Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free DNA derived from healthy cells has proven challenging, particularly in non-metastatic solid tumors. In this study, distinct differences in fragment length size between ctDNAs and normal cell-free DNA are defined. Human ctDNA in rat plasma derived from human glioblastoma multiforme stem-like cells in the rat brain and human hepatocellular carcinoma in the rat flank were found to have a shorter principal fragment length than the background rat cell-free DNA (134–144 bp vs. 167 bp, respectively). Subsequently, a similar shift in the fragment length of ctDNA in humans with melanoma and lung cancer was identified compared to healthy controls. Comparison of fragment lengths from cell-free DNA between a melanoma patient and healthy controls found that the BRAF V600E mutant allele occurred more commonly at a shorter fragment length than the fragment length of the wild-type allele (132–145 bp vs. 165 bp, respectively). Moreover, size-selecting for shorter cell-free DNA fragment lengths substantially increased the EGFR T790M mutant allele frequency in human lung cancer. These findings provide compelling evidence that experimental or bioinformatic isolation of a specific subset of fragment lengths from cell-free DNA may improve detection of ctDNA.

Background and Purpose-MRI is able to quantify carotid plaque size and composition with good accuracy and reproducibility and provides an opportunity to prospectively examine the relationship between plaque features and subsequent cerebrovascular events. We tested the hypothesis that the characteristics of carotid plaque, as assessed by MRI, are possible predictors of future ipsilateral cerebrovascular events. Methods-A total of 154 consecutive subjects who initially had an asymptomatic 50% to 79% carotid stenosis by ultrasound with Ն12 months of follow-up were included in this study. Multicontrast-weighted carotid MRIs were performed at baseline, and participants were followed clinically every 3 months to identify symptoms of cerebrovascular events. Results-Over a mean follow-up period of 38.2 months, 12 carotid cerebrovascular events occurred ipsilateral to the index carotid artery. Cox regression analysis demonstrated a significant association between baseline MRI identification of the following plaque characteristics and subsequent symptoms during follow-up: presence of a thin or ruptured fibrous cap (hazard ratio, 17.0; PՅ0.001), intraplaque hemorrhage (hazard ratio, 5.2; Pϭ0.005), larger mean intraplaque hemorrhage area (hazard ratio for 10 mm 2 increase, 2.6; Pϭ0.006), larger maximum %lipid-rich/necrotic core (hazard ratio for 10% increase, 1.6; Pϭ0.004), and larger maximum wall thickness (hazard ratio for a 1-mm increase, 1.6; Pϭ0.008). Conclusions-Among patients who initially had an asymptomatic 50% to 79% carotid stenosis, arteries with thinned or ruptured fibrous caps, intraplaque hemorrhage, larger maximum %lipid-rich/necrotic cores, and larger maximum wall thickness by MRI were associated with the occurrence of subsequent cerebrovascular events. Findings from this prospective study provide a basis for larger multicenter studies to assess the risk of plaque features for subsequent ischemic events. (Stroke. 2006;37:818-823.)

"Vulnerable" plaques are atherosclerotic plaques that have a high likelihood to cause thrombotic complications, such as myocardial infarction or stroke. Plaques that tend to progress rapidly are also considered to be vulnerable. Besides luminal stenosis, plaque composition and morphology are key determinants of the likelihood that a plaque will cause cardiovascular events. Noninvasive magnetic resonance (MR) imaging has great potential to enable characterization of atherosclerotic plaque composition and morphology and thus to help assess plaque vulnerability. A classification for clinical, as well as pathologic, evaluation of vulnerable plaques was recently put forward in which five major and five minor criteria to define vulnerable plaques were proposed. The purpose of this review is to summarize the status of MR imaging with regard to depiction of the criteria that define vulnerable plaques by using existing MR techniques. The use of MR imaging in animal models and in human disease in various vascular beds, particularly the carotid arteries, is presented.

Cross-relaxation imaging (CRI) is a quantitative magnetic resonance technique that measures the kinetic parameters of magnetization transfer between protons bound to water and protons bound to macromolecules. In this study, in vivo, four-parameter CRI of normal rat brains (N=5) at 3.0 T was first directly compared to histology. The bound pool fraction, f, was strongly associated with myelin density (Pearson's r = 0.99, p <0.001). The correlation persisted in separate analyses of gray matter (GM; r = 0.89, p =0.046) and white matter (WM; r = 0.97, p =0.029). Subsequently, a new time-efficient approach for solely capturing the whole-brain parametric map of f was proposed, validated with histology, and used to estimate myelin density. Since the described approach for the rapid acquisition of f applied constraints to other CRI parameters, a theoretical analysis of error was performed. Estimates of f in normal and pathologic tissue were expected to have <10% error. A comparison of values for f obtained from the traditional four-parameter fit of CRI data versus the proposed rapid acquisition of f was within this expected margin for in vivo rat brain gliomas (N=4; mean ± SE; 3.9 ± 0.2% vs. 4.0 ± 0.2%, respectively). In both whole-brain f maps and myelin density maps, replacement of normal GM and WM by proliferating and invading tumor cells could be readily identified. The rapid, whole-brain acquisition of the bound pool fraction may provide a reliable method for detection of glioma invasion in both GM and WM during animal and human imaging.

Purpose:To compare the diagnostic performances of three T1-weighted 3.0-T magnetic resonance (MR) sequences at carotid intraplaque hemorrhage (IPH) imaging, with histologic analysis as the reference standard. Materials and Methods:Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Twenty patients scheduled for carotid endarterectomy underwent 3.0-T carotid MR imaging, including two-dimensional fast spin-echo, three-dimensional time-of-fl ight (TOF), and three-dimensional magnetization-prepared rapid acquisition gradient-echo (RAGE) sequences. Two reviewers blinded to the histologic fi ndings assessed the presence, area, and signal intensity of IPH with each sequence. Detection statistics (sensitivity, specifi city, and Cohen k values) and agreement between area measurements (Pearson correlation coeffi cient [r] values) were calculated for each sequence. Results:When all 231 available MR sections were included for analysis, the magnetization-prepared RAGE ( k = 0.53) and fast spin-echo ( k = 0.42) sequences yielded moderate agreement between MR and histologic measurements, while the TOF sequence yielded fair agreement (k = 0.33). However, when 47 sections with either small IPHs or heavily calcifi ed IPHs were excluded, sensitivity, specifi city, and k values, respectively, were 80%, 97%, and 0.80 for magnetizationprepared RAGE imaging; 70%, 92%, and 0.63 for fast spinecho imaging; and 56%, 96%, and 0.57 for TOF imaging. MR imaging-histologic analysis correlation for IPH area was highest with magnetization-prepared RAGE imaging ( r = 0.813), followed by TOF ( r = 0.745) and fast spin-echo ( r = 0.497) imaging. The capability of these three sequences for IPH detection appeared to be in good agreement with the quantitative contrast of IPH versus background plaque tissue. Conclusion:The magnetization-prepared RAGE sequence, as compared with the fast spin-echo and TOF sequences, demonstrated higher diagnostic capability for the detection and quantifi cation of IPH. Potential limitations of 3.0-T IPH MR imaging are related to hemorrhage size and coexisting calcifi cation.q RSNA, 2010

Automated analysis tools are capable of providing accurate and reproducible measurements of carotid atherosclerotic burden and composition when compared with manually outlined results.

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Atherosclerosis is now widely recognized as a multifactorial disease with outcomes that arise from complex factors such as plaque components, blood flow, and inflammation. Despite recent advances in understanding of plaque biology, diagnosis, and treatment, atherosclerosis remains a leading cause of morbidity and mortality. Further research into the development and validation of reliable indicators of the high-risk individual is greatly needed. Carotid MRI is a histologically validated, noninvasive imaging method that can track disease progression and regression, and quantitatively evaluate a spectrum of parameters associated with in vivo plaque morphology and composition. Intraplaque hemorrhage and the lipid-rich necrotic core are the best indicators of lesion severity currently visualized by carotid MRI. However, MRI methods capable of imaging other important aspects of carotid atherosclerotic disease in vivo-including inflammation, neovascularization, and mechanical forces-are emerging and may aid in advancing our understanding of the pathophysiology of this multifactorial disease.