Dynamic contrast-enhanced MRI in mouse tumors at 11.7 T: comparison of three contrast agents with different molecular weights to assess the early effects of combretastatin A4.

Dynamic contrast-enhanced (DCE)-MRI is useful to assess the early effects of drugs acting on tumor vasculature, namely anti-angiogenic and vascular disrupting agents. Ultra-high-field MRI allows higher-resolution scanning for DCE-MRI while maintaining an adequate signal-to-noise ratio. However, increases in susceptibility effects, combined with decreases in longitudinal relaxivity of gadolinium-based contrast agents (GdCAs), make DCE-MRI more challenging at high field. The aim of this work was to explore the feasibility of using DCE-MRI at 11.7 T to assess the tumor hemodynamics of mice. Three GdCAs possessing different molecular weights (gadoterate: 560 Da, 0.29 mmol Gd/kg; p846: 3.5 kDa, 0.10 mmol Gd/kg; and p792: 6.47 kDa, 0.15 mmol Gd/kg) were compared to see the influence of the molecular weight in the highlight of the biologic effects induced by combretastatin A4 (CA4). Mice bearing transplantable liver tumor (TLT) hepatocarcinoma were divided into two groups (n = 5-6 per group and per GdCA): a treated group receiving 100 mg/kg CA4, and a control group receiving vehicle. The mice were imaged at 11.7 T with a T1 -weighted FLASH sequence 2 h after the treatment. Individual arterial input functions (AIFs) were computed using phase imaging. These AIFs were used in the Extended Tofts Model to determine K(trans) and vp values. A separate immunohistochemistry study was performed to assess the vascular perfusion and the vascular density. Phase imaging was used successfully to measure the AIF for the three GdCAs. In control groups, an inverse relationship between the molecular weight of the GdCA and K(trans) and vp values was observed. K(trans) was significantly decreased in the treated group compared with the control group for each GdCA. DCE-MRI at 11.7 T is feasible to assess tumor hemodynamics in mice. With K(trans) , the three GdCAs were able to track the early vascular effects induced by CA4 treatment.

Diagnostic Accuracy of Arterial Spin-Labeling, Dynamic Contrast-Enhanced, and DSC Perfusion Imaging in the Diagnosis of Recurrent High-Grade Gliomas: A Prospective Study.

BACKGROUND AND PURPOSE: For patients with high-grade gliomas, the appearance of a new, enhancing lesion after surgery and chemoradiation represents a diagnostic dilemma. We hypothesized that MR perfusion without and with contrast can differentiate tumor recurrence from radiation necrosis. MATERIALS AND METHODS: In this prospective study, we performed 3 MR perfusion methods: arterial spin-labeling, DSC, and dynamic contrast enhancement. For each lesion, we measured CBF from arterial spin-labeling, uncorrected relative CBV, and leakage-corrected relative CBV from DSC imaging. The volume transfer constant and plasma volume were obtained from dynamic contrast-enhanced imaging without and with T1 mapping using modified Look-Locker inversion recovery (MOLLI). The diagnosis of tumor recurrence or radiation necrosis was determined by either histopathology for patients who underwent re-resection or radiologic follow-up for patients who did not have re-resection. RESULTS: There were 26 patients with 32 lesions, 19 lesions with tumor recurrence and 13 lesions with radiation necrosis. Compared with radiation necrosis, lesions with tumor recurrence had higher CBF (P = .033), leakage-corrected relative CBV (P = .048), and plasma volume using MOLLI T1 mapping (P = .012). For differentiating tumor recurrence from radiation necrosis, the areas under the curve were 0.81 for CBF, 0.80 for plasma volume using MOLLI T1 mapping, and 0.71 for leakage-corrected relative CBV. A correlation was found between CBF and leakage-corrected relative CBV (r s = 0.54), volume transfer constant, and plasma volume (0.50 < r s< 0.77) but not with uncorrected relative CBV (r s = 0.20, P = .29). CONCLUSIONS: In the differentiation of tumor recurrence from radiation necrosis in a newly enhancing lesion, the diagnostic value of arterial spin-labeling-derived CBF is similar to that of DSC and dynamic contrast-enhancement-derived blood volume.

Noninvasive mapping of spontaneous fluctuations in tumor oxygenation using 19F MRI.

PURPOSE: Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and may be a poorly appreciated therapeutic problem as it can be associated with resistance to radiation therapy, impaired delivery of chemotherapeutic agents, or metastasis development. The objective of the present study was to use MR 19F relaxometry maps to analyze the spontaneous fluctuations of partial pressure of oxygen (pO2) over time in experimental tumors. METHODS: The pO2 maps were generated after direct intratumoral administration of a fluorine compound (hexafluorobenzene) whose relaxation rate (1/T1) is proportional to the % O2. The authors used a SNAP inversion-recovery sequence at 4.7 T to acquire parametric images of the T1 relaxation time with a high spatial and temporal resolution. Homemade routines were developed to perform regions of interest analysis, as well as pixel by pixel analysis of pO2 over time. RESULTS: The authors were able to quantify and probe the heterogeneity of spontaneous fluctuations in tumor pO2: (i) Spontaneous fluctuations in pO2 occurred regardless of the basal oxygenation state (i.e., both in oxygenated and in hypoxic regions) and (ii) spontaneous fluctuations occurred at a rate of 1 cycle/12-47 min. For validation, the analysis was performed in dead mice for which acute changes did not occur. The authors thereby demonstrated that 19F MRI technique is sensitive to acute change in pO2 in tumors. CONCLUSIONS: This is the first approach that allows quantitative minimally invasive measurement of the spontaneous fluctuations of tumor oxygenation using a look-locker approach (e.g., SNAP IR). This approach could be an important tool to characterize the phenomenon of tumor acute hypoxia, to understand its physiopathology, and to improve therapies.

Perfusion MRI in hips with metal-on-metal and metal-on-polyethylene total hip arthroplasty: A pilot study.

OBJECTIVES: Hips with metal-on-metal total hip arthroplasty (MoM THA) have a high rate of adverse local tissue reactions (ALTR), often associated with hypersensitivity reactions. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measures tissue perfusion with the parameter Ktrans (volume transfer constant of contrast agent). Our purpose was 1) to evaluate the feasibility of DCE-MRI in patients with THA and 2) to compare DCE-MRI in patients with MoM bearings with metal-on-polyethylene (MoP) bearings, hypothesising that the perfusion index Ktrans in hips with MoM THA is higher than in hips with MoP THA. METHODS: In this pilot study, 16 patients with primary THA were recruited (eight MoM, eight MoP). DCE-MRI of the hip was performed at 1.5 Tesla (T). For each patient, Ktrans was computed voxel-by-voxel in all tissue lateral to the bladder. The mean Ktrans for all voxels was then calculated. These values were compared with respect to implant type and gender, and further correlated with clinical parameters. RESULTS: There was no significant difference between the two bearing types with both genders combined. However, dividing patients by THA bearing and gender, women with MoM bearings had the highest Ktrans values, exceeding those of women with MoP bearings (0.067 min(-1) versus 0.053 min(-1); p-value < 0.05) and men with MoM bearings (0.067 min(-1) versus 0.034 min(-1); p-value < 0.001). Considering only the men, patients with MoM bearings had lower Ktrans than those with MoP bearings (0.034 min(-1) versus 0.046 min(-1); p < 0.05). CONCLUSION: DCE-MRI is feasible to perform in tissues surrounding THA. Females with MoM THA show high Ktrans values in DCE-MRI, suggesting altered tissue perfusion kinematics which may reflect relatively greater inflammation.Cite this article: Dr P. E. Beaule. Perfusion MRI in hips with metal-on-metal and metal-on-polyethylene total hip arthroplasty: A pilot stud. Bone Joint Res 2016;5:73-79. DOI: 10.1302/2046-3758.53.2000572.

Correlation of Tumor Immunohistochemistry with Dynamic Contrast-Enhanced and DSC-MRI Parameters in Patients with Gliomas.

BACKGROUND AND PURPOSE: Tumor CBV is a prognostic and predictive marker for patients with gliomas. Tumor CBV can be measured noninvasively with different MR imaging techniques; however, it is not clear which of these techniques most closely reflects histologically-measured tumor CBV. Our aim was to investigate the correlations between dynamic contrast-enhanced and DSC-MR imaging parameters and immunohistochemistry in patients with gliomas. MATERIALS AND METHODS: Forty-three patients with a new diagnosis of glioma underwent a preoperative MR imaging examination with dynamic contrast-enhanced and DSC sequences. Unnormalized and normalized cerebral blood volume was obtained from DSC MR imaging. Two sets of plasma volume and volume transfer constant maps were obtained from dynamic contrast-enhanced MR imaging. Plasma volume obtained from the phase-derived vascular input function and bookend T1 mapping (Vp_Φ) and volume transfer constant obtained from phase-derived vascular input function and bookend T1 mapping (Ktrans_Φ) were determined. Plasma volume obtained from magnitude-derived vascular input function (Vp_SI) and volume transfer constant obtained from magnitude-derived vascular input function (Ktrans_SI) were acquired, without T1 mapping. Using CD34 staining, we measured microvessel density and microvessel area within 3 representative areas of the resected tumor specimen. The Mann-Whitney U test was used to test for differences according to grade and degree of enhancement. The Spearman correlation was performed to determine the relationship between dynamic contrast-enhanced and DSC parameters and histopathologic measurements. RESULTS: Microvessel area, microvessel density, dynamic contrast-enhanced, and DSC-MR imaging parameters varied according to the grade and degree of enhancement (P < .05). A strong correlation was found between microvessel area and Vp_Φ and between microvessel area and unnormalized blood volume (rs ≥ 0.61). A moderate correlation was found between microvessel area and normalized blood volume, microvessel area and Vp_SI, microvessel area and Ktrans_Φ, microvessel area and Ktrans_SI, microvessel density and Vp_Φ, microvessel density and unnormalized blood volume, and microvessel density and normalized blood volume (0.44 ≤ rs ≤ 0.57). A weaker correlation was found between microvessel density and Ktrans_Φ and between microvessel density and Ktrans_SI (rs ≤ 0.41). CONCLUSIONS: With dynamic contrast-enhanced MR imaging, use of a phase-derived vascular input function and bookend T1 mapping improves the correlation between immunohistochemistry and plasma volume, but not between immunohistochemistry and the volume transfer constant. With DSC-MR imaging, normalization of tumor CBV could decrease the correlation with microvessel area.

Comparison of the Diagnostic Accuracy of DSC- and Dynamic Contrast-Enhanced MRI in the Preoperative Grading of Astrocytomas.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging parameters can be biased by poor measurement of the vascular input function. We have compared the diagnostic accuracy of dynamic contrast-enhanced MR imaging by using a phase-derived vascular input function and "bookend" T1 measurements with DSC MR imaging for preoperative grading of astrocytomas. MATERIALS AND METHODS: This prospective study included 48 patients with a new pathologic diagnosis of an astrocytoma. Preoperative MR imaging was performed at 3T, which included 2 injections of 5-mL gadobutrol for dynamic contrast-enhanced and DSC MR imaging. During dynamic contrast-enhanced MR imaging, both magnitude and phase images were acquired to estimate plasma volume obtained from phase-derived vascular input function (Vp_Φ) and volume transfer constant obtained from phase-derived vascular input function (K(trans)_Φ) as well as plasma volume obtained from magnitude-derived vascular input function (Vp_SI) and volume transfer constant obtained from magnitude-derived vascular input function (K(trans)_SI). From DSC MR imaging, corrected relative CBV was computed. Four ROIs were placed over the solid part of the tumor, and the highest value among the ROIs was recorded. A Mann-Whitney U test was used to test for difference between grades. Diagnostic accuracy was assessed by using receiver operating characteristic analysis. RESULTS: Vp_ Φ and K(trans)_Φ values were lower for grade II compared with grade III astrocytomas (P < .05). Vp_SI and K(trans)_SI were not significantly different between grade II and grade III astrocytomas (P = .08-0.15). Relative CBV and dynamic contrast-enhanced MR imaging parameters except for K(trans)_SI were lower for grade III compared with grade IV (P ≤ .05). In differentiating low- and high-grade astrocytomas, we found no statistically significant difference in diagnostic accuracy between relative CBV and dynamic contrast-enhanced MR imaging parameters. CONCLUSIONS: In the preoperative grading of astrocytomas, the diagnostic accuracy of dynamic contrast-enhanced MR imaging parameters is similar to that of relative CBV.

Preoperative prognostic value of dynamic contrast-enhanced MRI-derived contrast transfer coefficient and plasma volume in patients with cerebral gliomas.

BACKGROUND AND PURPOSE: The prognostic value of dynamic contrast-enhanced MR imaging-derived plasma volume obtained in tumor and the contrast transfer coefficient has not been well-established in patients with gliomas. We determined whether plasma volume and contrast transfer coefficient in tumor correlated with survival in patients with gliomas in addition to other factors such as age, type of surgery, preoperative Karnofsky score, contrast enhancement, and histopathologic grade. MATERIALS AND METHODS: This prospective study included 46 patients with a new pathologically confirmed diagnosis of glioma. The contrast transfer coefficient and plasma volume obtained in tumor maps were calculated directly from the signal-intensity curve without T1 measurements, and values were obtained from multiple small ROIs placed within tumors. Survival curve analysis was performed by dichotomizing patients into groups of high and low contrast transfer coefficient and plasma volume. Univariate analysis was performed by using dynamic contrast-enhanced parameters and clinical factors. Factors that were significant on univariate analysis were entered into multivariate analysis. RESULTS: For all patients with gliomas, survival was worse for groups of patients with high contrast transfer coefficient and plasma volume obtained in tumor (P < .05). In subgroups of high- and low-grade gliomas, survival was worse for groups of patients with high contrast transfer coefficient and plasma volume obtained in tumor (P < .05). Univariate analysis showed that factors associated with lower survival were age older than 50 years, low Karnofsky score, biopsy-only versus resection, marked contrast enhancement versus no/mild enhancement, high contrast transfer coefficient, and high plasma volume obtained in tumor (P < .05). In multivariate analysis, a low Karnofsky score, biopsy versus resection in combination with marked contrast enhancement, and a high contrast transfer coefficient were associated with lower survival rates (P < .05). CONCLUSIONS: In patients with glioma, those with a high contrast transfer coefficient have lower survival than those with low parameters.

Diagnostic accuracy of dynamic contrast-enhanced MR imaging using a phase-derived vascular input function in the preoperative grading of gliomas.

BACKGROUND AND PURPOSE: The accuracy of tumor plasma volume and K(trans) estimates obtained with DCE MR imaging may have inaccuracies introduced by a poor estimation of the VIF. In this study, we evaluated the diagnostic accuracy of a novel technique by using a phase-derived VIF and "bookend" T1 measurements in the preoperative grading of patients with suspected gliomas. MATERIALS AND METHODS: This prospective study included 46 patients with a new pathologically confirmed diagnosis of glioma. Both magnitude and phase images were acquired during DCE MR imaging for estimates of K(trans)_φ and V(p_)φ (calculated from a phase-derived VIF and bookend T1 measurements) as well as K(trans)_SI and V(p_)SI (calculated from a magnitude-derived VIF without T1 measurements). RESULTS: Median K(trans)_φ values were 0.0041 minutes(-1) (95 CI, 0.00062-0.033), 0.031 minutes(-1) (0.011-0.150), and 0.088 minutes(-1) (0.069-0.110) for grade II, III, and IV gliomas, respectively (P ≤ .05 for each). Median V(p_)φ values were 0.64 mL/100 g (0.06-1.40), 0.98 mL/100 g (0.34-2.20), and 2.16 mL/100 g (1.8-3.1) with P = .15 between grade II and III gliomas and P = .015 between grade III and IV gliomas. In differentiating low-grade from high-grade gliomas, AUCs for K(trans)_φ, V(p_φ), K(trans)_SI, and V(p_)SI were 0.87 (0.73-1), 0.84 (0.69-0.98), 0.81 (0.59-1), and 0.84 (0.66-0.91). The differences between the AUCs were not statistically significant. CONCLUSIONS: K(trans)_φ and V(p_)φ are parameters that can help in differentiating low-grade from high-grade gliomas.

Accurate and rapid quantitative dynamic contrast-enhanced breast MR imaging using spoiled gradient-recalled echoes and bookend T(1) measurements.

A method is presented that converts dynamic T(1)-weighted spoiled gradient-recalled echo (SGRE) image intensities into estimates of T(1) without the errors associated with imperfections in the slice profile and transmitter coil magnetic field (B(1)). The method involves T(1) measurements performed before and after a series of dynamic SGRE images. These measurements serve to calibrate and correct the SGRE signal strength equation used to estimate T(1). Simulations and phantom experiments were performed to test the method for slice-selective (two-dimensional) and slab-selective (three-dimensional) imaging, as well as for imaging performed with optimized and un-optimized B(1). For nearly all test conditions, T(1) was estimated accurately (within 10%) over a range of T(1) values expected in vivo ( approximately 1200 --> 300 msec). This method should be useful for quantifying dynamic SGRE imaging for many different applications including breast MR imaging. Magn Reson Med 42:746-753, 1999.

Application of a quantitative model to differentiate benign from malignant breast lesions detected by dynamic, gadolinium-enhanced MRI.

Both benign and malignant breast lesions may exhibit intense contrast enhancement when imaged using gadolinium-enhanced MRI. We propose a quantitative approach for fitting dynamic signal intensity (SI) data that may distinguish benign from malignant lesions. We studied 78 lesions in 75 women (18 malignancies, 16 fibroadenomas, and 44 other benign breast lesions) to determine the potential of this model for decreasing false-positive MR results. Twenty-eight lesions showed no enhancement; all were benign. One lesion showed a complex pattern not amenable to region-of-interest analysis and was considered a false positive. SI versus time data for the remaining 49 lesions were fit to the proposed model. We found that one parameter, M, the normalized slope of the SI enhancement profile evaluated at half the maximal signal intensity, seemed to be highly correlated with malignancy and offered improved discrimination between malignant and benign lesions compared to a previously published two-point slope method.