title: Dynamic contrast-enhanced computed tomography imaging biomarkers correlated with immunohistochemistry for monitoring the effects of sorafenib on experimental prostate carcinomas.
abstract: OBJECTIVE
  To investigate dynamic contrast-enhanced computed tomography (DCE-CT) for monitoring the effects of sorafenib on experimental prostate carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation.
  
  
  METHODS
  Prostate carcinoma allografts (MLLB-2) implanted subcutaneously in male Copenhagen rats (n=16) were imaged at baseline and after a 1-week treatment course of sorafenib using DCE-CT with iopromide (Ultravist 370, Bayer Pharma, Berlin, Germany) on a dual-source 128-slice CT (Somatom Definition FLASH, Siemens Healthcare, Forchheim, Germany). Scan parameters were as follows: detector width, 38.4 mm; contrast agent volume, 2 mL/kg bodyweight; injection rate, 0.5 mL/s; scan duration, 90 seconds; and temporal resolution, 0.5 seconds. The treatment group (n=8) received daily applications of sorafenib (10 mg/kg bodyweight) via gavage. Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min), endothelial permeability-surface area product (PS, mL/100 mL/min), and tumor vascularity (plasma volume, %) were calculated using a 2-compartment uptake model. DCE-CT parameters were correlated with immunohistochemical assessments of tumor vascularity (RECA-1), cell proliferation (Ki-67), and apoptosis (TUNEL).
  
  
  RESULTS
  Sorafenib significantly (P < 0.05) suppressed tumor perfusion (25.1 ± 9.8 to 9.5 ± 6.0 mL/100 mL/min), tumor vascularity (15.6% ± 11.4% to 5.4% ± 2.1%), and PS (8.7 ± 4.5 to 2.7 ± 2.5 mL/100 mL/min) in prostate carcinomas during the treatment course. Immunohistochemistry revealed significantly lower tumor vascularity in the therapy group than in the control group (RECA-1; 181 ± 24 vs. 314 ± 47; P < 0.05). In sorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 7132 ± 3141 vs. 3722 ± 1445; P < 0.05) and significantly less proliferating cells (Ki-67; 9628 ± 1.298 vs. 17,557 ± 1446; P < 0.05) were observed than those in the control group. DCE-CT tumor perfusion correlated significantly (P < 0.05) with tumor cell proliferation (Ki-67; r=0.55). DCE-CT tumor vascularity correlated significantly (P < 0.05) with immunohistochemical tumor cell apoptosis (TUNEL; r=-0.59) and tumor cell proliferation (Ki-67; r=0.68). DCE-CT endothelial PS correlated significantly (P < 0.05) with immunohistochemical tumor cell apoptosis (TUNEL; r=-0.6) and tumor vascularity (RECA-1; r=0.53). While performing corrections for multiple comparisons, we observed a significant correlation only between DCE-CT tumor vascularity (RECA-1) and tumor cell proliferation (Ki-67).
  
  
  CONCLUSIONS
  Sorafenib significantly suppressed tumor perfusion, tumor vascularity, and PS quantified by DCE-CT in experimental prostate carcinomas in rats. These functional CT surrogate markers showed moderate correlations with antiangiogenic, antiproliferative, and proapoptotic effects observed by immunohistochemistry. DCE-CT may be applicable for the quantification of noninvasive imaging biomarkers of therapy response to antiangiogenic therapy.
authors.affiliation: Department of Clinical Radiology, Center for Experimental Radiology, University Hospitals Munich-Campus Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany. Clemens.Cyran@med.lmu.de
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Cyran
authors.forename: Jobst C
authors.initials: JC
authors.lastname: von Einem
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Paprottka
authors.forename: Bettina
authors.initials: B
authors.lastname: Schwarz
authors.forename: Michael
authors.initials: M
authors.lastname: Ingrisch
authors.forename: Olaf
authors.initials: O
authors.lastname: Dietrich
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Christiane J
authors.initials: CJ
authors.lastname: Bruns
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Clevert
authors.forename: Ralf
authors.initials: R
authors.lastname: Eschbach
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Reiser
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Wintersperger
authors.forename: Konstantin
authors.initials: K
authors.lastname: Nikolaou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D045744:Cell Line, Tumor; D003287:Contrast Media; D007472:Iohexol / Q000031:analogs & derivatives*; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000077157:Sorafenib; D013223:Statistics as Topic; D014057:Tomography, X-Ray Computed / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D015415:Biomarkers; D003287:Contrast Media; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D007472:Iohexol; C038192:iopromide; D000077157:Sorafenib