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Dynamic contrast-enhanced magnetic resonance imaging as a predictor of clinical outcome in canine spontaneous soft tissue sarcomas treated with thermoradiotherapy.

ABSTRACT: This study tests whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters obtained from canine patients with soft tissue sarcomas, treated with hyperthermia and radiotherapy, are predictive of therapeutic outcome.Thirty-seven dogs with soft tissue sarcomas had DCE-MRI done before and following the first hyperthermia. Signal enhancement for tumor and reference muscle were fitted empirically, yielding a washin/washout rate for the contrast agent and tumor area under the signal enhancement curve (AUC) calculated from 0 to 60 seconds, 90 seconds, and the time of maximal enhancement in the reference muscle. These parameters were then compared with local tumor control, metastasis-free survival, and overall survival.Pretherapy rate of contrast agent washout was positively predictive of improved overall and metastasis-free survival with hazard ratio of 0.67 (P = 0.015) and 0.68 (P = 0.012), respectively. After the first hyperthermia washin rate, AUC60, AUC90, and AUCt-max were predictive of improved overall and metastasis-free survival with hazard ratio ranging from 0.46 to 0.53 (P < 0.002) and 0.44 to 0.55 (P < 0.004), respectively. DCE-MRI parameters were compared with extracellular pH and (31)P MR spectroscopy results (previously published) in the same patients showing a correlation. This suggested that an increase in perfusion after therapy was effective in eliminating excess acid from the tumor.This study shows that DCE-MRI has utility predicting overall and metastasis-free survival in canine patients with soft tissue sarcomas. To our knowledge, this is the first time that DCE-MRI parameters are predictive of clinical outcome for soft tissue sarcomas.

SUBMITTER: Viglianti BL

PROVIDER: S-EPMC2763531 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Dynamic contrast-enhanced magnetic resonance imaging as a predictor of clinical outcome in canine spontaneous soft tissue sarcomas treated with thermoradiotherapy.

Viglianti Benjamin L BL Lora-Michiels Michael M Poulson Jeanie M JM Lan Lan L Yu Daohai D Sanders Linda L Craciunescu Oana O Vujaskovic Zeljko Z Thrall Donald E DE Macfall James J Charles Cecil H CH Wong Terence T Dewhirst Mark W MW

Clinical cancer research : an official journal of the American Association for Cancer Research 20090721 15

<h4>Purpose</h4>This study tests whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters obtained from canine patients with soft tissue sarcomas, treated with hyperthermia and radiotherapy, are predictive of therapeutic outcome.<h4>Experimental design</h4>Thirty-seven dogs with soft tissue sarcomas had DCE-MRI done before and following the first hyperthermia. Signal enhancement for tumor and reference muscle were fitted empirically, yielding a washin/washout rate for th ...[more]

PMID: 19622579

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Project description:While hyperthermia has been shown to be an effective adjuvant anti-tumor treatment to radiotherapy, we still do not completely understand effects thermoradiotherapy on tumor phenotype or how these effects vary among different tumors. Here, we performed gene expression analysis in 22 spontaneous canine sarcomas before and after the first hyperthermia treatment that was administered as an adjuvant to radiotherapy. Diffusion weighted MRI (DWI) was done prior to the treatment course and at the end of therapy. Using supervised analysis, we identified significant correlation of DWI with several genes involved in VEGF signaling, telomerase, Wnt pathways and fatty acid synthesis. When the change of gene expression caused by treatment was examined, we found that thermoradiotherapy led to the induction of well known cycle regulators p21 and mdm2 and reduced cellular proliferation in most treated tumors. We also identified two tumor subtypes with dramatic differences in the gene expression response and treatment response at the end of therapy. In the subtype with strong expression and increase in DWI, the mRNA level of hsp70, POT1 and centrosomal proteins was significantly higher. In the other subtype with modest response to hyperthermia, levels of CD31, vWF and transferrin was noted to be significantly higher. It is also possible to build a predictive model based on the pre-treatment gene expression to predict the likely treatment response of the tumors. The differential expression between the two tumor subtypes was used to interrogate connectivity map and identify linkages to an HDAC inhibitor and geldanamycin, an HSP90 inhibitor. Both HDAC inhibitors and hsp90 inhibitor geldanamycin are shown to synergerize with thermoradiotherapy in reducing cell survival in clonogenic assays. Taken together, the gene expression studies of hyperthermia-treated spontaneous canine tumors shed mechanistic insights into the heterogeneity of thermoradiotherapy response and identified pathway-targeting compounds with synergistic potential to enhance its therapeutic benefits. To our knowledge, this is one of the first successful attempts to link genomic and functional imaging changes together. This is the first demonstration of using such associations to understand the connection between cellular and physiologic responses to treatment.

Project description:Rationale: To establish a spatially exact co-registration procedure between in vivo multiparametric magnetic resonance imaging (mpMRI) and (immuno)histopathology of soft tissue sarcomas (STS) to identify imaging parameters that reflect radiation therapy response of STS. Methods: The mpMRI-Protocol included diffusion-weighted (DWI), intravoxel-incoherent motion (IVIM), and dynamic contrast-enhancing (DCE) imaging. The resection specimen was embedded in 6.5% agarose after initial fixation in formalin. To ensure identical alignment of histopathological sectioning and in vivo imaging, an ex vivo MRI scan of the specimen was rigidly co-registered with the in vivo mpMRI. The deviating angulation of the specimen to the in vivo location of the tumor was determined. The agarose block was trimmed accordingly. A second ex vivo MRI in a dedicated localizer with a 4 mm grid was performed, which was matched to a custom-built sectioning machine. Microtomy sections were stained with hematoxylin and eosin. Immunohistochemical staining was performed with anti-ALDH1A1 antibodies as a radioresistance and anti-MIB1 antibodies as a proliferation marker. Fusion of the digitized microtomy sections with the in vivo mpMRI was accomplished through nonrigid co-registration to the in vivo mpMRI. Co-registration accuracy was qualitatively assessed by visual assessment and quantitatively evaluated by computing target registration errors (TRE). Results: The study sample comprised nine tumor sections from three STS patients. Visual assessment after nonrigid co-registration showed a strong morphological correlation of the histopathological specimens with ex vivo MRI and in vivo mpMRI after neoadjuvant radiation therapy. Quantitative assessment of the co-registration procedure using TRE analysis of different pairs of pathology and MRI sections revealed highly accurate structural alignment, with a total median TRE of 2.25 mm (histology - ex vivo MRI), 2.22 mm (histology - in vivo mpMRI), and 2.02 mm (ex vivo MRI - in vivo mpMRI). There was no significant difference between TREs of the different pairs of sections or caudal, middle, and cranial tumor parts, respectively. Conclusion: Our initial results show a promising approach to obtaining accurate co-registration between histopathology and in vivo MRI for STS. In a larger cohort of patients, the method established here will enable the prospective identification and validation of in vivo imaging biomarkers for radiation therapy response prediction and monitoring in STS patients via precise molecular and cellular correlation.

Dataset Information

Dynamic contrast-enhanced magnetic resonance imaging as a predictor of clinical outcome in canine spontaneous soft tissue sarcomas treated with thermoradiotherapy.

Publications

Dynamic contrast-enhanced magnetic resonance imaging as a predictor of clinical outcome in canine spontaneous soft tissue sarcomas treated with thermoradiotherapy.

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