Analysis Of Dynamic Contrast Enhanced MRI Research Articles

Tracer kinetic model selection for dynamic contrast-enhanced magnetic resonance imaging of locally advanced cervical cancer

Background. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a unique capability to probe tumour microvasculature. Different analysis of the acquired data will possibly lead to different conclusions. Therefore, the objective of this study was to investigate under which conditions the Tofts (TM), extended Tofts (ETM), compartmental tissue uptake model (C-TU) and 2-compartment exchange model (2CXM) were the optimal tracer kinetic models (TKMs) for the analysis of DCE-MRI in patients with cervical cancer.Material and methods. Ten patients with locally advanced cervical cancer (FIGO: IIA/IIB/IIIB/IVA – 1/5/3/1) underwent DCE-MRI prior to radiotherapy. From the two-parameter TM it was possible to extract the forward volume transfer constant (Ktrans) and the extracellular-extravascular volume fraction (ve). From the three-parameter ETM, additionally the plasma volume fraction (vp) could be extracted. From the three-parameter C-TU it was possible to extract information about the blood flow (Fp), permeability-surface area product (PS) and vp. Finally, the four-parameter 2CXM extended the C-TU to include ve. For each voxel, corrected Akaike information criterion (AICc) values were calculated, taking into account both the goodness-of-fit and the number of model parameters. The optimal model was defined as the model with the lowest AICc.Results. All four TKMs were the optimal model in different contiguous regions of the cervical tumours. For the 24 999 analysed voxels, the TM was optimal in 17.0%, the ETM was optimal in 2.2%, the C-TU in 23.4% and the 2CXM was optimal in 57.3%. Throughout the tumour, a high correlation was found between Ktrans(TM) and Fp(2CXM), ρ = 0.91.Conclusion. The 2CXM was most often optimal in describing the contrast agent enhancement of pre-treatment cervical cancers, although this model broke down in a subset of the tumour voxels where overfitting resulted in non-physiological parameter estimates. Due to the possible overfitting of the 2CXM, the C-TU was found more robust and when 2CXM was excluded from comparison the C-TU was the preferred model.

Assessment of irradiated brain metastases using dynamic contrast-enhanced magnetic resonance imaging

The purpose of this study was to evaluate the effect of stereotactic radiosurgery (SRS) on cerebral metastases using the transfer constant (K trans) assessed by dynamic contrast-enhanced (DCE) MRI. Furthermore, we aimed to evaluate the ability of K trans measurements to predict midterm tumor outcomes after SRS. The study received institutional review board approval, and informed consent was obtained from all subjects. Twenty-six adult patients with a total of 34 cerebral metastases underwent T1-weighted DCE MRI in a 1.5-T magnet at baseline (prior to SRS) and 4-8 weeks after treatment. Quantitative analysis of DCE MRI was performed by generating K trans parametric maps, and region-of-interest-based measurements were acquired for each metastasis. Conventional MRI was performed at least 16 weeks after SRS to assess midterm tumor outcome using volume variation. The mean (±SD) K trans value was 0.13 ± 0.11 min(-1) at baseline and 0.08 ± 0.07 min(-1) after 4-8 weeks post-treatment (p < 0.001). The mean (±SD) total follow-up time was 7.9 ± 4.7 months. Seventeen patients (22 lesions) underwent midterm MRI. Of those, nine (41 %) lesions had progressed at the midterm follow-up. An increase in K trans after SRS was predictive of tumor progression (hazard ratio = 1.50; 95 % CI = 1.16-1.70, p < 0.001). An increase of 15 % in K trans showed a sensitivity of 78 % and a specificity of 85 % for the prediction of progression at midterm follow-up. SRS was associated with a reduction of K trans values of the cerebral metastases in the early post-treatment period. Furthermore, K trans variation as assessed using DCE MRI may be helpful to predict midterm outcomes after SRS.

A Review Study on the Efficacy of Quantitative DCE-MRI in Breast Lesion Diagnosis

: Breast cancer is the most common cancer among women, for which a successful treatment depends in part, on early diagnosis. Accurate differentiation of lesions may greatly affect the outcome of treatment. In this regard, anatomical along with physiological MR imaging modalities, such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) which provide accurate, repeatable and noninvasive physiological biomarkers of tumor growth, have been increasingly used as secondary characterizing tools to ultrasonography (US) and mammography. The aim of this study is to present a thorough review on available scholarly works, especially where quantitative DCE-MRI has been employed for diagnostic decisions on breast cancer, concluding if the modality is either necessary for better sensitivity/specificity, or for a reliable surgery/treatment planning. US and mammography are the conventional screening modalities for breast cancer diagnosis. The overall sensitivity of mammography is 70%90%. However, this sensitivity is variable and can range from as high as 80%98% in women with fatty breast tissue to as low as 30%48% in women with dense breast tissue. Sonographic classification of benign and malignant tumors has a high sensitivity of as high as 98% but a low specificity of about 32%. The low specificity of mammography and US methods and the need for extracting biomarkers, has led to rising interest in employing physiological MR imaging methods for characterizing breast cancers. DCE-MR images can be analyzed in a semi-quantitative (non-model-abased) or quantitative (model-based) approach. The sensitivity and specificity of semi-quantitative DCE-MRI in detecting breast cancer reaches 88.1% and 67.7%, respectively. While it has been proved that DCE-MR imaging features could be useful to noninvasively distinguish highly aggressive breast carcinomas, they are not as useful in discriminating benign from malignant non-mass lesions (such as DCIS). On the other hand, the pharmacokinetic (or model-based) analysis of DCE-MRI can be useful in monitoring and predicting response to therapy, as the changes in tumor vascularization in responder patients precede changes in tumor size, and may better describe tumor response to therapy. Pharmacokinetic model analysis of DCE-MRI data provided a sensitivity and specificity of 100% and 78%, respectively. In comparison with semi-quantitative DCE-MRI, Quantitative DCE-MRI has significantly improved the sensitivity and specificity of breast cancer diagnosis. Other physiological MR imaging alternatives like DW-MRI and MRS have also been employed for breast cancer diagnosis. In a pooled analysis on clinical breast MRS gathered from five independent centers around the world, the sensitivity and specificity of breast MRS were 83% and 85%, respectively. In a study on 78 patients (110 lesions), the sensitivity and specificity of DWI in detection of malignant and benign lesions was reported at 86%. Although the sensitivity and specificity of imaging could be influenced by the selected values of ADC cut-off, the ADC-values may still be used to characterize breast lesions. The diagnosis of breast cancer is a very challenging issue, as early detection may allow for conservative surgery as an alternative to mastectomy. Although mammography and US allow earlier detection of cancers and have been shown to improve the survival of women with breast cancer, with a relatively high sensitivity in women older than 50 years, monitoring the breast cancer is limited by low specificity. DCE-MRI is a powerful imaging tool that has shown utility in delineating the extent of disease in patients with known breast cancer and in screening women at high risk for breast cancer. Semi-quantitative DCE-MRI has high sensitivity but only moderate specificity, because of an overlap between benign and malignant lesions, independent of breast density, tumor type, and menopausal status. Quantitative analysis of DCE-MRI is used by many researchers for detecting and evaluating breast diseases and is a means of increasing the specificity of breast MR examination. MRS of the breast has been proposed as an adjunct to the anatomical MRI examination to improve the specificity of distinguishing malignant from benign breast tumors, however, MRS alone is not suitable in lactating women. Nevertheless, many studies have reported that DWI-MRI may help to differentiate between benign and malignant lesions with good specificity. These findings suggest that incorporating MRS and DW-MRI may increase the overall specificity of quantitative analysis of breast DCE-MRI.

Variations of Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Evaluation of Breast Cancer Therapy Response: A Multicenter Data Analysis Challenge

Pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) time-course data allows estimation of quantitative parameters such as Ktrans (rate constant for plasma/interstitium contrast agent transfer), ve (extravascular extracellular volume fraction), and vp (plasma volume fraction). A plethora of factors in DCE-MRI data acquisition and analysis can affect accuracy and precision of these parameters and, consequently, the utility of quantitative DCE-MRI for assessing therapy response. In this multicenter data analysis challenge, DCE-MRI data acquired at one center from 10 patients with breast cancer before and after the first cycle of neoadjuvant chemotherapy were shared and processed with 12 software tools based on the Tofts model (TM), extended TM, and Shutter-Speed model. Inputs of tumor region of interest definition, pre-contrast T1, and arterial input function were controlled to focus on the variations in parameter value and response prediction capability caused by differences in models and associated algorithms. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) values for Ktrans and vp being as high as 0.59 and 0.82, respectively. Parameter agreement improved when only algorithms based on the same model were compared, e.g., the Ktrans intraclass correlation coefficient increased to as high as 0.84. Agreement in parameter percentage change was much better than that in absolute parameter value, e.g., the pairwise concordance correlation coefficient improved from 0.047 (for Ktrans) to 0.92 (for Ktrans percentage change) in comparing two TM algorithms. Nearly all algorithms provided good to excellent (univariate logistic regression c-statistic value ranging from 0.8 to 1.0) early prediction of therapy response using the metrics of mean tumor Ktrans and kep (= Ktrans/ve, intravasation rate constant) after the first therapy cycle and the corresponding percentage changes. The results suggest that the interalgorithm parameter variations are largely systematic, which are not likely to significantly affect the utility of DCE-MRI for assessment of therapy response.

A comparison of two methods for estimating DCE-MRI parameters via individual and cohort based AIFs in prostate cancer: A step towards practical implementation

Multi-parametric Magnetic Resonance Imaging, and specifically Dynamic Contrast Enhanced (DCE) MRI, play increasingly important roles in detection and staging of prostate cancer (PCa). One of the actively investigated approaches to DCE MRI analysis involves pharmacokinetic (PK) modeling to extract quantitative parameters that may be related to microvascular properties of the tissue. It is well-known that the prescribed arterial blood plasma concentration (or Arterial Input Function, AIF) input can have significant effects on the parameters estimated by PK modeling. The purpose of our study was to investigate such effects in DCE MRI data acquired in a typical clinical PCa setting. First, we investigated how the choice of a semi-automated or fully automated image-based individualized AIF (iAIF) estimation method affects the PK parameter values; and second, we examined the use of method-specific averaged AIF (cohort-based, or cAIF) as a means to attenuate the differences between the two AIF estimation methods.Two methods for automated image-based estimation of individualized (patient-specific) AIFs, one of which was previously validated for brain and the other for breast MRI, were compared. cAIFs were constructed by averaging the iAIF curves over the individual patients for each of the two methods. Pharmacokinetic analysis using the Generalized kinetic model and each of the four AIF choices (iAIF and cAIF for each of the two image-based AIF estimation approaches) was applied to derive the volume transfer rate (Ktrans) and extravascular extracellular volume fraction (ve) in the areas of prostate tumor. Differences between the parameters obtained using iAIF and cAIF for a given method (intra-method comparison) as well as inter-method differences were quantified.The study utilized DCE MRI data collected in 17 patients with histologically confirmed PCa. Comparison at the level of the tumor region of interest (ROI) showed that the two automated methods resulted in significantly different (p<0.05) mean estimates of ve, but not of Ktrans. Comparing cAIF, different estimates for both ve, and Ktrans were obtained. Intra-method comparison between the iAIF- and cAIF-driven analyses showed the lack of effect on ve, while Ktrans values were significantly different for one of the methods.Our results indicate that the choice of the algorithm used for automated image-based AIF determination can lead to significant differences in the values of the estimated PK parameters. Ktrans estimates are more sensitive to the choice between cAIF/iAIF as compared to ve, leading to potentially significant differences depending on the AIF method. These observations may have practical consequences in evaluating the PK analysis results obtained in a multi-site setting.

Early assessment of breast cancer response to neoadjuvant chemotherapy by semi-quantitative analysis of high-temporal resolution DCE-MRI: Preliminary results

PurposeTo evaluate whether semi-quantitative analysis of high temporal resolution dynamic contrast-enhanced MRI (DCE-MRI) acquired early in treatment can predict the response of locally advanced breast cancer (LABC) to neoadjuvant chemotherapy (NAC). Materials and MethodsAs part of an IRB-approved prospective study, 21 patients with LABC provided informed consent and underwent high temporal resolution 3T DCE-MRI before and after 1cycle of NAC. Using measurements performed by two radiologists, the following parameters were extracted for lesions at both examinations: lesion size (short and long axes, in both early and late phases of enhancement), radiologist's subjective assessment of lesion enhancement, and percentages of voxels within the lesion demonstrating progressive, plateau, or washout kinetics. The latter data were calculated using two filters, one selecting for voxels enhancing ≥50% over baseline and one for voxels enhancing ≥100% over baseline. Pretreatment imaging parameters and parameter changes following cycle 1 of NAC were evaluated for their ability to discriminate patients with an eventual pathological complete response (pCR). ResultsAll 21 patients completed NAC followed by surgery, with 9 patients achieving a pCR. No pretreatment imaging parameters were predictive of pCR. However, change after cycle 1 of NAC in percentage of voxels demonstrating washout kinetics with a 100% enhancement filter discriminated patients with an eventual pCR with an area under the receiver operating characteristic curve (AUC) of 0.77. Changes in other parameters, including lesion size, did not predict pCR. ConclusionSemi-quantitative analysis of high temporal resolution DCE-MRI in patients with LABC can discriminate patients with an eventual pCR after one cycle of NAC.

Combination therapy with gefitinib and doxorubicin inhibits tumor growth in transgenic mice with adrenal neuroblastoma

Highly relevant mouse models of human neuroblastoma (NB) are needed to evaluate new therapeutic strategies against NB. In this study, we characterized transgenic mice with bilateral adrenal tumors. On the basis of information from the tumoral gene expression profiles, we examined the antitumor effects of unencapsulated and liposomal doxorubicin (DXR), alone and in combination with gefitinib, on adrenal NB. We showed that intravenous injection of unencapsulated or liposomal DXR alone inhibited tumor growth in a dose-dependent manner, as assessed by magnetic resonance imaging (MRI). However, liposomal DXR did not exhibit greater antitumor effect than unencapsulated DXR. Immunohistochemical analysis revealed that the adrenal tumor vasculature with abundant pericyte coverage was a less leaky structure for liposomes. Combination therapy with unencapsulated or liposomal DXR plus gefitinib strongly suppressed tumor growth and delayed tumor regrowth than treatment with unencapsulated or liposomal DXR alone, even at a lower dose of DXR. Dynamic contrast-enhanced MRI analysis revealed that gefitinib treatment increased blood flow in the tumor, indicating that gefitinib treatment changes the tumor vascular environment in a manner that may increase the antitumor effect of DXR. In conclusion, the combination of gefitinib and DXR induces growth inhibition of adrenal NBs in transgenic mice. These findings will provide helpful insights into new treatments for NB.

MRI‐based prediction of pulsed high‐intensity focused ultrasound effect on tissue transport in rabbit muscle

To design an algorithm for optimizing pulsed high intensity focused ultrasound (p-HIFU) treatment parameters to maximize tissue transport while minimizing thermal necrosis based on MR image guidance. P-HIFU power, duty cycle, and treatment duration were varied to generate different levels of thermal and mechanical deposition in rabbit muscle. Changes in T2-weighted and T1 contrast-enhanced (CE) signal were assessed immediately following treatment and at 24 h. Transport parameters were extracted by means of T1-weighted dynamic contrast-enhanced MRI (DCE-MRI) technique at 0 and 24-h time points. Successful p-HIFU treatment was indicated by focal hyperintensity on the T2-weighted image immediately post-treatment, suggesting increased fluid (edema), with little intensity change in CE image. After 24 h, the affected region expanded along the muscle fiber accompanied by clear hyperintensity in CE image (contrast uptake). Quantitative DCE-MRI analysis revealed statistically significant increases in both leakage rate and extracellular space, accompanied by a decrease in clearance rate. Successful p-HIFU treatment was mainly correlated to tissue heating. Tissue transport properties following treatment success would result in improved contact between drug and targets in both time and space. MRI is the key to controlling treatment by means of thermometry and also monitoring efficacy by means of T2-weighted imaging.

Dynamic Contrast-Enhanced MRI in Determining Disease Activity in Perianal Fistulizing Crohn Disease: A Pilot Study

The objective of our study was to perform a semiquantitative analysis of dynamic contrast-enhanced MRI for the evaluation of disease activity and therapeutic response in patients with perianal fistulizing Crohn disease. Sixteen consecutively registered patients with perianal Crohn disease underwent pelvic MRI. A dynamic contrast-enhanced sequence was performed at 3 T (temporal resolution, 4.2 seconds) during i.v. contrast injection. Maximum enhancement, initial slope of increase, volume transfer constant (K(trans)), and the extravascular space fractional volume (x028B;(e)) were calculated in a region of interest drawn around the fistula. Perianal disease activity index, C-reactive protein concentration, and an MRI-based activity score were calculated as reference standards. Six patients underwent a second MRI examination 6 weeks after starting treatment with anti-tumor necrosis factor α (anti-TNF-α). Perianal disease activity index moderately correlated with maximum enhancement (r = 0.67, p = 0.005), initial slope of increase (r = 0.58, p = 0.018), and volume of enhancing pixels (r = 0.79, p < 0.001) but not with K(trans) or x028B;(e). Volume of enhancing pixels also correlated with C-reactive protein concentration and the MRI-based score (r = 0.52, p = 0.041; r = 0.79, p < 0.001). The K(trans) values had decreased significantly 6 weeks after the start of anti-TNF-α therapy. Maximum enhancement and initial slope of increase correlate with disease activity in perianal Crohn disease. K(trans) may be an indicator of the effect of therapy on patients starting anti-TNF-α treatment.

Computer Assisted Analysis of MR-Mammography Reveals Association between Contrast Enhancement and Occurrence of Distant Metastasis

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is able to detect breast cancer with high sensitivity. Furthermore, this method provides functional information on tissue composition and vascularization. This study aims to identify the potential of DCE-MRI to predict distant metastasis in breast cancer patients using computer assisted interpretation of dynamic enhancement data. For this purpose, 59 consecutive patients with newly diagnosed invasive breast cancer received pretherapeutic DCE-MRI at 1.5 Tesla according to international recommendations. In all patients, follow up interval and occurrence of distant metastasis was documented. For DCE-MRI analysis dedicated software was used (Brevis, Siemens Healthcare, Erlangen, Germany). It allows semiautomatic identification of the most suspect curve in a lesion analyzed. Enhancement parameters assessed were "Initial Enhancement", "Washout", "Peak-Enhancement", and "Time to Peak Enhancement". Cox proportional hazards regression (CPHR) was used to analyze the effect of these parameters on the probability of metachronous distant metastasis. Median follow up period was 52.0 months. 6 patients developed distant metastases between 11 and 35 months after breast cancer diagnosis. In CPHR, Washout could be identified as significant and independent predictor for occurrence of distant metastasis (P = 0.0134). Our initial data demonstrate an association between computer measured enhancement parameters in DCE-MRI and occurrence of distant metastasis by quantification of Washout.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) in Preclinical Studies of Antivascular Treatments

Antivascular treatments can either be antiangiogenic or targeting established tumour vasculature. These treatments affect the tumour microvasculature and microenvironment but may not change clinical measures like tumour volume and growth. In research on antivascular treatments, information on the tumour vasculature is therefore essential. Preclinical research is often used for optimization of antivascular drugs alone or in combined treatments. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an in vivo imaging method providing vascular information, which has become an important tool in both preclinical and clinical research. This review discusses common DCE-MRI imaging protocols and analysis methods and provides an overview of preclinical research on antivascular treatments utilizing DCE-MRI.

Assessing liver function using dynamic Gd‐EOB‐DTPA‐enhanced MRI with a standard 5‐phase imaging protocol

To evaluate liver function obtained by tracer-kinetic modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data acquired with a routine gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced protocol. Data were acquired from 25 cases of nonchronic liver disease and 94 cases of cirrhosis. DCE-MRI was performed with a dose of 0.025 mmol/kg Gd-EOB-DTPA injected at 2 mL/sec. A 3D breath-hold sequence acquired 5 volumes of 72 slices each: precontrast, double arterial phase, portal phase, and 4-minute postcontrast. Regions of interest (ROIs) were selected semiautomatically in the aorta, portal vein, and whole liver on a middle slice. A constrained dual-inlet two-compartment uptake model was fitted to the ROI curves, producing three parameters: intracellular uptake rate (UR), extracellular volume (Ve), and arterial flow fraction (AFF). Median UR dropped from 4.46 10(-2) min(-1) in the noncirrhosis to 3.20 in Child-Pugh A (P = 0.001), and again to 1.92 in Child-Pugh B (P < 0.0001). Median Ve dropped from 6.64 mL 100 mL(-1) in the noncirrhosis to 5.80 in Child-Pugh A (P = 0.01). Other combinations of Ve and AFF changes were not significant for any group. UR obtained from tracer kinetic analysis of a routine DCE-MRI has the potential to become a novel index of liver function.

Early changes in angiogenesis and hypoxia following bevacizumab therapy in primary breast cancer.

1066 Background: Bevacizumab (BV), a monoclonal antibody directed against vascular endothelial growth factor (VEGF), is an approved anti-angiogenic agent, but despite its widespread use, little is known about how tumours develop resistance to BV. We have conducted a window-of-opportunity study in which BV is administered as a short-term first-line treatment for primary breast cancer (PBC) patients, and assessed histological markers of tumour angiogenesis and hypoxia before and after therapy. Methods: 47 patients with locally advanced breast cancer were prospectively enrolled. Informed consent was obtained from all patients. A single infusion of BV (15 mg/kg) was given 2 weeks before starting neoadjuvant chemotherapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and core biopsies for immunohistochemistry (IHC) analysis were performed immediately prior to and 2 weeks after BV. 36 patients with invasive ductal carcinoma and good quality MRI scans and core biopsies were included in this analysis. Wilcoxon rank test and Spearman’s correlation test were used for statistical analysis. Results: IHC revealed a significant upregulation of carbonic anhydrase 9 (P = 0.04) and hypoxia inducible factor-1a (P = 0.001) following BV therapy along with a significant reduction in plasmalemma vesicle associated protein (PLVAP) (p=0.01) and Ki67 (p= 0.006). DCE-MRI analysis revealed a significant reduction in vessel permeability and blood flow following BV, as measured by a decrease in the forward transfer constant Ktrans (P &lt; 0.0001) and the reverse rate constant kep (P &lt; 0.0001). In addition, we found a significant negative correlation between CA9 levels and median Ktrans at baseline (Spearman’s rho = -0.46; P = 0.01). Conclusions: Using combined DCE-MRI and IHC analysis, we found that PBC patients treated with single-agent BV showed a decrease in markers of tumour angiogenesis, together with a corresponding increase in tumour hypoxia. Our results suggest that tumour hypoxia may be a key mechanism governing the early onset of resistance to BV therapy, and argue for the use of suitable combination therapies to overcome the resistance and ultimately improve patient survival.

Parametric Histogram Analysis of Dynamic Contrast-enhanced MRI in Multiple Myeloma: A Technique to Evaluate Angiogenic Response to Therapy?

From dynamic contrast-enhanced magnetic resonance imaging, it is known that microcirculation patterns in multiple myeloma differ depending on the infiltration pattern. The purpose of this study was to evaluate histogram analysis of dynamic contrast-enhanced magnetic resonance imaging in MM to monitor early treatment response on the basis of microcirculation patterns. A total of 51 patients with multiple myeloma requiring therapy were examined. Dynamic contrast-enhanced magnetic resonance imaging of the lumbar spine was performed before and after conventional or high-dose chemotherapy with autologous stem cell transplantation. Statistical analysis included 245 vertebrae and dynamic microcirculation parameters as displayed in histograms. Resulting parameters (amplitude, exchange rate constant, skewness, kurtosis, and left shift) were correlated with therapeutic response. More than 70% of histograms derived from the microcirculation parameters showed a difference between the maximum peak before and after therapy (left shift). However, there was no significant difference between the particular treatment. Significantly different skewness of amplitude in 98% and kurtosis of exchange rate constant (94.1% and 98%) were seen in the patients who responded to treatment (P for each < .05). Histogram analysis revealed early changes after therapy resulting in a shift toward more (kurtosis) and lower values (skewness) of microcirculation parameters. Therefore, histogram analysis can determine and describe if a chosen therapy works at all. However, there were no differences between the chosen therapies. This needs to be reevaluated in a larger number of treated patients. Histogram analysis can also be an adjunct to a subjective visual analysis but is hampered by heterogeneous infiltration pattern seen in multiple myeloma.

Phase I/II and Pharmacodynamic Study of Dovitinib (TKI258), an Inhibitor of Fibroblast Growth Factor Receptors and VEGF Receptors, in Patients with Advanced Melanoma

Dovitinib (TKI258) is an orally available inhibitor of fibroblast growth factor (FGF), VEGF, and platelet-derived growth factor receptors. This phase I/II dose-escalation study was conducted to evaluate the safety, pharmacodynamics, and preliminary efficacy of dovitinib in the treatment of advanced melanoma. Patients with advanced melanoma resistant or refractory to standard therapies or for whom no standard therapy was available were enrolled. Dovitinib was administered at doses ranging from 200 to 500 mg/d. Forty-seven patients were enrolled. The most frequently reported adverse events were fatigue (77%; grade ≥3, 28%), diarrhea (77%; grade ≥3, 11%), and nausea (77%; grade ≥3, 9%). Six dose-limiting toxicities were observed in the 400-mg and 500-mg dose cohorts, which consisted of grade 3 nausea, fatigue, and diarrhea and grade 4 fatigue events. The maximum tolerated dose was 400 mg/d. The best tumor response was stable disease, which was observed in 12 patients. Increases in plasma FGF23, VEGF, and placental growth factor and decreases in soluble VEGF receptor 2 were noted during the first cycle of treatment, consistent with FGF receptor (FGFR) and VEGF receptor (VEGFR) inhibition. Dynamic contrast-enhanced MRI analysis showed a dose-dependent decrease in tumor blood flow and vascular permeability with dovitinib therapy. A decrease in FGFR phosphorylation was observed in paired tumor biopsy samples from a patient treated with dovitinib at a dose of 400 mg/d. At a dose of 400 mg/d, dovitinib showed an acceptable safety profile and limited clinical benefit and inhibited FGFR and VEGFR.

Endocardial and epicardial myocardial perfusion determined by semi-quantitative and quantitative myocardial perfusion magnetic resonance

This study aims to quantify subendocardial and subepicardial myocardial blood flow (MBF) from dynamic contrast-enhanced MRI and to compare semi-quantitative and quantitative analysis methods. 17 healthy volunteers (9 males, mean age 34 ± 8) were scanned during adenosine stress and at rest. A "semi-quantitative" myocardial perfusion index (MPI) was calculated based on maximal upslopes of signal intensity-time profiles for a mid-ventricular myocardial slice. In addition, absolute MBF (ml/g/min) was estimated using Fermi-constrained deconvolution. On semi-quantitative analysis, the ratio of subendocardial to subepicardial MPI was 0.98 ± 0.1 at stress and 1.16 ± 0.09 at rest, P < 0.0001. The MPRI (i.e. the ratio of stress over rest MPI) for the subendocardium was 1.54 ± 0.3 versus 1.81 ± 0.35 for the subepicardium, P = 0.03. For quantitative analysis, the ratio of subendocardial to subepicardial MBF was 0.91 ± 0.11 at stress versus 1.17 ± 0.16 at rest, P < 0.0001. The subendocardial MBF reserve was also lower than in the subepicardium (2.6 ± 0.75 vs. 3.32 ± 0.93, P = 0.027). In conclusion, semi-quantitative and quantitative analysis of dynamic contrast-enhanced MRI shows higher subendocardial blood flow at rest and reduced subendocardial perfusion reserve compared to the subepicardium.

Impact of nonrigid motion correction technique on pixel‐wise pharmacokinetic analysis of free‐breathing pulmonary dynamic contrast‐enhanced MR imaging

To investigates the impact of nonrigid motion correction on pixel-wise pharmacokinetic analysis of free-breathing DCE-MRI in patients with solitary pulmonary nodules (SPNs). Misalignment of focal lesions due to respiratory motion in free-breathing dynamic contrast-enhanced MRI (DCE-MRI) precludes obtaining reliable time-intensity curves, which are crucial for pharmacokinetic analysis for tissue characterization. Single-slice 2D DCE-MRI was obtained in 15 patients. Misalignments of SPNs were corrected using nonrigid B-spline image registration. Pixel-wise pharmacokinetic parameters K(trans) , v(e) , and k(ep) were estimated from both original and motion-corrected DCE-MRI by fitting the two-compartment pharmacokinetic model to the time-intensity curve obtained in each pixel. The "goodness-of-fit" was tested with χ(2) -test in pixel-by-pixel basis to evaluate the reliability of the parameters. The percentages of reliable pixels within the SPNs were compared between the original and motion-corrected DCE-MRI. In addition, the parameters obtained from benign and malignant SPNs were compared. The percentage of reliable pixels in the motion-corrected DCE-MRI was significantly larger than the original DCE-MRI (P = 4 × 10(-7) ). Both K(trans) and k(ep) derived from the motion-corrected DCE-MRI showed significant differences between benign and malignant SPNs (P = 0.024, 0.015). The study demonstrated the impact of nonrigid motion correction technique on pixel-wise pharmacokinetic analysis of free-breathing DCE-MRI in SPNs.

Dynamische kontrastmittelunterstützte MRT der Prostata: Vergleich von zwei Auswerteverfahren

To evaluate the usefulness of a commercially available post-processing software tool for detecting prostate cancer on dynamic contrast-enhanced magnetic resonance imaging (MRI) and to compare the results to those obtained with a custom-made post-processing algorithm already tested under clinical conditions. Forty-eight patients with proven prostate cancer were examined by standard MRI supplemented by dynamic contrast-enhanced dual susceptibility contrast (DCE-DSC) MRI prior to prostatectomy. A custom-made post-processing algorithm was used to analyze the MRI data sets and the results were compared to those obtained using a post-processing algorithm from In vivo Corporation (Dyna CAD for Prostate) applied to dynamic T 1-weighted images. Histology was used as the gold standard. The sensitivity for prostate cancer detection was 78 % for the custom-made algorithm and 60 % for the commercial algorithm and the specificity was 79 % and 82 %, respectively. The accuracy was 79 % for our algorithm and 77.5 % for the commercial software tool. The chi-square test (McNemar-Bowker test) yielded no significant differences between the two tools (p = 0.06). The two investigated post-processing algorithms did not differ in terms of prostate cancer detection. The commercially available software tool allows reliable and fast analysis of dynamic contrast-enhanced MRI for the detection of prostate cancer.

On the scope and interpretation of the Tofts models for DCE‐MRI

The Tofts model (TM) and extended Tofts model (ETM) have become a standard for the analysis of dynamic contrast-enhanced MRI. In this study, a mathematical analysis is used to identify exactly in which tissue types the Tofts models may be applied. The results show that the TM is accurate if and only if the tissue is weakly vascularised (small blood volume). The ETM is additionally accurate in highly perfused tissues (high blood flow). In tissues that are highly vascularised, or where tracer exchange is very fast or very slow, TM and ETM accurately fit the data but lead to a misinterpretation of the parameters. In tissue types with intermediate vascularity, perfusion and tracer exchange, neither model offers a good fit to the tissue concentrations. A good fit can be obtained with a measured input function by reducing the temporal resolution, but this does not improve the accuracy of the parameters. In conclusion, the Tofts models only produce reliable parameter values if the tissue is weakly vascularized (TM or ETM) or highly perfused (ETM). Without prior knowledge that at least one of these constraints is fulfilled, the physiological interpretation of the values produced by the Tofts models is unclear.

Correlations of 3T DCE-MRI Quantitative Parameters with Microvessel Density in a Human-Colorectal-Cancer Xenograft Mouse Model

ObjectiveTo investigate the correlation between quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) parameters and microvascular density (MVD) in a human-colon-cancer xenograft mouse model using 3 Tesla MRI.Materials and MethodsA human-colon-cancer xenograft model was produced by subcutaneously inoculating 1 × 106 DLD-1 human-colon-cancer cells into the right hind limbs of 10 mice. The tumors were allowed to grow for two weeks and then assessed using MRI. DCE-MRI was performed by tail vein injection of 0.3 mmol/kg of gadolinium. A region of interest (ROI) was drawn at the midpoints along the z-axes of the tumors, and a Tofts model analysis was performed. The quantitative parameters (Ktrans, Kep and Ve) from the whole transverse ROI and the hotspot ROI of the tumor were calculated. Immunohistochemical microvessel staining was performed and analyzed according to Weidner's criteria at the corresponding MRI sections. Additional Hematoxylin and Eosin staining was performed to evaluate tumor necrosis. The Mann-Whitney test and Spearman's rho correlation analysis were performed to prove the existence of a correlation between the quantitative parameters, necrosis, and MVD.ResultsWhole transverse ROI of the tumor showed no significant relationship between the MVD values and quantitative DCE-MRI parameters. In the hotspot ROI, there was a difference in MVD between low and high group of Ktrans and Kep that had marginally statistical significance (ps = 0.06 and 0.07, respectively). Also, Ktrans and Kep were found to have an inverse relationship with MVD (r = -0.61, p = 0.06 in Ktrans; r = -0.60, p = 0.07 in Kep).ConclusionQuantitative analysis of T1-weighted DCE-MRI using hotspot ROI may provide a better histologic match than whole transverse section ROI. Within the hotspots, Ktrans and Kep tend to have a reverse correlation with MVD in this colon cancer mouse model.