Detection of single-phase CTA occult vessel occlusions in acute ischemic stroke using CT perfusion-based wavelet-transformed angiography.

OBJECTIVES: To determine the detection rate of intracranial vessel occlusions using CT perfusion-based wavelet-transformed angiography (waveletCTA) in acute ischemic stroke patients, in whom single-phase CTA (spCTA) failed to detect an occlusion. METHODS: Subjects were selected from a cohort of 791 consecutive patients who underwent multiparametric CT including whole-brain CT perfusion. Inclusion criteria were (1) significant cerebral blood flow (CBF) deficit, (2) no evidence of vessel occlusion on spCTA and (3) follow-up-confirmed acute ischemic infarction. waveletCTA was independently analysed by two readers regarding presence and location of vessel occlusions. Logistic regression analysis was performed to identify predictors of waveletCTA-detected occlusions. RESULTS: Fifty-nine patients fulfilled the inclusion criteria. Overall, an occlusion was identified using waveletCTA in 31 (52.5 %) patients with negative spCTA. Out of 47 patients with middle cerebral artery infarction, 27 occlusions (57.4 %) were detected by waveletCTA, mainly located in the M2 (15) and M3 segments (8). The presence of waveletCTA-detected occlusions was associated with larger CBF deficit volumes (odds ratio (OR) = 1.335, p = 0.010) and shorter times from symptom onset (OR = 0.306, p = 0.041). CONCLUSIONS: waveletCTA is able to detect spCTA occult vessel occlusions in about half of acute ischemic stroke patients and may potentially identify more patients eligible for endovascular therapy. KEY POINTS: • waveletCTA is able to detect spCTA occult vessel occlusions in stroke patients. • waveletCTA-detected occlusions are associated with larger cerebral blood flow deficits. • waveletCTA has the potential to identify more patients eligible for endovascular therapy. • waveletCTA implies neither additional radiation exposure nor extra contrast agent.

Wavelet-Based Angiographic Reconstruction of Computed Tomography Perfusion Data: Diagnostic Value in Cerebral Venous Sinus Thrombosis.

OBJECTIVE: The aim of this study was to test the diagnostic value of wavelet-based angiographic reconstruction of CT perfusion data (waveletCTA) to detect cerebral venous sinus thrombosis (CVST) in patients who underwent whole-brain CT perfusion imaging (WB-CTP). MATERIALS AND METHODS: Datasets were retrospectively selected from an initial cohort of 2863 consecutive patients who had undergone multiparametric CT including WB-CTP. WaveletCTA was reconstructed from WB-CTP: the angiographic signal was generated by voxel-based wavelet transform of time attenuation curves (TACs) from WB-CTP raw data. In a preliminary clinical evaluation, waveletCTA was analyzed by 2 readers with respect to presence and location of CVST. Venous CT and MR angiography (venCTA/venMRA) served as reference standard. Diagnostic confidence for CVST detection and the quality of depiction for venous sections were evaluated on 5-point Likert scales. Thrombus extent was assessed by length measurements. The mean CT attenuation and waveletCTA signal of the thrombus and of flowing blood were quantified. RESULTS: Sixteen patients were included: 10 patients with venCTA-/venMRA-confirmed CVST and 6 patients with arterial single-phase CT angiography (artCTA)-suspected but follow-up-excluded CVST. The reconstruction of waveletCTA was successful in all patients. Among the patients with confirmed CVST, waveletCTA correctly demonstrated presence, location, and extent of the thrombosis in 10/10 cases. In 6 patients with artCTA-suspected but follow-up-excluded CVST, waveletCTA correctly ruled out CVST in 5 patients. Reading waveletCTA in addition to artCTA significantly increased the diagnostic confidence concerning CVST compared with reading artCTA alone (4.4 vs 3.6, P = 0.044). The mean flowing blood-to-thrombus ratio was highest in waveletCTA, followed by venCTA and artCTA (146.2 vs 5.9 vs 2.6, each with P < 0.001). In waveletCTA, the venous sections were depicted better compared with artCTA (4.2 vs 2.6, P < 0.001), and equally well compared with venCTA/venMRA (4.2 vs 4.1, P = 0.374). CONCLUSIONS: WaveletCTA was technically feasible in CVST patients and reliably identified CVST in a preliminary clinical evaluation. WaveletCTA might serve as an additional reconstruction to rule out or incidentally detect CVST in patients who undergo WB-CTP.

Classification of arterial and venous cerebral vasculature based on wavelet postprocessing of CT perfusion data.

PURPOSE: The purpose of this study was to propose and evaluate a new wavelet-based technique for classification of arterial and venous vessels using time-resolved cerebral CT perfusion data sets. METHODS: Fourteen consecutive patients (mean age 73 yr, range 17-97) with suspected stroke but no pathology in follow-up MRI were included. A CT perfusion scan with 32 dynamic phases was performed during intravenous bolus contrast-agent application. After rigid-body motion correction, a Paul wavelet (order 1) was used to calculate voxelwise the wavelet power spectrum (WPS) of each attenuation-time course. The angiographic intensity A was defined as the maximum of the WPS, located at the coordinates T (time axis) and W (scale/width axis) within the WPS. Using these three parameters (A, T, W) separately as well as combined by (1) Fisher's linear discriminant analysis (FLDA), (2) logistic regression (LogR) analysis, or (3) support vector machine (SVM) analysis, their potential to classify 18 different arterial and venous vessel segments per subject was evaluated. RESULTS: The best vessel classification was obtained using all three parameters A and T and W [area under the curve (AUC): 0.953 with FLDA and 0.957 with LogR or SVM]. In direct comparison, the wavelet-derived parameters provided performance at least equal to conventional attenuation-time-course parameters. The maximum AUC obtained from the proposed wavelet parameters was slightly (although not statistically significantly) higher than the maximum AUC (0.945) obtained from the conventional parameters. CONCLUSIONS: A new method to classify arterial and venous cerebral vessels with high statistical accuracy was introduced based on the time-domain wavelet transform of dynamic CT perfusion data in combination with linear or nonlinear multidimensional classification techniques.

Monitoring Cell Death in Regorafenib-Treated Experimental Colon Carcinomas Using Annexin-Based Optical Fluorescence Imaging Validated by Perfusion MRI.

OBJECTIVE: To investigate annexin-based optical fluorescence imaging (OI) for monitoring regorafenib-induced early cell death in experimental colon carcinomas in rats, validated by perfusion MRI and multiparametric immunohistochemistry. MATERIALS AND METHODS: Subcutaneous human colon carcinomas (HT-29) in athymic rats (n = 16) were imaged before and after a one-week therapy with regorafenib (n = 8) or placebo (n = 8) using annexin-based OI and perfusion MRI at 3 Tesla. Optical signal-to-noise ratio (SNR) and MRI tumor perfusion parameters (plasma flow PF, mL/100mL/min; plasma volume PV, %) were assessed. On day 7, tumors underwent immunohistochemical analysis for tumor cell apoptosis (TUNEL), proliferation (Ki-67), and microvascular density (CD31). RESULTS: Apoptosis-targeted OI demonstrated a tumor-specific probe accumulation with a significant increase of tumor SNR under therapy (mean Δ +7.78±2.95, control: -0.80±2.48, p = 0.021). MRI detected a significant reduction of tumor perfusion in the therapy group (mean ΔPF -8.17±2.32 mL/100 mL/min, control -0.11±3.36 mL/100 mL/min, p = 0.036). Immunohistochemistry showed significantly more apoptosis (TUNEL; 11392±1486 vs. 2921±334, p = 0.001), significantly less proliferation (Ki-67; 1754±184 vs. 2883±323, p = 0.012), and significantly lower microvascular density (CD31; 107±10 vs. 182±22, p = 0.006) in the therapy group. CONCLUSIONS: Annexin-based OI allowed for the non-invasive monitoring of regorafenib-induced early cell death in experimental colon carcinomas, validated by perfusion MRI and multiparametric immunohistochemistry.

Validation of a method to differentiate arterial and venous vessels in CT perfusion data using linear combinations of quantitative time-density curve characteristics.

OBJECTIVES: We aimed to develop and evaluate a new method that reliably differentiates between cerebral arteries and veins using voxel-wise CT-perfusion-derived parameters. MATERIALS AND METHODS: Fourteen consecutive patients with suspected stroke but without pathological findings were examined on a multi-detector CT system: 32 dynamic phases (∆t = 1.5 s) during application of 35 mL iomeprol-350 were acquired at 80 kV/200mAs. Three hemodynamic parameters were calculated for 18 arterial and venous vessel segments: A (maximum of the time-density-curve), T (time-to-peak), and W (full-width-at-half-maximum). Using receiver operator characteristic (ROC) curve analysis and Fisher's linear discriminant analysis (FLDA), the performance of every classifier (A, T, W) and of all linear combinations for the differentiation of arterial and venous vessels was determined. RESULTS: A maximum area under the ROC-curve (AUC) of 0.945 (accuracy = 86.8%) was obtained using the FLDA combination of A&T or the triplet FLDA of A&T&W for the classification of venous and arterial vessels. The best single parameter was T with an AUC of 0.871 (accuracy = 79.0%), which performed significantly worse than the combination A&T (p < 0.001). CONCLUSIONS: Arteries and veins can be accurately differentiated based on dynamic CT perfusion data using the maximum of the time-density curve, its time-to-peak, its width, and FLDA combinations of these parameters, which yield accuracies up to 87%. KEY POINTS: • For classification of cerebral vasculature, time-to-peak has the best single-parameter accuracy. • Fisher's linear discriminant analysis improves the performance of the individual classifiers. • Combining signal maximum and time-to-peak parameters significantly increased the classifying potential. • Pre-processing of time-density-curves by Gaussian filtering or fitting can improve diagnostic accuracy.

Correlation of perfusion MRI and 18F-FDG PET imaging biomarkers for monitoring regorafenib therapy in experimental colon carcinomas with immunohistochemical validation.

OBJECTIVES: To investigate a multimodal, multiparametric perfusion MRI / 18F-fluoro-deoxyglucose-(18F-FDG)-PET imaging protocol for monitoring regorafenib therapy effects on experimental colorectal adenocarcinomas in rats with immunohistochemical validation. MATERIALS AND METHODS: Human colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 17 (n = 10 therapy group; n = 7 control group) female athymic nude rats (Hsd:RH-Foxn1rnu). Animals were imaged at baseline and after a one-week daily treatment protocol with regorafenib (10 mg/kg bodyweight) using a multimodal, multiparametric perfusion MRI/18F-FDG-PET imaging protocol. In perfusion MRI, quantitative parameters of plasma flow (PF, mL/100 mL/min), plasma volume (PV, %) and endothelial permeability-surface area product (PS, mL/100 mL/min) were calculated. In 18F-FDG-PET, tumor-to-background-ratio (TTB) was calculated. Perfusion MRI parameters were correlated with TTB and immunohistochemical assessments of tumor microvascular density (CD-31) and cell proliferation (Ki-67). RESULTS: Regorafenib significantly (p<0.01) suppressed PF (81.1±7.5 to 50.6±16.0 mL/100mL/min), PV (12.1±3.6 to 7.5±1.6%) and PS (13.6±3.2 to 7.9±2.3 mL/100mL/min) as well as TTB (3.4±0.6 to 1.9±1.1) between baseline and day 7. Immunohistochemistry revealed significantly (p<0.03) lower tumor microvascular density (CD-31, 7.0±2.4 vs. 16.1±5.9) and tumor cell proliferation (Ki-67, 434.0 ± 62.9 vs. 663.0 ± 98.3) in the therapy group. Perfusion MRI parameters ΔPF, ΔPV and ΔPS showed strong and significant (r = 0.67-0.78; p<0.01) correlations to the PET parameter ΔTTB and significant correlations (r = 0.57-0.67; p<0.03) to immunohistochemical Ki-67 as well as to CD-31-stainings (r = 0.49-0.55; p<0.05). CONCLUSIONS: A multimodal, multiparametric perfusion MRI/PET imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and 18F-FDG-PET validated by immunohistochemistry.

Wavelet-based calculation of cerebral angiographic data from time-resolved CT perfusion acquisitions.

OBJECTIVES: To evaluate a new approach for reconstructing angiographic images by application of wavelet transforms on CT perfusion data. METHODS: Fifteen consecutive patients with suspected stroke were examined with a multi-detector CT acquiring 32 dynamic phases (∆t = 1.5s) of 99 slices (total slab thickness 99mm) at 80kV/200mAs. Thirty-five mL of iomeprol-350 was injected (flow rate = 4.5mL/s). Angiographic datasets were calculated after initial rigid-body motion correction using (a) temporally filtered maximum intensity projections (tMIP) and (b) the wavelet transform (Paul wavelet, order 1) of each voxel time course. The maximum of the wavelet-power-spectrum was defined as the angiographic signal intensity. The contrast-to-noise ratio (CNR) of 18 different vessel segments was quantified and two blinded readers rated the images qualitatively using 5pt Likert scales. RESULTS: The CNR for the wavelet angiography (501.8 ± 433.0) was significantly higher than for the tMIP approach (55.7 ± 29.7, Wilcoxon test p < 0.00001). Image quality was rated to be significantly higher (p < 0.001) for the wavelet angiography with median scores of 4/4 (reader 1/reader 2) than the tMIP (scores of 3/3). CONCLUSIONS: The proposed calculation approach for angiography data using temporal wavelet transforms of intracranial CT perfusion datasets provides higher vascular contrast and intrinsic removal of non-enhancing structures such as bone. KEY POINTS: • Angiographic images calculated with the proposed wavelet-based approach show significantly improved contrast-to-noise ratio. • CT perfusion-based wavelet angiography is an alternative method for vessel visualization. • Provides intrinsic removal of non-enhancing structures such as bone.

Color-coded cerebral computed tomographic angiography: implementation of a convolution-based algorithm and first clinical evaluation in patients with acute ischemic stroke.

OBJECTIVE: The objective of this study was to develop a new method of displaying dynamic cerebral computed tomographic (CT) angiography (CTA) data sets in which the time delay to maximum enhancement (Tdelay) is displayed in a range of colors (color-coded CT angiography [cCTA]). MATERIALS AND METHODS: This institutional review board-approved study included multiparametric CT data sets from 16 patients with different types of supra-aortic large vessel occlusions. Color-coded CT angiography was reconstructed from CT perfusion raw data sets. All voxel enhancement curves were fitted to f(t) = α · AIFmtt(t - Δt), with AIFmtt(t), indicating enhancement of AIF dilated by convolution with boxcar function (with mean transit time [mtt]); α, scaling factor; and [INCREMENT]t, transition along the time. The time delay to maximum enhancement was defined as Tdelay = Δt +0.5 · mtt. Values of Tdelay were color-coded and superimposed on temporal maximum intensity projections CTA resulting in colored angiographic composite images. For a pilot clinical evaluation, diagnostic confidence in determining the pathology, quality of the visualization of leptomeningeal collaterals, and additional diagnostic information were assessed. RESULTS: The reconstruction of cCTA was technically feasible in all 16 patients. Both diagnostic confidence (P < 0.01) and the quality of the visualization of collaterals (P < 0.0001) were significantly higher when using the combination of single-phase CTA and cCTA compared with single-phase CTA alone. Additional diagnostic information was obtained with cCTA regarding occlusion type (reader 1: 5 cases and reader 2: 4 cases), differentiation between arteries and veins (11/13), differentiation between antegrade and retrograde filling (12/13), as well as leptomeningeal collateralization (13/14). CONCLUSIONS: Color-coded CT angiography is a technically feasible technique that provides additional information on cerebral hemodynamics in ischemic stroke patients.

Material characterization of dual-energy computed tomographic data using polar coordinates.

The purpose of this study was to evaluate a new dual-energy computed tomographic postprocessing approach on the basis of the transformation of dual-energy radiodensity data into polar coordinates. Given 2 corresponding dual-energy computed tomographic images, the attenuation data D(U1), D(U2) in Hounsfield units of both tube voltages (U1,U2) were transformed for each voxel to polar coordinates: r (distance to the radiodensity coordinate origin) is an approximate measure of electron density and φ (angle to the abscissa) differentiates between materials.

DCE-MRI biomarkers for monitoring an anti-angiogenic triple combination therapy in experimental hypopharynx carcinoma xenografts with immunohistochemical validation.

BACKGROUND: Novel anti-angiogenic treatments are increasingly complementing established cancer therapy strategies in head and neck tumors. Contrast-enhanced magnetic resonance imaging (MRI) can be applied for early and non-invasive therapy monitoring by non-invasive quantitative assessment of tumor microcirculation as in vivo imaging biomarkers of therapy response. PURPOSE: To monitor the anti-angiogenic effects of a novel combination therapy on experimental head and neck squamous cell carcinomas (HNSCC) with dynamic contrast-enhanced (DCE)-MRI. MATERIAL AND METHODS: Athymic rats (n = 18) with subcutaneous HNSCC xenografts were investigated by DCE-MRI before and after 7 days of a daily triple therapy regimen combining the COX-II-inhibitor celecoxib, the matrix-metalloproteinase-inhibitor GM6001, and the uPA-inhibitor upamostat. Quantitative measurements of tumor blood flow (tBF), tumor blood volume (tBV), and permeability-surface area product (PS) were calculated and validated by immunohistochemistry. RESULTS: Mean tBF and tBV in triple-therapy animals decreased significantly from day 0 to day 7 (tBF, 41.0 ± 14.2 to 20.4 ± 5.7 mL/100 mL/min; P < 0.01; tBV, 17.7 ± 3.9 to 7.5 ± 3.3%; P < 0.01). No significant effects on PS were observed in either group (P > 0.05). Immunohistochemical analysis showed a significantly lower tumor vascularity in the therapy group than in the control group (CD31), significantly fewer Ki-67+ proliferating tumor cells and significantly more Capase-3+ apoptotic tumor cells (P < 0.05). Significant (P < 0.05) correlations were observed between tBF/tBV and CD31 (tBF, r = 0.84; tBV, r = 0.70), tBV and Ki-67 (r = 0.62), as well as tBF and caspase-3 (r = -0.64). CONCLUSION: DCE-MRI may be a suitable tool for the non-invasive monitoring of the anti-vascular effects of this innovative triple therapy regimen with potential for clinical translation.

Regorafenib effects on human colon carcinoma xenografts monitored by dynamic contrast-enhanced computed tomography with immunohistochemical validation.

OBJECTIVE: To investigate dynamic contrast-enhanced computed tomography for monitoring the effects of regorafenib on experimental colon carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation. MATERIALS AND METHODS: Colon carcinoma xenografts (HT-29) implanted subcutaneously in female athymic rats (n = 15) were imaged at baseline and after a one-week treatment with regorafenib by dynamic contrast-enhanced computed tomography (128-slice dual-source computed tomography). The therapy group (n = 7) received regorafenib daily (10 mg/kg bodyweight). Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min), endothelial permeability (PS, mL/100 mL/min), and tumor vascularity (plasma volume, %) were calculated using a 2-compartment uptake model. Dynamic contrast-enhanced computed tomography parameters were validated with immunohistochemical assessments of tumor microvascular density (CD-31), tumor cell apoptosis (TUNEL), and proliferation (Ki-67). RESULTS: Regorafenib suppressed tumor vascularity (15.7±5.3 to 5.5±3.5%; p<0.05) and tumor perfusion (12.8±2.3 to 8.8±2.9 mL/100 mL/min; p = 0.063). Significantly lower microvascular density was observed in the therapy group (CD-31; 48±10 vs. 113±25, p<0.05). In regorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 11844±2927 vs. 5097±3463, p<0.05) were observed. Dynamic contrast-enhanced computed tomography tumor perfusion and tumor vascularity correlated significantly (p<0.05) with microvascular density (CD-31; r = 0.84 and 0.66) and inversely with apoptosis (TUNEL; r = -0.66 and -0.71). CONCLUSIONS: Regorafenib significantly suppressed tumor vascularity (plasma volume) quantified by dynamic contrast-enhanced computed tomography in experimental colon carcinomas in rats with good-to-moderate correlations to an immunohistochemical gold standard. Tumor response biomarkers assessed by dynamic contrast-enhanced computed tomography may be a promising future approach to a more personalized and targeted cancer therapy.

Improved fat water separation with water selective inversion pulse for inversion recovery imaging in cardiac MRI.

PURPOSE: To develop an improved chemical shift-based water-fat separation sequence using a water-selective inversion pulse for inversion recovery 3D contrast-enhanced cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: In inversion recovery sequences the fat signal is substantially reduced due to the application of a nonselective inversion pulse. Therefore, for simultaneous visualization of water, fat, and myocardial enhancement in inversion recovery-based sequences such as late gadolinium enhancement imaging, two separate scans are used. To overcome this, the nonselective inversion pulse is replaced with a water-selective inversion pulse. Imaging was performed in phantoms, nine healthy subjects, and nine patients with suspected arrhythmogenic right ventricular cardiomyopathy plus one patient for tumor/mass imaging. In patients, images with conventional turbo-spin echo (TSE) with and without fat saturation were acquired prior to contrast injection for fat assessment. Subjective image scores (1 = poor, 4 = excellent) were used for image assessment. RESULTS: Phantom experiments showed a fat signal-to-noise ratio (SNR) increase between 1.7 to 5.9 times for inversion times of 150 and 300 msec, respectively. The water-selective inversion pulse retains the fat signal in contrast-enhanced cardiac MR, allowing improved visualization of fat in the water-fat separated images of healthy subjects with a score of 3.7 ± 0.6. Patient images acquired with the proposed sequence were scored higher when compared with a TSE sequence (3.5 ± 0.7 vs. 2.2 ± 0.5, P < 0.05). CONCLUSION: The water-selective inversion pulse retains the fat signal in inversion recovery-based contrast-enhanced cardiac MR, allowing simultaneous visualization of water and fat.