Daniel B. Vigneron, Ph.D. Dan.Vigneron@radiology.ucsf.edu Associate Director of the Surbeck Imaging Lab Professor in Radiology, UCSF

Research Program

My research focuses on the development of metabolic Magnetic Resonance Imaging (MRI) techniques for both basic research and clinical assessments of human diseases. This requires the development of new hardware/software and MR protocols to provide biochemical information in addition to the anatomic information provided y clinical MRI. My initial focus was on developing 3-dimensional MR spectroscopic imaging (MRSI) for the non-invasive assessment of brain tumor metabolism. The assessment of tumor presence and extent before and after therapy are critical factors in the clinical management of these cancers and conventional MRI cannot reliably provide this data.
This brain tumor MRSI research has been carried out by a multidisciplinary team involving Radiologists (primarily Dr. William Dillon), Neurosurgeons, Neuro-oncologists, Radiation Oncologists, Neuro-pathologists and researchers from the Brain Tumor Research Center and the UCSF Cancer Center. I am also working with GE Medical Systems to make these novel MRSI techniques into a routine clinical product that is now available nationally and internationally at 1.5T and 3T. Currently I am overseeing the technical development of new 7 Tesla techniques for anatomic, metabolic and diffusion imaging of brain tumors and other CNS disorders on the Mission Bay 7 T scanner.

Another major research focus, dating back to my graduate studies, is the characterization of prostate cancer using novel MR metabolic imaging techniques. The development of specialized acquisition techniques for prostate cancer MRSI has been a major project for me, funded since 1993 by an NIH RO1 which was recently competitively renewed for years 14-19. These studies have demonstrated not only the feasibility of this metabolic imaging method, but also, significant improvements in the sensitivity and specificity of clinical prostate cancer staging. These studies have been collaborative studies with a multidisciplinary team from Radiology, Urology, Radiation Oncology and Pathology. The application studies have been directed by my colleagues Drs. John Kurhanewicz Ph.D, Fergus Coakley MD, and Aliya Qayyum MD. My group’s focus has been on the technical developments of MRSI acquisitions to provide robust metabolic assessments of prostate cancer metabolism. These techniques have now been used in over 5000 research and clinical studies at UCSF. Recently we were awarded an NIH Bioengineering Research Partnership grant to fund a collaborative multisite academic- industry project with GE Medical Systems to develop 3T prostate MR techniques which can be widely disseminated. I have also with worked with Dr. Aliya Qayyum to expand these body MRS and Diffusion MRI techniques to study liver disease as well and with Dr. Bonnie Joe to study fetal lung maturity.

Over the past eight years, I have assisted Dr. A. James Barkovich (Radiology) in his pediatric studies using high resolution MRI to detect epiletogenic lesions in pediatric epilepsy patients and MR spectroscopy to assess neonatal brain metabolism. The latter has become a major new research focus for my group, funded initially by the Neonatal Brain Disorders Program Project (PI: Donna Ferriero MD, Neurology) and the Pediatric Clinical Research Center. I and my colleagues were awarded a 5 year NIH RO1 in 2001 to develop new MR hardware and techniques specialized for neonatal MR studies of normal and abnormal brain metabolism. We have also developed a new MR compatible incubator with funding from the Packard Foundation (PI Ron Arenson) and GE Medical Systems that allows the study of sick newborns in a well-monitored, temperature-controlled environment. We have submitted an NIH Program Project Grant focused on fetal and neonatal MR research and I lead a project on technical development.

With the acquisition of 3 Tesla MR scanners and now a 7T MR system, my group has been developing a novel coil and software techniques for high field MRI, MR spectroscopy and MR diffusion imaging techniques. We have optimized these 3T MR methods for studies of brain tumors with Dr. Nelson’s group, traumatic brain injury with Dr. Mukherjee, and prostate cancer with Drs. Kurhanewicz and Coakley. Over the past two years, I have overseen the rather formidable technical issues involved in getting the UCSF 7T MR scanner (first on the west coast and one of only a few in the world) to produce unprecedented anatomic, metabolic and diffusion images. In collaboration with Drs. Sarah Nelson, Sharmila Majumdar, Pratik Mukherjee, Daniel Pelletier and others, we have now established a major program in ultra high field human MR and its application to novel medical applications. I also have overseen the technical development aspects for our Hyperpolarized Carbon-13 MR project with GE Healthcare and with NIH funding. This exciting new technology provides an unprecedented 50,000+ signal enhancement for 13C labeled compounds which then can be injected into animals (and ultimately in patients) in an MR scanner to detect not only the uptake of the targeted molecule but also its metabolism in vivo.

Current Research Grants
Metabolic Imaging of the Prostate Using 3D MRSI
R01 CA59897-15

Abstract
Accurate characterization of prostate cancers is a major problem facing both for managing individual patients and for the selection and monitoring of subjects in clinical trials. This project is focused on the development and application of 3D MR spectroscopic imaging to address this clinical problem by providing metabolic assessments of the presence and extent of human prostate cancers. This project has been extremely successful, resulting in the technical development of specialized MR methods, improved understanding of metabolite levels in normal and cancerous prostate tissues, and also in supporting the development of clinical prostate MRSI products that are now widely available on commercial 1.5T scanners. Although 1.5T prostate MRSI is now FDA approved and widely used, there is increasing desire from referring physicians, radiologists, prostate cancer research community, and even patients themselves for 3T prostate MRSI with its potential doubling in performance. The development of 3T prostate MRSI has, however, turned out to be a highly complex task and has required a major redesign of virtually all aspects of the acquisition and analysis techniques developed for 1.5T. In this renewal project, we will develop and apply new 3T MRSI methods with the goal of improving the sensitivity and accuracy for characterizing prostate cancer presence and extent. Our preliminary 3T studies have demonstrated challenges in applying this technique at high field, but also have shown major improvements in SNR and spectral resolution that indicate a great potential for significant improvements in accurately measuring prostate cancer extent before and following therapy. While our preliminary 3T MRSI results have shown dramatic improvements in spatial and spectral resolution for prostate cancer characterization, the prototype methods require further development and the benefit of 3T prostate MRSI is yet to be defined. In this project we will develop new specialized 3T prostate MRSI techniques and apply them in patient studies to determine: a) improvements over 1.5T studies, b) sensitivity, specificity and volume accuracy measurements in prostatectomy patients, and the c) ability to detect and monitor hormone therapy response

Related Articles

1. Males RG, Vigneron DB, Star-Lack J, Falbo SC, Nelson SJ, Hricak H, and Kurhanewicz J. Clinical Applications of Improved Water and Lipid Suppression for Prostate Cancer Staging and Localization using In vivo 3D H-1 Magnetic Resonance Spectroscopic Imaging. Magn. Reson. In Med. 43:17-22, 2000.

2. Tran T-K C, Vigneron DB, Sailasuta N, Tropp J, Le Roux P, Kurhanewicz J, Nelson SJ, Hurd R. Very Selective Suppression Pulses for Clinical MRSI Studies of Brain and Prostate Cancer. Magn. Reson. In Med. 43:23-33, 2000.

3. Kurhanewicz, J, Vigneron, DB, and Nelson SJ. “Three-Dimensional Magnetic Resonance Spectroscopic Imaging of Brain and Prostate Cancer” Neoplasia. 2000; 2 (1-2), 166-189.

4. Wefer AE, Hricak H, Vigneron DB, Coakley FV, Lu Y, Wefer J, Mueller-Lisse U, Carroll PR, Kurhanewicz J. Sextant localization of Prostate Cancer: Comparison of Sextant biopsy, Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic Imaging with Step-Section Histology. Journal of Urology, 2000; 164:400-404.

5. Mueller-Lisse UG, Swanson MG, Vigneron DB, Hricak H, Bessette A, Males RG, Wood PJ, Noworolski S, Nelson SJ, Barken I, Carroll PR, Kurhanewicz J. Time-Dependent Effects Of Hormone-Deprivation Therapy On Prostate Metabolism As Detected By Combined Magnetic Resonance Imaging And 3D Magnetic Resonance Spectroscopic Imaging. Magn Reson Med. 2001 Jul; 46(1): 49-57.

6. Mueller-Lisse UG, Vigneron DB, Hricak H, Swanson MG, Carroll PR, Bessette A, Scheidler J, Srivastava A, Males RG, Cha I, Kurhanewicz J. Localized Prostate Cancer: Effect Of Hormone Deprivation Therapy Measured By Using Combined Three-Dimensional 1H MR Spectroscopy And MR Imaging: Clinicopathologic Case-Controlled Study. Radiology. 2001 Nov; 221(2):380-90.

7. Kurhanewicz J, Swanson MG, Wood PJ, Vigneron DB. Magnetic Resonance Imaging and Spectroscopic Imaging: Improved Patient Selection and Potential for Metabolic Intermediate Endpoints in Prostate Cancer Chemoprevention Trials. Urology 57: 124-128, 2001.

8. Swanson MG., Vigneron DB, Tran T-K C, Kurhanewicz J. “Magnetic Resonance Imaging and Spectroscopic Imaging of Prostate Cancer” Cancer Investigation, 19:519-532, 2001.

9. Swanson MG, Vigneron DB, Tran T-K C, Sailasuta N, Hurd RE, Kurhanewicz J. Single Voxel Oversampled J-Resolved Spectroscopy of In Vivo Human Prostate Tissue. Magn. Reson. Med 45:973-980, 2001.

10. Schricker AA, Pauly JM, Kurhanewicz J, Swanson MG, Vigneron DB. Dualband Spectral-Spatial RF Pulses for Prostate MR Spectroscopic Imaging. Magn. Reson in Med. 46: 1079-1087, 2001.

11. Kurhanewicz J, Swanson MG, Nelson SJ, and Vigneron DB. A combined Magnetic Resonance Imaging and Spectroscopic Imaging approach to molecular imaging of prostate cancer. J Magn Reson Imaging. Oct;16(4):451-63, 2002.

12. Swanson MG, Vigneron DB, Tabatabai ZL, Males RG, Schmitt L, Carroll PR, James JK, Hurd RE, and Kurhanewicz J. Proton HR-MAS spectroscopy and quantitative pathologic analysis of MRI/3D-MRSI-targeted post-surgical prostate tissues. Magn Reson Med 2003; 50: 944-954.

13. Pouliot J, Kim Y, Lessard E, Hsu IC, Vigneron DB, Kurhanewicz J. Inverse Planning for HDR Prostate Brachytherapy Used To Boost Dominant Intraprostatic Lesions Defined By Magnetic Resonance Spectroscopy Imaging. Int J Radiat Oncol Biol Phys 2004; 59:1196-1207.

14. Jung JA, Coakley FV, Vigneron DB, Swanson MG, Qayyum A, Weinberg V, Jones KD, Carroll PR, Kurhanewicz J. Prostate Depiction at Endorectal MR Spectroscopic Imaging: Investigation of a Standardized Evaluation System. Radiology. 2004; 233:701-708.

15. Coakley FV, Teh HS, Qayyum A, Swanson MG, Lu Y, Roach M 3rd, Pickett B, Shinohara K, Vigneron DB, Kurhanewicz J. Endorectal MR imaging and MR spectroscopic imaging for locally recurrent prostate cancer after external beam radiation therapy: preliminary experience. Radiology. 2004 Nov;233(2):441-448.

16. Vigneron DB, Swanson MG, Kurhanewicz J. Advances in Prostate MR Imaging: MR Spectroscopic Imaging at 1.5T and 3.0T. SMRT Educational Seminars, 2004; 7:11-21.

17. Zektzer AS, Swanson MG, Jarso S, Nelson SJ, Vigneron DB, Kurhanewicz J. Improved signal to noise in high-resolution magic angle spinning total correlation spectroscopy studies of prostate tissues using rotor-synchronized adiabatic pulses. Magn. Reson. Med. 2005; 53:41-48.

18. Noworolski SM, Henry RG, Vigneron DB, Kurhanewicz J. Dynamic Contrast-Enhanced MRI in Normal and Abnormal Prostate Tissues as Defined by Biopsy, MRI and 3D MRSI. Magn Reson Med 2005; 53(2): 249-255.

19. Cunningham CH, Vigneron DB, Marjanska M, Chen AP, Xu D, Hurd RE, Kurhanewicz J, Garwood M, Pauly JM. Sequence Design for MR Spectroscopic Imaging of Prostate Cancer at 3 Tesla. Magn. Reson. In Med. 2005; 53:1033-1039.

20. Kim Y, Noworolski SM, Pouliot J, Hsu IC, Vigneron DB, and Kurhanewicz J. Expandable and Rigid Endorectal Coils for Prostate Magnetic Resonance Imaging and Spectroscopic Imaging: Impact on Prostate Distortion and Image Registration. Med Phys. 2005; 32:3569-3578.

21. Swanson MG, Zektzer AS, Tabatabai ZL, Simko J, Jarso S, Keshari KR, Schmitt L, Carroll PR, Shinohara K, Vigneron DB, Kurhanewicz J. Quantitative analysis of prostate metabolites using 1H HR-MAS spectroscopy. Magn Reson Med 2006; 55:1257-1264.

22. Chen AP, Cunningham CH, Kurhanewicz J, Xu D, Hurd RE, Pauly JM, Carvajal L, Karpodinis K, Vigneron DB. High-Resolution 3D MR Spectroscopic Imaging of the Prostate at 3 Tesla with MLEV-PRESS sequence. Magn Reson Imaging. 2006; 24:825-832.

23. Mueller-Lisse UG, Swanson MG, Vigneron DB, Kurhanewicz J. Magnetic resonance spectroscopy in patients with locally confined prostate cancer: Association of prostatic citrate and metabolic atrophy with time on hormone therapy, PSA level, and biopsy Gleason score. European Radiology 2007; 17:371-378.

24. Chen AP, Cunningham CH, Ozturk E, Xu D, Hurd RE, Kelley DAC, Pauly JM, Kurhanewicz, Nelson SJ, Vigneron DB. High Speed 3T MR Spectroscopic Imaging of Prostate with Flyback Echo Planar Encoding. J Magn Reson Imaging. 2007; 25:1288-1292.

25. Noworolski SM, Crane JC, Vigneron DB, Kurhanewicz J. A Clinical Comparison of Rigid and Inflatable Endorectal Coil Probes for MRI and 3D MRSI of the Prostate. J. Magn Reson Imag. (submitted).

3D MR Spectroscopic Imaging of the Newborn Brain
R01NS40117

Abstract
Brain injury in term and preterm neonates is a serious problem. Of the approximately 42,000 infants born yearly in the United States with a birth weight less than 1500 g, approximately 85 percent survive and, of these 5-10 percent exhibit major motor deficits and another 25-50 percent exhibit developmental and visual difficulties. Hypoxia and ischemia frequently occur during the birth process; however, the amount of brain damage in these patients and the long-term neurologic outcome varies considerably from patient to patient. There is a need, particularly in this group, to identify new clinical diagnostic tools that will improve early prediction of neurodevelopmental abnormalities and therefore allow for pharmacological interventions. The goal of this bioengineering research project is to develop and implement advanced Magnetic Resonance spectroscopic imaging techniques to detect the distribution of metabolite levels throughout the brain of neonates. Studies by ourselves and others have indicated an important role for single voxel MRS in the assessment of the neurologic status of neonates, especially premature infants and those with suspected neonatal hypoxia. However, these techniques provide very limited coverage of the brain and at poor spatial resolution. In this study, we aim to develop and optimize MRSI techniques to provide, for the first time, a study of the 3D distribution of metabolite levels in the newborn brain. This information will define the normal variation in metabolite levels with anatomic location and post-conceptional age. The database of normal MRSI spectra will improve our understanding of brain development and provide a reference for detecting abnormal metabolism in neonatal patients with neurologic damage. Also in this project, we aim to develop a noninvasive metabolic imaging technique to address this important problem.

Related Articles

1. Coskun A, Lequin M, Segal M, Vigneron D, Ferriero DM, Barkovich AJ. "Quantitative Analysis Of MR Images In Asphyxiated Neonates: Correlation With Neurodevelopmental Outcome", American Journal of Neuroradiology 2001; 22:400-405.

2. Barkovich AJ, Westmark KD, Bedi HS, Partridge JC, Ferriero DM, Vigneron DB. Proton Spectroscopy And Diffusion Imaging On The First Day Of Life After Perinatal Asphyxia: Preliminary Report. AJNR Am J Neuroradiol 22: 1786-1794, 2001.

3. Gelal FM, Grant PE, Fischbein NJ, Henry RG, Vigneron DB, Barkovich AJ. The Role of Isotropic Diffusion MRI in Children under 2 Years of Age. Eur Radiol. 11:1006-14, 2001.

4. Vigneron DB, Barkovich AJ, Noworolski SM, von dem Bussche M, Henry RG, Lu Y, Partridge JC, Gregory GA, and Ferriero DM. Three-Dimensional Proton MR Spectroscopic Imaging of Premature and Term Neonates. American Journal of Neuroradiology. 22: 1424-1433, 2001.

5. Miller SP, Weiss J, Barnwell A, Ferriero DM, Latal-Hajnal B, Ferrer-Rogers A, Newton N, Partridge JC, Glidden DV, Vigneron DB, Barkovich AJ. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002; 58(4):542-8.

6. Dumoulin CL, Rohling KW, Piel JE, Rossi CJ, Giaquinto RO, Watkins RD, Vigneron DB, Barkovich AJ, Newton N. An MRI compatible neonate incubator. Concepts in Magnetic Resonance (Magn Reson Engineering) 15: 117-128, 2002.

7. Miller SP, Vigneron DB, Henry RG, Bohland MA, Ceppi-Cozzio C, Hoffman C, Newton N, Partridge JC, Ferriero DM, Barkovich AJ. Serial Quantitative Diffusion Tensor MRI of the Premature Brain: Development in Newborns With and Without Injury. JMRI 16:621-632, 2002.

8. Miller SP, Cozzio CC, Goldstein R, Ferriero DM, Partridge JC, Vigneron DB, Barkovich AJ. Comparing the Diagnosis of White Matter Injury in Premature Newborns with Serial MR Imaging and Transfontanel Ultrasonography Findings. AJNR. Am J Neuroradiol 24:1661-1669, 2003.

9. Glenn OA, Henry RG, Berman JI, Chang PC, Miller SP, Vigneron DB, Barkovich AJ. DTI-based three-dimensional tractography detects differences in the pyramidal tracts of infants and children with congenital hemiparesis. J Magn Reson Imaging 2003; 18:641-648.

10. Vigneron DB. Magnetic resonance spectroscopic imaging of human brain development. Neuroimaging Clin N Am. 2006;16:75-85.

11. Miller SP, McQuillen PS, Vigneron DB, Glidden DV, Barkovich AJ, Ferriero DM, Hamrick SEG, Azakie A, and Karl T. Preoperative Brain Injury in Newborns with Transposition of the Great Arteries. Annals of Thoracic Surgery 2004; 77:1698-1706.

12. Maas LC, Mukherjee P, Carballido-Gamio J, Veeraraghavan S, Miller SP, Ferriero DM, Partridge SC, Henry RG, Barkovich AJ, Vigneron DB. Early laminar organization of the human cerebrum demonstrated with diffusion tensor imaging in extremely premature infants. NeuroImage 2004; 22(3):1134-1140.)

13. Partridge SC, Mukherjee P, Henry R, Miller SP, Berman JI, Jin H, Lu Y, Glenn O, Ferriero DM, Barkovich AJ and Vigneron DB. Diffusion Tensor Imaging: Serial Quantitation of White Matter Tract Maturity in Premature Newborns. NeuroImage 2004; 22(3):1302-1314.

14. Xu D, Henry RG, Carvajal L, Miller SP, Barkovich AJ, Vigneron DB. Single-shot fast spin-echo diffusion tensor imaging of the brain and spine with head and phased-array coils at 1.5T and 3.0T. Magnetic Reson. Imaging 2004; 22:751-759.

15. Bartha AI, Foster-Barber A, Miller SP, Vigneron DB, Glidden DV, Barkovich, AJ, Ferriero DM. Neonatal Encephalopathy: Association of Cytokines with MR Spectroscopy and Outcome. Pediatr Res. 2004; 56: 960-966.

16. deIpolyi AR, Mukherjee P, Gill K, Henry RG, Partridge SC, Veeraraghavan S, Jin H, Lu Y, Miller SP, Ferriero DM, Vigneron DB, Barkovich AJ. Comparing Microstructural and Macrostructural Development of the Cerebral Cortex in Premature Newborns: Diffusion Tensor Imaging versus Cortical Gyration. Neuroimage 2005; 27:579-586.

17. Partridge SC, Mukherjee P, Berman JI, Henry R, Miller SP, Lu Y, Glenn O, Ferriero DM, Barkovich AJ and Vigneron DB. Tractography-Based Quantitation of Diffusion Tensor Imaging Parameters in White Matter Tracts of Preterm Newborns. J. Magn. Reson. Imaging 2005; 22:467-474.

18. Berman JI, Mukherjee P, Partridge SC, Miller SP, Ferriero DM, Barkovich AJ, Vigneron DB, Henry RG. Quantitative Diffusion Tensor MRI Fiber Tractography of Sensorimotor White Matter Development in Premature Infants. NeuroImage 2005 27:862-871.

19. Rousseau F, Glenn O, Iordanova B, Rodriguez-Carranza C, Vigneron D, Barkovich J, Studholme C. A novel approach to high resolution fetal brain MR imaging. Med Image Comput Comput Assist Interv. 2005;8:548-55.

20. Partridge SC, Vigneron DB, Charlton NN, Berman JI, Henry RG, Mukherjee P, McQuillen PS, Karl TR, Barkovich AJ, Miller SP. Vigneron DB. Pyramidal tract maturation after brain injury in newborns with heart disease. Annals of Neurology 2006; 59:640-51.

21. Barkovich AJ, Miller SP, Bartha A, Newton N, Hamrick SE, Mukherjee P, Glenn OA, Xu D, Partridge JC, Ferriero DM, Vigneron DB. MR imaging, MR spectroscopy, and diffusion tensor imaging of sequential studies in neonates with encephalopathy. AJNR Am J Neuroradiol. 2006;27:533-547.

22. Kim D-H, Barkovich AJ, Vigneron DB. Short Echo Time Magnetic Resonance Spectroscopic Imaging for Neonatal Pediatric Imaging. AJNR Am J Neuroradiol. 2006; 27:1370-2.

23. Rousseau F, Glenn OA, Iordanova B, Rodriguez-Carranza C, Vigneron DB, Barkovich JA, Studholme C. Registration-based approach for reconstruction of high-resolution in utero fetal MR brain images. Acad Radiol. 2006;13:1072-81.

24. Rodriguez-Carranza C, Mukherjee P, Vigneron D, Barkovich J, Studholme C. A system for measuring regional surface folding of the neonatal brain from MRI. Med Image Comput Comput Assist Interv. 2006;9(Pt 2):201-8.

25. Bartha AI, Yap KR, Miller SP, Jeremy R, Nishimoto M, Vigneron DB, Barkovich AJ, Ferriero DM. MR Imaging, Diffusion Tensor Imaging, and 3D MR Spectroscopy in Healthy Term Neonates. AJNR Am J Neuroradiol. 2007; 28:1015-1021.

26. Glenn OA, Ludeman N, Berman JI, Wu Y, Bartha A, Vigneron DB, Ferriero DM, Barkovich AJ, and Henry RG. Diffusion tensor MR imaging tractography of the pyramidal tracts correlates with clinical motor function in children with congenitally hemiparetic. AJNR Am J Neuroradiol. 2007 Oct;28(9):1796-802.

27. Miller SP, McQuillen PS, Hamrick S, Xu D, Charlton NN, Glidden D, Karl T, Barkovich AJ, and Vigneron DB. Abnormal Brain Development in Newborns with Congenital Heart Disease Prior to Cardiac Surgery. N Engl J Med 2007; 357(19):1928-1938

28. Glass HC, Miller SP, Fujimoto S, Ceppi-Cozzio C, Bartha A, Vigneron DB, Barkovich AJ, Glidden DV, Ferriero DM. White Matter Injury is Associated with Impaired Gaze in Premature Infants. Pediatr Neuro 2008; 38:10-15.

29. Kim D-H, Chung S, Vigneron DB, Barkovich AJ, Glenn O. Diffusion Weighted Imaging of the Fetal Brain In Vivo, Magn. Reson. In Med. (In Press).

MR Diffusion Tensor Imaging of Prostate Cancer
R01 CA103934

The goal of this study is to develop and evaluate MR diffusion tensor imaging to improve the delineation and characterization of prostate cancer. Our initial studies indicate that this technique has clear potential to greatly improve current prostate MR exams. Diffusion tensor imaging (DTI) has demonstrated great research and clinical value for brain applications, but due to technical limitations has been of little utility outside of the head. Recent diffusion MRI studies of prostate cancer have demonstrated significant differences in water diffusivity between cancer and normal prostatic tissues. The initial studies used echo- planar imaging (EPI) techniques similar to those typically used in the brain, but this technique suffers from susceptibility-induced spatial distortions and limited compatibility with endorectal coils used clinically for prostate MR exams. In this project we will use a DTI sequence based on single-shot fast spin-echo method (SSFSE), which due to rf refocusing negates the spatial distortions inherent in EPI. In our preliminary results, we demonstrate the feasibility of this technique for high quality diffusion imaging of the prostate that can be directly compared to anatomic locations with negligible spatial distortions. Its compatibility with endorectal coils allows both easy incorporation into routine clinical MR protocols and the advantage of the great ~10fold SNR advantage of endorectal coils over external coils. Our preliminary results demonstrated significant differences in mean diffusivity <D> and fractional anisotropy (FA) between cancer and normal and BPH tissues. In this project we aim to validate DTI of the prostate, define normal diffusion variations due to zonal anatomy and age-related changes in age-matched controls, and correlate diffusion values in pre- prostatectomy patients with post-surgical step-sectioned histopathologic studies. In addition to measuring the DTI parameters corresponding to specific histologically-defined tissue types, we will investigate the accuracy of DTI cancer volume measurements, the ability of DTI to detect small volume cancers and the improvement in sensitivity and specificity for cancer localization provided by this method. Our multidisciplinary research team has extensive experience in both the development and the validation studies required to translate the exciting preliminary findings into a valuable research and clinical imaging protocol for prostate cancer characterization.

Related Articles

1. Kurhanewicz J, Swanson MG, Nelson SJ, and Vigneron DB. A combined Magnetic Resonance Imaging and Spectroscopic Imaging approach to molecular imaging of prostate cancer. J Magn Reson Imaging. Oct;16(4):451-63, 2002.

2. Vigneron DB, Swanson MG, Kurhanewicz J. Advances in Prostate MR Imaging: MR Spectroscopic Imaging at 1.5T and 3.0T. SMRT Educational Seminars, 2004; 7:11-21.

3. Evelhoch J, Garwood M, Vigneron D, Knopp M, Sullivan D, Menkens A, Clarke L, Liu G. Expanding the Use of Magnetic Resonance in the Assessment of Tumor Response to Therapy: Workshop Report. Cancer Res 2005; 65:7041-7044.

4. Kurhanewicz, J, Swanson, MG, and Vigneron, DB. Chapter 8, Progress of Nuclear Magnetic Resonance Spectroscopy in the Study of Prostate Diseases” in " Nuclear Magnetic Resonance Spectroscopy in the Study of Neoplastic Tissue” (Editors: R. Tosi and V. Tugnoli ), Nova Science Publishers, Inc., Hauppauge, NY 2005; 211-239.

Morphological, Metabolic & Functional Prostate Imaging
R01 CA111291

Abstract
Prostate cancer is extremely common and demonstrates a tremendous range of biologic aggressiveness and varying responses to therapy. Current diagnostic tools are limited in their ability to detect and characterize prostate cancer within the gland, as well as for metastases. Accurate radiological assessment remains a major problem in treating individual prostate cancer patients and for monitoring clinical trials of emerging therapies. Recently, new MR metabolic, perfusion and diffusion MRI techniques have been investigated to address this pressing clinical need. These studies have, however, been limited by the performance of conventional 1.5 Tesla MR scanners and non-optimal techniques for prostate cancer imaging. The goal of this Bioengineering Research Partnership (BRP) is to develop, test and translate into the clinical setting new 3 Tesla magnetic resonance imaging methods that are aimed ultimately to improve radiological monitoring of prostate cancer patients. The new MR imaging techniques will be designed to improve the noninvasive assessment of prostate cancer presence, extent, metabolism, perfusion, and lymph node involvement. Preliminary results have shown dramatic improvements are feasible with the new techniques which may represent major advances in prostate cancer imaging. Following the technique development and initial optimization, quantitative performance testing of the new prostate MR imaging methods will be conducted. The objective is to determine the improvements over current techniques and to obtain initial preliminary data and experience required for the design of future clinical trials of the proposed methodologies. This partnership will combine the efforts of MR imaging scientists from UCSF, and Stanford with industry collaborators from two companies, GE Healthcare Technologies and its subsidiary USA Instruments, that have major interests in prostate cancer imaging. The groups in this partnership have extensive bioengineering experience in the development of biomedical imaging techniques in general and specifically in prostate cancer MR imaging. The industry partners will assist in the technical developments and are required for the translation of the new imaging techniques into commercially available tools that can be widely disseminated to allow their use in research and ultimately clinical investigations world-wide. With the development of new high-field, high performance MR systems, novel acquisition techniques and advances in computational hardware and algorithm development, we believe the time has come to combine these new advances in a collaborative partnership to develop the following: 1) High Field MR Imaging of the prostate 2) High field, high-resolution Metabolic MRSI 3) Diffusion MR imaging of the prostate 4) Contrast-enhanced & pefusion MR imaging of the prostate 5) Development of Improved MR Data Analysis Methods.

Related Articles

1. Cunningham CH, Vigneron DB, Marjanska M, Chen AP, Xu D, Hurd RE, Kurhanewicz J, Garwood M, Pauly JM. Sequence Design for MR Spectroscopic Imaging of Prostate Cancer at 3 Tesla. Magn. Reson. In Med. 2005; 53:1033-1039.

2. Kim Y, Noworolski SM, Pouliot J, Hsu IC, Vigneron DB, and Kurhanewicz J. Expandable and Rigid Endorectal Coils for Prostate Magnetic Resonance Imaging and Spectroscopic Imaging: Impact on Prostate Distortion and Image Registration. Med Phys. 2005; 32:3569-3578.

3. Chen AP, Cunningham CH, Kurhanewicz J, Xu D, Hurd RE, Pauly JM, Carvajal L, Karpodinis K, Vigneron DB. High-Resolution 3D MR Spectroscopic Imaging of the Prostate at 3 Tesla with MLEV-PRESS sequence. Magn Reson Imaging. 2006; 24:825-832.

4. Chen AP, Cunningham CH, Ozturk E, Xu D, Hurd RE, Kelley DAC, Pauly JM, Kurhanewicz, Nelson SJ, Vigneron DB. High Speed 3T MR Spectroscopic Imaging of Prostate with Flyback Echo Planar Encoding. J Magn Reson Imaging. 2007; 25:1288-1292.

5. Rigid and Inflatable Endorectal Coil Probes for MRI and 3D MRSI of the Prostate. J. Magn Reson Imag. (submitted).


Technique Development for Hyperpolarized C-13 MR Studies
R01 EB007588

This proposed project is focused on developing new acquisition and analysis techniques specifically for hyperpolarized 13C in vivo studies. This extraordinary new technique has the potential to become a major new MR metabolic imaging technique by directly observing key cellular bioenergetic processes in vivo by MR. Hyperpolarized 13C imaging provides a >10,000 fold signal enhancement for detecting 13C probes of endogenous, nontoxic substances such as pyruvate to monitor metabolic fluxes through multiple key biochemical pathways (glycolysis, citric acid cycle and fatty acid synthesis). Recent in vivo MR studies of injected 13C labeled substrates, pre-polarized via dynamic nuclear polarization, have demonstrated unprecedented 13C signal enhancement and the ability to not only observe uptake but also metabolism in vivo. Our preliminary results using a DNP polarizer developed by the GE-Amersham Malmo group have shown the ability to acquire 3D metabolic imaging of preclinical mouse models, for the first time, at high spatial resolution (0.125cm3) and high SNR for not only the hyperpolarized pyruvate, but also the metabolic products of lactate and alanine in only 10 seconds. However, these studies have also demonstrated the need for the development of specialized MR acquisition and analysis techniques to realize the full potential of this powerful new metabolic imaging method. To address this need, we have assembled a multidisciplinary research team from UCSF, Stanford University and GE Healthcare who will work together to develop new techniques for obtaining and interpreting hyperpolarized 13C MR data. Through this project we aim to develop specialized hyperpolarized 13C MR pulse sequences, rf detectors and data analysis tools and evaluate them in preclinical animal models to detect abnormal metabolism and, for the first time, investigate metabolic changes in response to therapy with this powerful new imaging technique. Although we have focused the proposed technique evaluation on a transgenic model of prostate cancer and specific drug therapies, the techniques developed in this project would be applicable to a variety of other animal models of disease and drug evaluations. Ultimately these techniques will presumably also benefit future clinical studies of this powerful metabolic imaging technique.

Related Articles

1. Cunningham CH, Chen AP, Albers MJ, Kurhanewicz J, Hurd RE, Yen Y-F, Pauly JM, Nelson SJ, Vigneron DB. Double Spin Echo Sequence For Rapid Spectroscopic Imaging of Hyperpolarized 13C. J. Magn Reson. 2007; 187:357-362.

2. Kohler SJ, Yen Y-F, Wolber J, Chen AP, Albers MJ, Bok R, Zhang V, Tropp J, Nelson SJ, Vigneron DB, Kurhanewicz J, Hurd RE. In vivo 13Carbon Metabolic Imaging at 3T with Hyperpolarized 13C-1-Pyruvate. Magn. Reson. Med. 2007; 58:65-69.

3. Chen AP, Albers MJ, Cunnigham CH, Kohler SJ, Yen Y, Hurd RE, Tropp J, Bok R, Pauly JM, Nelson SJ, Kurhanewicz J, Vigneron DB. High-Resolution Hyperpolarized C-13 Spectroscopic Imaging of the TRAMP mouse at 3T – Initial Experience. Magn. Reson. Med. 2007; 29;58(6):1099-1106.

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Development of High Field MR Imaging and Spectroscopy Techniques
LSIT 01-10107

Technical Abstract
As advances in molecular and cellular biology provide an increased understanding of the genetic basis of human diseases, the development of non-invasive imaging modalities that are sensitive and specific to changes in the properties of different tissues have become critical for basic and disease oriented research. Improvements in the hardware and software associated with whole body Magnetic Resonance (MR) scanners have made possible the development and practical implementation of a whole new range of imaging and spectroscopy techniques. While these have shown promising results at the standard clinical field strength of 1.5T, the increase in signal to noise and spectral resolution associated with higher field strengths are critical for developing new functional and metabolic imaging techniques with the best possible sensitivity and specificity. The objective of this proposal is to support collaborative research between the California based research and development group of General Electric Medical Systems (GEMS) and scientists at the Institute for Quantitative Biomedical Research (QB3), which is one of the four California Institutes for Science and Innovation. The focus of the project will be the optimization of 3T and 7T whole body scanners for biological and medical research. Specific Aim 1 will address the optimization of translational research on the 3T system. This will be an extension of previous research performed at UCSF in high resolution MRI and MRSI that has resulted in several important applications such as the evaluation of pediatric epilepsy, osteoporosis and prostate cancer. Specific Aim 2 will provide a validation of in vivo MR parameters and will identify new targets for high field MR spectroscopy by performing ex vivo MR spectroscopy and immunohistochemistry of tissue samples obtained under well-controlled conditions from uniform population of patients participating in clinical trials. Specific Aim 3 will address the use of the 7T whole body magnet and will require a much higher degree of engineering development associated with optimizing gradient and radiofrequency coils, the design of new pulse sequences and the design of algorithms for data reconstruction and analysis. Specific Aim 4 will provide training in both practical and theoretical aspects of high field MR for students and postdoctoral fellows from UCSF, UCB, and UCSC. This collaboration will provide critical resources for the researchers participating in QB3, as well as other many other academic and industrial partners in California.

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Hyperpolarized 13C NMR Studies of Prostate Cancer
R21 EB005363

Abstract
An extraordinary new technique utilizing hyperpolarized 13C labeled probes has the potential to revolutionize the observation of key cellular metabolic processes noninvasively in vivo by MR. Proof-of-principle animal studies have demonstrated up to 40,000 fold polarization enhancements of 13C labeled pyruvate, providing sufficient signal for rapid imaging of the tumor metabolites alanine and lactate. In this collaborative project with GE Healthcare scientists, we aim to, for the first time, combine hyperpolarized 13C labeled probes such as pyruvate and acetate with high field human MR scanners, optimized rf receivers and fast spectroscopic imaging pulse sequences, to obtain an ~4 order of magnitude increase in sensitivity for 13C metabolic imaging of prostate cancer. The accurate detection and characterization of prostate cancer remains a major problem in the clinical management of individual prostate cancer patients and in monitoring therapy. While a combination of MRI and 1H MR spectroscopic imaging has shown great promise for improving prostate cancer detection and characterization prior to and following therapy, the value of this technique is currently limited by its coarse spatial and spectral resolution. The use of 13C labeled pyruvate, and acetate provide the potential to simultaneously assess changes in metabolic fluxes through multiple biochemical pathways (glycolysis, citric acid cycle and fatty acid synthesis) simultaneously. All three of these pathways have been shown to have metabolic perturbations associated with the evolution and progression of human prostate cancer. In a series of studies involving ex vivo HR-MAS spectroscopic analysis of intact human prostate biopsies, human prostate cell lines cultured with 13C labeled substrates, and transgenic mice injected with 13C labeled substrate we will; (1) determine the key 13C labeled metabolites that best identify the presence of prostate cancer and characterize its aggressiveness, and (2) determine the kinetics of incorporation of 13C labels into the key metabolites as well as the T1 and T2 relaxation times of the 13C labeled metabolites. This data will be combined with specialized rf detectors, fast 13C spectroscopic imaging pulse sequences, and data reconstruction and analysis protocols to detect hyperpolarized 13C labeled metabolic imaging probes in preliminary studies of prostate cancer patients.

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