Tumor Therapy Response

                  2696.     Molecular NMR and EPR in Vivo Detection of Cell Death Using Specific Phosphatidylserine-Targeted Iron Oxide Particles.

Kim Anne Radermacher¹, Sébastien Boutry², Isabelle Mahieu², Sophie Laurent², Luce Vander Elst², Caroline Bouzin³, Julie Magat¹, Vincent Grégoire⁴, Olivier Feron³, Robert N. Muller², Bénédicte F. Jordan¹, Bernard Gallez¹

¹Biomedical Magnetic Resonance Unit, Catholic University of Louvain, Bruxelles, Belgium; ²NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium; ³Unit of Pharmacology and Therapeutics, Catholic University of Louvain, Bruxelles, Belgium; ⁴Center for Molecular Imaging and Experimental Radiotherapy, Catholic University of Louvain, Bruxelles, Belgium

The aim was to develop a molecular marker for non invasive monitoring of tumor cell death as a response to treatment. The phosphatidylserine-targeted peptide E3 was coupled to ultrasmall particles of iron oxide (USPIO). The USPIO concentration was evaluated in irradiated and untreated tumors by EPR and MRI in vivo. We also compared USPIO-E3 accumulation in three different tumor models presenting different degrees of radiosensitivity (fibrosarcoma is less radiosensitive than hepatocarcinoma which is less radiosensitive than lymphoma). The major finding of the present investigation is that USPIO-E3 allows the sensitive detection of tumor cell death after cytotoxic treatment.

                  2697.     Evaluation of Radiotherapy Using Manganese-Enhanced MRI (MEMRI)

Shigeyoshi Saito^1,2, Sumitaka Hasegawa, Takako Furukawa, Tetsuya Suhara, Iwao Kanno, Ichio Aoki

¹Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan; ²National Institute of Radiological Sciences, Chiba, Japan

Radiotherapy is the use of high-energy x-rays or particles to treat malignancies with the intention of destroying or inactivating cells while preserving normal tissue integrity. We found demonstrated that MEMRI ; 1) Cellular viability after radiation exposure could be evaluated usingsignal enhancementmanganese-labeling  was reduced after x-ray irradiation for both in-vitro and in-vivo models. MEMRI may be used to evaluate the cellular viability of tumor after radiotherapy.

                  2698.     Dynamic-Contrast-Enhanced-MRI Shows Radiation Resistant Tumor (Nu61) Is Also Resistant to TNFalpha Treatment – Pilot Study

Chad R. Haney¹, Xiaobing Fan¹, Gregory S. Karczmar¹, Charles A. Pelizzari², Marta Zamora¹, Erica Markiewicz¹, Helena J. Mauceri², Ralph R. Weichselbaum²

¹Radiology, University of Chicago, Chicago, IL, United States; ²Radiation & Cellular Oncology, University of Chicago, Chicago, IL, United States

Ionizing radiation is a staple for treating tumors.  However, failure to cure tumors is thought to be due to an intrinsic tumor cell radioresistance and its microenvironment.  DCE-MRI was used to characterize the response of two tumor cell lines – one radioresistant and the other radiosensitive.  A genetically modified adenoviral vector was used, which causes infected cells to produce tumor necrosis factor alpha (a potent antivascular agent), only when irradiated.  The radioresistant tumors showed no significant changes in the rate transfer constant and fractional volume accessible to the contrast agent.  However, the radiosensitive tumors showed significant reduction in both kinetic parameters.

                  2699.     Dichloroacetate Treatment Resulted in Altered Phospholipid Metabolism and Compromised Tumour Bioenergetics in Human Colon Carcinoma Xenografts

Yuen-Li Chung¹, Helen Troy¹, Geoffrey S. Payne¹, Marion Stubbs², Ian R. Judson³, John R. Griffiths², Martin O. Leach¹

¹CR-UK and ESPRC Cancer Imaging Centre, Institute of Cancer Research, Sutton, Surrey, United Kingdom; ²Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom; ³CR-UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom

Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase (PDK) inhibitor and is found to be an anti-cancer agent.  The aim of this work was to develop a non-invasive and robust biomarker for tumour response following PDK inhibition.   In vivo and in vitro 1H- and 31P-MRS of HT29 xenografts and tumour extracts were used.  DCA treatment caused tumour growth inhibition and altered phospholipid metabolism and tumour bioenergetics.  The drop in total choline and phosphomonoesters may have potential as non-invasive markers for tumour response following treatment with DCA or other PDK inhibitors.

                  2700.     Resistance and Sensitivity to Docetaxel Treatment of Breast Cancer Tissue in Mice Assessed by Analysis of Choline Compounds with HRMAS NMR Spectroscopy

Jack van Asten^1,2, Tone F. Bathen³, Tessa Buckle⁴, Chantal Beekman⁴, Ingrid Gribbestad³, Fijs van Leeuwen⁴, Arend Heerschap¹

¹Radiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; ²Biophysical Chemistry, Radboud University Nijmegen, Nijmegen, Netherlands; ³Dept. of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; ⁴Radiology and Nuclear Medicine, Division of Diagnostic Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Breast cancers may be resistant to docetaxel treatment. We investigated the metabolic profile of breast cancer tissue in mouse strains resistant and sensitive to treatment by docetaxel. A typical choline compound profile was found to be predictive for treatment efficiency.

                  2701.     Nitric Oxide Synthase Silencing by Bimodal Liposomes May Reduce Perfusion in Tumours as Assessed by DCE-MRI

Tammy Louise Kalber¹, Gavin D. Kenny¹, Nazila Kamaly^1,2, Willy Gsell³, Marzena Wylesinska-Arridge³, Leigh P. Brody¹, Andrew D. Miller², Jimmy D. Bell¹

¹Metabolic and Molecular Imaging Group, Imaging Sciences Department, MRC, Imperial College London, Hammersmith Hospital, London, United Kingdom; ²Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, London, United Kingdom; ³The Biological Imaging Centre, Imperial College London, London, United Kingdom

Human colon adenocarcinoma cells, transfected to overexpress inducible nitric oxide synthase (iNOS) were used to characterize the delivery of iNOS siRNA by bimodal liposomes in vitro and in vivo. Incubation in vitro  resulted in a significant decrease in nitrite by day 72. Whereas, iNOS overexpressing tumours administered with iNOS siRNA liposomes resulted in decreased T₁ over 24 hours, consistent with gradual accumulation within the tumour. Tumour volume measurements showed growth restriction and regression suggestive of siRNA release resulting in gene silencing and therapeutic effect after ~ 5 days. However, DCE-MRI was not able to evaluate changes in tumour perfusion leading.

                  2702.     Early Accumulation of 1H MRS Detected Lipids and Lactate in Rat 9L Glioma to Anti-Angiogenic Treatment

Enrico C. Lallana¹, Kyle A. Brong², Khan Hekmatyar¹, Neil Jerome¹, Martin Wilson³, Camilo E. Fadul¹, Risto A. Kauppinen⁴

¹Dartmouth Medical School; ²Dartmouth College; ³University of Birmingham; ⁴Dartmouth Medical School, Hanover, NH, United States

A rodent anti-VEGF-antibody, B20-4.1.1, was used to treat orthotopic 9L glioma bearing rats. During the first week of treatment kinetics of T1-weighted signal enhancement following rapid Magnevist iv-bolus slowed down greatly, reflecting reduced vascular leakiness and perfusion. At the same time, 1H MRS showed large increase both in relative lactate and 1.3ppm and 0.9ppm lipids, while water diffusion in treated gliomas was unchanged. These results indicate that 1H MRS provides endogenous imaging biomarkers for tumour cell responses during anti-angiogenic therapy, that are not obtained by contrast enhanced MRI or diffusion.

                  2703.     In Vivo MR Detection of Inhibition of Signaling Transduction in Non-Hodgkin's Lymphoma

Seung Cheol Lee¹, Michal Marzec², Xiabin Liu², Suzanne Wehrli³, Mariusz Wasik², Jerry David Glickson¹

¹Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States; ²Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States; ³NMR Core Facility, Children's Hospital of Philadelphia, Philadelphia, PA, United States

More and more drugs for cancer are being developed in the context of signaling transduction. Some of such drugs are already in clinical trial. A noninvasive method to early detect the effect of these drugs is demanding. NMR is a promising candidate to meet this request as it can be applied in vivo to measure metabolic perturbations in tumors following various therapies. We're investigating to see effects of the inhibitor of mammalian target of rapamycin (mTOR) which is a highly conserved serine/threonine kinase that controls cell growth and metabolism in response to nutrients, growth factors, cellular energy, and stress.

                  2704.     Preclinical Therapeutic Sequencing Using a Dual-Tracer Multi-Animal DCE-MRI Platform

James A. Bankson¹, David L. Schwartz², Douglas Webb¹, Charles V. Kingsley¹, Jorge Delacerda¹, Marc S. Ramirez¹, Garth Powis¹

¹Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States; ²Department of Radiation Medicine, North Shore-LIJ Health System, New Hyde Park, NY, United States

A dual-tracer multi-animal DCE-MRI platform has been used to compare response of a xenograft model of pancreatic cancer to combinations of radiation therapy and PX-478, a novel selective HIF-1a inhibitor currently in Phase I clinical trial.  Six groups of eight animals were administered sham, single-agent, concurrent, or sequential therapies.  Dual-tracer multi-animal DCE-MRI evaluation of vascular changes detected most pronounced response in group given combined therapy compared to controls as early as +3d after completion of therapy, preceding detectable differences in tumor growth by >7d.  The dual-tracer multi-animal DCE-MRI platform enabled high-throughput evaluation of response to therapy.

                  2705.     Theranostic Effect of Serial MEMRI on the HESC Induced Teratoma

Jaehoon Chung¹, Rajesh Dash¹, Kehkooi Kee², Joelle Barral³, Irving Weissmann⁴, Dwight Nishimura³, Robert Robbins⁵, Renee Reijo Pera², Phillip C. Yang¹

¹Cardiovascular medicine, Stanford University, Stanford, CA, United States; ²Stem cell biology and regenerative medicine, Stanford University, Stanford, CA, United States; ³Electrical engineering, Stanford University, Stanford, CA, United States; ⁴Pathology, Stanford University, Stanford, CA, United States; ⁵Cardiothoracic surgery, Stanford University, Stanford, CA, United States

Systemic administration of MnCl2 enabled simultaneous monitoring and selective elimination of hESC induced teratoma cells by higher intracellular accumulation of Mn2+. This is the first study to demonstrate MEMRI has a theranostic effect in both detecting and eliminating early teratoma formation.

                  2706.     MRI Molecular Imaging Monitors Downstream Anti-Angiogenic Effects of MTOR Inhibition

Robert Ross¹, Jose L. Figueiredo², Peter Waterman², Ralph Weissleder³, Alexander R. Guimaraes^4,5

¹Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Boston, MA, United States; ²Center for Systems Biology, Massachusetts General Hospital, Boston, mA, United States; ³Center for Systems Biology, Massachusetts General Hospital, Boston, MA, United States; ⁴Radiology, Massachusetts General Hospital/Martinos Center for Biomedical Imaging, Charlestown, MA, United States; ⁵Center for Systems Biology, Massachusetts General Hospital/Martinos Center for Biomedical Imaging, Boston, mA, United States

Inhibitors of the mammalian target of rapamycin (mTOR) are approved in patients with metastatic renal cell cancer (RCC).  Our aim was to evaluate in vivo, mTOR inhibition on the vascularity of a RCC mouse model using magnetic nanoparticle enhanced MRI and to compare these effects to the established VEGF inhibitor, sorafenib.   There was excellent correlation (R^2 0.95) of MRI measures of vascular volume fraction to histologic microvessel density . VVF in all treatment arms differed from control (p<0.05) at end of therapy. This study demonstrates that MRI can monitor noninvasively, the in vivo antiangiogenic effects of chemotherapeutic agents.

                  2707.     The Effects of SDF-CXCR4 Signaling on Tumor Growth: The Involvement of Neural Progenitor Cells

Nai-Wei Yao¹, Chiao-Chi V. Chen¹, Chen Chang¹

¹Functional and Micro-magnetic Resonance Imaging Center, Institution of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

Neural progenitor cells (NPCs) and glioma cells share many common features, including the expression of several cellular markers (such as nestin and CD133), a robust proliferative potential, and pluripotency. The present study demonstrates that tumors exhibited rapid growth following NPCs transplantation while the migration was promoted by the signaling of the stromal cell¡Vderived factor-1 (SDF-1) / CXC chemokine receptor 4 (CXCR4) axis. The finding identified a role of NPCs in tumor expansion.

                  2708.     Optimization of Combined Bevacizumab Plus Irinotecan Therapy in Brain Tumors Using MRI Measures of Relative Cerebral Blood Volume

Kimberly R. Pechman^1,2, Deborah L. Donohoe, ^2,3, Devyani P. Bedekar, ^2,3, Kathleen M. Schmainda, ^2,4

¹Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, United States; ²Translational Brain Tumor Program, Medical College of Wisconsin, Milwaukee, WI, United States; ³Radiology, Medical College of Wisconsin, Milwaukee, WI, United States; ⁴Radiology and Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States

Few systematic studies have been performed to determine the optimal timing for combining anti-angiogenic therapy with chemotherapy for the treatment of brain tumors. Standard MRI measures of enhancing tumor volume are not appropriate since anti-angiogenic drugs decrease contrast enhancement. The purpose of this study was to evaluate the utility of using rCBV, derived from DSC imaging, to optimize the combination of bevacizumab and irinotecan for the treatment of brain tumors.  The studies, performed in the U87 brain tumor model, demonstrate that the optimal combination, occurs when irinotecan is administered two days before or after treatment with bevacizumab.

                  2709.     Reference Region Based Modeling in DCE-MRI Allows Reliable Therapy Response Monitoring Despite Drug Induced Systemic Changes in a Rat Liver Tumor Model

Andreas Steingoetter^1,2, Jonas Svensson³, Yvonne Kosanke¹, Ernst Rummeny¹, Rickmer Braren¹

¹Institute of Radiology, Klinikum rechts der Isar der TU München, Munich, Germany; ²Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland; ³Department of Medical Radiation Physics, Malmo University Hospital, Lund University, Malmo, Sweden

A limitation in DCE-MRI is the difficulty of simultaneous measurement of arterial input function and CA concentration in tumor tissue. In this study, two anaesthesia protocols, resulting in a ~ 30% change in heart rate, were used to simulate systemic changes in AIF to analyze the robustness of popAIF vs RR modeling in an orthotopic HCC rat tumor model. Different anaethesisa protocols resulted in a significant systematic offset for popAIF based ktrans and ve modeling compared to RR. This study highlights the robustness and feasibility of the reference region approach.

                  2710.     Captopril and S-Nitrosocaptopril as Potent Radiosensitizers:  Comparative MR Study and Underlying Mechanisms.

Benedicte F. Jordan¹, Julie Peeterbroeck¹, Oussama Karroum¹, Caroline Diepart¹, Julie Magat¹, Vincent Gregoire², Bernard Gallez¹

¹Biomedical Magnetic Resoncance Unit, Universite Catholique de Louvain, Brussels, Belgium; ²IMRE, Universite Catholique de Louvain

EPR and 19F-MRI oximetry were used to monitor acute changes in tumor hemodynamics after administration of potential NO-mediated radiation co-treatments. For this purpose, S-nitrosocaptopril, a converting enzyme inhibitor with vasodilatory properties combined to a nitric oxide donor, was tested in experimental tumors. Tumor oxygenation was significantly increased 30 minutes after administration of the co-treatment. This effect was the result of an increase in tumor blood flow along with a decrease in tumor oxygen consumption by tumor cells.   This oxygen effect contributed to the increase in efficacy of radiation therapy with 10Gy of X-rays, an effect that was not observed with captopril alone.

                  2711.     In Vivo and in Vitro MR Biomarkers for Choline Kinase Inhibition in Human Colon Cancer HCT-116

Moses Darpolor¹, Peter Kennealey², H. Carl Le¹, Kristen Zakian¹, Ellen Ackerstaff¹, Asif Rizwan¹, Jin-Hong Chen², Eliot Sambol², Gary Schwartz³, Samuel Singer², Jason Koutcher^1,3

¹Medical Physics, MSKCC, New York, NY, United States; ²Surgery, MSKCC, New York, NY, United States; ³Medicine, MSKCC, New York, NY, United States

Combined irinotecan and flavopiridol therapy is in clinical trials to treat human colon malignancies. Using in vivo and in vitro MR measurements we report here several critical HCT-116 cellular markers from the treatment. We have shown that flavopiridol is effective in inhibiting choline kinase by lowering phosphocholine/choline levels in vitro, while 31P MRSI detected an in vivo transient decrease in phosophocholine level following the treatment with both drugs. Detectable cholesterol/CH3 levels were observed to increase in tandem with HCT-116 cancer cell apoptotic fraction.

                  2712.     Early Measures of ADC Response to Radiotherapy And/or Sunitinib in a Murine Intracranial Model of Human Glioblastoma Multiforme

Warren Foltz¹, Caroline Chung¹, Jesper Kallehauge¹, Kelly Burrell², Patricia Lindsay¹, David Jaffray¹, Gelareh Zadeh², Cynthia Ménard¹

¹Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada; ²Brain Tumor Research Centre, University Health Network, Toronto, Ontario, Canada

ADC can monitor early tumor response to cytotoxic therapy and predict clinical outcomes.  This study monitored early ADC response and tumor growth following sunitinib and/or radiotherapy in a murine intracranial model of human glioblastoma multiforme.  Imaging proceeded at 3-7 day intervals following base-line MRI and image-based stratification into treatment arms.  RT trial arms demonstrated considerable early ADC elevation, and persistent elevation during growth delay.  Sunitinib monotherapy maintained ADC below other arms, and constrained tumor growth.  Control animals displayed moderate ADC elevation and earliest exponential tumor growth.  Early ADC changes may be a useful biomarker of treatment response and growth delay.

                  2713.     In Vivo Delivery of Liposomal Encapsulated Survivin SiRNA Leads to a Reduction in Tumour Growth Rate

Gavin David Kenny¹, Tammy Louise Kalber¹, Nazila Kamaly^1,2, Leigh Pauline Brody¹, Andrew David Miller², Jimmy David Bell¹

¹Metabolic and Molecular Imaging Group, Imperial College, London, United Kingdom; ²Genetic Therapies Centre, Imperial College, London, United Kingdom

Survivin is a gene upregulated in the majority of cancers, but not expressed in normal tissue and is therefore a possible target for tumour therapy. In this study siRNA targeted to Survivin was encapsulated in to liposomes and the delivery to the tumour monitored using MRI and corroborated by fluorescence microscopy. The Survivin siRNA delivered by the liposomes significantly reduced the growth rate of the tumours for at least 72 hours when compared to a control siRNA and therefore could potentially be used as a cancer therapy.

                  2714.     Evaluation of Diffusion MR as a Biomarker for Nanoparticle Therapy Response in Lymphoma

Thomas Sheung Chee Ng^1,2, Daniel Procissi¹, Hargun Sohi¹, Andrew A. Raubitschek³, Russell E. Jacobs¹

¹California Institute of Technology, Pasadena, CA, United States; ²University of Southern California, Los Angeles, CA, United States; ³Beckman Institute, City of Hope, Duarte, CA, United States

IT-101 is a novel nanoparticle therapy that specifically targets the tumor mass. We evaluated whether diffusion MR is sensitive to early IT-101 response in a mouse model of lymphoma.

                  2715.     Response of Orthotopic PC3 Prostate Tumors to the HIF Pathway Inhibitor NSC-134754 Assessed by Diffusion Weighted MRI and Immunohistochemistry

Lauren CJ Baker¹, Jessica KR Boult¹, Yann Jamin¹, Simon Walker-Samuel¹, Margaret A. Ashcroft², Simon P. Robinson¹

¹CR-UK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, United Kingdom; ²University College London, London, United Kingdom

The hypoxia-inducible factor pathway (HIF) is a key regulator in tumor cell adaptation to the hypoxic microenvironment. Small molecule HIF inhibitors have been identified and are currently being evaluated in vivo using non-invasive magnetic resonance (MR) methods. In this study, we show that diffusion-weighted magnetic resonance imaging (DW-MRI) can detect tumor response to the HIF pathway inhibitor NSC-134754 24h post administration in a murine orthotopic model of prostate cancer. Complimentary ex vivo histology of parameters including hypoxia, perfused vessels and necrosis further provided an insight into tumor physiology and microenvironment alterations induced by NSC-134754.

                  2716.     Multi-Parametric Imaging of Tumor Treatment Response to VEGF Blockade

Benjamin A. Hoff¹, Mahaveer S. Bhojani², Alnawaz Rehemtulla², Brian D. Ross¹, Craig J. Galban¹

¹Radiology, University of Michigan, Ann Arbor, MI, United States; ²Radiation Oncology, University of Michigan

This study investigates permeability and diffusion-weighted imaging as surrogate biomarkers of tumor response to anti-angiogenic therapy.   Vascular permeability, and plasma volume fractions and apparent diffusion coefficient (ADC) maps were acquired pre and post treatment initiation of VEGF-Trap, an anti-angiogenic agent, or vehicle in a rodent glioma model.  Permeability parameters dropped significantly following treatment, whereas ADC, an indirect measure of cellularity, remained unchanged. Confirmed by histology, tumor cellularity were consistent between groups, whereas, vascular disruption was visible in treated animals resulting in a drop in cell proliferation as determined by ki-67.

                  2717.     Apparent Diffusion Coefficient as an Early Quantitative Biomarker of Radiation Response in Prostate Cancer

Warren Foltz¹, Andy Wu¹, Masoom Haider^2,3, Peter Chung¹, Andrew Bayley¹, Charles Catton¹, Cynthia Ménard¹

¹Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada; ²Medical Imaging, University Health Network, Toronto, Ontario, Canada; ³Medical Imaging, University of Toronto

Apparent diffusion coefficent (ADC) increases with cytoxic interventions, and may provide an early response biomarker for prostate radiotherapy. This study evaluated prostate zonal and tumor ADC using clinically normal and high b-values in low/intermediate risk patients at baseline and at 2-week intervals throughout their 8-week radiation treatment. Central gland ADC elevated moderately but significantly throughout treatment, while uninvolved peripheral zone ADC trended towards a late reduction.  Tumor ADC was elevated in all follow-up scans, to 15% at week 8.  SNR analysis at each b-value identified the minimum region volume for noise-insensitive measurements, to guide protocol design for future voxel-based assessment.

                  2718.     Serial R₂* MRI to Evaluate Response to Tumour Vascular Disruptive Treatment in a Clinical Phase I Trial

Martin Zweifel¹, Daniel Patterson¹, N J. Taylor², J J. Stirling², David J. Collins³, James A. d'Arcy³, Martin O. Leach³, Gordon J. Rustin¹, Anwar R. Padhani²

¹Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, United Kingdom; ²Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, United Kingdom; ³CRUK-EPSRC Cancer Imaging Centre, Institute of Cancer Research & Royal Marsden Hospital, Sutton, Surrey, SM2 5PT, United Kingdom

This is a report of the first, in man study of serial BOLD MRI after a vascular disruptive agent in a translational phase I clinical trial of OXi4503. Changes observed in R₂* were used to define onset of VDA activity and results are compared to DCE-MRI changes at 4 hours. R₂*showed significant VDA within the 1st few hours. Both R₂*and DCE-MRI show positive dose-response relationships. If both R₂*and DCE-MRI parameters are used to assess OXI4503 activity (by significant increases in R₂*and decreases in K^trans/IAUGC₆₀), then 52% of lesions show MRI changes consistent with VDA effect.

                  2719.     Comparison of Diffusion and DCE-MRI as Markers for Response to Therapy in HCC Patients

Edward Andrew Ashton¹, Renuka Iyer²

¹R&D, VirtualScopics, Inc., Rochester, NY, United States; ²Oncology, Roswell Park Cancer Center, Buffalo, NY, United States

This study assessed ADC measurement as a marker for response in oncology trials.  An evaluation of variability in ADC in liver tissue was carried out using twelve volunteers.  Results showed that ADC can be measured in liver with CoV < 10%. Subsequently, ADC changes from baseline were measured in HCC patients after therapy with an anti-angiogenic agent and/or chemoembolization.  Ktrans measurements were also obtained for these patients using DCE- MRI, which is known to be a good marker for changes associated with these therapies.  Results show that changes in Ktrans are highly correlated with changes ADC.

                  2720.     Vascular Response of Hepatocellular Carcinoma to Pazopanib Measured by Dynamic Contrast-Enhanced MRI: Pharmacokinetic and Clinical Activity Correlations

Philip Stephen Murphy¹, Caleb Roberts², Brandon Whitcher³, Frank Stornanti⁴, Jennifer Gauvin⁵, Thomas Yau⁶, Pei-Jer Chen⁷, Martin Curtis⁵, Ben Suttle⁵, Thangam Arumugham⁵, Jeffrey Hodge⁵, Mohammed Dar⁵, Ronnie Poon⁶, Geoff JM Parker²

¹Oncology Clinical R&D, GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom; ²Imaging Science and Biomedical Engineering, School of Cancer and Imaging Sciences, University of Manchester, Manchester, United Kingdom; ³Clinical Imaging Centre, GlaxoSmithKline, London, United Kingdom; ⁴Perceptive Informatics, Billerica, United States; ⁵Oncology Research, GlaxoSmithKline, Research Triangle Park, United States; ⁶Queen Mary Hospital, Hong Kong, China; ⁷National Taiwan University Hospital, Taipei, Taiwan

When performing dynamic contrast enhanced MRI (DCE-MRI) in the dose-ranging setting, correlating the readout to individual pharmacokinetic (PK) parameters is more informative than relating to dose alone. In a study of the VEGF receptor inhibitor pazopanib in hepatocellular carcinoma (HCC), relationships between image-based measures of vascular function, PK parameters, and clinical activity were observed.

                  2721.     Comparison of Tracer Kinetic Models with DCE-MRI to Evaluate a Phase 1 Anti-Angiogenic Trial

Choon Hua Thng¹, Tong San Koh², Septian Hartono¹, Bee Choo Tai³, Puor Sherng Lee¹, Helmut Rumpel⁴, Ai Bee Ong⁵, Norita Sukri⁵, Chiung-Ing Wong⁵, Ross Soo⁵, Albert Su Chong Low⁴, Rod Humerickhouse⁶, Boon Cher Goh⁵

¹National Cancer Centre Singapore, Singapore, Singapore; ²Nanyang Technological University, Singapore, Singapore; ³National University of Singapore, Singapore; ⁴Singapore General Hospital, Singapore; ⁵National University Hospital, Singapore; ⁶Abbott Laboratories, United States

Dynamic contrast enhanced MRI (DCE-MRI) with tracer kinetic modeling has been proposed as a biomarker of angiogenesis imaging. Three tracer kinetic models were studied as methods of angiogenesis assessment: conventional compartmental (model developed by Brix et al. (1), adiabatic approach to tissue homogeneity model developed by St. Lawrence and Lee (2), and distributed parameter model developed by Koh et al. (3) All models enable derivation of tissue microcirculatory parameters such as blood flow and capillary permeability-surface area product. We aim to examine the association between the above parameters with drug exposure and patient outcome in a Phase I anti-angiogenic trial.

Tumor Perfusion & Permeability

                  2722.     The Effects of Locally Estimated Arterial Input Functions on Pharmacokinetic Parameters in DCE-MRI

Jacob Fluckiger¹, Matthias Schabel, Ed DiBella

¹Bioengineering, University of Utah, Salt Lake City, UT, United States

The authors present a method for determining the accuracy of locally estimated arterial input functions in DCE-MRI. Preliminary results from clinical data are presented.

                  2723.     A Versatile 3 T Phantom for Intravoxel-Incoherent Motion (IVIM) Sensitization of Microvascular Flow

Gene Young Cho¹, Eric E. Sigmund¹, Sungheon Kim¹, Jens H. Jensen¹, Daniel K. Sodickson¹

¹Center for Biomedical Imaging, Radiology, NYU School of Medicine, New York, United States

Diffusion-weighted imaging (DWI) can be sensitized to both tissue structure and microvascular flow in tumors. Capillary networks can present intravoxel-incoherent motion (IVIM), creating a pseudodiffusion coefficient that tracks microvascular flow. A versatile flow phantom was constructed for IVIM validation in a full body 3T scanner. This system allows technique optimization for ongoing IVIM-based studies of in vivo tumor pathologies. Biexponential analysis of DWI showed an increase in pseudodiffusivity with increasing flow and a decrease with increased impedance, simulating relevant microvascular processes. Spatial mapping of the IVIM coefficients showed strong contrast between pseudodiffusion and background diffusion. Future applications are discussed.

                  2724.     Study on Effect of Water Exchange in Dynamic Contrast Enhanced MRI and Pharmacokinetic Model Analysis

Jin Zhang¹, Sungheon Kim²

¹Department of Finance and Risk Engineering, Polytechnic Institute of New York University, New York, NY, United States; ²Center for Biomedical Imaging, Radiology, NYU School of Medicine, New York, NY, United States

Extracting physiologically relevant parameters from DCE-MRI data is still a challenging problem since the effect of contrast agent is indirectly measured in proton MRI. The purpose of the current study was to use a numerical simulation method to generate DCE-MRI data with water exchange effect and to investigate its effects on the pharmacokinetic model parameters. Realistic MRI data were simulated using the BTEX model and a three-site two-exchange model. Two conventional pharmacokinetic models were fitted to the simulated data. The preliminary results demonstrate the significance of the water exchange effect in estimating pharmacokinetic model parameters.

                  2725.     Selective Blood-Brain Barrier Permeabilization of F98 Rat Glioma to a High Molecular Weight Contrast Agent by an Inducible Kinin B1 Receptor Agonist

Jerome Cote¹, Luc Tremblay¹, Fernand Jr Gobeil², David Fortin³, Martin Lepage¹

¹Nuclear medecine and radiobiology, Université de Sherbrooke, Sherbrooke, QC, Canada; ²Pharmacology, Université de Sherbrooke, Sherbrooke, QC, Canada; ³Surgery, Université de Sherbrooke, Sherbrooke, QC, Canada

Dynamic contrast-enhanced magnetic resonance imaging with intravenous Gd-DTPA or Gadomer was used to monitor the selective increase of blood-brain barrier permeability (BBB) at the tumor of glioma-bearing rats, induced by either the natural kinin B1 receptor (B1R) agonist LDBK, or NG29, a synthetic high-affinity agonist. Post-contrast images revealed that only NG29 modulates topographic uptake profiles of both contrast agents within rat glioma and brain tissue surrounding the tumor, as observed by increase of both contrast agents distribution volume and mean Gd concentration in the implanted hemisphere. Our results confirm the use of B1R agonists to permeabilize the BBB around tumors.

                  2726.     Towards Robust and Automated Identification of Vascular Input Function in DCE-MRI

Kim Mouridsen¹, Dominique Jennings¹, Elisa Gelasca¹, Elizabeth Gerstner¹, Tracy Batchelor², Gregory Sorensen¹

¹Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, United States; ²Stephen E. & Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, United States

Dynamic contrast enhanced MRI (DCE-MRI) holds potential for characterizing key physiological markers of tumor vascularity such as blood brain-barrier-permeability. Reproducibility of pharmacokinetic parameters in multicenter settings is contingent on reliable characterization of the vascular input function (VIF). This is compromised by signal attenuating T2* effects at high concentrations and insensitivity of typical T1-weighted sequences at peak bolus passage, as well as non-reproducible manual identification of VIFs. We demonstrate that a completely automatic VIF identification procedure combined with T2* based estimation of peak concentration yields VIF reproducibility comparable to expert manual selection in two pre-treatment baseline scans of 10 glioblastoma patients.

                  2727.     MRI T2* and T1 Ratio for Assessment of Transport of Macromolecular Contrast Agent in Tumor Interstitium

Ramesh Paudyal¹, Hassan Bagher-Ebadian^1,2, Swayamprava Panda¹, Joseph D. Fenstemacher³, James R. Ewing^1,2

¹Neurology, Henry Ford Hospital, Detroit, MI, United States; ²Physics, Oakland University, Rochester, MI, United States; ³Anestheisology, Henry Ford Hospital, Detroit, MI, United States

Contrast-enhanced (CE-MRI) utilizes T1 and T2* contrast mechanism and paramagnetic labeled contrast agents (CAs) to characterize the resultant kinetic parameters of cerebral tissue.  In this study, the dynamic maps of the ratio of T2* and T1, i.e.Ã2 (the ratio of the relaxivities of T2* and T1), are employed to track the movement of the macromolecular CAs in tumors interstitium. The velocity wave fronts show the redistribution of CAs after extravasation in interstitium which allows monitoring the delivery of the chemotherapeutic agent in tissue

                  2728.     Using DCE-MRI Model Selection to Investigate the Disrupted Microvascular Charateristics of Tumour-Bearing Livers

Anita Banerji^1,2, Josephine H. Naish^1,2, Yvon Watson^1,2, Giovanni A. Buonaccorsi^1,2, Geoff J. Parker^1,2

¹Imaging Sciences and Biomedical Engineering, School of Cancer and Imaging Sciences, The University of Manchester, Manchester, United Kingdom; ²Biomedical Imaging Institute, Manchester, United Kingdom

Healthy liver tissue has highly leaky sinusoids, a dual blood supply and can be characterised using the one-compartment dual-input Materne model, whereas the two-compartment single-input extended Kety model is often used to describe tumours that contain capillaries and have an arterial supply. We use the Akaike model selection criterion applied to dynamic contrast-enhanced MR data of liver tumours. We demonstrate that the extended Kety model is preferred within the tumour with a trend towards the Materne model within non-tumour liver tissue. This has implications for the identification of tumours in the liver and for partial volume errors.

                  2729.     A Semi-Automated Method for Obtaining the Arterial Input Function in Dynamic Breast Data

Xia Li^1,2, E. Brian Welch³, A. Bapsi Chakravarthy⁴, Ingrid Mayer⁵, Mark Kelley⁶, Ingrid Meszoely⁷, Julie Means-Powell⁶, John C. Gore, ²⁸, Thomas E. Yankeelov^1,2

¹Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, United States; ²Institute of Imaging Science, Nashville, TN, United States; ³Philips Healthcare, Nashville, TN, United States; ⁴Radiation Oncology, Vanderbilt University; ⁵Medical Oncology, Vanderbilt University; ⁶Surgical Oncology, Vanderbilt University; ⁷Radiology, Vanderbilt University; ⁸Radiology and Radiological Sciences , Vanderbilt University, Nashville, TN, United States

Quantitative analysis of dynamic contrast enhanced MRI (DCE-MRI) data requires the accurate determination of the time rate of change of the concentration of contrast agent, Cp, in the blood pool; what is typically referred to as the arterial input function, or AIF. While there have been several methods suggested for capturing AIF kinetics, many are difficult to apply in the particular case of breast cancer. Here, we propose a simple and effective approach to obtain the AIF from breast DCE-MRI data.  The method is based on tracking an initial seed point placed within the axillary artery.

                  2730.     Tissue Estimated Vascular Input Functions Improve DCE-MRI Model  Fitting

Michael Germuska¹, Sophie Riches¹, David Collins¹, Geoffrey Payne¹, Nandita deSouza¹, Martin Leach¹, Matthew Orton¹

¹CR-UK and EPSRC Cancer Imaging Centre, Institute of Cancer Research and Royal Marsden Hospital, Sutton, London, United Kingdom

Dynamic contrast enhanced MRI requires an estimate or measurement of the arterial input function (AIF) to model pharmacokinetic behaviour. To reduce the variability in a measured AIF, a population AIF is often used. Alternatively it is possible to obtain an AIF from local tissue. Pharmacokinetic models driven by AIFs extracted from the prostate tissue were compared to a population AIF for 12 prostate cancer patients. Tissue estimated AIFs were found to out performed the population AIF in terms of fitting residuals and variability in KTrans estimates. The results show tissue estimated AIFs can be used to improve DCE-MRI model fitting.

                  2731.     Identification of Hypoxic Regions In Vivo in the Prostate

Radka Stoyanova¹, Ellen Ackerstaff², HyungJoon Cho², Jason A. Koutcher², Alan Pollack¹

¹Radiation Oncology, University of Miami, Miami, FL, United States; ²Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, United States

We present an application of Pattern Recognition techniques to identify the characteristic temporal pattern of hypoxia in Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI). The approach is confirmed in DCE-MRI data from an animal model, acquired concurrently with several complementary imaging modalities including pimonidazole staining. The technique is also applied to DCE-MRI data from the tumor of a prostate cancer patient where a similar temporal pattern is uncovered in parts of the tumor. Our results suggest that by applying this approach we can potentially deconvolve the hypoxic temporal pattern in in vivo data from patients with prostate cancer.

                  2732.     Assessment of Tumor Hypoxia with DCE-MRI: A Preclinical Study on Human Melanoma Tumor Lines

Tormod André Mjelde Egeland¹, Jon-Vidar Gaustad¹, Berit S. Mathiesen¹, Einar Kåre Rofstad¹

¹Department of Radiation Biology, The Norwegian Radium Hospital, Oslo, Norway

Purpose: To study the potential usefulness of DCE-MRI for assessing the extent of tumor hypoxia. Methods: Gd-DTPA-based DCE-MRI was performed on human melanoma xenografts from 8 different tumor lines grown orthotopically in mice. v_e and K^trans from Tofts model were obtained on a voxel-by-voxel-basis, and compared with the radiobiologically hypoxic fraction (HF_rad). Results: A strong linear correlation between v_e and HF_rad (p<0.002 for all quartiles) and a non-linear relationship between K^trans and HF_rad was found. Conclusions: This study suggests that it may be possible to obtain information on tumor oxygenation in patients from DCE-MRI studies.

                  2733.     Volume Transfer Constants Spatial Distribution Across Breast Tumors: Evidence of Interstitial Fluid Pressure?

Pierluigi Di Giovanni¹, Trevor Sean Ahearn¹, Scott I K Semple², Che A. Azlan^1,3, Fiona J. Gilbert¹, Thomas W. Redpath¹

¹Radiology, University of Aberdeen, Aberdeen, Scotland, United Kingdom; ²Medical Physics, University of Edinburgh, Edinburgh, Scotland, United Kingdom; ³Biomedical Imaging, University of Malaya, Kuala Lumpur, Malaysia

Among the physiological features found in tumors is the increased interstitial fluid pressure (IFP). Dynamic contrast enhanced MRI (DCE-MRI) can be used to generate a parametric map of the volume transfer constant going from the intravascular space into the lesion interstitial space (K^trans_in) and in opposite direction (K^trans_out). We have studied the spatial distribution of the ratio K^trans_out/K^trans_in in breast cancers. Our parametric maps reveal that those tumors having a central non-enhancing region show a very similar pattern in the imbalance between the two transfer constants. We argue that what we observe is linked to the spatial distribution of IFP.

                  2734.     A Comparison Between Individual and Population Based Arterial Input Functions in the Analysis of DCE-MRI Breast Cancer Data

Xia Li¹, E. Brian Welch², A. Bapsi Chakravarthy³, Lei Xu⁴, Mary Loveless⁵, Ingrid Mayer⁶, Mark Kelley⁷, Ingrid Meszoely⁸, Julie Means-Powell⁷, John C. Gore⁹, Thomas E. Yankeelov¹

¹Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, United States; ²Philips Healthcare, Nashville, TN, United States; ³Radiation Oncology, Vanderbilt University; ⁴Biostatistics, Vanderbilt University; ⁵Biomedical Engineering, Vanderbilt University; ⁶Medical Oncology, Vanderbilt University; ⁷Surgical Oncology, Vanderbilt University; ⁸Radiology, Vanderbilt University; ⁹Radiology and Radiological Sciences , Vanderbilt University, Nashville, TN, United States

The accurate determination of the arterial input function, or AIF, plays an important role to quantitative analysis of dynamic contrast enhanced MRI (DCE-MRI) data. We have proposed (in a separate abstract) a simple and efficient method to obtain the AIF, through tracking an initial seed point placed within the axillary artery. Using this method, we obtain the AIF for each individual patient (AIFind) and the population averaged AIF (AIFpop). We apply the AIFs to two DCE-MRI pharmacokinetic models to compare the physiological parameters.

                  2735.     The Relationships Between ADC, T₁ and DCE-MRI Tracer Kinetic Parameters in Solid Ovarian Tumors

Caleb Roberts^1,2, Josephine H. Naish^1,2, Claire L. Mitchell³, Yvonne Watson^1,2, Sue Cheung^1,2, Gio A. Buonaccorsi^1,2, Gordon C. Jayson³, John C. Waterton, ^2,4, Jean Tessier⁴, Geoff J. Parker^1,2

¹Imaging Science and Biomedical Engineering, School of Cancer and Imaging Sciences, The University of Manchester, Manchester, United Kingdom; ²The University of Manchester Biomedical Imaging Institute, The University of Manchester, Manchester, United Kingdom; ³Cancer Research UK Dept Medical Oncology, Christie Hospital and University of Manchester, Manchester, United Kingdom; ⁴AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom

While there is a good understanding of microvascular function and structure  described by tracer kinetic model-based analyses of dynamic contrast-enhanced (DCE)-MRI data, the interpretation of apparent water diffusion coefficient (ADC) is less clear. Besides ADC, the parameter that is most sensitive to the water distribution and geometry is T₁. In this study, we acquire DCE-MRI and diffusion weighted images from a group of ovarian tumors and find significant relationships between ADC, T₁, and v_e that offer insight into the physiological meaning of these parameters in ovarian tumors.

                  2736.     A Method to Estimate Sample Sizes for DCE-MRI-Based Studies of Heterogeneous Tumors

Chris James Rose^1,2, James P. O'Connor^1,2, Caleb Roberts^1,2, Gio A. Buonaccorsi^1,2, Yvon Watson^1,2, Sue Cheung^1,2, Gordon Jayson³, Geoff J. Parker^1,2

¹Imaging Science and Biomedical Engineering, The University of Manchester, Manchester, United Kingdom; ²The University of Manchester Biomedical Imaging Institute, Manchester, United Kingdom; ³Cancer Research UK and University of Manchester Department of Medical Oncology, The Christie Hospital, Manchester, United Kingdom

DCE-MRI is of great utility for studying tumor microvasculature, particularly in early phase clinical trials. Most analysis methods assume homogeneous tumors, which is often incorrect and a problem when planning trials, because the magnitude of effect observed using DCE-MRI will be attenuated, for example, by contributions from necrotic tissue. By simulating maps of K^transusing a model of tumor heterogeneity, we present a method to estimate the distribution of required sample size. We illustrate the method’s application using data from a trial of bevacizumab in CRC metastases and show that by considering heterogeneity, more powerful studies can be planned.

                  2737.     Simultaneous Vessel Size and Blood Volume Measurement in a Human Tumor Outside the Brain

Stefanie Remmele¹, Janine Ring², Julien Sénégas¹, Walter Heindel², Wolfgang E. Berdel³, Christoph Bremer⁴, Thorsten Persigehl²

¹Philips Research Europe, Hamburg, Germany; ²Department of Radiology, University of Muenster, Muenster, Germany; ³Department of Oncology, University of Muenster, Muenster, Germany; ⁴Department of Radiology, Franziskus Hospital, Muenster, Germany

This work presents results from the first simultaneous steady-state blood volume and vessel size measurement in a human tumor outside the brain (phleomorphic sarcoma in the pubic bone). Images were free of artifacts, sequence timing allowed for appropriate coverage of the signal decays pre and post injection and the dR2*/dR2 values of the tumor were sufficiently high to generate robust physiologic maps, which appeared to be independent from contrast agent washout.

                  2738.     Population-Generalized Vs. Individual-Specific AIF in Human Prostate DCE-MRI Pharmacokinetic Analysis

Ian Tagge¹, Ryan A. Priest², Tomasz M. Beer^3,4, Mark G. Garzotto^5,6, William J. Woodward¹, Wei Huang¹, Charles S. Springer, Jr. ^1,4, Xin Li¹

¹Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, United States; ²Radiology, Oregon Health & Science University, Portland, OR, United States; ³Hematology/Oncology, Oregon Health & Science University, Portland, OR, United States; ⁴Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; ⁵Urology, Oregon Health & Science University, Portland, OR, United States; ⁶Portland VA Medical Center, Portland, OR, United States

Dynamic-contrast-enhanced magnetic resonance imaging (DCE-MRI) has shown promise in diagnostic medicine, particularly as applied to breast cancer screening. Pharmacokinetic parameter determination relies on arterial input function (AIF) validity. However, reliable AIFs are not easily obtained and often cannot be. Thus, it is often necessary to rely on an averaged, population AIF. The latter is also desired for data post processing simplification. Here, the standard model (SM) and first generation “shutter-speed” model (SSM) are used to assess the impact of a generic AIF on the pharmacokinetic parameter Ktrans (volume contrast reagent (CR) transfer constant) estimation in human prostate studies.

                  2739.     In Vivo Measurement of Pharmacokinetic Parameters in Small Animal DCE-MRI Using Cardiac Sampling of the Vascular Input Function

Dustin K. Ragan¹, Stephen Yenzen Lai², James A. Bankson¹

¹Department of Imaging Physics, M. D. Anderson Cancer Center, Houston, TX, United States; ²Department of Head and Neck Surgery, M. D. Anderson Cancer Center, Houston, TX, United States

Measurement of pharmacokinetic parameters in small animal models of cancer is a frequently-used tool in preclinical investigations of novel interventions.  One source of uncertainty from these measurements arises from the challenges of quantifying the concentration time course of a contrast agent in blood.  We have proposed performing this measurement in the heart, which allows reduced-artifact high temporal resolution sampling.  A pilot study was performed in a thyroid tumor model comparing the inter-subject variation produced by cardiac sampling with conventional sampling in a local blood vessel, and found a large reduction in variation with the proposed approach.

Perfusion Permeability Methodology

                  2740.     Parameter Optimization and Demonstration of Simultaneous Time Resolved Angiography and Perfusion Measurement in the Lower Extremities at Rest and with Exercise

Katherine L. Wright¹, Nicole Seiberlich², Stephen R. Yutzy¹, Raymond F. Muzic^1,2, Mark A. Griswold^1,2, Vikas Gulani²

¹Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States; ²Department of Radiology, Case Western Reserve University/University Hospitals, Cleveland, OH, United States

In this work, Time resolved angiography WIth Stochastic Trajectories (TWIST) accelerated with parallel imaging, partial Fourier acquisition and view sharing, was used to obtain simultaneous angiography and dynamic contrast enhanced (DCE) perfusion measurements in muscle with a single contrast dose. Parameter optimization was performed to select combinations of undersampling schemes that provided the best temporal resolution while still limiting artifact power and error in perfusion measurements. The results were used to obtain MRA and perfusion exams on volunteer lower extremities during rest and exercise, demonstrating the ability of the technique to measure physiological perfusion changes.

                  2741.     Withdrawn by Author

                  2742.     Simultaneous Characterization of the Tumor Vascular Permeability, Vessel Size and Density by Using First-Pass Function/ Structure MR Imaging

Chia-Ming Shih^1,2, Chien-Yuan Lin², Chih-Yuan Chen², Ta-Wei Chou², Sui-Shan Lin², Cheng-Hung Chou², Yen-Yu Shih², Jyh- Horng Chen¹, Chen Chang²

¹Institute of Biomedical Electronics and Bioinformatics, National Taiwan Unversity, Taipei, Taiwan; ²Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan

Two different contrast agents with different approaches were needed for assessing the vascular permeability and structure including vessel size and vessel density. In the present study, First-Pass Function/Structure MR Imaging (First Pass F/S MRI) technique was proposed to simultaneously evaluate vascular function and structure. The proposed technique can reduce scan time and assess the correlation between functional and structural changes in brain tumor.

                  2743.     In Vitro Validation of Permeability-Surface Area Product Derived by Distributed Parameter Model with DCE-MRI

Septian Hartono^1,2, Choon Hua Thng¹, Tong San Koh², Puor Sherng Lee¹, Fang Keang Lim¹, Theng Boon Lee¹, Helmut Rumpel³, Quan Sing Ng¹

¹National Cancer Centre Singapore, Singapore, Singapore; ²Nanyang Technological University, Singapore, Singapore; ³Singapore General Hospital, Singapore

Hollow Fiber Bioreactors (HFBs), typically used for cell culture, mimicks well the human capillary system and thus is ideal to be used to validate the microcirculatory parameters obtained by tracer kinetic modeling. The aim of this study is to validate the permeability-surface area product (PS) obtained by tracer kinetic models with DCE-MRI in a HFB. Linear relationship was found between PS derived from the tracer kinetic models and pore size area of the HFBs.

                  2744.     Measurement of Intracellular Water Preexchange Lifetime in Perfused “Brains on Beads” System

Qingqing Ye¹, William M. Spees², Jim E. Huettner³, Joseph J. Ackerman^1,2, Jeffrey J. Neil^2,4

¹Department of Chemistry, Washington University in St. Louis, St. Louis, MO, United States; ²Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States; ³Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, United States; ⁴Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Preexchange lifetimes of intracellular water (τ _in) are of fundamental significance to many experimental and theoretical studies, especially for modeling water behavior in tissue. Many methodologies have been developed to obtain this value for various cell types. Herein, we employed the method of perfusion of microbead-adherent cells, which allowed τ _in  measurement by highly effective suppression of the extracellular water MR signal and thus selective and direct observation of the intracellular water MR signals. Histologic evaluation confirmed that neurons and astrocytes grown on microbeads maintain key morphologic features. We found that τ _in’s for neurons and astrocytes are similar.

                  2745.     Quantitative Dynamic 19F MRI Oximetry in a Phantom Simulating Hypoxia

Steven H. Baete^1,2, Yves De Deene^1,2

¹Laboratory for Quantitative Nuclear Magnetic Resonance in Medicine and Biology, ECNURAD, Ghent University, Ghent, Belgium; ²MEDISIP-IBBT, Ghent University, Ghent, Belgium

Tumor hypoxia is well known to reduce cancer treatment efficacy. Fluor-19 MRI oximetry can be used to map oxygen concentrations in hypoxic tissue. In this study a reproducible phantom which mimics oxygen consuming tissue is used for quantitative dynamic fluor-19 MRI oximetry. The phantom consists of a hemodialysis filter of which the outer compartment is filled with a gelatin matrix containing viable yeast cells and perfluorocarbon vesicles which simulate the absorption of perfluorocarbons from intravenous emulsions in tissue. The phantom can be used for hypoxia simulations and for validating computational biophysical models of hypoxia, as measured with fluor-19 MRI oximetry.

                  2746.     Detection of Skeletal Muscle Perfusion Differences with DCE-MRI: Contrast Agent and Pharmacokinetic Model

Karolien Jaspers^1,2, Tim Leiner^1,2, Petra Dijkstra³, Marlies Oostendorp^1,2, Jolanda MCG van Golde⁴, Mark J. Post^1,5, Walter H. Backes^1,2

¹Cardiovascular Research Insitute Maastricht, Maastricht, Netherlands; ²Radiology, Maastricht University Medical Centre, Maastricht, Netherlands; ³Central Animal Facilities, Maastricht University, Maastricht, Netherlands; ⁴Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; ⁵Physiology, Maastricht University, Maastricht, Netherlands

Adequate introduction of therapeutic neovascularization in patients with peripheral arterial disease requires functional monitoring of vascular responses. The potential of the medium-sized contrast agent Gadomer for detecting (patho-) physiological perfusion differences with DCE-MRI was tested in a rabbit hind limb ischemia model. The lower extravasation rate of Gadomer requires a pharmacokinetic model that includes the blood plasma fraction vp rather than a model that accounts for reflux. Gadomer proved equally successful as Gd-DTPA in detecting flow differences between red (soleus) and white (tibialis) muscle, and between ischemic and normal soleus muscle tissue, while facilitating better image quality.

                  2747.     Hybrid Reference Tissue Calibrated Dual-Bolus 3D Quantitative Dynamic Contrast-Enhanced MRI in a Rabbit VX2 Tumor Model

Alexander Yowei Sheu¹, Dingxin Wang¹, Johnathan Chung², Robert K. Ryu², Reed A. Omary^1,3, Debiao Li¹, Andrew C. Larson^1,3

¹Departments of Radiology and Biomedical Engineering, Northwestern University, Chicago, IL, United States; ²Department of Radiology, Northwestern University, Chicago, IL, United States; ³Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, United States

Quantitative DCE-MRI can be used to measure pharmacokinetic parameters (Ktrans, ve, and vp) that indicate tumor angiogenesis and perfusion. The purpose of this study was to develop an innovative hybrid reference tissue calibrated dual-bolus 3D quantitative DCE-MRI method. Tissue contrast enhancement was quantified using 3D GRE DCE-MRI during first-bolus, AIF was monitored using 2D SR GRE DCE-MRI during second-bolus, and reference tissue (back muscle) was used to provide the final calibration. Our results support the use of quantitative DCE-MRI to differentiate hypervascular tumor tissue from the necrotic core, providing valuable diagnostic information about the stage and segmentation of a tumor.

                  2748.     Phase Contrast Velocity Imaging Using Compressed Sensing

Daniel J. Holland¹, Dmitry M. Malioutov², Andrew Blake², Lynn F. Gladden¹, Andrew J. Sederman¹

¹Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom; ²Microsoft Research Cambridge, Cambridge, United Kingdom

This work describes a method for accelerating the acquisition of phase-encoded velocity images using compressed sensing.  Results are shown for both experimental and simulated measurements of liquid and gas flow through a model porous material.  Using this approach, acceleration factors for Cartesian data of between 2 and 5 are achieved with minimal reconstruction error.  By combining this reconstruction algorithm with a variable density spiral acquisition, a full order of magnitude decrease in imaging time is achieved.  This approach is applicable to MR angiography and perfusion studies in clinical MRI and to other phase imaging techniques.

                  2749.     Intravoxel Incoherent Motion (IVIM) Imaging at Different Field Strengths – What Is Feasible ?

Anna Rydhög¹, Matthias J. P. van Osch², Markus Nilsson¹, Jimmy Lätt³, Freddy Ståhlberg^1,4, Ronnie Wirestam¹, Linda Knutsson¹

¹Department of Medical Radiation Physics, Lund University, Lund, Sweden; ²Department of Radiology, LUMC, Leiden, Netherlands; ³Department of Image and function, University Hospital Lund, Lund, Sweden; ⁴Department of Diagnostic Radiology, Lund University, Lund, Sweden

Intravoxel Incoherent Motion (IVIM) is a non-invasive method which has the potential to quantify perfusion parameters such as  CBV and CBF from signal-versus-b data. Simulations was performed usinga synthetic voxel consisting of four different compartments (tissue, CSF, arterial and venous blood ) for comparison of the expected signal curves at three field strength (1.5, 3 and 7 T). Confirmation of the simulated results was obtained from in vivo measurements on a volunteer.  We conclude that for higher field strengths the relative contribution from venous blood decreases suggesting that IVIM at 7 T would primarily reflect arterial blood volume.

                  2750.     The Detection of Tumor Sub-Regions Based on T₁ and ADC Clustering

Caleb Roberts^1,2, Chris Rose^1,2, Josephine H. Naish^1,2, Yvonne Watson^1,2, Sue Cheung^1,2, Gio A. Buonaccorsi^1,2, Gordon C. Jayson³, John C. Waterton, ^2,4, Jean Tessier⁴, Geoff J. Parker^1,2

¹Imaging Science and Biomedical Engineering, School of Cancer and Imaging Sciences, The University of Manchester, Manchester, United Kingdom; ²The University of Manchester Biomedical Imaging Institute, The University of Manchester, Manchester, United Kingdom; ³Cancer Research UK Dept Medical Oncology, Christie Hospital and University of Manchester, Manchester, United Kingdom; ⁴AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom

Tracer kinetic model-based analyses of dynamic contrast-enhanced (DCE)-MRI data typically report summary statistics that treat tumors as being homogeneous. However, since anti-angiogenic therapies often preferentially affect certain parts of heterogeneous tumors there is interest in the development of methods to provide insight into regional changes.  We present a method that uses k-means clustering of T₁ and the apparent water diffusion coefficient (ADC) measured in a group of ovarian tumors to sub-divide tumors into distinct regions and demonstrate that differences in tracer kinetic parameters exist between these regions and the overall tumor median statistic.

                  2751.     Maximizing Accuracy and Precision on Pharmacokinetic Parameter Estimates in DCE-MRI: What Is the Optimal Flip Angle?

Olivier Maciej Girard¹, Paul O. Scheibe², David R. Vera¹, Robert F. Mattrey¹

¹Department of Radiology , University of California, San Diego, CA, United States; ²Ixzar, Inc., Arroyo Grande, CA, United States

Dynamic Contrast Enhanced (DCE) MRI is a promising tool to investigate microvascular tissue properties. Although it has been applied in various clinical studies its accuracy still remains subject to debate since numerous errors may bias the pharmacokinetic (PK) parameter estimates. Here we propose to study the propagation of measurement noise and flip angle (FA) uncertainty up to the PK parameter estimates using a MonteCarlo simulation. Our results show that in the high FA regime, a high FA uncertainty leads to a much lower bias in the PK parameter estimates while keeping the standard error due to noise close to its minimum.

                  2752.     Temporal Resolution and SNR Requirements for Accurate DCE-MRI Measurement of Microvascular Blood Flow and Permeability Using the AATH Model

Lucy Elizabeth Kershaw¹, Hai-Ling Margaret Cheng^1,2

¹The Research Institute and Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada; ²Department of Medical Biophysics, The University of Toronto, Toronto, Ontario, Canada

This simulation study investigated parameter accuracy for the AATH model, which allows separate measurements of flow and permeability.  The influence of three key factors was assessed: temporal resolution, signal to noise ratio and error in the AIF peak height measurement.  Results showed that a high temporal resolution is the most critical factor in ensuring parameter accuracy but this requirement can be relaxed if larger biases can be permitted and T_c need not be accurately measured.  An error of 10 % in the measurement of the AIF peak height resulted in an error of at most 10 % in each parameter.

                  2753.     A General Dual-Bolus Approach for High Resolution Quantitative DCE-MRI

Lucy Elizabeth Kershaw¹, Marine Beaumont¹, Hai-Ling Margaret Cheng^1,2

¹The Research Institute and Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada; ²Department of Medical Biophysics, The University of Toronto, Toronto, Ontario, Canada

This study presents a dual-bolus technique to measure the arterial input function (AIF) for DCE-MRI.  A low-dose prebolus was used to estimate the AIF for a tissue uptake curve measured from a second high-dose injection.  AIFs were measured in the rabbit aorta using a high temporal resolution TRICKS acquisition.  The scaled prebolus AIF was shown to match the main bolus AIF closely.  Measurement of the AIF in a separate acquisition allows the tissue of interest to be imaged at high spatial resolution in a DCE-MRI experiment.

                  2754.     Scope and Interpretation of the Modified Tofts Model

Steven Sourbron¹

¹Ludwig-Maximilian-University Munich, Munich, Bavaria, Germany

We present a theoretical analysis which shows that the modified Tofts model only applies to tissues that are weakly vascularized and permeability-limited. In other regimes, a model of exactly the same form applies, but the parameter typically interpreted as plasma volume has a mixed interpretation. Hence, if a modified Tofts model is found to describe the data well, none of the physical parameters are measureable without further assumptions on the state of the tissue. These ambiguities can only be resolved by sampling the data fast and precise enough, so that the complete two-compartment exchange model can be fitted.

                  2755.     Improved Correlation to Quantitative DCE-MRI Pharmacokinetic Parameters Using a Modified Initial Area Under the Uptake Curve (MIAUC) Approach

Hai-Ling Margaret Cheng^1,2

¹Research Institute & Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada; ²Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

Non-model DCE-MRI parameters such as the initial area under the uptake curve (IAUC) do not require arterial input function (AIF) measurement or model-fitting, and can hence be more robust than pharmacokinetic modeling. However, the IAUC is intractably correlated with biological parameters such as the transfer constant Ktrans and interstitial space ve. Herein, a modified IAUC (mIAUC) method is presented. The mIAUC parameters are strongly correlated with true Ktrans and ve, and are outperformed by pharmacokinetic parameters only when a rapidly sampled AIF is used. The proposed mIAUC method retains advantages of non-model DCE-MRI while providing stronger correlation with underlying physiology.

Cancer: Cells Biopsies & Biofluids

                  2756.     MEK1/2 Signalling Inhibition in Human Melanoma Cells Leads to Reduced Lactate Production Via Inhibition of Glucose Uptake and Lactate Dehydrogenase Activity

Maria Falck Miniotis¹, Thomas R. Eykyn¹, Paul Workman², Martin O. Leach¹, Mounia Beloueche-Babari¹

¹CRUK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research & The Royal Marsden Hospital, Sutton, Surrey, United Kingdom; ²CRUK Centre for Cancer Therapeutics, The Institute of Cancer Research & The Royal Marsden Hospital, Sutton, Surrey, United Kingdom

Deregulated RAS-BRAF-MEK1/2-ERK1/2 signalling is frequently observed in cancer and considerable effort is focused towards developing MEK1/2-targeted therapy. We previously reported that MEK1/2 inhibition causes a reduction in 1H MRS-detectable lactate in human cancer cells. Here we analyse the time-course of the response and investigate the mechanism behind this effect by assessing glucose uptake and lactate dehydrogenase (LDH) activity. We demonstrate that MEK1/2 inhibition leads to decreased lactate production through down-regulation of both glucose uptake and LDH activity. These results show lactate as a potential non-invasive MRS biomarker of response to MEK1/2-targeted therapeutics.

                  2757.     Metabolic Consequences of Perifosine Treatment

Judy S. Hwang¹, Sabrina M. Ronen¹

¹Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States

Perifosine is a novel anticancer alkylphospholipid that is in clinical trials for treatment of cancer. This study investigates the changes in choline metabolism of MCF-7 human breast cancer cells modulated by perifosine treatment. Cells were incubated with ¹³C labeled choline and ¹H, ¹³C, and ³¹P MR spectra of cell extracts were recorded.  The overall inhibition of phosphatidylcholine synthesis via the Kennedy pathway was observed upon treatment. The accumulation of perifosine was also detected in the cell membrane. The observed changes in choline metabolism upon perifosine treatment could reflect its mechanism of action or its effect on PI3K signaling.

                  2758.     Changes in Choline Metabolism as Potential Biomarkers of HSP90 Inhibition in NEU/HER2-Driven Mammary Carcinoma Oncomouse^®  Cells

Nada M.S. Al-Saffar¹, Laura L. Jackson¹, Swee Sharp², Loreta Rodrigues³, John R. Griffiths³, Paul Workman², Martin O. Leach¹

¹CR-UK and EPSRC Cancer Imaging Centre, Institute of Cancer Research, Sutton, Surrey, United Kingdom; ²CR-UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom; ³CR-UK Cambridge Research Institute, Cambridge, United Kingdom

17-AAG is a novel anticancer drug that inhibits heat shock protein 90 (HSP90) leading to combinatorial degradation of many oncogenic client proteins including NEU/HER2 and its downstream proteins, which have key roles in cell growth and survival. NEU/HER2 is overexpressed in 25% of human breast cancers.  In this study, we have used 1H and 31P-MRS to establish biomarkers for HSP90 inhibition in cells isolated from a NEU/HER2-driven mammary carcinoma Oncomouse^®. We report a 2-fold increase in choline-containing metabolites which was associated with a decrease in NEU/HER2 expression. Hence these MRS changes could serve as biomarkers for HSP90 inhibition in cells/tumors driven by NEU/HER2.

                  2759.     Evaluation of the Early Metabolic Response Induced by 5-Fluorouracil on Mouse Mammary Cancer Cells Under Fasting Conditions Using Hyperpolarized 13C-Labeled Pyruvate.

Hitoshi Kubo¹, Masafumi Harada¹, Takamasa Abe², Hiroshi Maezawa³, Hiromu Nishitani⁴

¹Department of Medical Imaging, University of Tokushima, Tokushima, Japan; ²SBD/MR Division, Oxford Instruments KK., Tokyo, Japan; ³Department of Radiation Physics, Engineering and Biology, University of Tokushima, Tokushima, Japan; ⁴Department of Radiology, University of Tokushima, Tokushima, Japan

The early metabolic response of pyruvate and lactate induced by 5-fluorouracil (5FU) on mouse mammary cancer cells under normal and fasting conditions was evaluated by NMR measurement using hyperpolarized 1-13C-pyruvate and absorption spectroscopy. This study measured four combinations of nutritional status and treatment with 5FU. The rate constant of pyruvate-lactate metabolism was changed by the nutritional conditions without and with 5FU treatment. The results suggested that this technique allows the detection of the early metabolic response induced by an anticancer agent.

                  2760.     Metabolic Changes in Luminal-Like Orthotopic Breast Cancer Xenografts Following Estrogen Supplement Withdrawal

Siver Andreas Moestue¹, Vickie Yi Zhang², Else Marie Huuse¹, Beathe Sitter¹, Gunhild Mari Mælandsmo³, Olav Engebråten³, Ingrid Susann Gribbestad¹

¹Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; ²Department of Radiology and Biomedical Imaging, UCSF, San Francisco, United States; ³Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway

An estrogen-dependent luminal-like breast cancer xenograft model was used to study choline metabolites after endocrine therapy using HR MAS MRS. The data suggested that choline metabolite concentrations do not change following endocrine therapy wheras taurine and lactate do change.

                  2761.     Myc Regulates a Transcriptional Program That Stimulates Glutaminolysis

David R. Wise¹, Anthony Mancuso, Ralph Deberardinis², Sayed Nabil, Xiao-Yong Zhang³, Harla K. Pfeiffer³, Ilana Nissim⁴, Evgueni Daikhind⁴, Marc Yudkoff⁴, Steven B. McMahon³, Craig B. Thompson

¹Cancer Biology, University of Pennsylvania, Philadelphia, PA, United States; ²University of Texas South Western Medical Center; ³Thomas Jefferson Medical College; ⁴Children's Hospital of Philadelphia

High levels of both glucose and glutamine consumption are required for rapid proliferation of most cancer cells.  In this work, the role of myc in regulating the transcriptional control of glutaminolysis was examined.  Two different models were used: immortalized mouse embryo fibroblasts (MEF) with inducible myc activity and human glioma cells with naturally high myc levels that were knocked down with short-hairpin RNA.  Elevated myc activity was associated with increased glutamine transport, glutaminase activity and lactate dehydrogenase activity as demonstrated by PCR.  It was also associated with increased overall glutimolytic flux as evidenced by ¹³C NMR.

                  2762.     MR Determind Metabolites May Serve as Prognostic Factors in Breast Cancer

Tone Frost Bathen¹, Beathe Sitter¹, Guro F. Giskeødegård¹, Lutgarde Buydens², Geert Postma², Hans Fjøsne³, Steinar Lundgren^1,4, Ingrid S. Gribbestad¹

¹Dept. of Circulation and Medical Imaging, NTNU, Trondheim, Norway; ²Dept. of Analytical Chemistry, Radboud University Nijmegen, Nijmegen, Netherlands; ³Dept. of Surgery, St. Olavs University Hospital, Trondheim, Norway; ⁴Dept. of Oncology, St.Olavs University Hospital, Trondheim, Norway

The purpose of the current study was to define new prognostic factors for breast cancer based on HR MAS MRS. Proton MR spin echo spectra were acquired from excised breast cancer tissue. 5-years follow-up data were available for all included patients. The spectra were analysed with PCA. Using ROC and Kaplan-Meyer survival analysis of score values, two groups with significant different cumulative survival were defined. Higher levels of glycerophosphocholine, betaine and creatine, and lower levels of lactate and glycine were associated to good prognosis. A combination of MR determined metabolites may serve as an additional prognostic factor in breast cancer.

                  2763.     ³¹P NMR of Phospholipid Metabolites in Prostate Cancer and Benign Prostatic Hyperplasia

Richard A. Komoroski¹, John C. Holder², Alex A. Pappas², Alex E. Finkbeiner², Sadhna Verma¹

¹University of Cincinnati, Cincinnati, OH, United States; ²University of Arkansas for Medical Sciences, Little Rock, AR, United States

Although ³¹P NMR is an excellent method for probing the phospholipid (PL) metabolites in prostate cancer, it has been little used recently. We report an in vitro ³¹P NMR comparison of prostate cancer and benign prostatic hyperplasia (BPH), focusing on the levels of major PL metabolites. Unlike phosphocholine (pc) and glycerophosphocholine (gpc), phosphoethanolamine (pe) and glycerophosphoethanolamine (gpe) (and their ratio) were significantly different between cancer and BPH. The levels of pe and gpe relative to those of pc and gpc are consistent with the former being major contributors to the “total choline” resonance observed by ¹H MRS in vivo.

                  2764.     Detection Of Cancer In Cervical Tissue Biopsies Using Mobile Lipid Resonances Measured With Diffusion-Weighted 1h Magnetic Resonance Spectroscopy

Dominik Zietkowski¹, Robert L. Davidson¹, Thomas R. Eykyn¹, Sonali S. De Silva¹, Nandita M. deSouza¹, Geoffrey S. Payne¹

¹CR-UK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

An optimised diffusion-weighted stimulated echo sequence with bipolar gradients attenuated low molecular weight metabolites in cervical cancer tissue samples giving improved visibility and characterisation of mobile lipid resonances (MLR). Linear discriminant analysis (LDA) of MLR peaks almost completely separated cervical biopsies containing cancer from those that did not, reflecting underlying differences in MLR composition. Generated Receiver Operating Characteristic (ROC) curves and calculated area under the curve (0.962) validated high sensitivity and specificity of the technique.

                  2765.     Choline Metabolite Ratios from NMR as Markers of Human Breast Cancer

Mary C. Mahoney¹, Jing Huei Lee², Wen Jang Chu², John M. Pearce², Kim M. Cecil³, Stephen M. Strakowski², Richard A. Komoroski²

¹Radiology, University of Cincinnati, Cincinnati, OH, United States; ²Center for Imaging Research, University of Cincinnati, Cincinnati, OH, United States; ³Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States

In vivo ¹H MRS of breast cancer lesions can detect a signal assigned to total choline (tCho), which arises from a variety of choline-containing metabolites. The contribution of each metabolite to the increased tCho peak in vivo is not known. Here we report in vitro ¹H NMR spectroscopy results on fine-needle aspirate (FNA) biopsies of lesions from breast cancer patients, several of whom were also studied by in vivo MRS. Phosphocholine was usually the major metabolite, whereas the contribution of glycerophosphocholine varied substantially, and that of Cho was always minor.

                  2766.     Role of  Choline Kinase and Phosphatidylcholine Phospholipase C in  Aberrant  Choline Metabolism in Human Epithelial Ovarian Cancer

Egidio Iorio¹, Marina Bagnoli², Alessandro Ricci¹, Maria Elena Pisanu¹, Kristine Glunde³, Giancarlo Castellano², Elisa Venturini⁴, Zaver M Bhujwalla³, Delia Mezzanzanica², Silvana Canevari², Franca Podo¹

¹Istituto Superiore di Sanità, Roma, Italy; ²Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; ³Johns Hopkins University School of Medicine, Baltimore, MD, United States; ⁴Cogentech-Consortium for Genomic Technologies, Milano, Italy

Altered phosphatidylcholine (PC) metabolism in epithelial ovarian cancer (EOC) can provide choline-based imaging approaches as powerful tools to improve diagnosis and identify new therapeutic targets. Measurements  are reported on  protein  expression and enzyme activation of choline kinase (ChoK) and PC-specific phospholipase C (PC-plc) in EOC  cell lines compared with  non tumoral counterparts. The role of  Chok and PC-plc in the intracellular accumulation of PCho in EOC cells was investigated by RNA silencing and pharmacological inhibition respectively. Analyses are also reported on ChoKá mRNA expression and on ChoK and PC-plc protein expression in a set of surgical specimens from EOC patients.

                  2767.     Comparison of Fatty Acid and Phosphatidylcholine Levels in Breast and Prostate Cancer Cells and Tumors

Noriko Mori¹, Flonne Wides², Tomoyo Takagi², Kristine Glunde², Zaver M. Bhujwalla²

¹JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science, , The Johns Hopkins University School of Medicine, Baltimore, MD, United States; ²JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science,, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Elevated lipogenesis is a characteristic feature of cancer.  Fatty acid synthase overexpression has been found in many human cancers.  Both tumor cells in culture and solid tumor models are essential tools to study cancer biology.  To understand the differences in lipid components between tumor cells in culture and solid tumors, we compared fatty acid and phosphatidylcholine levels with 1H MRS of lipid-soluble cell or tumor extracts derived from prostate and breast cancer cell lines.  Significantly different patterns of fatty acid levels between cells in culture and in tumors, demonstrate the importance of the tumor microenvironment in lipid metabolism.

                  2768.     Metabolic Profile of Lipid Extracts Obtained by Astrocytic Brain Tumors

Frauke Nehen¹, Wieland Willker¹, Laura Columbano², Rudolf Fahlbusch², Dieter Leibfritz¹

¹Institute of Organic Chemistry, University of Bremen, Bremen, Germany; ²International Neuroscience Institute Hannover, Hannover, Germany

Lipophilic tissue extracts of astrocytic brain tumors were analyzed by ¹H-NMR spectroscopy. Tumor core, tumor margin and reference tissue differ significantly with respect to their content of galactosyl cerebrosides and one unknown metabolite. Lipid separation with solid phase extraction of eight lipid extracts, enrichment by combining fractions in which the unknown metabolite was observed and analysis by various 2D-NMR methods revealed that the unknown metabolite is an isoprene derivative.

                  2769.     Peak Alignment of MR Spectra

Guro Fanneløb Giskeødegård¹, Tom Bloemberg², Lutgarde Buydens², Geert Postma², Ingrid Susanne Gribbestad¹, Tone Frost Bathen¹

¹Dept. of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; ²Dept. of Analytical Chemistry, Radboud University Nijmegen, Nijmegen, Netherlands

Correction of misaligned peaks is an important part of multivariate preprocessing of MR spectra. In this study, three different peak alignment algorithms were tested on HR MAS MRS data from breast cancer tissue. The datasets were used to predict the prognostic factor ER status, which is shown to be related to metabolic profile.  Correlation optimized warping (COW) and peak alignment by genetic algorithm (PAGA) resulted in greatly improved PLS-DA classification of ER status compared to unaligned data. Parametric time warping (PTW) did not improve the classification error, indicating that PTW may not be as suitable for metabolomic MR data.

                  2770.     Magnetic Resonance Spectroscopy-Based CTP:choline-Phosphate Cytidylyltransferase Activity Measurement Technique

Christopher S. Ward¹, Sabrina M. Ronen¹

¹Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States

CTP:choline-phosphate cytidylyltransferase (CCT) is the enzyme responsible for catalyzing the addition of CTP to phosphocholine to form CDP-choline, which is generally accepted to be the rate-limiting reaction in the formation of phosphatidylcholine. This study introduces a dynamic ³¹P MR-based means to measure the kinetics of the cytidylyltransferase-catalyzed reaction. The results suggest the potential of this technique to quantitatively assess modulations in CCT activity.

                  2771.     Metabolic Changes Associated with HPV Infection in Cancer Cells Observed with 1H MRS

Dominik Zietkowski¹, Geoffrey S. Payne¹, Nandita M. deSouza¹

¹CR-UK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

This study investigates the metabolic effects of HPV infection and tests whether 1H MRS can detect these in a model consisting of isogenic HPV-16 E6 transfected derivatives of A2780 ovarian cell line (E6 is the key cancer-causing HPV protein). It was possible to observe in the HPV-E6 transfects higher cholines, lower lactate, glycine, lipids and their (poly-) unsaturation. These changes seem to be related to changes in E6 transfects proliferation. Similar changes may also apply to HPV infection in cervix and documenting these may provide insights to understand the metabolic ‘field effect’ observed around cervical tumor and into viral oncogenesis.

                  2772.     Detection of Apoptotic Cell Death in Vitro Using Quantitative Magnetization Transfer

Colleen Bailey^1,2, Kimberly L. Desmond^1,2, Gregory J. Czarnota^1,2, Greg J. Stanisz^1,2

¹Sunnybrook Health Sciences Centre, Toronto, ON, Canada; ²University of Toronto, Toronto, ON, Canada

Acute myeloid leukemia cells were treated with cisplatin to induce apoptosis and spun into a cell sample for imaging. Magnetization transfer scans were performed at 427 and 243 Hz peak power, for sixteen offset frequencies logarithmically spaced from 0.12 to 200 kHz. The magnetization transfer ratio at 2320 Hz showed a statistically significant increase from 24.8% in control cells to 28.0% thirty-six hours after cisplatin treatment and 30.3% forty-eight hours after cisplatin treatment, preceding T1 changes. Quantitative fitting showed an increase macromolecular/free water proton exchange and a decrease in T_2B, which characterizes the width of the macromolecular lineshape.

Animal Models of Cancer

                  2773.     Hyperpolarized ¹³C Biomarkers of Androgen Independent Prostate Cancer

Paniz Vafaei¹, Robert Bok¹, Lynn DeLosSantos, Vicki Zhang, Phillip Guan, Dan Vigneron, John Kurhanewicz

¹Radiology, University of California, San Francisco, San Francisco, CA, United States

Androgen independence of prostate cancer is an important clinical status to identify, but no well-defined biomarkers for this state exist.  In this study we used fast 13C-MRSI after injection of hyperpolarized [1-13C] pyruvate and pathological and biochemical analysis of the tumor to determine hyperpolarized (HP) biomarkers of androgen dependent and androgen independent prostate cancer. Androgen independent phenotype had a significantly higher HP lactate/noise, Total Hyperpolarized Carbon, HP lactate/pyruvate, and LDH activity relative to the androgen dependent phenotype.

                  2774.     Multi-Parametric Characterization of an Experimental Model of Cancer Cachexia

Marie-France Penet¹, Sridhar Nimmagadda¹, Mayur Gadiya¹, Balaji Krishnamachary¹, Martin G. Pomper¹, Zaver M. Bhujwalla¹

¹JHU ICMIC Program, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Cachexia is a life-threatening syndrome of progressive weight loss that occurs with a high frequency in several cancers.  A better in vivo characterization of cachectic tumors is important to identify new targets and improve treatment to arrest or reverse this condition.  Here we have characterized differences in vascular properties, quantified by 1H magnetic resonance imaging of the intravascular agent albumin-GdDTPA, between cachectic and non-cachectic tumors.  We also performed 18F-deoxyglucose PET imaging to study the glycolytic activity of those tumors.  We found significantly less permeable vasculature and increased glycolytic activity in the cachectic tumors compared to the non-cachectic ones.

                  2775.     Adjustible Curie-Temperature Nanoparticles for Imaging and Highly Controllable Hyperthermia Cancer Therapy

Boris Odintsov¹, Vadim Aleksandrovich Atsarkin², Viktor Demidov³, Andrey Kaul⁴, Mariya Popova⁴, Carolina Soto⁵, Edward Roy⁶

¹Biomedical Imaging Center, University of Illinois , Urbana-Champaign, IL, United States; ²IRE RAN, Moscow, Russian Federation; ³IRE RAN, Russian Federation; ⁴Moscow University, Russian Federation; ⁵UIUC, IL, United States; ⁶University of Illinois, Urbana-Champaign, IL, United States

New nanomaterials recently synthesized in our group are lanthanum manganite doped with silver ions. The unique feature of the doped manganites is the possibility to control their Curie temperature in the range of tumor hyperthermia interest (41-43oC). At its Curie temperature, a ferromagnetic particle loses its magnetic properties; this metal-insulator phase transition is tunable and reversible. New ferromagnetic particles adopt the superparamagnetic behavior and are comparable to iron oxide as an MRI contrast agents. The goal of this presentation is to introduce newly synthesized nanomaterials and create a new platform for highly controllable hyperthermia cancer therapy and imaging.

                  2776.     High Resolution MRI of Tumors in the Smo/Smo Mouse Medulloblastoma Model

Donghoon Lee¹, Stacey Hansen², Richard Ellenbogen¹, Miqin Zhang¹, James Olson²

¹University of Washington, Seattle, WA, United States; ²Fred Hutchinson Cancer Research Center, Seattle, WA, United States

This work describes MRI methods for diagnosis and staging of tumors in the Smo/Smo genetically engineered mouse model of medulloblastoma. High resolution MRI was performed to attain T2 weighted imaging to screen tumors, T1 weighted imaging to examine the blood brain barrier integrity, and diffusion weighted imaging to improve tumor delineation. Sub-millimeter sized tumors in mice as young as 2 months were imaged even though animals were asymptomatic by other criteria. MRI findings were well correlated with histopathology. Thus, high resolution MR imaging is an excellent way to detect and stage tumors in mouse medulloblastoma models.

                  2777.     Fast, High-Resolution, 3-Dimensional Imaging of the Mouse Prostate with BSSFP

Christiane L. Mallett^1,2, Paula J. Foster^1,2

¹Imaging Research Laboratories, Robarts Research Institute, London, Ontario, Canada; ²Medical Biophysics, The University of Western Ontario, London, Ontario, Canada

Purpose: To obtain high-quality images of the mouse prostate for studies of prostate cancer. Methods: Mice were imaged with balanced steady state free precession (bSSFP), T1- and T2-weighted spin-echo sequences. Results: We obtained whole-body images at 200 micron resolution that included the prostate, popliteal and inguinal lymph nodes in ~25 mins. 2D T1- and T2-weighted SE sequences had inferior SNR per slice thickness and prostate-fat CNR relative to bSSFP. Conclusion: bSSFP gives fast, high resolution, 3D mouse prostate and body imaging with high SNR and CNR. This will be used in studies of prostate cancer and metastasis.

                  2778.     MRI Characterisation of a Novel Transgenic Mouse Model of Neuroblastoma

Yann Jamin¹, Elizabeth Ruth Cullis², Lynsey Vaughan², Dow-Mu Koh¹, Louis Chesler², Simon P. Robinson¹

¹Cancer Research UK and EPSRC Cancer Imaging Center, The Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom; ²Section of  Paediatric Oncology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

This study characterises the novel transgenic murine TH-MYCN  model of high–risk human neuroblastoma, the most common extracranial childhood solid tumour, with MRI, especially the anatomical presentation, the longitudinal development of the tumour in situ, and its established response to the chemotherapeutic agent cyclophosphamide in vivo. In addition, quantitative MRI parameters, and interrogation of the tumour vasculature by DCE-MRI, are also reported. We demonstrate that MRI screening would be a crucial asset in the development of novel MYCN-targeted therapeutics for neuroblastoma and would accelerate their clinical development by allowing simultaneous evaluation of preclinical MRI biomarkers of treatment response.

                  2779.     Interstitial Fluid Pressure Correlates with Water Diffusion Coefficient in Mouse Mammary Tumor Model

Sungheon Kim¹, Lindsey DeCarlo², Gene Young Cho¹, Jens H. Jensen¹, Daniel K. Sodickson¹, Linda Moy¹, Silvia Formenti³, Robert J. Schneider², Eric E. Sigmund¹

¹Center for Biomedical Imaging, Radiology, New York University, New York, NY, United States; ²Microbiology, New York University, New York, NY, United States; ³Radiation Oncology, New York University, New York, NY, United States

Effective delivery of therapeutic drug is often impeded by physiological barriers including elevated interstitual fluid pressure (IFP). In this study, we investigated the feasibility of using Intra-Voxel-Incoherent-Motion (IVIM) diffusion weighted imaging (DWI) to measure tumor blood flow and the association of IVIM diffusion coefficients with IFP. From a study of 10 mice with 4T1 mouse mammary tumor model, strong correlations (R² > 0.64) were observed between the elevated IFP (> 5 mmHg) and diffusion coefficients estimated using monoexponential as well as biexponential diffusion models. This result suggests a high potential of DWI parameters as surrogate markers for IFP.

                  2780.     Multi-Modal Assessment of Longitudinal Growth of Liver Metastases in a Mouse Model of Colon Carcinoma

Prachi Pandit^1,2, Samuel M. Johnston^1,2, Yi Qi², Jennifer Story³, Beth Hollister³, G A. Johnson^1,2

¹Biomedical Engineering, Duke University, Durham, NC, United States; ²Center for In Vivo Microscopy, Duke University, Durham, NC, United States; ³Piedmont Research Center, Morrisville, NC, United States

In this work we present a longitudinal, multi-modality study to monitor the growth of liver metastases in mouse model of colon carcinoma. We have compared the relative merits of using high-field T2-weighting MRI and contrast-enhanced microCT as a preclinical cancer imaging technique in free-breathing mice. The advantages of microCT lie in the fast acquisition of high-resolution isotropic datasets. MRI, on the other hand has higher contrast resolution, and requires neither contrast injection nor radiation dose. Both techniques, ungated MRI and respiratory-gated MicroCT, perform well in the presence of motion, and are sufficiently fast and non-invasive to allow repeated scanning.

                  2781.     Imaging of Tumor Angiogenesis in a Novel Skin Chamber Using MRI and Optical Imaging

Tobias Bäuerle¹, Clarissa Gillmann², Reiner Umathum¹, Margareta M. Müller³, Michal Neeman⁴, Wolfhard Semmler², Michael Bock¹

¹Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany, Germany; ²Medical Physics in Radiology, German Cancer Research Center , Heidelberg, Germany, Germany; ³Tumor- and Microenvironment, German Cancer Research Center, Heidelberg, Germany, Germany; ⁴Biological Regulations, The Weizmann Institute of Science, Rehovot, Israel

Tumor angiogenesis in animal models is often visualized using optical imaging or MRI. In this work we present a subcutaneous skin chamber for simultaneous optical and MR imaging to study the tumor-induced growth of blood vessels in vivo. The fully MR-compatible chamber features an optical window, and can be combined with a dedicated external loop coil.

                  2782.     MR Characterization of the Tumor Microenvironment After Arsenic Trioxide Treatment: Evidence for an Effect on Oxygen Consumption That Radiosensitizes Solid Tumors

Caroline Diepart¹, Oussama Karroum, Julie Magat, Olivier Feron, Bénédicte Jordan, Bernard Gallez

¹UCL, Brussels, Belgium

As2O3 inhibits mitochondrial respiratory function in human leukemia cells. We hypothesized that As2O3 could also be an important modulator of tumor oxygenation by affecting the oxygen consumption of solid tumors. We observed an increase in tumor pO2 in two tumor models after arsenic treatment using oximetry techniques based on EPR and 19F NMR relaxometry. This effect was explained by a decrease in oxygen consumption of the tumors. Finally, the irradiation of tumors showed a regrowth delay that was significantly increased in arsenic-treated mice. As2O3 is an important modulator of pO2 by decreasing oxygen consumption and enhances the response of tumors to radiotherapy.

                  2783.     Improving Tumour ADC Estimates and Elucidating Tumour Heterogeneity Using Adaptive Bayesian Markov Random Field Monte Carlo

Simon Walker-Samuel¹, Matthew Orton¹, Jessica K R Boult¹, Simon P. Robinson¹

¹Cancer Research UK & EPSRC Cancer Imaging Centre, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

A method for improving ADC estimates using an adaptive Bayesian Markov random field analysis is described and evaluated using simulations and in vivo tumour models. Via the sharing of information between neighbouring pixels, the uncertainty and error in ADC estimates are significantly reduced by a factor of up to 80%. The approach also enables the segmentation of homogeneous tissue components and a novel measure of tissue (tumour) heterogeneity is described.

                  2784.     Serial Multiparametric MRI in Study Design and Response Evaluation of Radiation and Antiangiogenic Therapy in an Intracranial Murine Glioblastoma Model

Caroline Chung¹, Warren Foltz¹, Petra Wildgoose¹, Kelly Burrell², Patricia Lindsay¹, Andrea Kassner³, David Jaffray¹, Gelareh Zadeh^4,5, Cynthia Menard¹

¹Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada; ²SickKids' Hospital, Toronto, Ontario, Canada; ³SickKids Hospital, Toronto, Onatario, Canada; ⁴Brain Tumour Research Centre, Toronto, Ontario, Canada; ⁵Toronto Western Hospital, Canada

This study demonstrates feasibility of using multiparametric micro-MRI to overcome the challenges of intracranial mouse tumour models. Baseline T2w images were used to select mice with visible tumours and to stratify mice to treatment arms based on tumour size. Serial multiparametric MRI was used to measure tumour growth and vascular changes on DCE-MRI (iAUC60) with radiation (RT) and/or sunitinib (SU) anti-angiogenic treatment. Early rises in iAUC60 were noted following both RT and SU monotherapy, while the combination of RT and SU resulted in an early significant decrease in iAUC60. These early measured DCE-MRI changes show promise as useful early biomarkers for treatment response.

                  2785.     A Multiple Coil Array Approach for Mouse Brain Tumor Imaging

Lilia V. Ileva¹, Marcelino Bernardo^2,3, Diane Palmieri⁴, Patricia Steeg⁴, Joseph Kalen¹, Peter Choyke²

¹Small Animal Imaging Program, SAIC-Frederick, NCI-Frederick, Frederick, MD, United States; ²Molecular Imaging Program, NCI, NIH,  Bethesda, MD, United States; ³Imaging Physics, SAIC-Frederick, NCI-Frederick, Frederick, MD, United States; ⁴Laboratory of Molecular Pharmacology, NCI, NIH, Bethesda, MD, United States

Multiple mouse MRI is of critical importance in preclinical cancer research when longitudinal studies with multiple animals is required. This work presents a four-mouse brain imaging coil system and its application in the development of a breast cancer brain metastasis mouse model. The four-mouse SENSE array is integrated in a single platform with physiological support system. Six imaging sessions on 18 mice were performed weekly to monitor the initiation and progression of the brain metastases. The usage of the multiple mouse brain coil system significantly improved the efficiency of MRI studies involving serial imaging of multiple small animals.

                  2786.     13C HR MAS MRS Reveals Differences in the Glucose Metabolism Between Two Breast Cancer Xenograft Models with Different Gene Expression Pattern

Maria Tunset Grinde¹, Siver Andreas Moestue¹, Øystein Risa¹, Olav Engebraaten², Ingrid Susann Gribbestad¹

¹Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway; ²Department of Tumor Biology, Cancer Research Institute, Oslo University Hospital, Oslo, Norway

13C HR MAS MR spectroscopy has been used to study two breast cancer xenograft models, representing a human luminal-like and a basal-like genetic profile. The models received a bolus injection of [1-13C]glucose and the conversion from glucose to lactate and alanine was observed 10 or 15 minutes after. The luminal-like model showed a significantly lower ratio of glucose/alanine and glucose/lactate compared to the basal-like model. This can be explained by a lower uptake of glucose and/or a higher rate of glucose metabolism towards alanine and lactate in the luminal-like compared to the basal-like model.

                  2787.     DMSO as a Potential Contrast Agent for Brain Tumours

Teresa Delgado-Goni^1,2, Rui V. Simoes, ¹², Milena Acosta, ¹², Juana Martin-Sitjar^1,2, Silvia Lope-Piedrafita, ^2,3, Carles Arus^1,2

¹Bioquimica i Biologia Molecular, Universitat Autonoma of Barcelona, Cerdanyola del Valles, Barcelona, Spain; ²CIBER-BBN, Zaragoza, Spain; ³Servei de Ressonancia Magnetica Nuclear, Universitat Autonoma of Barcelona, Cerdanyola del Valles, Barcelona, Spain

We describe here the application of Dimethyl Sulfoxide (DMSO) as a potential contrast agent for brain tumour imaging. DMSO crosses the blood-brain-barrier, but its differential wash-out kinetics produces a clear contrast enhancement in mouse brain glioblastoma compared to nearby/peritumoral brain parenchyma, measured by SV MRS and MRSI sequences.

                  2788.     Predicting and Monitoring Response to Chemotherapy by Benzamide Riboside in Hepatocellular Carcinoma Using Apparent Diffusion Coefficient of Water

Andriy Babsky¹, Shenghong Ju², Beena George, Stacy Bennett, Mingsheng Huang, Hiremagalur N. Jayaram, Gordon McLennan, Navin Bansal

¹Radiology, Indiana University, Indianapolis, IN, United States; ²Indiana  University

Implantation of N1S1 cells in the rat liver can be used as an intrahepatic hepatocellular carcinoma (HCC) model for pre-clinical study of transarterial therapy with the apoptotic agent benzamide riboside (BR). Water apparent diffusion coefficient (ADC) in HCC was higher than in nearby normal liver tissue. Intrahepatic infusion of BR was a semi-effective treatment of HCC in rats. BR therapy did not change the water ADC value, regardless of tumor sensitivity. A higher initial ADC level could be a promising sign for effective BR treatment, and in contrast, tumors with a lower initial ADC value are most likely to be resistant to BR-treatment.

                  2789.     Dynamic Contrast-Enhanced Magnetic Resonance Imaging Reveals Differences in Xenografts with Luminal Like and Basal Like Gene Expression Pattern

Else Marie Huuse¹, Siver Andre Moestue¹, Olav Engebråten^2,3, Tone Frost Bathen¹, Ingrid Susann Gribbestad¹

¹Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; ²Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway; ³Oslo University Hospital , Oslo, Norway

Molecular sub-classification of breast cancer based on gene expression pattern represents clinically distinct patient groups with different outcome. Two breast cancer xenograft models reflecting two of these groups: Basal like (ER-, poor prognosis) and luminal like (ER+, better prognosis), were characterized using DCE-MRI. Our results shows a significant higher Ktrans in basal like than in luminal like small tumors, however, this difference disappears for large tumors. Estradiol withdrawal had minor effect on growth and DCE-MRI derived parameters for the basal like tumors. The luminal like tumors ceased to grow and had a significant increase in Ktrans and ve .

                  2790.     Comparative Analysis of Gd Vs Dy in DSC-MRI Studies of a High Grade Glioma Murine Model

Rocío Pérez-Carro¹, Jesús Pacheco-Torres¹, Sebastián Cerdán¹, Pilar Lopez-Larrubia¹

¹Insituto de Investigaciones Biomedicas, CSIC/UAM, Madrid, Spain

Gd(III) is the lanthanide ion more widely used as longitudinal relaxation enhancer due to its long electronic relaxation time. Stable Gd complexes are the T1 contrast agents more used for MRI studies. Other paramagnetic lanthanides as Dy(III) are also employed as contrast agents in dynamic susceptibility contrast MRI. We used both Gd and Dy containing chelates in perfusion studies to yield parametric maps (CBF, CBV and MTT) in a high grade glioma rat model. The goal is to establish an optimal method to delimit and characterize brain regions in the murine model to test the effectiveness of antiangiogenic therapies.

                  2791.     Modulations of Intra and Extracellular PH in Tumor Variants Defective in Either Respiration or Glycolysis, Observed by in Vivo MRS

Norbert W. Lutz¹, Johanna Chiche², Yann Le Fur¹, Christophe Vilmen¹, Frédéric Frassineti³, Laurent Daniel³, Jacques Pouysségur², Patrick J. Cozzone¹

¹CRMBM UMR 6612 CNRS, Aix-Marseille University, Medical School, Marseille, PACA, France; ²Institute of Developmental Biology and Cancer Research CNRS UMR 6543, Centre A. Lacassagne, Nice; ³Inserm UMR 911-CRO2, Aix-Marseille University, Medical School

The current use of angiogenesis inhibitors for cancer treatment requires further modifications of the hypoxic tumor microenvironment to achieve complete tumor regression. To  contribute to the development of a new treatment strategy, we investigated effects of modulations of multiple mechanisms of glycolytic activity and pH regulation on intracellular and extracellular pH (pH_i, pH_e) by ³¹P NMR spectroscopy of tumor xenografts in nude mice. Three ras-transformed fibroblast variants were compared: wild-type CCL39, and mutants defective in either glycolysis or respiration. Compared to CCL39, pH_i was increased in either mutant, and pH_e was less heterogenous due to a reduction of low-pH_e regions.

                  2792.     Single Dose (0.1mmol/kg) Brain Magnetic Resonance Imaging with Gadobutrol at 1.5T and 3.0T: Comparison to 0.15mmol/kg Gadoterate Meglumine

Harald Kramer¹, Val M. Runge², L Gill Naul², Alan T. Loynachan³, Maximilian F. Reiser¹, Bernd J. Wintersperger¹

¹Department of Clinical Radiology, University Hospital Munich, Munich, Germany; ²Scott and White Memorial Hospital, TX, United States; ³University of Kentucky, KY, United States

The detection of a link between the application of Gd contrast agents highlights the need for dedicated application protocols. The purpose of the study was to evaluate the efficacy of single dose gadobutrol compared to a substantially higher dose gadoterate meglumine in a tumor model at 1.5T and 3.0T. All animals were implanted Glioma cells using an implanted plastic brain cannula. After 7 days brain MR exams were performed whether with gadobutrol or gadoterate meglumine with a 24h interval. After the second MRI brains harvested for histopathologic assessment. Data were evaluated regarding SNR, CNR and lesion enhancement (LE).

                  2793.     Integrated MRI Approaches to Interrogate Tumor Oxygenation and Vascular Perfusion of Orthotopic Brain Tumors in a Mouse Model

Heling Zhou¹, Amyn A. Habib¹, Ralph P. Mason¹, Dawen Zhao¹

¹Radiology, UT Southwestern Medical Center, Dallas, TX, United States

Glioma is a lethal cancer. It is imperative to non-invasively evaluate intracranial tumor microenvironment. We applied multiple MRI approaches to evaluate tumor microenvironment in orthotopic gliomas in a mouse model. An interleaved T2*-weighted and T1-weighted sequence, sensitive to both blood and tissue oxygen tension, was applied to assess tumor oxygenation. Our results showed significantly increased signal intensity in intracranial tumors with oxygen inhalation. Dynamic susceptibility contrast MRI was used to evaluate vascular perfusion and correlate with change in oxygenation. Our study suggests the integrated MRI approaches will be useful to evaluate interplay of tumor oxygenation and hemodynamics.

Breast Cancer: Spectroscopy & More

                  2794.     Intrinsic Susceptibility Contrast (R₂*) in the Evaluation of Tumour Oxygenation at Baseline and in Response to Neoadjuvant Chemotherapy in Breast Cancer

Sonia P. Li¹, N J. Taylor², J J. Stirling², Mei-Lin W. Ah-See¹, Mark J. Beresford¹, David J. Collins³, James A. d'Arcy³, Andreas Makris¹, Anwar R. Padhani²

¹Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, United Kingdom; ²Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, United Kingdom; ³CR-UK Clinical MR Research Group, Royal Marsden Hospital, Sutton, Surrey, SM2 5PT, United Kingdom

R₂* has potential to provide information about tumour oxygenation but is underexplored in breast cancer. Here, primary carcinomas were imaged with multiparametric MRI before and after 2 cycles of neoadjuvant chemotherapy. Correlations between R₂* and kinetic parameters were investigated. R₂* as a predictor of pathological benefit was compared with DCE/DSC-MRI parameters. Significant inverse correlations between R₂* and blood flow/volume in untreated cancers confirm that R₂* reflects blood oxygenation; however this relationship disappears after treatment. Increases in R₂* in responders suggest that cancers become more hypoxic with successful treatment. R₂* was a relatively poor response predictor compared with some DCE and DSC-MRI parameters.

                  2795.     Phospholipid Contents Measured in Human Breast Cancer and in Healthy Glandular Breast Tissue in Vivo at 7T

Dennis WJ Klomp¹, Bart van de Bank¹, Alexander Raaijmakers², Mies Korteweg¹, Cecilia Possanzini³, Vincent Boer¹, Nico van de Berg², Maurice van de Bosch¹, Peter Luijten¹

¹Radiology, University Medical Center Utrecht, Utrecht, Netherlands; ²Radiotherapy, University Medical Center Utrecht, Utrecht, Netherlands; ³Philips Health Care

In this work we demonstrate the ability to detect multiple phospholipid metabolites in vivo in the human female breast using focused field coils at 7T. For the first time ever, these signals are detected locally with a spatial resolution of 10 ml. The signals are detected from breast cancer tissue, which has a high concentration of choline levels and even from healthy, glandular  breast tissue as well, which has low levels of total choline (i.e. < 0.5 mM).

                  2796.     A Total Choline Quantification Method for Water- And Lipid-Suppressed Breast Spectra at 3T

Chenguang Zhao¹, Patrick Bolan², Melanie Royce³, Anne Marie Wallace⁴, Laurel Sillerud⁵, Steven Eberhardt⁶, Robert Rosenberg⁶, Lesley Lomo⁷, Stefan Posse

¹Department of Neurology, University of New Mexico, Albuquerque, NM, United States; ²Center of Magnetic Resonance Research, University of Minnesota; ³Cancer Research & Treatment Center, Univeristy of New Mexico; ⁴Department of Surgery, University of New Mexico; ⁵Biochemistry and Molecular Biology, University of New Mexico; ⁶Department of Radiology, University of New Mexico; ⁷Pathology, University of New Mexico

Quantification of total Choline compounds in breast spectra is challenging due to the contamination of unsuppressed lipids. In vivo breast spectra in healthy controls were acquired using proton echo planar spectroscopic imaging. Localized spectra were fitted across the 4.0-2.0ppm range by LCModel using a basis-set with singlet resonances for tCho and lipid peaks. LCModel fitting enables identification of the tCho baseline and quantification of the peak area by spectral integration. In vivo tCho concentrations were consistent with literature values. This method is suitable for automatic tCho quantification of breast spectroscopic imaging data of low quality.

                  2797.     Digital Breast Phantom for Evaluating Dynamic Accelerated Imaging Methods

Leah Christine Henze¹, Catherine J. Moran², Matthew R. Smith², Frederick Kelcz³, Alexey Samsonov³, Sean B. Fain², Walter F. Block, ¹²

¹Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States; ²Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States; ³Department of Radiology, University of Wisconsin-Madison, Madison, WI, United States

Improving temporal resolution without compromising spatial resolution has the potential to improve differential diagnosis in breast cancer.  Several accelerated imaging methods exist that may aid in this endeavor but it is difficult to quantitatively measure and compare their respective performance. To address this problem, we have created a digital breast phantom comprised of enhancing lesions surrounded by normal background breast tissue.   This phantom provides realistic, simulated k-space data for both Cartesian and non Cartesian acceleration methods.  We describe the creation of this phantom and demonstrate its use.

                  2798.     Time-To-Peak and Spherical Shape Index from Dynamic Contrast Enhanced MRI as Combined Predictors of Tumor Malignancy

Fang Liu^1,2, Anat Kornecki³, Olga Shmuilovich³, Neil Gelman^1,2

¹Lawson Imaging, Lawson Health Research Institute, London, Ontario, Canada; ²Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada; ³Department of Diagnostic Imaging, St. Joseph's Health Center, London, Ontario, Canada

Most previous quantitative studies using dynamic contrast enhanced MRI of the breast have analyzed either signal time evolution features or morphological features as predictors of malignancy. However, combined use of both types of features should provide stronger predictors. In this study, a time evolution feature (time to peak (TTP)) and a 3D morphological feature (spherical shape index (SSI)), both obtained from tumor regions segmented automatically with K-means clustering, were investigated as independent and combined predictors of malignancy. Results suggest that the combination provides stronger discrimination of malignant versus benign lesions than either feature alone.

                  2799.     Improving Suspicious Breast Lesion Characterization Using Lesion Fractional Volume Washout Kinetic Analysis

Jie Huang¹, Lori Hoisington¹, Sarah Schafer¹, Xiaopeng Zong¹, Kevin Berger¹

¹Department of Radiology, Michigan State University, East Lansing, MI, United States

This study investigated using lesion fractional volume washout (WO) kinetic analysis for improving the characterization of suspicious contrast-enhancing breast lesions. The WO volume fraction was found to be significantly different between the biopsy-proven benign and malignant lesions of all the suspicious breast lesions with BI-RADS assessment of 4 or 5. It showed a potential to improve the positive predictive value of the biopsies by an improvement rate of 86.8%, and consequently would yield a 72.2% reduction rate to the total number of unnecessary biopsies.

                  2800.     Qualitative and Quantitative Assessment of Breast Tumour Appearance in Diffusion-Weighted Imaging and Correlation with Molecular Prognostic Factors

Giuseppe Petralia¹, Luke Bonello¹, Paul Summers¹, Sara Raimondi², Ala Malasevschi¹, Roberto Di Filippi¹, Dow-Mu Koh³, Marzia Locatelli⁴, Giuseppe Curigliano⁴, Massimo Bellomi¹

¹Radiology, Istituto Europeo di Oncologia, Milan, Lombardia, Italy; ²Epidemiology and Biostatistics, Istituto Europeo di Oncologia, Milan, Lombardia, Italy; ³Radiology, Royal Marsden Hospital, Sutton, United Kingdom; ⁴Medical Oncology, Istituto Europeo di Oncologia, Milan, Lombardia, Italy

We performed a qualitative analysis of diffusion weighted magnetic resonance imaging (DW-MRI) of breast tumours to identify common semiotic characteristics, and a quantitative analysis in 28 patients to examine the correlation of DW-MRI with molecular prognostic factors, and to assess the interobserver variability in the calculation of ADC values. Hyper-intensity in DW images and low ADC values (mean 1.1 x 10-3mm2/sec) were common characteristics in the breast tumours studied. Interobserver variability was 20%.A marginally significant correlation between ADC value and percentage of PgR and possible higher mean ADC values for the LUMINAL A subtype warrant further study.

Prostate Cancer - Clinical

                  2801.     DCE-MRI at 3T in Patients with Advanced Prostate Cancer Undergoing Androgen Deprivation Therapy

Tristan Barrett¹, Andrew Gill^1,2, Masako Kataoka¹, Vincent J. Gnanapragasam³, Andrew Priest^1,2, Ilse Joubert¹, Mary McLean^2,4, Martin J. Graves¹, David J. Lomas¹, John R. Griffiths², David Neal^3,5, Evis Sala¹

¹Radiology, Addenbrooke's Hospital, Cambridge, United Kingdom; ²Medical Physics, Addenbrooke's Hospital, Cambridge, United Kingdom; ³Urology, Addenbrooke's Hospital, Cambridge, United Kingdom; ⁴ Cambridge Research Institute, Cancer Research UK,, Cambridge, United Kingdom; ⁵Cambridge Research Institute, Cancer Research UK, Cambridge, United Kingdom

Prostate cancer is the commonest malignancy in UK men. Androgen deprivation therapy (ADT) remains an important treatment. However, 51% eventually develop resistance, making it necessary to identify quantitative markers that demonstrate ADT response. We used dynamic-contrast-enhancement (DCE)-MRI to measure permeability parameters before and 3 months after ADT in 12 patients with biopsy-proven prostate cancer. There was a significant reduction in all parameters measured (Ktrans, kep, Ve, IAUGC-90), whereas ‘normal’ tissue showed no significant change. These results suggest that DCE-MRI has potential to monitor ADT response and select to patients with AD resistance at early time-points, allowing consideration of other treatments.

                  2802.     Can Ex-Vivo MRI Be Used for Correlating Diffusion Weighted Imaging Parameters to Pathology for Validation of In-Vivo Multiparametric MRI

Michael A. Jacobs^1,2, Vadappuram Chacko¹, Baasil Okollie¹, Tamara Lotan³, Katarzyna J. Macura¹

¹The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; ²Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine; ³Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

By using a multiparametric approach to investigate the in-vivo and ex-viso characteristics of prostate cancer a better understanding of prostate cancer aggressiveness and tumor staging can be realized.  This radiological-pathological correlation will assist in detection, localization, assessment of the tumor microenvironment. Such a comprehensive approach offers more power to evaluate prostate disease than any single measure alone.

                  2803.     The Effect of Spatial Resolution on the Correspondence Between Hematoxylin-Eosin Stained Sections and MR Images for Prostate Cancer

Greetje Groenendaal¹, Maaike R. Moman¹, Johannes G. Korporaal¹, Paul J. van Diest², Marco van Vulpen¹, Marielle E.P. Philippens¹, Uulke A. van der Heide¹

¹Radiotherapy, University Medical Center Utrecht, Utrecht, Netherlands; ²Pathology, University Medical Center Utrecht, Utrecht, Netherlands

Sensitivity and specificity values of DW-MRI and DCE-MRI for prostate cancer are often based on the correspondence of imaging and pathology within relatively large volumes inside the prostate. However, for prognosis, therapy selection and focal therapy, decisions on a voxel level are required. We investigated at which spatial resolution validation of MR images with hematoxylin-eosin stained sections is meaningful. We found that the chance is small that matching tumor voxels are found on the MR images and pathology within a volume smaller than 0.4 cc. This puts limitations on the accuracy at which tumor volume and extent can be determined.

                  2804.     Echo Planar Spectroscopic Imaging with Peak-Enhanced 2D-Capon Analysis for Prostate Studies

Fred J. Frigo¹, Andreas Ebel¹

¹GE Healthcare, Waukesha, WI, United States

Two-dimensional echo planar spectroscopic imaging (EPSI) may be used for clinical evaluation of the human prostate. The results of EPSI studies are typically represented as the set of MRS absorption spectra in which the concentration of each metabolite can be determined on the basis of its frequency representation in the voxel of interest.  In addition to frequency information, the damping characteristics of each metabolite can also be determined by using two-dimensional Capon analysis.   This damping information may be used in conjunction with the frequency information to more easily identify metabolites during clinical diagnosis of EPSI prostate studies.

                  2805.     31P MR Spectroscopy for Prostate Cancer Characterization at 7Tesla

Catalina Arteaga¹, Uulke A. van der Heide¹, Marco van Vulpen¹, Peter R. Luijten², Dennis W.J. Klomp²

¹Radiotherapy, UMC Utrecht, Utrecht, Netherlands; ²Radiology, UMC Utrecht, Utrecht, Netherlands

We showed the feasibility of obtaining 31P MRS in the prostate area at 7T with the use of anatomy imaging and optimized B0 shimming. Individual detection of PC, GPC, GPE and GPC was feasible, illustrating the benefit of going to higher spectral resolutions that can be obtained at higher fields like 7T.

                  2806.     Signal Characterization of a Novel Two-Channel Rigid Endorectal Coil for MR Imaging of the Prostate

Niranjan Venugopal^1,2, Axel Krieger³, Herve Momo Jeufnack⁴, Ken Bradshaw⁴, Boyd McCurdy⁵, Lawrence Ryner⁶

¹Physics and Astronomy, University of Manitoba, Winnipeg, MB, Canada; ²Medical Physics, CancerCare Manitoba, Winnipeg, MB, Canada; ³Sentinelle Medical, Toronto, Ontario, Canada; ⁴Sentinelle Medical Inc.; ⁵Medical Physic, CancerCare Manitoba, Winnipeg, MB, Canada; ⁶National Research Council Institute for Biodiagnostics, Winnipeg, MB, Canada

We present a comparison of a newly designed dual-channel, rigid endorectal coil for both imaging and spectroscopic imaging of the prostate with  a standard, single-channel, inflatable endorectal coil, demonstrating a SNR improvement of up to ~500% in the near-coil area (where the prostate peripheral zone is located), and up to ~150%  at depth (where the prostate central zone is located). This huge SNR improvement allows for greatly improved MR/MRSI  imaging of the prostate.

                  2807.     Short Echo Time in Vivo Prostate MRSI

Niranjan Venugopal¹, Boyd McCurdy², Darrel Drachenberg³, Salem Al Mehari³, Aziz Alamri³, Gurudarshan Sandhu³, Sri Sivalingam³, Lawrence Ryner⁴

¹Physics and Astronomy, University of Manitoba, Winnipeg, MB, Canada; ²Medical Physics, CancerCare Manitoba, Winnipeg, MB, Canada; ³Urology, University of Manitoba, Winnipeg, MB, Canada; ⁴National Research Council Institute for Biodiagnostics, Winnipeg, MB, Canada

We present a robust method improve the quality of in vivo prostate MRSI data acquisition by utilizing an optimized conformal voxel technique coupled with a spatial-spectral excitation PRESS pulse sequence for short echo time acquisitions.The PRESS pulse sequence was modified to include the optimized conformal voxel MR spectroscopic imaging technique (CV-MRS).  In vivo implementation of this optimized MRSI technique confirms the reduction in peripheral lipid contamination, and improved the quality of spectra throughout the prostate. In summary we have demonstrated the utility of short TE in vivo prostate MRSI acquisitions, which provides significant signal increase and reveal short TE metabolites to potentially improve prostate cancer detection.

                  2808.     Clinical Prostate T1 Quantification Using a Magnetization-Prepared Spiral Technique

Warren Foltz¹, Masoom Haider^2,3, Peter Chung¹, Andrew Bayley¹, Charles Catton¹, Venkat Ramanan⁴, David Jaffray¹, Graham Wright⁴, Cynthia Ménard¹

¹Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada; ²Medical Imaging, University Health Network, Toronto, Ontario, Canada; ³Medical Imaging, University of Toronto; ⁴Sunnybrook Research Institute, Toronto, Ontario, Canada

A magnetization-prepared spiral imaging strategy with RF cycling has been adapted for time-efficient multi-slice clinical prostate T1 quantification at 1.5T.  In vitro testing validated an overall robustness to RF offsets.  Pilot studies in patients without prior external beam radiation demonstrated an equivalence between zonal T1, with reduced T1 in peripheral zone tumors.  Intra-patient zonal T1 variabilities motivate individial measurements for dynamic studies of vascular metrics.  SNR analysis identified useful region volumes for thermal-noise insensitive measurements, to guide protocol design for future voxel-based prostate T1 mapping.  High RF insensitivity combined with time-efficiency suggests method potential for robust implementation on stronger magnets.

                  2809.     Multi-Slice Parametric Mapping in Prostate DCE-MRI

Ryan Alexander Priest¹, Xin Li², Ian J. Tagge², William J. Woodward², Tomasz M. Beer^3,4, Charles S. Springer, Jr. ^2,4, Mark G. Garzotto^5,6

¹Diagnostic Radiology, Oregon Health & Science University, Portland, OR, United States; ²Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, United States; ³Hematology/Oncology, Oregon Health & Science University, Portland, OR, United States; ⁴Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; ⁵Urology, Oregon Health & Science University, Portland, OR, United States; ⁶Portland VA Medical Center, Portland, OR, United States

Pharmacokinetic analysis of data generated using Dynamic-Contrast-Enhanced MRI (DCE-MRI) has proven to be a valuable tool in the evaluation of the vascular pathophysiology of prostate adenocarcinoma.  With improved hardware, multi-slice parametric mapping has become feasible and could provide valuable insight to complement conventional T2*-weighted images.   In this study multi-slice parametric mapping was performed with DCE-MRI data using both the standard model (SM) and the first generation shutter-speed model (SSM1).   Parametric maps were then compared with biopsy results.

                  2810.     Ability of Combined DTI and DCE MRI to Predict Pathologic Gleason Score

Piotr Kozlowski^1,2, Silvia D. Chang², Edward C. Jones³, Ran Meng¹, Nicholas Buchan⁴, S Larry Goldenberg, ^4,5

¹UBC MRI Research Centre, Vancouver, BC, Canada; ²Radiology, Univeristy of British Columbia, Vancouver, BC, Canada; ³Pathology and Laboratory Medicine, Univeristy of British Columbia, Vancouver, BC, Canada; ⁴Vancouver Prostate Centre, Vancouver, BC, Canada; ⁵Urologic Sciences, Univeristy of British Columbia, Vancouver, BC, Canada

DTI and DCE MRI were carried out in 27 prostate cancer patients. Mean diffusivity, fractional anisotropy and pharmacokinetic modeling parameters calculated from MRI data were correlated with Gleason score determined by biopsy and prostatectomy specimens. Mean diffusivity and fractional anisotropy correlated significantly with Gleason score, as demonstrated by the Spearman’s rank correlation test and the ordinal logistic regression modelling. These results strongly suggest that DTI MRI is capable of non-invasively grading prostate tumours.

                  2811.     Investigation of Prostate Cancer Using Diffusion Weighted IVIM Imaging

Jörg Döpfert¹, Andreas Lemke¹, Anja Weidner², Lothar Rudi Schad¹

¹Department of Computer Assisted Clinical Medicine, Heidelberg University, Mannheim, Germany; ²Institute of Radiology and Nuclear Medicine, Heidelberg University, Mannheim, Germany

In this work, the decrease of the apparent diffusion coefficient (ADC) in cancerous prostate tissue compared to healthy prostate tissue is investigated using the Intravoxel Incoherent Motion (IVIM) Theory. Moreover , the extracted parameters and the calculated parameter maps are analyzed with regard to the differentiation between cancerous and healthy tissue. Therefore, diffusion weighted images of the prostate of 9 patients with prostate carcinoma were acquired and evaluated, yielding a significant decrease of the ADC and the perfusion fraction in cancerous tissue compared to healthy tissue. The results suggest that the decrease of the ADC primarily comes from perfusion effects.

                  2812.     Comparison of HASTE & EPI Diffusion Weighted Images in the Prostate

Ben Babourina-Brooks¹, Gary Cowin¹, Deming Wang¹

¹Centre for Magnetic Resonance, University of Queensland, Brisbane, Queensland, Australia

A comparison of two diffusion weighted imaging sequences, Echo Planar Imaging (EPI) and Half fourier Aquisition Single shot Turbo spin echo (HASTE), was conducted in the prostate. EPI, which is currently the main DWI method, is highly susceptible to artifacts, namely magnetic susceptibility and chemical shift. We propose to use a HASTE sequence, which is less affected by these artifacts, to gain more reproducible Apparent Diffusion Coefficient (ADC) values and increase ADC map quality. Advancements in this area will lead to more accurate prostate cancer localisation.

                  2813.     3T MR Spectroscopic Imaging with and Without Endorectal Coil in Localizing Prostate Cancer: An Initial Experience

Derya Yakar¹, Stijn Heijmink, Jelle Barentsz, Christina Hulsbergen - Van de Kaa, Jurgen Fütterer, Tom Scheenen

¹Radboud University Nijmegen Medical Centre, Nijmegen, Gelderland, Netherlands

Currently used techniques in localizing prostate cancer (Pca) have definite shortcomings. We studied the potential of 3D- magnetic resonance spectroscopic imaging (MRSI) with and without an endorectal coil (ERC) at 3T in improving the localization of Pca. Eighteen patients with histologically proven Pca underwent an MRSI examination with and without the use of an ERC. The areas under the receiver operating characteristic curve were improved for all of the readers with the use of an ERC. For one reader this improvement was statistically significant (p< .05). Overall the AUC for all readers was quite low, with and without the use of an ERC. Emphasis have to be made on the fact that these results concern an initial experience based on a first cohort of patients examined at 3T with 3D-MRSI in our institution. In our experience more recent data of patients examined with 3D-MRSI at 3T in our institution are far more promising due to higher signal-to-noise ratios resulting in better fitted spectra and less non ratable ROIs.

                  2814.     Clinical Prostate T2 Quantification Using a Magnetization-Prepared Spiral Technique

Warren Foltz¹, Supriya Chopra¹, Peter Chung¹, Andrew Bayley¹, Charles Catton¹, David Jaffray¹, Graham Wright², Masoom Haider^3,4, Cynthia Ménard¹

¹Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada; ²Sunnybrook Research Institute, Toronto, Ontario, Canada; ³Medical Imaging, University Health Network, Toronto, Ontario, Canada; ⁴Medical Imaging, University of Toronto

A magnetization-prepared spiral imaging technique, termed T2prep, was adapted for robust time-efficient clinical prostate evaluation, and piloted in two prostate cancer cohorts.  The patient groups presented with: (A) no prior history of external beam radiation; and (B) biochemical failure after radiotherapy.  Cohorts were scanned (A) without and (B) with an endo-rectal coil in tandem with a torso phased-array, respectively.  Prostate zonal and tumor T2 values supported known trends.  For each cohort, an SNR analysis was performed to identify minimum region volumes for thermal-noise insensitive measurements, and to guide protocol design for future voxel-based anlaysis.

                  2815.     Early Quantititative T1 and T2 Response of the Prostate Gland During Radiotherapy

Warren Foltz¹, Andy Wu¹, Anna Kirilova¹, Peter Chung¹, Andrew Bayley¹, Charles Catton¹, David Jaffray¹, Masoom Haider², Cynthia Ménard¹

¹Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada; ²Medical Imaging, University Health Network, Toronto, Ontario, Canada

Magnetization-prepared spiral imaging techniques were adapted for quantitative T2 and T1 characterization of early radiation response in patients with low/intermediate risk of localized cancer throughout 8-weeks of radiotherapy.  Early central gland T2 elevation preceded persistent tumor T2 elevation, and late reduction in peripheral zone T2; observations which support a known loss of contrast in diagnostic images, and a complementary role for T2 in ADC and DCE radiation response evaluation.  Zonal and tumor T1 measures were insensitive to radiotherapy.  However, considerable inter-patient but minor intra-patient  T1 heterogeneities support a sufficiency of baseline T1 scanning for serial quantitative perfusion analysis during radiotherapy.

Cancer (Miscellaneous)

                  2816.     MRI-Based ‘Wait-And-See’ Policy in Clinical Complete Responders to Chemoradiation in Rectal Cancer: A Promising Alternative

Monique Maas¹, Doenja Lambregts¹, Ronald van Dam², Patty Nelemans³, Guido Lammering⁴, Rob Jansen⁵, Regina Beets-Tan¹, Geerard Beets²

¹Radiology, Maastricht University Medical Center, Maastricht, Limburg, Netherlands; ²Surgery, Maastricht University Medical Center, Maastricht, Limburg, Netherlands; ³Epidemiology, Maastricht University Medical Center, Maastricht, Limburg, Netherlands; ⁴Radiotherapy, Maastricht University Medical Center, Maastricht, Limburg, Netherlands; ⁵Medical Oncology, Maastricht University Medical Center, Maastricht, Limburg, Netherlands

When - after neoadjuvant chemoradiation for rectal cancer - imaging could accurately select the complete responders, surgery might safely be omitted and patients can undergo a wait-and-see policy. This study aims to evaluate whether MRI at 1.5T is accurate enough to select patients for wait-and-see and can safely be used as a follow-up tool.

                  2817.     N-Stage Assessment in Non-Small Cell Lung Cancer Patients: Comparison of Capability Among STIR Turbo SE Imaging, Diffusion-Weighted Imaging and FDG-PET/CT

Daisuke Takenaka¹, Yoshiharu Ohno¹, Keiko Matsumoto¹, Hisanobu Koyama¹, Yumiko Onishi¹, Munenobu Nogami¹, Nobukazu Aoyama², Hideaki Kawamitsu², Kazuro Sugimura¹

¹Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; ²Division of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan

FDG-PET/CT can assess morphological and metabolic information at same time, and widely utilized for N-stage assessment in non-small cell lung cancer (NSCLC) patients.  In the last decade, short inversion time inversion recovery (STIR) turbo spin-echo (SE) imaging has been determined at least as valuable as PET/CT in this setting.  Recently, diffusion-weighted image (DWI) is suggested as new technique for differentiation of metastatic lymph nodes from non-metastatic lymph nodes.  The purpose of this study was to prospectively and directly compare capability of N-stage assessment among integrated FDG-PET/CT, STIR turbo SE imaging and DWI in NSCLC patients.

                  2818.     Assessment of the Early Response to Chemotherapy with Diffusion-Weighted MRI in Advanced Lung Cancer Patients-Comparison with FDG-PET-

Tatsuro Tsuchida¹, Miwa Morikawa², Yukihiro Umeda², Masato Sasaki³, Tomohito Kamibayashi¹, Hirohiko Kimura¹

¹Dept. of Radiology, University of Fukui, Fukui, Japan; ²Dept. of Respiratory Medicine, University of Fukui, Fukui, Japan; ³Dept. of Thoracic Surgery, University of Fukui, Fukui, Japan

The purpose of this study was to examine the utility of DWI-MRI for the assessment of early response to chemotherapy in patients with advanced lung cancer by comparing FDG-PET. Twenty-two lung cancer patients received MRI, FDG-PET, and CT examination before and after 1 cycle of chemotherapy.  Progression-free survival (PSF) between responder and non-responder against chemotherapy was compared by means of % change of ADC and SUV.  Both index indicated that responder demonstrated significant longer PSF and DWI-MRI will be a promising tool for the assessment of the early response to chemotherapy.

                  2819.     Perfusion MRI of Solitary Pulmonary Nodules at 3T: Assessment of Perfusion Parameters and Correlation with Histology

Hatsuho Mamata¹, Junichi Tokuda¹, Ritu Gill¹, Robert F. Padera², Robert E. Lenkinski³, David J. Sugarbaker⁴, Hiroto Hatabu¹

¹Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; ²Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; ³Radiology, Beth Israel Decones Medical Center, Harvard Medical School, Boston, MA, United States; ⁴Thoracic surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

Solitary pulmonary nodule (SPN) is one of the most common findings in chest imaging. It is important to avoid unnecessary intervention for benign lesions, thereby lowering the associated mortality / morbidity. In this study, we applied perfusion MRI to evaluate perfusion characteristics of SPN and feasibility of perfusion MRI as a diagnostic tool to differentiate malignant from benign SPN. Perfusion MRI parameters and TI curve has great potential to differentiate malignant vs. benign SPN, thus to avoid unnecessary surgical interventions.

                  2820.     Feasibility of Detecting Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Patients Using Hyperpolarized Helium-3 MRI

Rob H. Ireland^1,2, Omar S. Din², James A. Swinscoe², Edwin JR van Beek³, Matthew QF Hatton², Jim M. Wild¹

¹Academic Unit of Radiology, University of Sheffield, Sheffield, United Kingdom; ²Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, United Kingdom; ³Department of Radiology, University of Iowa, Iowa, IA, United States

This preliminary work demonstrates the feasibility of pre-treatment assessment of lung ventilation and post-treatment detection of radiation-induced lung damage using 3He-MRI for NSCLC patients.

                  2821.     Intracellular Acidification of Human Melanoma Xenografts by the Respiratory Inhibitor Lonidamine Plus Hyperglycemia: A 31P Magnetic Resonance Spectroscopy Study

Kavindra Nath¹, Elliot C. Woods¹, Seung Cheol Lee¹, David S. Nelson¹, Dennis B. Leeper², Rong Zhou¹, Lin Li¹, Jerry D. Glickson¹

¹Radiology (Molecular Imaging Section), University of Pennsylvania, Philadelphia, PA, United States; ²Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, United States

In vivo 31P magnetic resonance spectroscopy illustrates that human melanoma xenografts can be acidified by induction of hyperglycemia combined with administration of lonidamine, an inhibitor of mitochondrial respiration.  In melanoma xenograft (10-13 mm diameter), intracellular pH (pHi, measured by chemical shift of the Pi resonance) was reduced by ~0.7 unit during i.v. infusion of glucose (0.6 M) for 120 min along with administration of lonidamine (50 mg/kg). Preliminary result of this study shows that lonidamine combined with hyperglycemia acidified human melanoma xenografts by reducing pHi, a more critical parameter for thermosensitization to improve tumor response to alkylating agents.

                  2822.     Monitoring Bone Marrow Changes During Chemoradiotherapy Using MRI Fat Quantification

Mark Bydder¹, Yun Liang², Huanzhou Yu³, Ann Shimakawa³, Jean Brittain³, Graeme Bydder¹, Loren Mell²

¹Radiology, University of California San Diego, San Diego, CA, United States; ²Radiation Oncology, University of California San Diego, San Diego, CA, United States; ³GE Healthcare, Applied Science Lab, United States

The goal of this study was to evaluate a non-invasive magnetic resonance imaging method of fat quantification as a measure of yellow bone marrow in the pelvis and spine. This is a new technology that will enable monitoring of response to therapy and assessment of the effectiveness of strategies to reduce hematology toxicity.

                  2823.     Motion-Sensitized Driven-Equilibrium (MSDE) Turbo Spin-Echo Sequence Increases Radiologists' Diagnostic Performance in Detection of Brain Metastasis

Eiki Nagao¹, Takashi Yoshiura¹, Akio Hiwatashi¹, Koji Yamashita¹, Hironori Kamano¹, Yukihisa Takayama¹, Tuvshinjargal Dashjamts¹, Makoto Obara², Tomoyuki Okuaki², Hiroshi Honda¹

¹Clinical radiology of Kyushu-university, Fukuoka, Japan; ²Philips Electoronics Japan

Motion-sensitized driven-equilibrium (MSDE) sequence has been reported to effectively suppress signals from flowing blood in vessels that can mimic the brain metastases on post-contrast T1-weighted images. We performed an observer test to determine whether use of a 3D turbo spin-echo (TSE) sequence with MSDE increases radiologists�f diagnostic performances in detecting brain metastases comparing to a conventional 3D gradient-echo sequence (MPRAGE). A jackknife free-response receiver operating characteristic (JAFROC) analysis showed that TSE with MSDE increases radiologists�f diagnostic performances compared to MPRAGE. The reading time was also significantly shortened by use of MSDE.

                  2824.     Correlation of a Priori DCE-MRI Data with Ki-67 and HIF-1α Expression Levels in Neck Nodal Metastases: Initial Analysis

Jacobus FA Jansen¹, Diane Carlson¹, Bhuvanesh Singh¹, Hilda Stambuk¹, Ya Wang¹, Dennis Kraus¹, Richard Wong¹, Snehal Patel¹, Jatin Shah¹, Jason Koutcher¹, Amita Shukla-Dave¹

¹MSKCC, NY, United States

Pretreatment DCE-MRI was performed on neck nodal metastases of 12 patients who underwent surgery. Surgical specimens were analyzed with immunohistochemistry (IHC) assays for Ki-67 (reflecting cellular proliferation) and HIF-1α (hypoxia inducible transcription factor). Spearman correlation was used to correlate DCE-MRI and molecular marker data. Significant correlation results were observed between DCE-MRI data (Ktrans and ve) and tumor hypoxia, and proliferation as measured by Ki67 and HIF-1á expression levels, respectively. Future studies with larger patient populations need to be carried out to confirm pretreatment DCE-MRI findings and molecular marker results in biopsy samples for better patient management.

                  2825.     Focused Primary Tumour Staging and WB-MRI Distant Disease Assessment: A Potential All-In-One Staging Tool

Martin D. Pickles¹, Lindsay W. Turnbull¹

¹Centre for MR Investigations, University of Hull, Hull, East Yorkshire, United Kingdom

Oncology patients undergo multiple imaging investigations to stage their disease. The aim of this study was to investigate the feasibility of a focused primary tumour (breast or prostate) examination in combination with a WB-MRI for staging of distant disease. If successful we propose the addition of this technique could allow the omission of other examinations, such as radionuclide imaging, thereby streamlining the current imaging pathway. We conclude that focused primary tumour examinations in combination with a WB-MRI for staging of distant disease is feasible. However, the technique needs to validated in a much larger cohort than the one studied.

                  2826.     Imaging Characteristics of Metastasis in Whole Body Diffusion Weighted Imaging of Renal Clear Cell Carcinoma

Jing Liu¹, XiaoYing Wang¹, XueXiang Jiang¹

¹Department of Radiology, Peking University First Hospital, BeiJing, China

The study aimed to explore the role of Whole-body DWI in clear cell renal cell carcinoma (RCC) and obtain the imaging characteristics of metastases. Ten patients with histologically confimed clear cell RCC and possible metastatic lesions were underwent standard Whole-body DWI, chest CT and routine MR examinations before chemotherapy. The results showed that the whole body DWI was very sensitive to the metastatic lesions in clear cell RCC and DWI showed its high rate of detection in pulmonary metastases. Whole body DWI had revealed great potential in metastatic screening of clear cell RCC.

                  2827.     Whole Body Imaging Multiparametric (T2/DWI/DCE) and Advanced Multimodality (PET/CT) for Detection of Recurrent Metastatic Cancer

Michael A. Jacobs¹, Li Pan², Katarzyna J. Macura¹, Thorsten Feiweier³, Wilhelm Horger³, Christine Lorenz², Richard L. Wahl¹

¹The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; ²Center for Applied Medical Imaging, Siemens Corporation, Corporate Research, Baltimore,, MD, United States; ³Siemens AG, Healthcare Sector, Magnetic Resonance, Germany

By using Whole Body MR and PET/CT approach to investigate metastatic disease can lead a better understanding of cancer aggressiveness. Functional imaging such as DWI/ADC, DCE-MR and 11C Choline PET is feasible and thus, combined DWI/ADC mapping, and PET/CT provides radiological biomarkers of molecular environment and could provide targets imaging treatment response.