,2, Kathleen M. Schmainda^1,2
1Translational Brain Tumor Program, Medical College of Wisconsin, Milwaukee, WI, United States; ²Dept. of Radiology, Medical College of Wisconsin, Milwaukee, WI, United States; ³Dept. of Neurology and Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, United States; ⁴Dept. of Neurology, Medical College of Wisconsin, Milwaukee, WI, United States; ⁵Dept. of Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States

Patients with malignant gliomas undergoing cytotoxic therapy have been shown to have an increase in the size of contrast-enhancing lesions due to radiation necrosis; however, growing or progressing gliomas also are trademarked by an increase in the size of contrast-enhancing lesions. This phenomenon, known as pseudoprogression, is of significant clinical interest because routine anatomical MRI techniques cannot relibly distinguish these two mechanisms of contrast enhancement during therapy. In the current study, we examine the kinetic profiles of hyper- and hypocellular volumes using functional diffusion maps (fDMs) applied in FLAIR abnormal regions in order to detect pseudoprogression from recurrent tumor in malignant glioma patients treated with cytotoxic therapies.