Extravascular Extracellular Volume Fraction Research Articles

Dynamic contrast enhanced MR imaging for evaluation of angiogenesis of hepatocellular nodules in liver cirrhosis in N-nitrosodiethylamine induced rat model.

To investigate whether dynamic contrast -enhanced MRI (DCE-MRI) can distinguish the type of liver nodules in a rat model with N-nitrosodiethylamine- induced cirrhosis. Liver nodules in cirrhosis were induced in 60 male Wistar rats via 0.01%N-nitrosodiethylamine in the drinking water for 35-100 days. The nodules were divided into three groups: regenerative nodule (RN), dysplastic nodule (DN), and hepatocellular carcinoma (HCC). DCE-MRI was performed, and parameters including transfer constant (Ktrans), rate constant (Kep), extravascular extracellular space volume fraction (Ve), and initial area under the contrast concentration versus time curve (iAUC) were measured and compared. The highest Ktrans and iAUC values were seen in HCC, followed by DN and RN (all P < 0.05). The area under the receiver operating characteristic curve (AUROC) for DN and HCC were 0.738 and 0.728 for Ktrans and iAUC, respectively. The AUROC for HCC were 0.850 and 0.840 for Ktrans and iAUC, respectively. Ordinal logistic regression analysis showed that Ktrans had a high goodness of fit (0.970, 95% confidence interval, 13.751-24.958). DCE-MRI is a promising method to differentiate of liver nodules. Elevated Ktrans suggested that the nodules may be transformed into HCC. • DCE-MRI is promising for differentiating among RN, DN, and HCC • K trans and iAUC positively correlated with malignancy degree of liver nodules • Elevated K trans suggests that the nodules may be transformed into HCC.

Prediction of the response of ocular adnexal lymphoma to chemotherapy using combined pretreatment dynamic contrast-enhanced and diffusion-weighted MRI.

Background There are no established biomarkers predictive of the efficacy of treatment for ocular adnexal lymphoma (OAL). Purpose To evaluate the effectiveness of pretreatment dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) in predicting the response of OAL to chemotherapy. Material and Methods Twenty-one patients, who were pathologically diagnosed with OAL, were retrospectively analyzed. According to the National Comprehensive Cancer Network (NCCN) response evaluation criteria for non-Hodgkin's lymphoma, patients were divided into responders (n = 14) and non-responders (n = 7). The volume transfer constant (Ktrans), rate constant (Kep), extracellular extravascular volume fraction (Ve), and apparent diffusion coefficient (ADC) were computed. Two independent-sample tests were applied for statistical analysis. For significantly different parameters, receiver-operator characteristics curve analysis was performed. Results The Ktrans value (min-1), Kep value (min-1), and ADC value (10-3 mm2/s) were 0.76 ± 0.36 vs. 0.47 ± 0.18 (mean ± SD), 4.43 ± 1.29 vs. 3.14 ± 1.37, and 0.51 ± 0.12 vs. 0.66 ± 0.15, respectively, in the responders and non-responders groups. Significant differences were found between the two groups regarding these parameters ( P < 0.05). However, no significant difference was observed in Ve (min-1) between the groups ( P > 0.05). Ktrans, Kep, and ADC had a moderately predictive sensitivity or specificity. When Ktrans and ADC or the three parameters were combined, a considerably higher sensitivity (85.7%) and specificity (85.7%) with a significant discriminative accuracy (area under the curve = 0.929; P = 0.002) was found. Conclusion Ktrans, Kep, and ADC could potentially predict OAL response to chemotherapy. A combination of these DWI and DCE-MRI quantitative parameters might increase sensitivity and specificity.

Diffusion-Related MRI Parameters for Assessing Early Treatment Response of Liver Metastases to Cytotoxic Therapy in Colorectal Cancer

The objective of our study was to evaluate early therapeutic response after cytotoxic chemotherapy in patients with liver metastasis from colorectal cancer (CRC) using intravoxel incoherent motion (IVIM) DWI and dynamic contrast-enhanced MRI (DCE-MRI). Nineteen patients with liver metastasis from CRC underwent DCE-MRI and IVIM DWI at baseline and after the first cycle of chemotherapy. IVIM DWI parameters including the apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) and DCE-MRI perfusion parameters including the volume transfer constant (K(trans)), reverse volume transfer constant (Kep), extravascular extracellular volume fraction (Ve), and initial area under the concentration curve in 60 seconds (iAUC) were calculated. The response evaluation was based on Response Evaluation Criteria in Solid Tumors version 1.1. There were eight responding and 11 nonresponding patients. ADC (baseline value vs value after first cycle of chemotherapy [mean ± SD]: 1191.9 ± 232.2 vs 1263.5 ± 266.4 × 10(-3) mm(2)/s; p = 0.012), D (1085.9 ± 232.9 vs 1173.5 ± 248.9 × 10(-3) mm(2)/s; p = 0.012), and f (173.7% ± 39.8% vs 133.5% ± 28.3%; p = 0.017) showed a significant change after the first cycle of chemotherapy in the response group, whereas ADC and D showed no significant change in the nonresponse group. In addition, DCE-MRI perfusion parameters showed no significant changes. A correlation was found between each of perfusion-related IVIM parameters and the DCE-MRI parameters before chemotherapy (r = 1.33, p > 0.05). Diffusion-related MRI parameters are useful for the early prediction of therapeutic response after cytotoxic chemotherapy for liver metastasis from CRC.

A role for dynamic contrast-enhanced magnetic resonance imaging in predicting tumour radiation response.

Background:Dynamic contrast-enhanced (DCE) MRI may provide prognostic insights into tumour radiation response. This study examined quantitative DCE MRI parameters in rat tumours, as potential biomarkers of tumour growth delay following single high-dose irradiation.Methods:Dunning R3327-AT1 prostate tumours were evaluated by DCE MRI following intravenous injection of Gd-DTPA. The next day tumours were irradiated (single dose of 30 Gy), while animals breathed air (n=4) or oxygen (n=4); two animals were non-irradiated controls. Growth was followed and tumour volume-quadrupling time (T4) was compared with pre-irradiation DCE assessments.Results:Irradiation caused significant tumour growth delay (T4 ranged from 28 to 48 days for air-breathing rats, and 40 to 75 days for oxygen-breathing rats) compared with the controls (T4=7 to 9 days). A strong correlation was observed between T4 and extravascular-extracellular volume fraction (ve) irrespective of the gas inhaled during irradiation. There was also a correlation between T4 and volume transfer constant (Ktrans) for the air-breathing group alone.Conclusions:The data provide rationale for expanded studies of other tumour sites, types and progressively patients, and are potentially significant, as many patients undergo contrast-enhanced MRI as part of treatment planning.

Bolus arrival time and its effect on tissue characterization with dynamic contrast-enhanced magnetic resonance imaging.

Matching the bolus arrival time (BAT) of the arterial input function (AIF) and tissue residue function (TRF) is necessary for accurate pharmacokinetic (PK) modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). We investigated the sensitivity of volume transfer constant ([Formula: see text]) and extravascular extracellular volume fraction ([Formula: see text]) to BAT and compared the results of four automatic BAT measurement methods in characterization of prostate and breast cancers. Variation in delay between AIF and TRF resulted in a monotonous change trend of [Formula: see text] and [Formula: see text] values. The results of automatic BAT estimators for clinical data were all comparable except for one BAT estimation method. Our results indicate that inaccuracies in BAT measurement can lead to variability among DCE-MRI PK model parameters, diminish the quality of model fit, and produce fewer valid voxels in a region of interest. Although the selection of the BAT method did not affect the direction of change in the treatment assessment cohort, we suggest that BAT measurement methods must be used consistently in the course of longitudinal studies to control measurement variability.

Quantitative Multiparametric MRI Features and PTEN Expression of Peripheral Zone Prostate Cancer: A Pilot Study.

The objective of our study was to investigate associations between quantitative image features of multiparametric MRI of the prostate and PTEN expression of peripheral zone prostate cancer. A total of 45 peripheral zone cancer foci from 30 patients who had undergone multiparametric prostate MRI before prostatectomy were identified by a genitourinary pathologist and a radiologist who reviewed histologic findings and MR images. Histologic sections of cancer foci underwent immunohistochemical analysis and were scored according to the percentage of tumor-positive cells expressing PTEN as negative (0-20%), mixed (20-80%), or positive (80-100%). Average and 10th percentile apparent diffusion coefficient (ADC) values, skewness of T2-weighted signal intensity histogram, and quantitative perfusion parameters (i.e., forward volume transfer constant [K(trans)], extravascular extracellular volume fraction [ve], and reverse reflux rate constant between the extracellular space and plasma [k(ep)]) from the Tofts model were calculated for each cancer focus. Associations between the quantitative image features and PTEN expression were analyzed with the Spearman rank correlation coefficient (r). Analysis of the 45 cancer foci revealed that 21 (47%) were PTEN-positive, 12 (27%) were PTEN-negative, and 12 (27%) were mixed. There was a weak but significant negative correlation between Gleason score and PTEN expression (r = -0.30, p = 0.04) and between k(ep) and PTEN expression (r = -0.35, p = 0.02). There was no significant correlation between other multiparametric MRI features and PTEN expression. This preliminary study of radiogenomics of peripheral zone prostate cancer revealed weak-but significant-associations between the quantitative dynamic contrast-enhanced MRI feature k(ep) and Gleason score with PTEN expression. These findings warrant further investigation and validation with the aim of using multiparametric MRI to improve risk assessment of patients with prostate cancer.

Abstract P6-01-03: Trastuzumab-induced hypoxia changes in a HER2+ murine model of breast cancer

Abstract Introduction: The primary goal of this study is to quantitatively map the changes in perfusion and hypoxia in response to trastuzumab treatment through imaging and immunohistochemical studies in a murine model of HER2+ breast cancer. Correlating quantitative imaging data with pathological validation of vessel architecture will identify the temporal changes in vascular function, which will enable optimizing the order and timing of multi-modal (i.e., trastuzumab, chemo- and radiation) therapy, leading to significantly improved anticancer response. Experimental Design: Mice were implanted subcutaneously with BT474 breast cancer cells (1×107) and randomly assorted into groups: treated (10 mg/kg trastuzumab) or control (saline). After tumors reached ∼225 mm3, animals (n = 20) were imaged with dynamic contrast enhanced-MRI (7.0 T MRI) before treatment (day 0), and 24 hours after each treatment (day 1 and day 4). Pharmacokinetic parameters, Ktrans and ve, were extracted. Subgroups of animals were sacrificed for histology between days 0 through 7 (n = 36). Tumor sections were paraffin-embedded and stained with CA-IX, CD31, α-SMA, Ki67 and H&amp;E. Slides were scanned in high resolution (20×) and quantitatively analyzed with Leica SCN400 software. Another cohort of animals (n = 32) was utilized to identify longitudinal changes in functional vascular (Hoechst 33342) and hypoxia (pimonidazole) through immunofluorescence. Agents were injected prior to sacrifice between days 0 through 7 and tumors were immediately frozen for processing. Results: Treated tumors exhibited a significant increase in Ktrans (p = 0.03) on day 4 compared to controls, indicative of heightened vessel perfusion and/or permeability. Additionally on day 4, treated tumors exhibited a significant increase in ve (p = 0.01), the extravascular extracellular volume fraction, indicating increased cell death. Significant decreases in Ki67 proliferation staining (p = 0.02) and tumor volume at day 7 (p = 0.04) in the treated group confirmed tumor response to trastuzumab. Immunohistochemical analyses revealed treated tumors have a significant decrease in CD31 microvessel density staining (p = 0.01), with a simultaneous significant increase in α-SMA pericyte coverage staining (p = 0.05) on day 4; thus, there was an overall increase in the "vessel maturation index" (ratio of α-SMA to CD31 staining) compared to controls (p = 0.01). CA-IX staining demonstrated increased hypoxia in the control group compared to treated, showing significant increases on day 3 (p = 0.03) and day 7 (p = 0.002). Qualitative differences were noted between control and treated groups for both functional vasculature and pimonidazole hypoxia fluorescent staining. Conclusion: Increased intratumoral vascular delivery (Ktrans) with a simultaneous increase in vessel maturation (immunohistochemistry) are exhibited on day 4 post trastuzumab treatment. Additionally, decreased hypoxia is revealed in treated tumors compared to controls. Hypoxic tumor cells show resistance to both radiation and chemotherapy, therefore temporarily improving the tumor's functional vasculature and decreasing hypoxia during trastuzumab treatment has potential to enhance the effectiveness of these combination therapies. Citation Format: Sorace AG, Quarles CC, Yankeelov TE. Trastuzumab-induced hypoxia changes in a HER2+ murine model of breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-01-03.

Application of Dynamic Contrast-Enhanced MRI Parameters for Differentiating Squamous Cell Carcinoma and Malignant Lymphoma of the Oropharynx.

The purpose of this study was to investigate the usefulness of histogram analysis of dynamic contrast-enhanced MRI (DCE-MRI) parameters for the differentiation of squamous cell carcinoma (SCC) and malignant lymphoma of the oropharynx. Pretreatment DCE-MRI was performed in 21 patients with pathologically confirmed oropharyngeal SCC and six patients with malignant lymphoma. DCE-MRI parameter maps including the volume transfer constant (K(trans)), flux rate constant (kep), and extravascular extracellular volume fraction (ve) based on the Tofts model were obtained. Enhancing tumors were manually segmented on each slice of the parameter maps, and the data were collected to obtain a histogram for the entire tumor volume. The Wilcoxon rank sum test was used to compare the histogram parameters of each DCE-MRI-derived variable of oropharyngeal SCC and lymphoma. Histogram analysis of K(trans) and ve maps revealed that the median and mode of K(trans) were significantly higher in SCC than in lymphoma (p = 0.039 and 0.032, respectively), and the mode, skewness, and kurtosis of ve were significantly different in SCC than in lymphoma (p = 0.046, 0.039, and 0.032, respectively). On ROC analysis, the kurtosis of ve had the best discriminative value for distinguishing between oropharyngeal SCC and lymphoma (AUC, 0.865; cutoff value, 2.60; sensitivity, 83.3%; specificity, 90.5%). Our preliminary evidence using histogram analysis of DCE-MRI parameters based on the whole tumor volume suggests that it might be useful for differentiating SCC from malignant lymphoma of the oropharynx.

Human Papillomavirus and Epidermal Growth Factor Receptor in Oral Cavity and Oropharyngeal Squamous Cell Carcinoma: Correlation With Dynamic Contrast-Enhanced MRI Parameters.

The objective of this study was to investigate differences in dynamic contrast-enhanced MRI (DCE-MRI) parameters on the basis of the status of human papillomavirus (HPV) and epidermal growth factor receptor (EGFR) biomarkers in patients with squamous cell carcinoma (SCC) of the oral cavity and oropharynx by use of histogram analysis. A total of 22 consecutive patients with oral cavity and oropharyngeal SCC underwent DCE-MRI before receiving treatment. DCE parameter maps of the volume transfer constant (K(trans)), the flux rate constant (kep), and the extravascular extracellular volume fraction (ve) were obtained. The histogram parameters were calculated using the entire enhancing tumor volume and were compared between the patient subgroups on the basis of HPV and EGFR biomarker statuses. The cumulative histogram parameters of K(trans) and kep showed lower values in the HPV-negative and EFGR-overexpression group than in the HPV-positive EGFR-negative group. These differences were statistically significant for the mean (p = 0.009), 25th, 50th, and 75th percentile values of K(trans) and for the 25th percentile value of kep when correlated with HPV status in addition to the mean K(trans) value (p = 0.047) and kep value (p = 0.004) when correlated with EGFR status. No statistically significant difference in ve was found on the basis of HPV and EGFR status. DCE-MRI is useful for the assessment of the tumor microenvironment associated with HPV and EGFR biomarkers before treatment of patients with oral cavity and oropharyngeal SCC.

Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results.

To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter K (trans) ) and the extravascular extracellular volume fraction (v e ) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in K (trans) (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in v e (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging method, following treatment with trastuzumab may provide an opportunity to optimize the scheduling and improve delivery of subsequent cytotoxic therapy.

Preliminary clinical study of sacroiliac activity in ankylosing spondylitis patients using quantitative dynamic contrast enhanced MRI

Objective To investigate the diagnostic values of DCE-MRI quantitative evaluation of the activity of sacroiliac joints in ankylosing spondylitis. Methods Forty two patients (36 male and 6 female) with ankylosing spondylitis in our hospital were enrolled prospectively according to the standard of diagnostic criteria for ankylosing spondylitis revised in 1984. All of them were evaluated with the blood sedimentation, C-reactive protein and ankylosing spondylitis activity index (BASDAI). We divided the patients with ankylosing spondylitis into stationary phase group and active phase group. We analyzed each of the MRI images of the two patients groups using the extended Tofts model to determine the quantitative parameters of DCE-MRI, such as contrast transfer coefficient (Ktrans) , reflux constant (Kep) , extravascular extracellular volume fraction (Ve) , plasma volume fraction (Vp). And then the differences of quantitative data between the two groups were compared. Spearman correlation analysis was performed between the parameters with statistically significant difference and BASDAI scores. Results Among the 42 patients, 22 patients (18 male and 4 female) were in active phase group and the other 20 patients (18 male and 2 female) were in stationary phase group. Ktrans, Kep, Ve were (0.750±1.130) /min, (1.008±0.732) /min, 0.460±1.735; (0.163 ± 0.401) /min, (0.505 ± 0.902) /min, 0.345 ± 3.460 for active phase group and the stationary phase group, respectively. The results of the active phase group was significantly higher than the stationary phase group (Z=3.727, 2.317, 3.696, respectively;all P 0.05). Strong correlations existed between Ktrans, Kep, Ve and BASDAI score, the correlation coefficients were 0.714, 0.430, and 0.676 (P<0.05). Conclusions Quantitative DCE-MRI parameters can evaluate the activity of the ankylosing spondylitis. Strong correlations exist between Ktrans, Kep, Ve and BASDAI score. Key words: Spondylitis, ankylosing; Magnetic resonance imaging; Sacroiliitis

DCE-MRI of hepatocellular carcinoma: perfusion quantification with Tofts model versus shutter-speed model--initial experience.

To quantify hepatocellular carcinoma (HCC) perfusion and flow with the fast exchange regime-allowed Shutter-Speed model (SSM) compared to the Tofts model (TM). In this prospective study, 25 patients with HCC underwent DCE-MRI. ROIs were placed in liver parenchyma, portal vein, aorta and HCC lesions. Signal intensities were analyzed employing dual-input TM and SSM models. ART (arterial fraction), K (trans) (contrast agent transfer rate constant from plasma to extravascular extracellular space), ve (extravascular extracellular volume fraction), kep (contrast agent intravasation rate constant), and τi (mean intracellular water molecule lifetime) were compared between liver parenchyma and HCC, and ART, K (trans), v e and k ep were compared between models using Wilcoxon tests and limits of agreement. Test-retest reproducibility was assessed in 10 patients. ART and v e obtained with TM; ART, ve, ke and τi obtained with SSM were significantly different between liver parenchyma and HCC (p < 0.04). Parameters showed variable reproducibility (CV range 14.7-66.5% for both models). Liver K (trans) and ve; HCC ve and kep were significantly different when estimated with the two models (p < 0.03). Our results show differences when computed between the TM and the SSM. However, these differences are smaller than parameter reproducibilities and may be of limited clinical significance.

On the Use of DSC-MRI for Measuring Vascular Permeability.

Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a).

Cluster analysis of DCE-MRI data identifies regional tracer-kinetic changes after tumor treatment with high intensity focused ultrasound.

Evaluation of high intensity focused ultrasound (HIFU) treatment with MRI is generally based on assessment of the non-perfused volume from contrast-enhanced T1-weighted images. However, the vascular status of tissue surrounding the non-perfused volume has not been extensively investigated with MRI. In this study, cluster analysis of the transfer constant K(trans) and extravascular extracellular volume fraction ve , derived from dynamic contrast-enhanced MRI (DCE-MRI) data, was performed in tumor tissue surrounding the non-perfused volume to identify tumor subregions with distinct contrast agent uptake kinetics. DCE-MRI was performed in CT26.WT colon carcinoma-bearing BALB/c mice before (n = 12), directly after (n = 12) and 3 days after (n = 6) partial tumor treatment with HIFU. In addition, a non-treated control group (n = 6) was included. The non-perfused volume was identified based on the level of contrast enhancement. Quantitative comparison between non-perfused tumor fractions and non-viable tumor fractions derived from NADH-diaphorase histology showed a stronger agreement between these fractions 3 days after treatment (R(2) to line of identity = 0.91) compared with directly after treatment (R(2) = 0.74). Next, k-means clustering with four clusters was applied to K(trans) and ve parameter values of all significantly enhanced pixels. The fraction of pixels within two clusters, characterized by a low K(trans) and either a low or high ve , significantly increased after HIFU. Changes in composition of these clusters were considered to be HIFU induced. Qualitative H&E histology showed that HIFU-induced alterations in these clusters may be associated with hemorrhage and structural tissue disruption. Combined microvasculature and hypoxia staining suggested that these tissue changes may affect blood vessel functionality and thereby tumor oxygenation. In conclusion, it was demonstrated that, in addition to assessment of the non-perfused tumor volume, the presented methodology gives further insight into HIFU-induced effects on tumor vascular status. This method may aid in assessment of the consequences of vascular alterations for the fate of the tissue.

Value of dynamic contrast-enhanced MRI parameters of Extended Tofts and Exchange model in the differential diagnosis of hepatocellular carcinoma and hepatic metastases

Objective To analyze the value of dynamic contrast-enhanced MRI(DCE-MRI) parameters of Extended Tofts and Exchange model in the differential diagnosis of hepatocellular carcinoma (HCC) and hepatic metastases of colorectal cancer. Methods A retrospective analysis of 40 pathologically confirmed cases was conducted, including 25 cases of HCC and 15 cases of hepatic metastases of colorectal cancer,all patients underwent DCE-MRI. Applying liver double blood supplement model, and respectively using Extended Tofts two-compartment model and Exchange model liver microvascular permeability parameters [volume transfer constant of the contrast agent(Ktrans), efflux rate from extracellular extravascular space to plasma(Kep), extravascular extracellular volume fraction(Ve)and blood plasma space volume fraction (Vp)] and the perfusion parameter hepatic arterial perfusion index(HPI) in the lesion parenchyma of HCC and metastases were calculated. We used t test to compare the differences of the parameters measured from the two types of tumors, statistically significant parameters between HCC and metastases were screened which compared with the gold standard of pathological findings in order to draw the ROC curves to evaluate the diagnostic efficacy of different model parameters, using χ2 test compared the diagnostic accuracy of optimal parameters between the two models. Results By using Extended Tofts and Exchange model, Ktrans value of HCC were (0.661±0.402)/min and (0.604±0.316)/min respectively, Ktrans value of hepatic metastases were (0.196±0.175)/min and (0.179±0.135)/min respectively; Vp value of HCC were (0.334±0.217) and (0.294±0.098), Vp value of hepatic metastases were (0.089±0.015) and (0.089±0.022),respectively; HPI value of HCC were (0.680±0.281) and (0.769±0.245), HPI value of hepatic metastases were (0.326±0.216), (0.373±0.298), respectively. There were significant differences between HCC and hepatic metastases in Ktrans, Vp and HPI values in both models(P 0.05).Drawn ROC curves of Ktrans, Vp, HPI, the Ktrans value (area under the curve of 0.869) among Extended Tofts model parameters was selected as optimal parameter to identify HCC and hepatic metastases; the HPI value (area under the curve of 0.845) among Exchange model parameters was selected as optimal parameter to differentiate these two types of tumors.The diagnostic accordance rate of Extended Tofts model and Exchange model were 80.0% (32/40) , 82.5% (33/40), respectively; There was no significant difference between them (χ2=0.082, P=0.775). Conclusions Parameters including Ktrans, Vp, HPI of the Extended Tofts model and Exchange model in DCE-MRI perfusion can be used to identify HCC and hepatic metastases of colorectal cancer. Among these parameters, Ktrans of Extended Tofts model and HPI of Exchange model have higher diagnostic value in differentiating HCC and hepatic metastases of colorectal cancer. Key words: Liver neoplasms; Magnetic resonance imaging; Comparative study

The Added Prognostic Value of Preoperative Dynamic Contrast-Enhanced MRI Histogram Analysis in Patients with Glioblastoma: Analysis of Overall and Progression-Free Survival.

The prognostic value of dynamic contrast-enhanced MR imaging in patients with glioblastoma is controversial. We investigated the added prognostic value of dynamic contrast-enhanced MR imaging to clinical parameters and molecular biomarkers in patients with glioblastoma by using histogram analysis. This retrospective study consisted of 61 patients who underwent preoperative dynamic contrast-enhanced MR imaging for glioblastoma. The histogram parameters of dynamic contrast-enhanced MR imaging, including volume transfer constant, extravascular extracellular volume fraction, and plasma volume fraction, were calculated from entire enhancing tumors. Univariate analyses for overall survival and progression-free survival were performed with preoperative clinical and dynamic contrast-enhanced MR imaging parameters and postoperative molecular biomarkers. Multivariate Cox regression was performed to build pre- and postoperative models for overall survival and progression-free survival. The performance of models was assessed by calculating the Harrell concordance index. In univariate analysis, patients with higher volume transfer constant and extravascular extracellular volume fraction values showed worse overall survival and progression-free survival, whereas plasma volume fraction showed no significant correlation. In multivariate analyses for overall survival, the fifth percentile value of volume transfer constant and kurtosis of extravascular extracellular volume fraction were independently prognostic in the preoperative model, and kurtosis of volume transfer constant and extravascular extracellular volume fraction were independently prognostic in the postoperative model. For progression-free survival, independent prognostic factors were minimum and fifth percentile values of volume transfer constant and kurtosis of extravascular extracellular volume fraction in the preoperative model and kurtosis of extravascular extracellular volume fraction in the postoperative model. The performance of preoperative models for progression-free survival was significantly improved when minimum or fifth percentile values of volume transfer constant and kurtosis of extravascular extracellular volume fraction were added. Higher volume transfer constant and extravascular extracellular volume fraction values are associated with worse prognosis, and dynamic contrast-enhanced MR imaging may have added prognostic value in combination with preoperative clinical parameters, especially in predicting progression-free survival.

Abstract 1492: Trastuzumab-induced normalization in a HER2+ murine model of breast cancer

Abstract Introduction: The primary goal of this study is to quantitatively map the vascular and cellular response to trastuzumab treatment in a murine model of HER2+ breast cancer. We report longitudinal dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and immunohistochemical studies hypothesized to identify timing windows of trastuzumab-induced vascular normalization. Experimental Design: Mice were subcutaneously implanted with BT474 breast cancer cells and randomly assigned to treated (10 mg/kg trastuzumab) and control (saline) groups. After tumors reached ∼225 mm3, animals (n = 20) were imaged (7.0 T MRI) before treatment (day 0), and 24 hours after each treatment (day 1 and day 4). Subgroups were sacrificed for histology between days 0 through 10 (n = 45). DCE-MRI analysis yielded parametric maps of blood vessel perfusion and permeability (Ktrans) and the extravascular extracellular volume fraction (ve). Tumor sections were paraffin-embedded and stained with CD31, α-SMA, Ki67 and H&amp;E. Slides were scanned in high resolution (20×) and quantitatively analyzed with Leica SCN400 software. Results: Compared to controls, treated tumors exhibited a significant increase in Ktrans (p = 0.03) on day 4, indicative of enhanced vessel perfusion and/or permeability. Additionally at day 4, treated tumors exhibited a significant increase in extravascular extracellular volume fraction measured via ve (p = 0.01), indicating increased cell death. These significant changes occurred prior to a significant change in tumor size at day 4 (p = 0.11). Decreased Ki67 proliferation staining (p = 0.02) at day 3 and a significant decrease in tumor volume at day 7 (p = 0.04) in the treated group confirmed tumor response to trastuzumab. The increase in Ktrans suggests properties of vessel normalization with potential to improve delivery of systemic therapies. Immunohistochemical analyses showed treated tumors have a significant decrease in microvessel density (CD31 staining, p &amp;lt; 0.01), with a simultaneous significant increase in α-SMA staining (pericyte coverage, p = 0.05) on day 4; thus, there was an overall increase in the “vessel maturation index” (ratio of α-SMA to CD31 staining) compared to controls (p = 0.01). Conclusion: These concordant (though preliminary) imaging and histological data suggest that trastuzumab treatment promotes vascular normalization, providing motivation for future studies designed to improve the efficacy of combination therapies in HER2+ breast cancer. For example, DCE-MRI has the potential to identify windows of vascular normalization thereby indicating optimal timing for treatment dosing with a cytotoxic therapy. As trastuzumab is currently given clinically in combination with various chemotherapies for HER2+ cancer, trastuzumab-induced vascular normalization could be utilized to improve drug delivery efficiency and enhance overall patient response without increasing dose or systemic toxicity. Citation Format: Anna G. Sorace, Jennifer G. Whisenant, J. Oliver McIntyre, Thomas E. Yankeelov. Trastuzumab-induced normalization in a HER2+ murine model of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1492. doi:10.1158/1538-7445.AM2015-1492

Dependence of DCE-MRI biomarker values on analysis algorithm.

BackgroundDynamic contrast-enhanced MRI (DCE-MRI) biomarkers have proven utility in tumors in evaluating microvascular perfusion and permeability, but it is unclear whether measurements made in different centers are comparable due to methodological differences.PurposeTo evaluate how commonly utilized analytical methods for DCE-MRI biomarkers affect both the absolute parameter values and repeatability.Materials and MethodsDCE-MRI was performed on three consecutive days in twelve rats bearing C6 xenografts. Endothelial transfer constant (K trans), extracellular extravascular space volume fraction (v e), and contrast agent reflux rate constant (k ep) measures were computed using: 2-parameter (“Tofts” or “standard Kety”) vs. 3-parameter (“General Kinetic” or “extended Kety”) compartmental models (including blood plasma volume fraction (v p) with 3-parameter models); individual- vs. population-based vascular input functions (VIFs); and pixel-by-pixel vs. whole tumor-ROI. Variability was evaluated by within-subject coefficient of variation (wCV) and variance components analyses.ResultsDCE-MRI absolute parameter values and wCVs varied widely by analytical method. Absolute parameter values ranged, as follows, median K trans, 0.09–0.18 min-1; k ep, 0.51–0.92 min-1; v e, 0.17–0.23; and v p, 0.02–0.04. wCVs also varied widely by analytical method, as follows: mean K trans, 32.9–61.9%; k ep, 11.6–41.9%; v e, 16.1–54.9%; and v p, 53.9–77.2%. K trans and k ep values were lower with 3- than 2-parameter modeling (p<0.0001); k ep and v p were lower with pixel- than whole-ROI analyses (p<0.0006). wCVs were significantly smaller for v e, and larger for k ep, with individual- than population-based VIFs.ConclusionsDCE-MRI parameter values and repeatability can vary widely by analytical methodology. Absolute values of DCE-MRI biomarkers are unlikely to be comparable between different studies unless analyses are carefully standardized.

Evaluation of quantitative dynamic contrast enhanced MRI in differential diagnosis of breast lesions

Objective To evaluate the value of quantitative 3T dynamic contrast enhanced MRI in the diagnosis of breast lesions. Methods One-hundred and eighteen patients suspected of breast lesions underwent MRI examination. A 3.0 T MR scanner was used to obtain the quantitative MR pharmacokinetic parameters: Ktrans( volume transfer constant), Kep (exchange rate constant) and Ve (extravascular extracellular volume fraction). The mean Ktrans, Kep and Ve of malignant, benign and normal glandular tissues were calculated and compared each other using LSD method. Independent sample t test was used between invasive ductal carcinoma and ductal carcinoma in situ (microinvasion included). Finally, the areas under the ROC curve (AUC) of Ktrans, Kep and Ve between malignant and benign lesions were compared. Results The mean Ktrans, Kep and Ve of malignant lesions (n=87) were (1.010±0.580) min-1, (1.634 ± 1.481) min-1 and (0.735 ±0.273); the mean Ktrans, Kep and Ve of benign lesions (n=23) were (0.331±0.192) min - 1, (0.417±0.324) min - 1 and (0.847±0.291); and the mean Ktrans, Kep and Ve of normal glandular tissues (n =83) were (0.051 ±0.028) min-1, (0.133±0.125) min-1 and (0.597±0.354), respectively. There were significant differences between normal glandular tissues and benign lesions, normal glandular tissues and malignant lesions, benign and malignant lesions in Ktrans (t=9.681, 11.189, 5. 590, respectively, P ＜ 0. 01 ), normal glandular tissues and malignant lesions, benign and malignant lesions in Kep(t =5. 287, 3. 874, P＜0. 05). There were a statistic differences between normal glandular tissues and benign lesions, normal glandular tissues and malignant lesions in Ve(t =2. 932, 2. 562 ,P ＜0. 05). There were no significant differences between normal glandular tissues and benign lesions in Kep, benign and malignant lesions in Ve ( t = 0. 760, 0. 832, P ＞ 0.05 ),invasive ductal carcinoma and ductal carcinoma in situ (microinvasion included) in Ktrans, Kep and Ve(t =0.834,0.075,0.454,P＞0.05). The areas under the ROC curve (AUC) of Ktrans, Kep and Ve between malignant and benign lesions were 0. 934, 0. 941 and 0. 659. The sensitivity of Ktrans, Kep and Ve were 77.01% ,91.95% ,56. 32% and the specificity of Ktrans, Kep and Ve were 95. 65%, 86. 96%, 78.26% for the differential diagnosis of breast lesions if taken the maximum Youden's index as cut-off. Conclusion The differential diagnosis of benign and malignant breast lesions by Ktrans, Kep is applicable. Key words: Breast neoplasms; Magnetic resonance imaging; Diagnosis,differential

Optimal acquisition and modeling parameters for accurate assessment of low Ktrans blood-brain barrier permeability using dynamic contrast-enhanced MRI.

To determine optimal parameters for acquisition and processing of dynamic contrast-enhanced MRI (DCE-MRI) to detect small changes in near normal low blood-brain barrier (BBB) permeability. Using a contrast-to-noise ratio metric (K-CNR) for Ktrans precision and accuracy, the effects of kinetic model selection, scan duration, temporal resolution, signal drift, and length of baseline on the estimation of low permeability values was evaluated with simulations. The Patlak model was shown to give the highest K-CNR at low Ktrans . The Ktrans transition point, above which other models yielded superior results, was highly dependent on scan duration and tissue extravascular extracellular volume fraction (ve ). The highest K-CNR for low Ktrans was obtained when Patlak model analysis was combined with long scan times (10-30 min), modest temporal resolution (<60 s/image), and long baseline scans (1-4 min). Signal drift as low as 3% was shown to affect the accuracy of Ktrans estimation with Patlak analysis. DCE acquisition and modeling parameters are interdependent and should be optimized together for the tissue being imaged. Appropriately optimized protocols can detect even the subtlest changes in BBB integrity and may be used to probe the earliest changes in neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis.