Evaluation of tracer kinetic parameters in cervical cancer using dynamic contrast-enhanced MRI as biomarkers in terms of biological relevance, diagnostic performance and inter-center variability.

Objectives: This study assessed the clinical value of parameters derived from dynamic contrast-enhanced (DCE) MRI with respect to correlation with angiogenesis and proliferation of cervical cancer, performance of diagnosis and reproducibility of DCE-MRI parameters across MRI scanners. Materials and Methods: A total of 113 patients with cervical carcinoma from two centers were included in this retrospective study. The DCE data were centralized and processed using five tracer kinetic models (TKMs) (Tofts, Ex-Tofts, ATH, SC, and DP), yielding the following parameters: volume transfer constant (Ktrans), extravascular extracellular volume (Ve), fractional volume of vascular space (Vp), blood flow (Fp), and permeability surface area product (PS). CD34 counts and Ki-67 PI (proliferation index) of cervical cancer and normal cervix tissue were obtained using immunohistochemical staining in Center 1. Results: CD34 count and Ki-67 PI in cervical cancer were significantly higher than in normal cervix tissue (p<0.05). Parameter Ve from each TKM was significantly smaller in cervical cancer tissue than in normal cervix tissue (p<0.05), indicating the higher proliferation of cervical cancer cells. Ve of each TKM attained the largest AUC to diagnose cervical cancer. The distributions of DCE parameters for both cervical cancer and normal cervix tissue were not significantly different between two centers (P>0.05). Conclusion: Parameter Ve was similar to the expression of Ki-67 in revealing the proliferation of tissue cells, attained good performance in diagnosis of cervical cancer, and demonstrated consistent findings on measured values across centers.

Endometrial carcinoma: use of tracer kinetic modeling of dynamic contrast-enhanced MRI for preoperative risk assessment.

BACKGROUND: To compare two tracer kinetic models in predicting of preoperative risk types in endometrial carcinoma (EC) using DCE-MRI. METHODS: A prospective study of patients with EC was conducted with institutional ethics approval and written informed consent. DCE-MRI data was analyzed using the extended Tofts (ET) and the distributed parameter (DP) models. DCE parameters blood flow (F), mean transit time, blood volume (Vp), extravascular extracellular volume (Ve), permeability surface area product (PS), extraction fraction, transfer constant (Ktrans), and efflux rate (Kep) between high- and low-risk EC were compared using the Mann-Whitney test. Bland-Altman analysis was utilized to compare parameter consistency and Spearman test to assess parameter correlation. Diagnostic performance of DCE parameters was analyzed by receiver-operating characteristic curve and compared with traditional MRI assessment. RESULTS: Fifty-one patients comprised the study group. Patients with high-risk EC exhibited significantly lower Ktrans, Kep, F, Vp and PS (P < 0.001). ET-derived Ktrans and DP-derived F attained AUC of 0.92 and 0.91, respectively. Bland-Altman analysis showed that the consistency of Ve or Vp between the two models was low (P < 0.001) while Spearman test showed a strong correlation (r = 0.719, 0.871). Both Ktrans and F showed higher accuracy in predicting EC risk types than traditional MRI assessment. CONCLUSIONS: Kinetic parameters derived from DCE-MRI revealed a more hypovascular microenvironment for high risk EC than to low- risk ones, providing potential imaging biomarkers in preoperative risk assessment that might improve individualized surgical planning and management of EC.

Utility of quantitative susceptibility mapping and diffusion kurtosis imaging in the diagnosis of early Parkinson's disease.

OBJECTIVE: To investigate the utility of quantitative susceptibility mapping (QSM) and diffusion kurtosis imaging (DKI) as complementary tools in characterizing pathological changes in the deep grey nuclei in early Parkinson's disease (PD) and their clinical correlates to aid in diagnosis of PD. METHOD: Patients with a diagnosis of PD made within a year and age-matched healthy controls were recruited. All participants underwent clinical evaluation using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) and Hoehn & Yahr stage (H&Y), and brain 3 T MRI including QSM and DKI. Regions-of-interest (ROIs) in the caudate nucleus, putamen, globus pallidus, and medial and lateral substantia nigra (SN) were manually drawn to compare the mean susceptibility (representing iron deposition) and DKI indices (representing restricted water diffusion) between PD patients and healthy controls and in correlation with MDS-UPDRS III and H&Y, focusing on susceptibility value, mean diffusivity (MD) and mean kurtosis (MK). RESULTS: There were forty-seven PD patients (aged 68.7 years, 51% male, disease duration 0.78 years) and 16 healthy controls (aged 67.4 years, 63% male). Susceptibility value was increased in PD in all ROIs except the caudate, and was significantly different after multiple comparison correction in the putamen (PD: 64.75 ppb, HC: 44.61 ppb, p = 0.004). MD was significantly higher in PD in the lateral SN, putamen and caudate, the regions with the lowest susceptibility value. In PD patients, we found significant association between the MDS-UPDRS III score and susceptibility value in the putamen after correcting for age and sex (ß = 0.21, p = 0.003). A composite DKI-QSM diagnostic marker based on these findings successfully differentiated the groups (p < 0.0001) and had "good" classification performance (AUC = 0.88). CONCLUSIONS: QSM and DKI are complementary tools allowing a better understanding of the complex contribution of iron deposition and microstructural changes in the pathophysiology of PD.

A comparative study of methods for determining Intravoxel incoherent motion parameters in cervix cancer.

BACKGROUND: To compare different fitting methods for determining IVIM (Intravoxel Incoherent Motion) parameters and to determine whether the use of different IVIM fitting methods would affect differentiation of cervix cancer from normal cervix tissue. METHODS: Diffusion-weighted echo-planar imaging of 30 subjects was performed on a 3.0 T scanner with b-values of 0, 30, 100, 200, 400, 1000 s/mm2. IVIM parameters were estimated using the segmented (two-step) fitting method and by simultaneous fitting of a bi-exponential function. Segmented fitting was performed using two different cut-off b-values (100 and 200 s/mm2) to study possible variations due to the choice of cut-off. Friedman's test and Student's t-test were respectively used to compare IVIM parameters derived from different methods, and between cancer and normal tissues. RESULTS: No significant difference was found between IVIM parameters derived from the segmented method with b-value cutoff of 200 s/mm2 and the simultaneous fitting method (P>0.05). Tissue diffusivity (D) and perfusion fraction (f) were significantly lower in cervix cancer than normal tissue (P< 0.05). CONCLUSIONS: IVIM parameters derived using fitting methods with small cutoff b-values could be different, however, the segmented method with b-value cutoff of 200 s/mm2 are consistent with the simultaneous fitting method and both can be used to differentiate between cervix cancer and normal tissue.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigratinib in High-FGFR-Expressing Hepatocellular Carcinoma Xenografts.

PURPOSE: Overexpression of fibroblast growth factor receptor (FGFR) contributes to tumorigenesis, metastasis, and poor prognosis of hepatocellular carcinoma (HCC). Infigratinib-a pan-FGFR inhibitor-potently suppresses the growth of high-FGFR-expressing HCCs in part via alteration of the tumor microenvironment and vessel normalization. In this study, we aim to assess the utility of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as a non-invasive imaging technique to detect microenvironment changes associated with infigratinib and sorafenib treatment in high-FGFR-expressing HCC xenografts. PROCEDURES: Serial DCE-MRIs were performed on 12 nude mice bearing high-FGFR-expressing patient-derived HCC xenografts to quantify tumor microenvironment pre- (day 0) and post-treatment (days 3, 6, 9, and 15) of vehicle, sorafenib, and infigratinib. DCE-MRI data were analyzed using extended generalized kinetic model and two-compartment distributed parameter model. After treatment, immunohistochemistry stains were performed on the harvested tumors to confirm DCE-MRI findings. RESULTS: By treatment day 15, infigratinib induced tumor regression (70 % volume reduction from baseline) while sorafenib induced relative growth arrest (185 % volume increase from baseline versus 694 % volume increase from baseline of control). DCE-MRI analysis revealed different changes in microcirculatory parameters upon exposure to sorafenib versus infigratinib. While sorafenib induced microenvironment changes similar to those of rapidly growing tumors, such as a decrease in blood flow (F), fractional intravascular volume (vp), and permeability surface area product (PS), infigratinib induced the exact opposite changes as early as day 3 after treatment: increase in F, vp, and PS. CONCLUSIONS: Our study demonstrated that DCE-MRI is a reliable non-invasive imaging technique to monitor tumor microcirculatory response to FGFR inhibition and VEGF inhibition in high-FGFR-expressing HCC xenografts. Furthermore, the microcirculatory changes from FGFR inhibition manifested early upon treatment initiation and were reliably detected by DCE-MRI, creating possibilities of combinatorial therapy for synergistic effect.

Application of Distributed Parameter Model to Assessment of Glioma IDH Mutation Status by Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

Previous studies using contrast-enhanced imaging for glioma isocitrate dehydrogenase (IDH) mutation assessment showed promising yet inconsistent results, and this study attempts to explore this problem by using an advanced tracer kinetic model, the distributed parameter model (DP). Fifty-five patients with glioma examined using dynamic contrast-enhanced imaging sequence at a 3.0 T scanner were retrospectively reviewed. The imaging data were processed using DP, yielding the following parameters: blood flow F, permeability-surface area product PS, fractional volume of interstitial space Ve, fractional volume of intravascular space Vp, and extraction ratio E. The results were compared with the Tofts model. The Wilcoxon test and boxplot were utilized for assessment of differences of model parameters between IDH-mutant and IDH-wildtype gliomas. Spearman correlation r was employed to investigate the relationship between DP and Tofts parameters. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis and quantified using the area under the ROC curve (AUC). Results showed that IDH-mutant gliomas were significantly lower in F (P = 0.018), PS (P < 0.001), Vp (P < 0.001), E (P < 0.001), and Ve (P = 0.002) than IDH-wildtype gliomas. In differentiating IDH-mutant and IDH-wildtype gliomas, Vp had the best performance (AUC = 0.92), and the AUCs of PS and E were 0.82 and 0.80, respectively. In comparison, Tofts parameters were lower in K trans (P = 0.013) and Ve (P < 0.001) for IDH-mutant gliomas. No significant difference was observed in Kep (P = 0.525). The AUCs of K trans, Ve, and Kep were 0.69, 0.79, and 0.55, respectively. Tofts-derived Ve showed a strong correlation with DP-derived Ve (r > 0.9, P < 0.001). K trans showed a weak correlation with F (r < 0.3, P > 0.16) and a very weak correlation with PS (r < 0.06, P > 0.8), both of which were not statistically significant. The findings by DP revealed a tissue environment with lower vascularity, lower vessel permeability, and lower blood flow in IDH-mutant than in IDH-wildtype gliomas, being hostile to cellular differentiation of oncogenic effects in IDH-mutated gliomas, which might help to explain the better outcomes in IDH-mutated glioma patients than in glioma patients of IDH-wildtype. The advantage of DP over Tofts in glioma DCE data analysis was demonstrated in terms of clearer elucidation of tissue microenvironment and better performance in IDH mutation assessment.

On the potential use of dynamic contrast-enhanced (DCE) MRI parameters as radiomic features of cervical cancer.

PURPOSE: To evaluate whether the analysis of high-temporal resolution DCE-MRI by various tracer kinetic models could yield useful radiomic features in discriminating cervix carcinoma and normal cervix tissue. METHODS: Forty-three patients (median age 51 yr; range 26-78 yr) diagnosed with cervical cancer based on postoperative pathology were enrolled in this study with informed consent. DCE-MRI data with temporal resolution of 2 s were acquired and analyzed using the Tofts (TOFTS), extended Tofts (EXTOFTS), conventional two-compartment (CC), adiabatic tissue homogeneity (ATH), and distributed parameter (DP) models. Ability of all kinetic parameters in distinguishing tumor from normal tissue was assessed using Mann-Whitney U test and receiver operating characteristic (ROC) curves. Repeatability of parameter estimates due to sampling of arterial input functions (AIFs) was also studied using intraclass correlation (ICC) analysis. RESULTS: Fractional extravascular, extracellular volume (Ve) of all models were significantly smaller in cervix carcinoma than normal cervix tissue, and were associated with large values of area under ROC curve (AUC 0.884-0.961). Capillary permeability PS derived from the ATH, CC, and DP models also yielded large AUC values (0.730, 0.860, and 0.797). Transfer constant Ktrans derived from TOFTS and EXTOFTS models yielded smaller AUC (0.587 and 0.701). Repeatability of parameters derived from all models was robust to AIF sampling, with ICC coefficients typically larger than 0.80. CONCLUSIONS: With the use of high-temporal resolution DCE-MRI, all tracer kinetic models could reflect pathophysiological differences between cervix carcinoma and normal tissue (with significant differences in Ve and PS) and potentially yield radiomic features with diagnostic value.

A Comparative Study of Two-Compartment Exchange Models for Dynamic Contrast-Enhanced MRI in Characterizing Uterine Cervical Carcinoma.

A variety of tracer kinetic methods have been employed to assess tumor angiogenesis. The Standard two-Compartment model (SC) used in cervix carcinoma was less frequent, and Adiabatic Approximation to the Tissue Homogeneity (AATH) and Distributed Parameter (DP) model are lacking. This study compares two-compartment exchange models (2CXM) (AATH, SC, and DP) for determining dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters in cervical cancer, with the aim of investigating the potential of various parameters derived from 2CXM for tumor diagnosis and exploring the possible relationship between these parameters in patients with cervix cancer. Parameters (tissue blood flow, F p; tissue blood volume, V p; interstitial volume, V e; and vascular permeability, PS) for regions of interest (ROI) of cervix lesions and normal cervix tissue were estimated by AATH, SC, and DP models in 36 patients with cervix cancer and 17 healthy subjects. All parameters showed significant differences between lesions and normal tissue with a P value less than 0.05, except for PS from the AATH model, F p from the SC model, and V p from the DP model. Parameter V e from the AATH model had the largest AUC (r = 0.85). Parameters F p and V p from SC and DP models and V e and PS from AATH and DP models were highly correlated, respectively, (r > 0.8) in cervix lesions. Cervix cancer was found to have a very unusual microcirculation pattern, with over-growth of cancer cells but without evident development of angiogenesis. V e has the best performance in identifying cervix cancer. Most physiological parameters derived from AATH, SC, and DP models are linearly correlated in cervix cancer.

MR diffusion kurtosis imaging predicts malignant potential and the histological type of meningioma.

PURPOSE: To explore the value of Diffusion kurtosis imaging (DKI) metrics in the differential diagnosis of meningioma. METHODS: For this study, we retrospectively enrolled 35 patients of cerebral meningioma with DKI which included axial diffusion coefficient (AD), radial diffusion coefficient (RD), mean diffusion coefficient (MD), fractional anisotropy (FA), axial kurtosis (AK), radial kurtosis (RK) and mean kurtosis (MK). All of these metrics were normalized according to contralateral normal-appearing white matter (NAWMc). Patients were divided into two groups (benign and malignant meningioma) and were further analyzed using the independent sample t-test and receiver operating characteristic (ROC) curve. A one-way ANOVA analysis was used to analyze four groups divided according to pathological subtypes. RESULTS: The metrics of AD, normalized AD, normalized MD, MK and normalized MK showed a significant difference between benign and malignant group, and MK showed relatively higher diagnostic ability with its cut-off value, area under the curve (AUC), sensitivity and specificity of 0.875, 0.780, 70% and 89%, respectively. The metrics of normalized MD, RD and normalized RD, FA and normalized FA, AK and normalized AK, and RK showed significant difference among four subtypes. MK and RK in meningioma were found to correlate positively with the Ki-67 labeling index (Ki-67 LI). CONCLUSIONS: DKI metrics may be used to differentiate benign from malignant meningioma, and also to distinguish some histological subtypes of meningioma. Moreover, DKI metrics may potentially reflect cellular proliferation.

Intravoxel incoherent imaging of renal fibrosis induced in a murine model of unilateral ureteral obstruction.

PURPOSE: To evaluate non-invasive imaging biomarkers for assessing renal fibrosis. DWI is used to assess renal function; intravoxel incoherent motion (IVIM) provides additional measures of perfusion-related diffusion (D*, blood flow; f, perfusion fraction). We aim to determine if reduced ADC seen in renal fibrosis is attributable to perfusion-related diffusion changes or to known reduction in tissue diffusivity (D). MATERIALS AND METHODS: Unilateral ureteral obstruction (UUO) was created in six mice to induce renal fibrosis. DWI was performed the day before and 7 days post-UUO. A range of b-values from 0 to 1200 s/mm(2) were used. IVIM parameters were obtained using region of interests drawn over the renal parenchyma. Histopathological analysis of both kidneys was performed in all mice. Results were analyzed using the paired t-test with P<0.05 considered statistically significant. RESULTS: D and f were significantly lower in the ligated kidneys at Day 7 compared to before ligation and no significant difference was found for D*. Comparing non-ligated and ligated kidneys within the same mouse at Day 7, significantly lower D values were observed in the ligated kidneys, while no significant difference was found for f and D*, although the values of f were generally lower. Histopathological analysis confirmed development of fibrosis and reduction in glomeruli in all the ligated kidneys at Day 7. CONCLUSION: Our study shows that the reduction in ADC seen in renal fibrosis is attributable not only to reduced D as previously encountered but also a decrease in vascularity as assessed by f. Reduction in f is possibly related to a reduction in glomeruli.

Metronomic vinorelbine (oral) in combination with sorafenib in advanced non-small cell lung cancer.

BACKGROUND: To date, biomarkers to predict benefit from anti-angiogenic therapy are still lacking. Sorafenib and metronomic oral vinorelbine combination was studied and changes in blood and DCE-MRI parameters were investigated as biomarkers for benefit. MATERIAL AND METHODS: Patients with advanced NSCLC were recruited to 3 successive cohorts. Each cohort was given a fixed metronomic (3 times a week) dose of oral vinorelbine at 60 mg/week, 90 mg/week, or 120 mg/week respectively. Within each cohort, patients received a starting dose of sorafenib at 200mg bid for 4 weeks. In the absence of dose-limiting toxicities, each patient's dose of sorafenib was escalated to 400mg bid for 4 weeks, 600 mg bid for 4 weeks and finally 800 mg bid. Biomarkers measured include DCE-MRI parameters, circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and plasma thrombospondin (TSP-1). RESULTS: 48 evaluable patients were analyzed. There were 4 (8.9%) patients with partial response (PR) and 7 (15.2%) with cavitary response (CaR). Two subpopulations of CECs (CEC(hi), CEC(lo)) were identified that trended in opposite directions during treatment, with CEC(hi) demonstrating an upward trend in contrast to CEC(lo). Higher baseline CEC(hi) and lower baseline blood flow (F) and fractional intravascular blood volume (V1) predicted for response. Multivariate analysis revealed a lower baseline V1, and dynamic changes of CEC during treatment (CEC increase, sum of CEC(hi) and CEC(lo)) predicted for improved survival. CONCLUSIONS: Sorafenib and metronomic oral vinorelbine is active in advanced NSCLC. Baseline levels and changes in DCE parameters and CEC may be useful predictive biomarkers.

Correlative assessment of tumor microcirculation using contrast-enhanced perfusion MRI and intravoxel incoherent motion diffusion-weighted MRI: is there a link between them?

The purpose of this study was to correlate intravoxel incoherent motion (IVIM) imaging with classical perfusion-weighted MRI metrics in human gliomas. Parametric images for slow diffusion coefficient (D), fast diffusion coefficient (D*), and fractional perfusion-related volume (f) in patients with high-grade gliomas were generated. Maps of Fp (plasma flow), vp (vascular plasma volume), PS (permeability surface-area product), ve (extravascular, extracellular volume), E (extraction ratio), ke (influx ratio into the interstitium), and tc (vascular transit time) from dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast-enhanced (DSC) MRI were also generated. A region-of-interest analysis on the contralateral healthy white matter and on the tumor areas was performed and the extracted parameter values were tested for any significant differences among tumor grades or any correlations. Only f could be significantly correlated to DSC-derived vp and tc in healthy brain tissue. Concerning the tumor regions, Fp was significantly positively correlated with D* and inversely correlated with f in DSC measurements. The D*, f, and f × D* values in the WHO grade III gliomas were non-significantly different from those in the grade IV gliomas. There was a trend to significant negative correlations between f and PS as well as between f × D* and ke in DCE experiments. Presumably due to different theoretical background, tracer properties and modeling of the tumor vasculature in the IVIM theory, there is no clearly evident link between D*, f and DSC- and DCE-derived metrics.

Perfusion imaging in liver MRI.

Liver perfusion magnetic resonance (MR) imaging is currently being actively investigated as a functional imaging technique that provides physiologic information on the microcirculation and microenvironment of liver tumors and the underlying liver. It has gained importance in light of antiangiogenic therapy for hepatocellular carcinoma and colorectal liver metastases. This article explains the various model-free and model-based approaches for liver perfusion MR imaging and their relative clinical utility. Relevant published works are summarized for each approach so that the reader can understand their relative strengths and weaknesses, to make an informed choice when performing liver perfusion MR imaging studies.

Assessment of tumor necrotic fraction by dynamic contrast-enhanced MRI: a preclinical study of human tumor xenografts with histopathologic correlation.

Contrary to the common notion that tumor necrotic regions are non-enhancing after contrast administration, recent evidence has shown that necrotic regions exhibit delayed and slow uptake of gadolinium tracer on dynamic contrast-enhanced MRI (DCE MRI). The purpose of this study is to explore whether the mapping of tumor voxels with delayed and slow enhancement on DCE MRI can be used to derive estimates of tumor necrotic fraction. Patient-derived tumor xenograft lines of seven human cancers were implanted in 26 mice which were subjected to DCE MRI performed using a spoiled gradient recalled sequence. Gadolinium tracer concentration was estimated using the variable flip angle technique. To identify tumor voxels exhibiting delayed and slow uptake of contrast medium, clustering analysis was performed using a k-means clustering algorithm that classified tumor voxels according to their contrast enhancement patterns. Comparison of the percentage of tumor voxels exhibiting delayed and slow enhancement with the tumor necrotic fraction estimated on histology showed a strong correlation (r = 0.962, p < 0.001). The mapping of tumor regions with delayed and slow contrast uptake on DCE MRI correlated strongly with tumor necrotic fraction, and can potentially serve as a non-invasive imaging surrogate for the in vivo assessment of necrotic fraction.

Intravoxel incoherent motion diffusion-weighted MR imaging of gliomas: feasibility of the method and initial results.

INTRODUCTION: The purpose of this study was to evaluate the feasibility of intravoxel incoherent motion (IVIM) imaging and its value in differentiating the histologic grade among human gliomas. METHODS: The IVIM model generated parametric images for apparent diffusion coefficient ADC, slow diffusion coefficient D (or D slow), fast diffusion coefficient D* (or D fast), and fractional perfusion-related volume f in 22 patients with gliomas (WHO grade II-IV) using monopolar Stejskal-Tanner diffusion-weighted imaging (DWI) scheme and 14 b values ranging from 0 s/mm2 to a maximum of 1,300 s/mm2. A region-of-interest analysis on the tumor as well as in the white matter was conducted. The parameter values were tested for significant differences. The repeatability of the measurements was tested by coefficient of variation and Bland-Altman plots. RESULTS: D, D*, and f in the high-grade gliomas demonstrated significant differences compared to the healthy white matter. D* and f showed a significant difference between low- and high-grade gliomas. D tended to be slightly lower in the WHO grade II compared to WHO grade III-IV tumors. f and D* demonstrated higher coefficients of variation than the ADC and D in tumor. The Bland-Altman plots demonstrated satisfactory results without any outliers outside the mean ± 1.96 standard deviation. CONCLUSION: The IVIM-fitted post-processing of DWI-signal decay in human gliomas could show significantly different values of fractional perfusion-related volume and fast diffusion coefficient between low- and high-grade tumors, which might enable a noninvasive WHO grading in vivo.

Primary colorectal cancer: use of kinetic modeling of dynamic contrast-enhanced CT data to predict clinical outcome.

PURPOSE: To compare four different tracer kinetic models for the analysis of dynamic contrast material-enhanced computed tomographic (CT) data with respect to the prediction of 5-year overall survival in primary colorectal cancer. MATERIALS AND METHODS: This study was approved by the ethical review board. Archival dynamic contrast-enhanced CT data from 46 patients with colorectal cancer, obtained as part of a research study, were analyzed retrospectively by using the distributed parameter, conventional compartmental, adiabatic tissue homogeneity, and generalized kinetic models. Blood flow, blood volume, mean transit time (MTT), permeability-surface area product, extraction fraction, extravascular extracellular volume (v(e)), and volume transfer constant (K(trans)) were compared by using the Friedman test, with statistical significance at 5%. Following receiver operating characteristic analysis, parameters of the different kinetic models and tumor stage were compared with respect to overall survival discrimination, with use of Kaplan Meier analysis and a univariate Cox proportional hazard model, with additional cross-validation and permutation testing. RESULTS: Blood flow was lower with the distributed parameter model than with the conventional compartmental and adiabatic tissue homogeneity models (P < .0001), and blood flow values determined with the conventional compartmental and adiabatic tissue homogeneity models were similar. Conversely, MTT was longer with the distributed parameter model than with the conventional compartmental and adiabatic tissue homogeneity models (P < .0001). Blood volume, permeability-surface area product, and v(e) were higher with the conventional compartmental model than with the adiabatic tissue homogeneity, distributed parameter, or generalized kinetic models (P < .0001). The extraction fraction was higher with the distributed parameter model than with the adiabatic tissue homogeneity model. With respect to 5-year overall survival, only the distributed parameter model-derived v(e) was predictive of 5-year overall survival with a threshold value of 15.48 mL/100 mL after cross-validation and permutation testing. CONCLUSION: Parameter values differ significantly between models. Of the models investigated, the distributed parameter model was the best predictor of 5-year overall survival. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120186/-/DC1.

Neuroendocrine tumor liver metastases: use of dynamic contrast-enhanced MR imaging to monitor and predict radiolabeled octreotide therapy response.

PURPOSE: To evaluate dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging for monitoring and assessing treatment response in patients with neuroendocrine liver metastases treated using yttrium 90 ((90)Y)-labeled octreotide ((90)Y-DOTATOC). MATERIALS AND METHODS: The study was approved by the local research and ethics committee and patient informed consent was obtained. Twenty patients with liver metastases from neuroendocrine tumors underwent T1-weighted DCE MR imaging of the liver before and at 2 months after intravenous (90)Y-DOTATOC treatment. Regions of interest were drawn around target lesions, as well as along liver outlines for each patient. A dual-input single-compartment model was used to compute parameters including fractional distribution volume and the arterial flow fraction. Pre- and posttreatment values were compared using Wilcoxon signed rank test. Treatment response was defined as showing a greater than 50% reduction in the nadir chromogranin A level within the 1st year after treatment. Pretreatment values of responders and nonresponders were compared using the Mann-Whitney test. A two-tailed P value of .008 or less, which accounts for multiple testing, was considered to indicate a significant difference. RESULTS: In responders, tumor and whole liver distribution volume significantly increased after treatment (median tumor distribution volume, 0.182 vs 0.244; median whole liver distribution volume, 0.175 vs 0.207; P = .008). The pretreatment whole liver distribution volume was significantly lower in responders (median, 0.175 vs 0.248; P = .003), while pretreatment tumor arterial flow fraction was significantly higher in responders (median, 1.000 vs 0.7 ± 1, P = .006). CONCLUSION: DCE MR imaging may be used to monitor the effects of peptide receptor radiolabeled targeted therapy in patients with neuroendocrine tumors liver metastases; a lower pretreatment distribution volume and high arterial flow fraction was associated with a better response to treatment.

Dynamic contrast-enhanced computed tomography in metastatic nasopharyngeal carcinoma: reproducibility analysis and observer variability of the distributed parameter model.

OBJECTIVES: To determine the reproducibility and observer variability of distributed parameter analysis of dynamic contrast-enhanced computed tomography (DCE-CT) data in metastatic nasopharyngeal carcinoma, and to compare 2 approaches of region-of-interest (ROI) analyses. METHODS: Following ethical approval and informed consent, 17 patients with nasopharyngeal carcinoma underwent paired DCE-CT examinations on a 64-detector scanner, measuring tumor blood flow (F, mL/100 mL/min), permeability surface area product (PS, mL/100 mL/min), fractional intravascular blood volume (v1, mL/100 mL), and fractional extracellular-extravascular volume (v2, mL/100 mL). Tumor parameters were derived by fitting (i) the ROI-averaged concentration-time curve, and (ii) the median value of parameters from voxel-level concentration-time curves. Measurement reproducibility and inter- and intraobserver variability were estimated using Bland-Altman statistics. RESULTS: Mean F, PS, v1, and v2 are 44.9, 20.4, 7.1, and 34.1 for ROI analysis, and 49.0, 18.7, 6.7, and 34.0 for voxel analysis, respectively. Within-subject coefficients of variation are 38.8%, 49.5%, 54.2%, and 35.9% for ROI analysis, and 15.0%, 35.1%, 33.0%, and 21.0% for voxel analysis, respectively. Repeatability coefficients are 48.2, 28.0, 10.7, and 33.9 for ROI analysis, and 20.3, 18.2, 6.1 and 19.8 for voxel analysis, respectively. Intra- and interobserver correlation coefficient ranged from 0.94 to 0.97 and 0.90 to 0.95 for voxel analysis, and 0.73 to 0.87 and 0.72 to 0.94 for ROI analysis, respectively. CONCLUSION: Measurements of F and v2 appear more reproducible than PS and v1. Voxel-level analysis improves both reproducibility and observer variability compared with ROI-averaged analysis and may retain information about tumor spatial heterogeneity.

Fundamentals of tracer kinetics for dynamic contrast-enhanced MRI.

Tracer kinetic methods employed for quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) share common roots with earlier tracer studies involving arterial-venous sampling and other dynamic imaging modalities. This article reviews the essential foundation concepts and principles in tracer kinetics that are relevant to DCE MRI, including the notions of impulse response and convolution, which are central to the analysis of DCE MRI data. We further examine the formulation and solutions of various compartmental models frequently used in the literature. Topics of recent interest in the processing of DCE MRI data, such as the account of water exchange and the use of reference tissue methods to obviate the measurement of an arterial input, are also discussed. Although the primary focus of this review is on the tracer models and methods for T(1) -weighted DCE MRI, some of these concepts and methods are also applicable for analysis of dynamic susceptibility contrast-enhanced MRI data.

Wash-out of hepatocellular carcinoma: quantitative region of interest analysis on CT.

INTRODUCTION: This study aims to determine if the quantitative method of region-of-interest (ROI) analysis of lesion attenuation on CT may be a useful adjunct to the conventional approach of diagnosis by visual assessment in assessing tracer wash-out in hepatocellular carcinomas. MATERIALS AND METHODS: From a surgical database of 289 patients from 2 institutions, all patients with complete surgical, pathological and preoperative multiphasic CT scans available for review were selected. For each phase of scanning, HU readings of lesion obtained (Lesion(arterial), Lesion(PV) and Lesion(equilibrium)) were analysed using receiver operating curves (ROC) to determine the optimal method and cut-off value for quantitative assessment of tumour wash-out (Lesion(arterial - equilibrium), Lesion(PV - equilibrium) or Lesion(peak - equilibrium)). RESULTS: Ninety-four patients with one lesion each met the inclusion criteria. The area under the curve (AUC) values for Lesion(arterial - equilibrium) (0.941) was higher than the AUC for Lesion(pv - equilibrium) (0.484) and for Lesion(peak - equilibrium) (0.667). Based on ROC analysis, a cut-off of 10HU value for Lesion(arterial - equilibrium) would yield sensitivity and specificity of 91.5% and 80.9%, respectively. ROI analysis detected 9/21 (42.9%) of lesions missed by visual analysis. Combined ROI and visual analysis yields a sensitivity of 82/94 (87.2%) compared to 73/94 (77.7%) for visual analysis alone. CONCLUSION: Using a cut-off of 10 HU attenuation difference between the arterial and equilibrium phases is a simple and objective method that can be included as an adjunct to visual assessment to improve sensitivity for determining lesion wash-out on CT.