Semiautomatic carotid intraplaque hemorrhage volume measurement using 3D carotid MRI.

BACKGROUND: Presence of intraplaque hemorrhage (IPH) is a known risk factor for stroke and plaque progression. Accurate and reproducible measurement of IPH volume are required for further risk stratification. PURPOSE: To develop a semiautomatic method to measure carotid IPH volume. STUDY TYPE: Retrospective. POPULATION: Patients scheduled for carotid endarterectomy and patients with 16-79% asymptomatic carotid stenosis by ultrasound. FIELD STRENGTH: 3T. SEQUENCE: Simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) MRI. ASSESSMENT: A semiautomated volumetric measurement of IPH using signal intensity thresholding of 3D SNAP volume was implemented. Fourteen carotid endarterectomy patients were enrolled to determine the signal intensity threshold of IPH using histology. Thirty-three patients with 16-79% asymptomatic stenosis were scanned twice within 1 month to evaluate reproducibility. The normalized SNAP intensity with the highest Youden index for predicting IPH on histology was used for thresholding. Scan-rescan reproducibility of IPH measurement was assessed using the intraclass correlation coefficient (ICC) and coefficient of variation (CV). STATISTICAL TESTS: Receiver operating characteristic curve, area under the curve, Cohen's kappa, intraclass correlation coefficient, coefficient of variance (CV), and paired t-test. RESULTS: IPH detection by the algorithm had substantial agreement with manual review (kappa: 0.92; 95% confidence interval [CI]: 0.83, 1.00) and moderate agreement with histology (kappa: 0.55; 95% CI: 0.34, 0.68). IPH volume measurements by the algorithm were strongly correlated with histology (Spearman's rho = 0.76, P = 0.002). IPH measurements were also reproducible, with ICCs of 0.86 (95% CI: 0.57, 0.96), 0.77 (95% CI: 0.32, 0.94), and 0.99 (95% CI: 0.93, 1.00) for maximum/mean normalized intensity and IPH volume, respectively. The corresponding CVs were 10.6%, 5.2%, and 11.8%. DATA CONCLUSION: IPH volume measurements on SNAP MRI are highly reproducible using semiautomatic measurement. Level of Evidence 2 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2019;50:1055-1062.

Minimally invasive in tumor multidrug comparative analysis with contrast-enhanced MRI in mice.

PURPOSE: To facilitate decision making in the oncology clinic, technologies have recently been developed to independently inject and assess multiple anticancer agents directly in a patient's tumor. To increase the flexibility of this approach beyond histological readouts of response, contrast-enhanced MRI was evaluated for the detection of cell death in living tumors after injection. METHODS: A six-needle arrayed microinjection device designed to provide head-to-head comparisons of chemotherapy responses in living tumors was used. Xenografted non-Hodgkin lymphoma tumors in athymic Nude-Foxn1(nu) mice were injected either with different doses of vincristine or with one needle each of vincristine, doxorubicin, bendamustine, prednisolone, mafosfamide, and a vehicle control. To assess drug responses, measurements of enhancement by T1-weighted contrast-enhanced MRI were made for individual sites at 24, 48, and 72 h after injection. For comparison, histological evaluations of cell death were obtained after tumor resection. RESULTS: Measurements of MRI enhancement at injection sites showed a significant (P < 0.001) positive regression slope as a function of vincristine dose. Average MRI measurements were closely correlated with cell death by hematoxylin and eosin staining (R = 0.81; P = 0.001). CONCLUSION: Contrast-enhanced MRI has the potential to replace or augment histological analyses of tumor responses to microinjected doses of chemotherapy agents with potential application in selecting optimal chemotherapy regimens. Magn Reson Med 76:946-952, 2016. © 2015 Wiley Periodicals, Inc.

Semi-automatic carotid intraplaque hemorrhage detection and quantification on Magnetization-Prepared Rapid Acquisition Gradient-Echo (MP-RAGE) with optimized threshold selection.

BACKGROUND: Intraplaque hemorrhage (IPH) is associated with atherosclerosis progression and subsequent cardiovascular events. We sought to develop a semi-automatic method with an optimized threshold for carotid IPH detection and quantification on MP-RAGE images using matched histology as the gold standard. METHODS: Fourteen patients scheduled for carotid endarterectomy underwent 3D MP-RAGE cardiovascular magnetic resonance (CMR) preoperatively. Presence and area of IPH were recorded using histology. Presence and area of IPH were also recorded on CMR based on intensity thresholding using three references for intensity normalization: the sternocleidomastoid muscle (SCM), the adjacent muscle and the automatically generated local median value. The optimized intensity thresholds were obtained by maximizing the Youden's index for IPH detection. Using leave-one-out cross validation, the sensitivity and specificity for IPH detection based on our proposed semi-automatic method and the agreement with histology on IPH area quantification were evaluated. RESULTS: The optimized intensity thresholds for IPH detection were 1.0 times the SCM intensity, 1.6 times the adjacent muscle intensity and 2.2 times the median intensity. Using the semi-automatic method with the optimized intensity threshold, the following IPH detection and quantification performance was obtained: sensitivities up to 59, 68 and 80 %; specificities up to 85, 74 and 79 %; Pearson's correlation coefficients (IPH area measurement) up to 0.76, 0.93 and 0.90, respectively, using SCM, the adjacent muscle and the local median value for intensity normalization, after heavily calcified and small IPH were excluded. CONCLUSIONS: A semi-automatic method with good performance on IPH detection and quantification can be obtained in MP-RAGE CMR, using an optimized intensity threshold comparing to the adjacent muscle. The automatically generated reference of local median value provides comparable performance and may be particularly useful for developing automatic classifiers. Use of the SCM intensity as reference is not recommended without coil sensitivity correction when surface coils are used.

Scan-rescan reproducibility of quantitative assessment of inflammatory carotid atherosclerotic plaque using dynamic contrast-enhanced 3T CMR in a multi-center study.

BACKGROUND: The aim of this study is to investigate the inter-scan reproducibility of kinetic parameters in atherosclerotic plaque using dynamic contrast-enhanced (DCE) cardiovascular magnetic resonance (CMR) in a multi-center setting at 3T. METHODS: Carotid arteries of 51 subjects from 15 sites were scanned twice within two weeks on 3T scanners using a previously described DCE-CMR protocol. Imaging data with protocol compliance and sufficient image quality were analyzed to generate kinetic parameters of vessel wall, expressed as transfer constant (K trans ) and plasma volume (v p ). The inter-scan reproducibility was evaluated using intra-class correlation coefficient (ICC) and coefficient of variation (CV). Power analysis was carried out to provide sample size estimations for future prospective study. RESULTS: Ten (19.6%) subjects were found to suffer from protocol violation, and another 6 (11.8%) had poor image quality (n=6) in at least one scan. In the 35 (68.6%) subjects with complete data, the ICCs of K trans and v p were 0.65 and 0.28, respectively. The CVs were 25% and 62%, respectively. The ICC and CV for v p improved to 0.73 and 28% in larger lesions with analyzed area larger than 25 mm2. Power analysis based on the measured CV showed that 50 subjects per arm are sufficient to detect a 20% difference in change of K trans over time between treatment arms with 80% power without consideration of the dropout rate. CONCLUSION: The result of this study indicates that quantitative measurement from DCE-CMR is feasible to detect changes with a relatively modest sample size in a prospective multi-center study despite the limitations. The relative high dropout rate suggested the critical needs for intensive operator training, optimized imaging protocol, and strict quality control in future studies.

Adventitial perfusion and intraplaque hemorrhage: a dynamic contrast-enhanced MRI study in the carotid artery.

BACKGROUND AND PURPOSE: Autopsy studies have suggested a relationship between intraplaque hemorrhage (IPH) and vasa vasorum, which arise primarily from the adventitia. Adventitial vasa vasorum can be characterized in the carotid arteries by estimating perfusion parameters via dynamic contrast-enhanced MRI. The purpose of this investigation was to use dynamic contrast-enhanced MRI to test in vivo in a clinical population whether adventitial perfusion, indicative of vasa vasorum microstructure, is associated with IPH. METHODS: Symptomatic patients with carotid plaque ipsilateral to the ischemic event underwent bilateral carotid artery MRI examination, which included multicontrast sequences for detecting IPH and a dynamic contrast-enhanced MRI sequence for characterizing adventitial perfusion. Kinetic modeling of the dynamic contrast-enhanced MRI time series was performed to estimate adventitial vp (fractional plasma volume, reflecting local blood supply) and K(trans) (transfer constant, reflecting vessel surface area, and permeability). RESULTS: From the 27 patients (22 men; 69 ± 10 years of age) recruited, adventitial perfusion parameters were obtained in 50 arteries. The presence of IPH was associated with a significantly higher value in adventitial K(trans) (0.142 ± 0.042 vs 0.112 ± 0.029 min(-1); P<0.001) but not in vp (0.163 ± 0.064 vs 0.149 ± 0.062; P=0.338). This relationship remained after adjusting for symptomatic status, degree of stenosis, and other confounding factors. CONCLUSIONS: This study demonstrated an independent pathophysiological link between the adventitia and IPH and related it to the microstructure of adventitial vasa vasorum. Adventitial perfusion imaging may be useful in studying plaque pathogenesis, but further examination through prospective studies is needed.

Progression of experimental lesions of atherosclerosis: assessment by kinetic modeling of black-blood dynamic contrast-enhanced MRI.

Pharmacokinetic modeling of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is used to noninvasively characterize neovasculature and inflammation in atherosclerotic vessels by estimating perfusion characteristics, such as fractional plasma volume vp and transfer constant Ktrans. DCE-MRI has potential to study the evolution of nascent lesions involving early pathological changes. However, currently used bright-blood DCE-MRI approaches are difficult to apply to small lesions because of the difficulty in separating the signal in the thin vessel wall from the adjacent lumen. By suppressing the lumen signal, black-blood DCE-MRI techniques potentially provide a better tool for early atherosclerotic lesion assessment. However, whether black-blood DCE-MRI can detect temporal changes in physiological kinetic parameters has not been investigated for atherosclerosis. This study of balloon-injured New Zealand White rabbits used a reference-region-based pharmacokinetic model of black-blood DCE-MRI to evaluate temporal changes in early experimental atherosclerotic lesions of the abdominal aorta. Six rabbits were imaged at 3 and 6 months after injury. Ktrans was found to increase from 0.10±0.03 min(-1) to 0.14±0.05 min(-1) (P=0.01). In histological analysis of all twelve rabbits, Ktrans showed a significant correlation with macrophage content (R=0.70, P=0.01). These results suggest black-blood DCE-MRI and a reference-region kinetic model could be used to study plaque development and therapeutic response in vivo.

Simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) imaging for carotid atherosclerotic disease evaluation.

A simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) MR imaging technique is proposed to detect both luminal stenosis and hemorrhage in atherosclerosis patients in a single scan. Thirteen patients with diagnosed carotid atherosclerotic plaque were admitted after informed consent. All scans were performed on a 3T MR imaging system with SNAP, 2D time-of-flight and magnetization-prepared 3D rapid acquisition gradient echo sequences. The SNAP sequence utilized a phase sensitive acquisition, and was designed to provide positive signals corresponding to intraplaque hemorrhage and negative signals corresponding to lumen. SNAP images were compared to time-of-flight images to evaluate lumen size measurements using linear mixed models and the intraclass correlation coefficient. Intraplaque hemorrhage identification accuracy was evaluated by comparing to magnetization-prepared 3D rapid acquisition gradient echo images using Cohen's Kappa. Diagnostic quality SNAP images were generated from all subjects. Quantitatively, the lumen size measurements by SNAP were strongly correlated (intraclass correlation coefficient = 0.96, P < 0.001) with those measured by time-of-flight. For intraplaque hemorrhage detection, strong agreement (κ = 0.82, P < 0.001) was also identified between SNAP and magnetization-prepared 3D rapid acquisition gradient echo images. In conclusion, a SNAP imaging technique was proposed and shows great promise for imaging both lumen size and carotid intraplaque hemorrhage with a single scan.

MRI of carotid atherosclerosis.

OBJECTIVE: Although MRI is widely used to observe atherosclerosis impacts on the vessel lumen, MRI also depicts the size of the plaque itself, its composition, and plaque inflammation, providing information beyond simple stenosis. This article summarizes the state of evidence for a clinical role for MRI of carotid atherosclerosis. CONCLUSION: MRI of carotid atherosclerosis has a proven role in pharmaceutical trials and may improve patient management once large-scale clinical trials have been completed.

Segmentation of carotid plaque using multicontrast 3D gradient echo MRI.

PURPOSE: To evaluate the performance of automatic segmentation of atherosclerotic plaque components using solely multicontrast 3D gradient echo (GRE) magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 15 patients with a history of recent transient ischemic attacks or stroke underwent carotid vessel wall imaging bilaterally with a combination of 2D turbo spin echo (TSE) sequences and 3D GRE sequences. The TSE sequences included T1-weighted, T2-weighted, and contrast-enhanced T1-weighted scans. The 3D GRE sequences included time-of-flight (TOF), magnetization-prepared rapid gradient echo (MP-RAGE), and motion-sensitized driven equilibrium prepared rapid gradient echo (MERGE) scans. From these images, the previously developed morphology-enhanced probabilistic plaque segmentation (MEPPS) algorithm was retrained based solely on the 3D GRE sequences to segment necrotic core (NC), calcification (CA), and loose matrix (LM). Segmentation performance was assessed using a leave-one-out cross-validation approach via comparing the new 3D-MEPPS algorithm to the original MEPPS algorithm that was based on the traditional multicontrast protocol including 2D TSE and TOF sequences. RESULTS: Twenty arteries of 15 subjects were found to exhibit significant plaques within the coverage of all imaging sequences. For these arteries, between new and original MEPPS algorithms, the areas per slice exhibited correlation coefficients of 0.86 for NC, 0.99 for CA, and 0.80 for LM; no significant area bias was observed. CONCLUSION: The combination of 3D imaging sequences (TOF, MP-RAGE, and MERGE) can provide sufficient contrast to distinguish NC, CA, and LM. Automatic segmentation using 3D sequences and traditional multicontrast protocol produced highly similar results.

Characterization of distensibility, plaque burden, and composition of the atherosclerotic carotid artery using magnetic resonance imaging.

PURPOSE: Arterial distensibility is a marker that can measure vessel wall functional and structural changes resulting from atherosclerosis with applications including estimation of mechanical properties of the wall. We sought to assess the feasibility of using magnetic resonance imaging (MRI) to include wall distensibility in the characterization of atherosclerotic carotid arteries and to analyze the relationship between distensibility and morphological and compositional plaque features. METHODS: Five healthy volunteers were imaged with a multiple-slice CINE MR sequence twice, within 24 h, to determine the interscan reproducibility of distensibility measurements. Twenty-one subjects with >15% carotid stenosis and the five healthy volunteers were imaged using a multicontrast carotid MRI protocol to characterize arterial wall morphology and composition. Normalized wall index (wall area∕total vessel area), maximum wall thickness and, if present, percentages of wall area occupied by calcification and lipid-rich necrotic core were determined. A multiple-slice CINE MR sequence was added to the multicontrast protocol to measure the distensibility coefficient (DC) at several locations spanning the bifurcation. The intraclass correlation coefficient (ICC) and the coefficient of variation were used to assess the reproducibility of DC measurements made on the healthy subjects. The DC was compared between arterial segments and between the healthy and diseased groups. Furthermore, within the diseased group, DC was correlated to plaque morphology and composition at each location as well as that averaged over the plaque. RESULTS: Distensibility measurements were highly reproducible: ICC (95% confidence interval) was 0.998 (0.96-1.0) for the common carotid segment and 0.990 (0.92-1.0) for the internal carotid segment. In healthy volunteers, we found significantly higher distensibility in the common segment of the carotid artery compared to the internal carotid segment (mean ± SD = 4.56 ± 1.02 versus 3.56 ± 1.32 × 10(-5)∕Pa; p < 0.05). However, no segmental differences were seen in the diseased group (3.25 ± 1.84 versus 3.26 ± 1.60 × 10(-5)∕Pa; p = 0.607). Location-to-location changes in DC were not found to correlate to changes in the local plaque morphology or composition nor were average DC found to be associated with aggregate plaque features. CONCLUSIONS: These results demonstrate the feasibility of MRI to measure distensibility in the carotid artery and to presumably detect changes in distensibility due to age and∕or disease. The results suggest that the effect of atherosclerosis on local distensibility may not strongly depend upon the specific underlying plaque features in mild to moderate stenotic carotid lesions though more diffuse or nonlocal changes in arterial distensibility could not be ruled out.

Characterization of carotid plaques on 3-dimensional ultrasound imaging by registration with multicontrast magnetic resonance imaging.

OBJECTIVES: The ability of magnetic resonance imaging (MRI) in carotid plaque component identification has been well established. However, compared to the costly nature of MRI, 3-dimensional (3D) ultrasound imaging is a more cost-effective assessment tool. Thus, an attractive alternative for carotid disease monitoring would be to establish a strategy in which 3D ultrasound imaging is used as a screening tool that precedes MRI. To develop and validate such a protocol, registration between ultrasound and MR images is required. This article introduces a surface-based algorithm for efficient ultrasound imaging-MRI registration. METHODS: A surface-based 3D iterative closest point registration method was developed to align surfaces reconstructed from outer wall boundaries segmented from 3D ultrasound and MR images. The 3D ultrasound image was transformed according to the registration result and resliced to match corresponding 2-dimensional transverse MR images. Although rigid iterative closest point registration was used, the cross-sectional ultrasound images produced by the reslicing procedure can be moved relative to the MR images by an expert observer using in-house software, making nonrigid registration possible. RESULTS: We evaluated the registration accuracy associated with the algorithm using a vascular phantom as well as in vivo ultrasound and MR images. Our registration method was shown to have an average error of 0.3 mm in the phantom study and less than 1 mm in the in vivo study. Our findings in terms of the average intensity of each component are consistent with histologically validated results described in previous ultrasound characterization studies. CONCLUSIONS: We have developed a surface-based algorithm capable of registering ultrasound and MR images with high accuracy. This registration tool will potentially play an important role in a cost-effective screening protocol in which ultrasound is used to identify patients with a suspicion of vulnerable plaques, who are then further studied with MRI.

Extended graphical model for analysis of dynamic contrast-enhanced MRI.

Kinetic analysis with mathematical models has become increasingly important to quantify physiological parameters in computed tomography (CT), positron emission tomography (PET), and dynamic contrast-enhanced MRI (DCE-MRI). The modified Kety/Tofts model and the graphical (Patlak) model have been widely applied to DCE-MRI results in disease processes such as cancer, inflammation, and ischemia. In this article, an intermediate model between the modified Kety/Tofts and Patlak models is derived from a mathematical expansion of the modified Kety/Tofts model. Simulations and an in vivo experiment involving DCE-MRI of carotid atherosclerosis were used to compare the new extended graphical model with the modified Kety/Tofts model and the Patlak model. In our simulated circumstances and the carotid artery application, we found that the extended graphical model exhibited lower noise sensitivity and provided more accurate estimates of the volume transfer constant (K(trans)) and fractional plasma volume (v(p)) than the modified Kety/Tofts model for DCE-MRI acquisitions of total duration less than 100-300 s, depending on kinetic parameters. In comparison with the Patlak model, we found that the extended graphical model exhibited 74.4-99.8% less bias in estimates of K(trans). Thus, the extended graphical model may allow kinetic modeling of DCE-MRI results with shortened data acquisition periods, without sacrificing accuracy in estimates of K(trans) and v(p).

Fast plaque burden assessment of the femoral artery using 3D black-blood MRI and automated segmentation.

PURPOSE: Vessel wall imaging techniques have been introduced to assess the burden of peripheral arterial disease (PAD) in terms of vessel wall thickness, area or volume. Recent advances in a 3D black-blood MRI sequence known as the 3D motion-sensitized driven equilibrium (MSDE) prepared rapid gradient echo sequence (3D MERGE) have allowed the acquisition of vessel wall images with up to 50 cm coverage, facilitating noninvasive and detailed assessment of PAD. This work introduces an algorithm that combines 2D slice-based segmentation and 3D user editing to allow for efficient plaque burden analysis of the femoral artery images acquired using 3D MERGE. METHODS: The 2D slice-based segmentation approach is based on propagating segmentation results of contiguous 2D slices. The 3D image volume was then reformatted using the curved planar reformation (CPR) technique. User editing of the segmented contours was performed on the CPR views taken at different angles. The method was evaluated on six femoral artery images. Vessel wall thickness and area obtained before and after editing on the CPR views were assessed by comparison with manual segmentation. Difference between semiautomatically and manually segmented contours were compared with the difference of the corresponding measurements between two repeated manual segmentations. RESULTS: The root-mean-square (RMS) errors of the mean wall thickness (t(mean)) and the wall area (WA) of the edited contours were 0.35 mm and 7.1 mm(2), respectively, which are close to the RMS difference between two repeated manual segmentations (RMSE: 0.33 mm in t(mean), 6.6 mm(2) in WA). The time required for the entire semiautomated segmentation process was only 1%-2% of the time required for manual segmentation. CONCLUSIONS: The difference between the boundaries generated by the proposed algorithm and the manually segmented boundary is close to the difference between repeated manual segmentations. The proposed method provides accurate plaque burden measurements, while considerably reducing the analysis time compared to manual review.

Localized measurement of atherosclerotic plaque inflammatory burden with dynamic contrast-enhanced MRI.

Inflammation plays an important role in progression and rupture of atherosclerotic plaque. Dynamic contrast-enhanced MRI has been proposed as a tool to evaluate inflammation in vivo by measuring the transfer constant and partial plasma volume, which are influenced by inflammation. This study sought to demonstrate the ability of dynamic contrast-enhanced MRI to provide localized measurements of transfer constant and partial plasma volume within plaque regions of different compositions. In order to do that, a highly automatic procedure for localized measurement of dynamic contrast-enhanced MRI parameters was developed. In 47 subjects, the average transfer constant and partial plasma volume were highest in loose matrix and fibrous tissue and substantially lower in intraplaque hemorrhage, lipid rich/necrotic core, and calcification. In addition, except for hemorrhage and calcification, statistically significant differences of transfer constant and partial plasma volume were observed for any pair of these components. This suggests that transfer constant and partial plasma volume could be helpful to differentiate different plaque components and that dynamic contrast-enhanced MRI has the potential to assess inflammatory burden in specific regions.

Cardiovascular magnetic resonance in carotid atherosclerotic disease.

Atherosclerosis is a chronic, progressive, inflammatory disease affecting many vascular beds. Disease progression leads to acute cardiovascular events such as myocardial infarction, stroke and death. The diseased carotid alone is responsible for one third of the 700,000 new or recurrent strokes occurring yearly in the United States. Imaging plays an important role in the management of atherosclerosis, and cardiovascular magnetic resonance (CMR) of the carotid vessel wall is one promising modality in the evaluation of patients with carotid atherosclerotic disease. Advances in carotid vessel wall CMR allow comprehensive assessment of morphology inside the wall, contributing substantial disease-specific information beyond luminal stenosis. Although carotid vessel wall CMR has not been widely used to screen for carotid atherosclerotic disease, many trials support its potential for this indication. This review summarizes the current state of knowledge regarding carotid vessel wall CMR and its potential clinical application for management of carotid atherosclerotic disease.

Three-dimensional shape analysis of right ventricular remodeling in repaired tetralogy of Fallot.

Understanding of right ventricular (RV) remodeling is needed to elucidate the mechanism of RV dysfunction in the overloaded right ventricle, but is hampered by the chamber's complex shape. We imaged 15 patients with repaired tetralogy of Fallot (TOF) and 8 normal subjects by magnetic resonance imaging in long- and short-axis views. We reconstructed the right ventricles in 3 dimensions using the piecewise smooth subdivision surface method. Shape was analyzed from cross-sectional contours generated by intersecting the right ventricle with 20 planes evenly spaced from apex to tricuspid annulus. Patients with TOF had dilated right ventricles compared with normal (end-diastolic volume index 216 +/- 99 vs 81 +/- 16 ml/m(2), p <0.001) but near-normal function (ejection fraction 40 +/- 9% vs 48 +/- 12%, respectively, p = NS). RV shape in patients with TOF differed from normal subjects in several ways. First, the right ventricle had a larger normalized cross-sectional area in patients with TOF (p <0.01 in apical planes). Second, the cross-sectional shape was rounder in patients with TOF (p <0.05 in apical planes). Also, the interventricular septum underwent relatively less enlargement so that it comprised only 27 +/- 4% of total RV surface area in patients with TOF, compared with 33 +/- 2% in normal subjects (p = 0.0001). In addition, the right ventricle in patients with TOF exhibited bulging basal to the tricuspid valve (4 +/- 4% of total RV length), unlike normals (1 +/- 2%, p <0.001). This basal bulging was amplified by tilting of the tricuspid annulus (29 +/- 11 degrees vs 15 +/- 7 degrees , respectively, p <0.005). In conclusion, the right ventricle remodels in several directions rather than following a shape continuum. Characterization of RV remodeling from 3-dimensional reconstructions provides novel insights.

Negative Carotid Artery Remodeling in Early Type 2 Diabetes Mellitus and Increased Carotid Plaque Vulnerability in Obesity as Assessed by Magnetic Resonance Imaging.

Background Ischemic stroke from carotid plaque embolism remains a major cause of morbidity in patients with type 2 diabetes mellitus (T2 DM ). However, the effect of early T2 DM and obesity on carotid remodeling and plaque burden remains elusive. We assessed carotid remodeling and plaque composition by carotid magnetic resonance imaging in patients with short-duration T2 DM compared with a sex- and age-matched control group. Methods and Results One hundred patients with T2 DM (duration <5 years) and 100 sex- and age-matched controls underwent bilateral carotid artery magnetic resonance imaging in a 1.5-T magnetic resonance imaging scanner. Plaque burden was quantified by normalized wall index, maximum wall thickness, maximum wall area, and minimum lumen size. Plaque morphology was quantified by calcified plaque volume, necrotic core volume, and loose matrix volume. Magnetic resonance imaging data were available for 149 and 177 carotid arteries from T2 DM patients and controls, respectively. Adjusted for age and sex, T2 DM was associated with increased plaque burden indicated by a higher normalized wall index (ratio 1.03 [95% confidence interval, 1.002; 1.06], P=0.03), and negative remodeling indicated by a lower minimum lumen area (ratio 0.81 [0.74; 0.89], P<0.001), and lower maximum wall area (ratio 0.94 [0.88; 1.00], P=0.048) compared with controls. In both T2 DM and controls, body mass index ≥30.0 kg/m2 was associated with an 80% increase in total calcified plaque volume, and a 44% increase in necrotic core volume compared with body mass index <25.0 kg/m2. Conclusions Short-duration T2 DM was associated with increased carotid plaque burden and negative remodeling. Obesity was associated with increased carotid artery necrotic core volume and calcification independently of diabetes mellitus status. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00674271.

Imaging of the high-risk carotid plaque: magnetic resonance imaging.

The emergence of the concept of high-risk atherosclerotic plaque has led to considerable interest in noninvasive imaging techniques to identify high-risk features before clinical sequelae. For plaques in the carotid arteries, magnetic resonance imaging has undergone considerable histologic validation to link imaging features to indicators of plaque instability, including plaque burden, intraplaque hemorrhage, fibrous cap disruption, lipid rich necrotic core, and calcification. Recently introduced imaging technologies, especially those focused on three-dimensional imaging sequences, are now poised for integration into the clinical workup of patients with suspected carotid atherosclerosis. The purpose of this article is to review the carotid plaque magnetic resonance imaging techniques that are most ready for integration into the clinic.

Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition.

Aberrant regulation of BCL-2 family members enables evasion of apoptosis and tumor resistance to chemotherapy. BCL-2 and functionally redundant counterpart, MCL-1, are frequently over-expressed in high-risk diffuse large B-cell lymphoma (DLBCL). While clinical inhibition of BCL-2 has been achieved with the BH3 mimetic venetoclax, anti-tumor efficacy is limited by compensatory induction of MCL-1. Voruciclib, an orally bioavailable clinical stage CDK-selective inhibitor, potently blocks CDK9, the transcriptional regulator of MCL-1. Here, we demonstrate that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL. When combined with venetoclax in vivo, voruciclib leads to model-dependent tumor cell apoptosis and tumor growth inhibition. Strongest responses were observed in two models representing high-risk activated B-cell (ABC) DLBCL, while no response was observed in a third ABC model, and intermediate responses were observed in two models of germinal center B-cell like (GCB) DLBCL. Given the range of responses, we show that CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL-1 targeted therapy. These findings suggest that the combination of voruciclib and venetoclax holds promise as a novel, exclusively oral combination therapy for a subset of high-risk DLBCL patients.

Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation.

The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. Cancer Res; 77(11); 2869-80. ©2017 AACR.