title: Correlation of perfusion MRI and 18F-FDG PET imaging biomarkers for monitoring regorafenib therapy in experimental colon carcinomas with immunohistochemical validation.
abstract: OBJECTIVE
  To investigate a multimodal, multiparametric perfusion MRI / 18F-fluoro-deoxyglucose-(18F-FDG)-PET imaging protocol for monitoring regorafenib therapy effects on experimental colorectal adenocarcinomas in rats with immunohistochemical validation.
  
  
  METHODS
  Human colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 17 (n = 10 therapy group; n = 7 control group) female athymic nude rats (Hsd:RH-Foxn1rnu). Animals were imaged at baseline and after a one-week daily treatment protocol with regorafenib (10 mg/kg bodyweight) using a multimodal, multiparametric perfusion MRI/18F-FDG-PET imaging protocol. In perfusion MRI, quantitative parameters of plasma flow (PF, mL/100 mL/min), plasma volume (PV, %) and endothelial permeability-surface area product (PS, mL/100 mL/min) were calculated. In 18F-FDG-PET, tumor-to-background-ratio (TTB) was calculated. Perfusion MRI parameters were correlated with TTB and immunohistochemical assessments of tumor microvascular density (CD-31) and cell proliferation (Ki-67).
  
  
  RESULTS
  Regorafenib significantly (p<0.01) suppressed PF (81.1±7.5 to 50.6±16.0 mL/100mL/min), PV (12.1±3.6 to 7.5±1.6%) and PS (13.6±3.2 to 7.9±2.3 mL/100mL/min) as well as TTB (3.4±0.6 to 1.9±1.1) between baseline and day 7. Immunohistochemistry revealed significantly (p<0.03) lower tumor microvascular density (CD-31, 7.0±2.4 vs. 16.1±5.9) and tumor cell proliferation (Ki-67, 434.0 ± 62.9 vs. 663.0 ± 98.3) in the therapy group. Perfusion MRI parameters ΔPF, ΔPV and ΔPS showed strong and significant (r = 0.67-0.78; p<0.01) correlations to the PET parameter ΔTTB and significant correlations (r = 0.57-0.67; p<0.03) to immunohistochemical Ki-67 as well as to CD-31-stainings (r = 0.49-0.55; p<0.05).
  
  
  CONCLUSIONS
  A multimodal, multiparametric perfusion MRI/PET imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and 18F-FDG-PET validated by immunohistochemistry.
authors: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Ralf S
authors: RS
authors: Eschbach
authors: Department of Nuclear Medicine, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Wolfgang P
authors: WP
authors: Fendler
authors: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Philipp M
authors: PM
authors: Kazmierczak
authors: Department of Nuclear Medicine, University Hospital Vienna, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors: Marcus
authors: M
authors: Hacker
authors: Department of Nuclear Medicine, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Axel
authors: A
authors: Rominger
authors: Department of Nuclear Medicine, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Janette
authors: J
authors: Carlsen
authors: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Heidrun
authors: H
authors: Hirner-Eppeneder
authors: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Jessica
authors: J
authors: Schuster
authors: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Matthias
authors: M
authors: Moser
authors: Department of Clinical Radiology, Josef Lissner Laboratory for Biomedical Imaging, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Lukas
authors: L
authors: Havla
authors: Department of Clinical Radiology, Josef Lissner Laboratory for Biomedical Imaging, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Moritz J
authors: MJ
authors: Schneider
authors: Department of Clinical Radiology, Josef Lissner Laboratory for Biomedical Imaging, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Michael
authors: M
authors: Ingrisch
authors: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Lukas
authors: L
authors: Spaeth
authors: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Maximilian F
authors: MF
authors: Reiser
authors: Department of Diagnostic and Interventional Radiology, University Hospital Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tuebingen, Germany.
authors: Konstantin
authors: K
authors: Nikolaou
authors: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany.
authors: Clemens C
authors: CC
authors: Cyran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D019788:Fluorodeoxyglucose F18; D064593:Heterografts / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D018810:Magnetic Resonance Angiography / Q000379:methods*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011923:Rats, Nude
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D011725:Pyridines; D019788:Fluorodeoxyglucose F18; C559147:regorafenib