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Yaron Hassid¹, raanan margalit¹, Erez Eyal¹, Edna Furman-Haran¹, Hadassa Degani¹

¹Weizmann Institute of Science, Rehovot, Israel

Many solid tumors show an increased interstitial fluid pressure (IFP), which forms a physical barrier to drug delivery. We developed a model-based analysis of slow infusion CE-MRI, which integrates GdDTPA pharmacokinetics during slow i.v. infusion and its distribution at steady state. This method was applied to test the efficacy of collagenase in modulating IFP in human H460 non-small-cell lung carcinoma xenografts that exhibited high IFP. Sequential CE-MRI monitoring studies have shown that collagenase significantly reduced tumor IFP within 5 h after its administration. This was further confirmed by the 'wick in needle' technique.

Eva Christina Woenne¹, ², Stefan Zwick¹, ², Ralph Strecker³, Arne Hengerer², Matthias Taupitz⁴, Joerg Schnorr⁴, ⁵, Margareta M. Mueller¹, Wolfhard Semmler¹, Fabian Kiessling¹

¹German Cancer Research Center, Heidelberg, Germany; ²Siemens Medical Solutions, Erlangen, Germany; ³Siemens Medical Solutions, Erlangen , Germany; ⁴Charité, Berlin, Germany; ⁵Ferropharm, Teltow, Germany

Vessel Size Imaging (VSI) can be used to determine the mean vessel diameter in tumors. In this study the effect of Matrix-Metallo-Proteinases inhibition (MMPI) on VSI and tumor vascularity (HF-VPDU) was investigated. Upon MMPI vascularity decreased, while mean tumor vessel diameter increased in tumor xenografts of nude mice. Taking into account histological analyzes, the increasing mean tumor vessel diameter can be explained by regression and maturation of small vessel and might be triggered by the change of VEGF und PDGF expression that we observed in vitro upon MMPI.

Melanie Heilmann¹, ², Steven Sourbron³, Christine Walczak¹, ², Andreas Biffar³, Julien Vautier¹, ², Michael Peller³, Andreas Volk¹, ²

¹Institut Curie, Orsay, France; ²INSERM, Orsay, France; ³Ludwig-Maximilian-University Munich, Munich, Germany

Combination of DCE and DSC MRI was realized by simultaneous measurement of T₁ and T₂* kinetics. In a subcutaneous xenograft model implanted in nude mice examined at 4.7T, a 6 kDa CA was suitable for assessing heterogeneous capillary permeability by measuring K^trans, whereas a 0.5kDa CA yielded perfusion weighted K^trans values. Furthermore, a description of R₂*(t) in the presence of CA leakage was proposed yielding the parameters κ ₂₀ and κ ₂₁. They are thought to be related to intra-voxel cellular distribution and vascular architecture. Combined DCE-DSC MRI holds potential to improve tumor characterization.

Susan Kraft¹, Nadira Trncic², Ed Ashton³, Susan LaRue¹

¹Colorado State University, Fort Collins, USA; ²Colorado State University, Fort Collins , USA; ³VirtualScopics Inc, Rochester, New York, USA

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) was performed on 9 dogs with naturally-occurring tumors before and after a 3 Gy fraction of radiation.  In conjunction with DCE-MRI, we measured tumor oxygen levels, microvascular perfusion and density, apoptosis and interstitial fluid pressure to investigate mechanisms involved in reoxygenation.   All hypoxic tumors became normoxic after the 3 Gy fraction, with increased mean/median pO2 and decreased hypoxic fraction, whereas mean Ktrans decreased.  This Ktrans decrease occurred in the presence of decreased interstitial fluid pressures and increased apoptosis, so improved vascular delivery did not explain the concurrent reoxygenation of tumors.

Hemant Sarin¹, ², Steve Huntz Fung, ¹², Ariel Shaya Kanevsky¹, Auh Sungyoung¹, John Alexander Butman¹

¹National Institutes of Health, Bethesda, USA; ²Massachusetts General Hospital, Boston, USA

Intravenous infusion of Cereport, a synthetic bradykinin analogue, has been shown by quantitative autoradiography (QAR) to temporarily enhance drug delivery to malignant gliomas. Although historically QAR has been utilized to measure tumor vascular parameters during systemic vasomodulation, the major limitations of this method include incompleteness of vascular input function (VIF) shape determination due to manual sampling of blood at only certain specific time points, and inability to acquire tumor tissue concentration data over time in the same animal. DCE MRI allows for continuous measurement of change in Gd-DTPA concentration within brain vasculature and glioma tissue over time. In this study we utilized Gd-DTPA DCE MRI to measure changes in tumor vascular parameters within the same RG-2 rat glioma at baseline and during systemic vasomodulation with short-acting and long-acting bradykinin analogues, Met-Lys-bradykinin (Met-Lys-BK) and Cereport, respectively.

Sharon E. Ungersma¹, Calvin Ho¹, Glenn Pacheco¹, Jed Ross¹, Joan M. Greve¹, Franklin V. Peale Jr. ¹, Sarajane Ross¹, Richard A. D. Carano¹

¹Genentech, Inc., South San Francisco, California , USA

Vessel size index MRI uses changes in T₂ and T₂* after introduction of an iron oxide contrast agent to determine the mean vessel size within a voxel. One method by which vessel size measurements of tumors have been done previously is ex vivo micro-CT angiography. Here, we validate the VSI measurement by correlation with micro-CT vessel size measurements of the same tumors. We restrict the VSI analysis to viable tumor tissue as determined with multispectral clustering. This requires no additional scans beyond the VSI measurement and can improve accuracy of MRI parameter measurement by eliminating necrotic regions from the analysis.

Jesus Pacheco-Torres¹, ², Dawen Zhao¹, Angelina Contero¹, Peter Peschke³, Ralph Peter Mason¹

¹The University of Texas Southwestern Medical Center, Dallas, Texas, USA; ² Instituto de Investigaciones Biomédicas "Alberto Sols" - CSIC, Madrid, Spain; ³DKFZ German Cancer Center, Heidleberg, Germany

Hypoxia influences tumor response to therapy: thus techniques are needed to assess hypoxia and potential modulation. T2*-weighted (BOLD) and T1-weighted (TOLD: Tissue Oxygen Level Dependant) contrast MRI should provide insight into tumor oxygenation. We examined these non-invasive techniques as surrogates for quantitative pO2 measurements for response to carbogen breathing of two tumor sublines (AT1 and HI) noted for their different levels of hypoxia and response to hyperoxic gas breathing. Changes in T1- and T2*-weighted signal intensities corresponded with quantitative 19F NMR oximetry. Since such measurements are entirely non-invasive they offer the potential rapid translation to the clinic.

Ross A. Little¹, Caleb Roberts¹, Yvon Watson¹, Marietta Scott², Gio A. Buonaccorsi¹, Susan Cheung¹, Karen Davies¹, James P. O'Connor¹, Geoff J. Parker¹

¹University of Manchester, Manchester, UK; ²AstraZeneca, Macclesfield, Cheshire, UK

This study investigates associations between arterial input functions (AIFs) and readily-available physiological measurements to assess whether change in AIF form between individuals is due to measurement noise and error or if there are detectable underlying physiological influences. Forward stepwise multiple linear regression models were constructed and first pass peak height (FPPH) and the ratio of second pass peak height to FPPH were found to be related to age (r² = 0.30 and 0.47 respectively). The measured AIF does seem to reflect underlying physiological variation and it may be possible to utilise this to improve the accuracy of population representative AIFs.

Sungheon Kim¹, Laurie A. Loevner¹, Larry Dougherty¹, Harry Quon¹, Eric J. Sherman¹, Gregory S. Weinstein¹, Harish Poptani¹

¹University of Pennsylvania, Philadelphia, USA

The purpose of this study was to evaluate the feasibility of using DCE-MRI data with the shutter-speed model (SSM) analysis to predict response to chemo/radiation therapy in the head and neck squamous cell carcinoma (HNSCC). MRI data was acquired from thirty two patients who were newly diagnosed with HNSCC with no prior treatment. Pretreatment transfer constant (K^trans) and intracellular water exchange time (t_i) showed significant difference between the complete responders and partial responders, determined at the end of the treatment. Classification of treatment response based on SSM parameters had a sensitivity of 100% and a specificity of 75%.

Jeffrey Moses Njus¹, Csanad G. Varallyay², John W. Grinstead³, Xin Li¹, Charles S. Springer, Jr. ¹, Edward A. Neuwelt², William D. Rooney¹

¹Oregon Health and Science University, Portland, Oregon, USA; ²Oregon Health and Science University, Portland, USA; ³Siemens Medical Solutions, Inc, Portland, USA