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Contempo Updates | Clinician's Corner

Molecular Imaging in the Clinical Arena

Farouc A. Jaffer, MD, PhD; Ralph Weissleder, MD, PhD
JAMA. 2005;293(7):855-862. doi:10.1001/jama.293.7.855.
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Molecular imaging is an emerging field that aims to integrate patient-specific and disease-specific molecular information with traditional anatomical imaging readouts. The information provided by this field may ultimately allow for noninvasive or minimally invasive molecular diagnostic capabilities, better clinical risk stratification, more optimal selection of disease therapy, and improved assessment of treatment efficacy. In this update, we first provide an overview of clinically relevant molecular imaging technologies and imaging agents. Next, their applications to disease detection, drug discovery, and biomedical research are discussed. To specifically demonstrate the potential of molecular imaging, we highlight recent advances in clinical and preclinical molecular imaging of cancer and atherosclerosis.

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Figure 1. Molecular Imaging for Cancer
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A, Positron emission tomography–computed tomography (PET-CT) fusion imaging using 2-[18F]fluoro-2-deoxy-D-glucose as an imaging agent and demonstrating a metabolically active hilar lung cancer (arrowhead) superimposed on the corresponding thoracic anatomy.33 B, Monocrystalline iron oxide nanoparticle (MION)–CT fusion imaging showing the spatial distribution of cancer metastases in pelvic lymph nodes from a series of patients with prostate cancer.14,37 The lymph node metastases (red colorized) were detected preoperatively using MION-enhanced magnetic resonance imaging and confirmed histologically. Image reproduced with permission from Mukesh Harisinghani, MD, Center for Molecular Imaging Research and Department of Radiology, Massachusetts General Hospital. C, Endoscopic near-infrared fluorescence (NIRF) imaging of protease activity in a murine model of colon cancer. After injection of a cathepsin B protease-activatable NIRF agent (see “Cancer Detection” section of text),24 a microscopic cancer becomes brightly fluorescent. The cancer is invisible with traditional white-light imaging (left) but is easily detectable in the NIRF channel (middle, and right colorized NIRF image). Images reproduced with permission from Umar Mahmood, MD, PhD, Center for Molecular Imaging Research and Department of Radiology, Massachusetts General Hospital.

Figure 2. Molecular Imaging of Vulnerable Atherosclerotic Plaque
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A, Noninvasive monocrystalline iron oxide nanoparticle–enhanced magnetic resonance imaging (MRI) of inflammatory macrophages in carotid atherosclerosis.45,46 Axial T2-weighted images through the same level of a symptomatic internal carotid artery lesion before infusion and 48 hours after infusion of iron oxide magnetic nanoparticles (ferumoxtran, 2.6 mg/kg). By 48 hours after infusion, an area of signal loss (arrowhead) becomes evident in the subendothelial region because of iron oxide uptake. The excised plaque shows typical features of the vulnerable plaque, including extensive macrophage infiltration (brown; immunostain using anti-CD68 macrophage antibody, DAB chromogen, Carazzi hematoxylin counterstain; original magnification ×100). The atherosclerotic macrophages colocalize with blue-stained iron particles (arrowheads; Perls iron stain, neutral red counterstain; original magnification × 400). Images reproduced with permission from Jonathan H. Gillard, MD, FRCR; Rikin Trivedi, MRCP, MRCS; Simon P. S. Howarth, MA, MRCS; and Martin Graves, MA; University Department of Radiology, Addenbrooke’s Hospital, Cambridge, England. B, Noninvasive imaging of unstable atherosclerotic carotid artery lesions using radiolabeled annexin A5.48 Left, patient 1 presented with a right-sided transient ischemic attack (TIA) 3 months before imaging. Single-photon emission computed tomography (SPECT) showed no enhanced uptake of radiolabeled annexin A5. Histopathological analysis of the endarterectomy specimen obtained 1 day later showed a stable lesion rich in smooth muscle cells, with negligible binding of annexin A5 and few macrophages (immunostain using antiannexin A5 antibody, original magnification ×100). Right, patient 2 had a left-sided TIA 4 days before imaging. In this patient, enhanced uptake of radiolabeled annexin A5 was evident on the side of the culprit lesion (arrowheads). Histopathological analysis of the endarterectomy specimen showed substantial infiltration of macrophages in the neointima, with extensive binding of annexin A5 (brown; original magnification ×100). These findings indicate lesion instability. Images reproduced with permission from Leonard Hofstra, MD, PhD, and Bas L. J. H. Kietselaer, MD, Department of Cardiology, University Hospital, Maastricht, the Netherlands. C, Near-infrared fluorescence (NIRF) imaging of protease activity in human carotid endarterectomy specimen.44 In a recent series of experiments, freshly excised carotid endarterectomy specimens were incubated with a cathepsin B protease-activatable NIRF agent for 24 hours. Left, light image of the resected specimen, with a confirmed severe carotid artery lesion. Middle, NIRF image after 24 hours of probe incubation, demonstrating focal signal in the plaque at the distal common carotid artery and its bifurcation involving the internal carotid artery. Right, fusion image highlighting the strong NIRF plaque signal, consistent with a highly inflamed carotid plaque lesion. Carotid endarterectomy specimen provided by Glenn LaMuraglia, MD, Vascular Surgery Division, Massachusetts General Hospital.

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