Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Early Therapy Evaluation of Combined Anti-EGFR Antibody and Irinotecan in Orthotopic Pancreatic Tumor Xenografts
Hyunki Kim¹, Karri Folks¹, Lingling Guo², Jeffery Sellers³, Naomi Fineberg⁴, Cecil Stockard³, William Grizzle⁵, Donald Buchsbaum⁶, Desiree Morgan¹, James George², Kurt Zinn^1
1Radiology, University of Alabama at Birmingham, Birmingham, AL, United States; ²Surgery, University of Alabama at Birmingham, Birmingham, AL, United States; ³Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States; ⁴Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States; ⁵Pathology, University of Alabama at Birmingham, Birmingham, AL, United States; ⁶Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, United States

This study evaluated DCE-MRI as an early prognostic tool for effective anti-EGFR therapy with/without concurrent chemotherapy in an orthotopic pancreatic-cancer murine model, and developed a novel timing-independent DCE-MRI biomarker for early therapy assessment, based on characterization of non-linear tumor response observed during serial imaging.

Bortezomib Treatment Reduces Tumor Blood Flow and Perfusion as Measured by Dynamic Contrast-Enhanced ¹H MRI
Ellen Ackerstaff¹, Xiaorong Sun^1,2, Mihai Coman (Deceased)¹, Ya Wang¹, Hung Tsung Hsiao¹, Fuqiu He¹, Ligang Xing^1,2, Sean Carlin¹, C Clifton Ling¹, Jason A. Koutcher¹, Gloria C. Li^1
1Memorial Sloan-Kettering Cancer Center, New York, NY, United States; ²Shandong Cancer Hospital and Institute, Jinan, Shandong, China

The proteasomes inhibitor Bortezomib possesses anti-angiogenic and anti-tumor properties and appears to selectively interfere in the hypoxia pathway. Our study aims to determine biomarkers characterizing treatment response. We studied in a colorectal cancer model the effects of Bortezomib on the tumor vasculature by in vivo DCE MRI and on the tumor hypoxia response ex vivo using immunohistochemistry. Our data suggest that Bortezomib treatment modifies the tumor microenvironment by decreasing tumor perfusion. Our ex vivo data indicate a reduced hypoxia response in central regions of the tumor and an increased hypoxia response in the tumor rim in response to Bortezomib treatment.

Evaluation of the Relationship Between LSO₂ MR Measurement and Hypoxia: Impact of an Antiangiogenic Treatment on a Gliosarcoma Model
Benjamin Lemasson¹, Thomas Christen^1,2, Raphaël Serduc³, Cecile Maisin¹, Audrey Bouchet³, Christopoh Segebarth¹, Géraldine Le Duc³, Chantal Rémy¹, Emmanuel Louis Barbier^1
1Inersm U836, Grenoble, France; ²Université Joseph Fourier, Grenoble Institut des Neurosciences, Grenoble, France; ³ESRF, Grenoble, France

Despite a highly vascular phenotype, most glioblastomas cells are in hypoxia. Monitoring of hypoxia could be useful for monitoring the effectiveness of anti-tumor therapies. In this study, we evaluate (i) the relationship between the oxygenation (lSO₂) estimated by MRI and tissue hypoxia estimated by immunohistology and (ii) the impact of an antiangiogenic (Sorafenib) treatment on the vasculature (Blood volume fraction; BVf) and the lSO₂ of gliosarcoma model (9L). lSO₂ estimate by MRI was correlated to tumor hypoxia observed by immunohistochimistry. Results of this study also suggest that lSO₂ could be a sensitive reporter of the hypoxic effects of antiangiogenic therapies.

Chronic Dosing with MLN0518 (Tandutinib), a Small Molecule PDGFRα/β Inhibitor, Reduces Tumour Growth, Hypoxia, and Perfusion in C6 Glioma Xenografts: An Investigation Using Susceptibility Contrast Enhanced MRI and Immunohistochemical Methods
Jessica Katherine Rowena Boult¹, Simon Walker-Samuel¹, Daniel P. Bradley², Simon P. Robinson^1
1CRUK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom; ²Imaging Sciences Group, Millennium: The Takeda Oncology Company, Cambridge, MA, United States

In this study, susceptibility MRI with ultra-small paramagnetic iron oxide (USPIO) and immunohistochemical methods were used to evaluate vascular and hypoxic response of C6 glioma xenografts to chronic treatment with MLN0518, a small molecule PDGFRα/β inhibitor. MLN0518 chronically limits the growth of C6 xenografts and reduces both the mean perfused vessel fraction and hypoxic area. No significant alteration in VSI, fractional blood volume or ADC were observed by MRI following 10 days treatment. These results are consistent with histological vessel measurements and quantification of necrosis, neither of which altered at this timepoint.

DCE-MRI as a Predictor of Outcome in Head and Neck Squamous Cell Carcinoma Patients with Nodal Metastases
A. Shukla-Dave¹, N. Y. Lee¹, J. F. Jansen¹, H. T. Thaler¹, H. E. Stambuk¹, M. G. Fury¹, E. Sherman¹, S. Karimi¹, Y. Wang¹, D. Kraus¹, S. G. Patel¹, J. P. Shah¹, D. G. Pfister¹, J. A. Koutcher^1
1Memorial Sloan-Kettering Cancer Center, New York, NY, United States

Currently one of the greatest challenges in the management of head and neck squamous cell carcinoma (HNSCC) is to identify and select prior to therapy, patients who are likely to fail the chosen treatment, for consideration of alternative risk adjusted therapies. The present study assesses whether pretreatment DCE-MRI parameters can reliably predict outcome in HNSCC patients with nodal metastases. DCE-MRI was performed in 74 patients studied prior to chemotherapy and radiation therapy (n=61) or surgery (n=13).  The results suggest that skewness of Ktrans was the strongest predictor of outcome in  HNSCC patients with stage IV disease.

Diffusion-Weighted Imaging of Ovarian-Related Peritoneal Carcinomatosis: Assessment of Chemotherapy Response in Relation to Anatomical Site
Stavroula Kyriazi^1,2, David J. Collins¹, Veronica A. Morgan², Sharon L. Giles², Nandita M. deSouza^1,2
1CR-UK and EPSRC Cancer Imaging Centre, Institute of Cancer Research, Sutton, Surrey, United Kingdom; ²Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom

Conventional biochemical and morphological criteria of chemotherapy efficacy in metastatic ovarian cancer are not sensitive in the early course of treatment and fail to reflect the frequently seen intra-patient differential response according to anatomical site of disease. The present study examines the value of Diffusion-Weighted Imaging in the early assessment of site-specific (peritoneal vs omental) chemotherapy response in ovarian-related carcinomatosis.

Intrinsic Susceptibility-Weighted MRI to Assess the Response of Combretastatin-A4-Phosphate During Radiotherapy for Prostate Cancer
Roberto Alonzi¹, Peter J. Hoskin¹, N Jane Taylor², Quan S. Ng¹, Henry Mandeville¹, Uma Patel¹, J James Stirling², James A. d'Arcy³, David J. Collins³, Martin O. Leach³, Anwar R. Padhani^2
1Marie Curie Research Wing, Mount Vernon Cancer Centre, Northwood, London, United Kingdom; ²Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, London, United Kingdom; ³CRUK-EPSRC Cancer Imaging Centre, Institute of Cancer Research & Royal Marsden Hospital, Sutton, Surrey, United Kingdom

Radiotherapy may be delivered in combination with vascular targeting agents. The performance of imaging biomarkers for response assessment may be compromised by the differing or conflicting effects between drug and radiation on tumor tissues. Previous studies have shown that DCE-MRI only partially describes the vascular changes in this setting. This study has evaluated the ability for Intrinsic Susceptibility-Weighted MRI to assess the response of Combretastatin-A4-Phosphate during radiotherapy for prostate cancer. We conclude that R2* has the potential to be an alternative, clinically useable, response biomarker for assessment of vascular disruptive therapy in combination with radiotherapy in prostate cancer.

The predominance of fat in adult marrow demands a systematic approach to interpretation of diffusion weighted (DW) magnetic resonance imaging (MRI) in bone. In marrow disease return of normal fatty marrow following treatment results in increased restriction of water diffusion1 and leads to an ADC fall. Focal necrosis however results in a conflicting ADC rise. This study examines the time course of ADC changes in bone with treatment comparing progressors and responders in order to establish changes associated with response on DW MRI.

Dynamic Contrast-Enhanced Magnetic Resonance for the Monitoring of Neoadjuvant Chemoradiation Therapy in Rectal Adenocarcinoma: Initial Experience with 20 Patients
Giuseppe Petralia¹, Gloria Castellazzi², Paul Summers¹, Roberto Di Filippi¹, Moreno Pasin², Maria Giulia Zampino³, Maria Cristina Leonardi⁴, Antonio Chiappa⁵, Stefano Viotti¹, Luke Bonello¹, Massimo Bellomi^1
1Radiology, Istituto Europeo di Oncologia, Milan, Lombardia, Italy; ²Struttura Complessa di Radiologia/Diagnostica per immagini, Istituto Neurologico IRCCS- Fondazione Casimiro Mondino, Pavia, Lombardia, Italy; ³Medical Care Unit, Department of Medicine, Istituto Europeo di Oncologia, Milan, Lombardia, Italy; ⁴Radiotherapy, Istituto Europeo di Oncologia, Milan, Lombardia, Italy; ⁵General and Laparoscopic Surgery, Istituto Europeo di Oncologia, Milan, Lombardia, Italy

We prospectively monitored changes in contrast agent pharmacokinetics values in advanced rectal adenocarcinoma over the course of neoadjuvant chemoradiation (NACR) therapy using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and evaluated whether DCE-MRI findings correlated with response to NACR in 20 patients. ANOVA revealed no inter-group differences (complete responders, non responders, local downstaging) for mean pre- and post-therapy values, and no changes in values during therapy. T-tests showed significant differences in post-therapy median Ktrans and IAUC60 and in fractional change of Kep between complete and non-responsive groups. Median values of Ktrans and Kep significantly decreased, whilst Ve significantly increased post-therapy.

Vascular Effects of the Vascular Targeting Agent NGR-HTNF in Patients with Advanced Solid Cancer: A Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) Study
Ingrid Desar¹, Carla M.L. van Herpen¹, J. J.A. van Asten², W. Fiedler³, A.S. Govaerts⁴, J. N.H. Timmer-Bonte¹, E. G.W. ter Voert², Antonio Lambiase⁵, C. Bordignon⁵, A. Heerschap², H. W.M. van Laarhoven^1
1Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; ²Radiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; ³Universitäts-Krankenhaus Hamburg-Eppendorf, Hamburg, Germany; ⁴EORTC Headquarters, Brussels, Belgium; ⁵Molmed, Milan, Italy

Vascular targeted TNF, NGR-hTNF, has antivascular properties. In a recent phase I study, it was not possible to select an optimal biological dose of NGR-hTNF from DCE-MRI measurements.(1) This study aims to examine the reasons for this. Our results suggests that this was caused by a combination of the following factors: (i) less adequate reproducibility in healthy liver tissue due to more than expected heterogeneity in vascular response, (ii) more than expected changes in healthy liver tissue which influences the amount of contrast between metastases and healthyliver tissue (iii) difference in the effect of NGR-hTNF between tumors related to tumor size and (iv) the development of soluble TNFá receptors.