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WIREs Nanomed Nanobiotechnol
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Ultra‐small superparamagnetic iron oxides for metastatic lymph node detection: back on the block

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In the past 15 years, encouraging clinical results for the detection of small lymph node metastases was obtained by the use of Combidex‐enhanced MRI (CEM, also known as magnetic resonance lymphography). Withdrawal of the European Medicines Agency approval application by the manufacturer made it impossible for patients to benefit from this agent; a loss, especially for men with prostate cancer. Current conventional imaging techniques are not as accurate as CEM is, thus a surgical diagnostic exploration (extended lymph node dissection) is still the preferred technique to evaluate the lymph nodes, resulting in peri‐ and postoperative complications. In 2013, the Radboud University Medical Center (Radboudumc) obtained all licenses and documentation for the production process of Combidex (ferumoxtran‐10), and manufactured the contrast agent under supervision of the Department of Pharmacy. Since 2014, 310 men with prostate cancer have been examined with CEM in the Radboudumc. Within this cohort, seven minor possibly contrast‐related adverse effects were observed after administration of Combidex. As the contrast agent is now back again in the Netherlands, this review highlights the working mechanism, previous results, observed side effects since the reintroduction, and the future perspectives for Combidex. WIREs Nanomed Nanobiotechnol 2018, 10:e1471. doi: 10.1002/wnan.1471 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Mechanism of action of Combidex‐enhanced magnetic resonance imaging (MRI). In normal (parts of) healthy lymph nodes iron oxide nanoparticles accumulate (a), whereas metastases contain less nanoparticles 24–36 h after Combidex administration. In iron‐sensitive MRI scans, the nanoparticles cause the MR signal to disappear, while metastatic (parts of) lymph nodes retain MRI signal (b). On the T1‐weighted Combidex image of a patient with metastasized prostate cancer, two nodes (circles) are visible close to the obturator nerve (arrow in c). Both their sizes are normal. On the T2*‐weighted iron‐sensitive image, one of these nodes is black because of the presence of iron oxide nanoparticles, and thus is normal (left circle in d), whereas the metastatic node retained MR signal intensity and is white (right circle in d). Because of its position, 2 cm behind the obturator nerve, the metastatic node would not be removed during a typical pelvic lymph node dissection.
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Nano‐magnetic resonance imaging (MRI) (Combidex‐enhanced MRI) at 3 T of a 53‐year‐old patient with recurrent prostate cancer after radical prostatectomy and radiotherapy (posttherapy PSA‐level 3.9 ng/mL). Twenty‐seven hours after administration of Combidex, metastatic lymph nodes remain white on the three‐dimensional (3D) iron‐sensitive MR‐images in contrast to benign lymph nodes who become black. A large (7 mm) metastatic lymph node was visible on nano‐MRI as a white spherical structure in two orthogonal planes through the node [blue circles in coronal (a) and axial images (b)]. A smaller metastatic white node (2 mm) is indicated with red circles in the coronal (c) and axial (d) reconstructions (orthogonal planes through the node of interest) of the 3D data set. The other small spherical structures are blood vessels, best appreciated when scrolling through the 3D image data set. Parameters: 3D T2*‐weighted MRI with echo time 12 ms (two combined echoes), resolution 0.85 × 0.85 × 0.85 mm, acquisition time 10:10 min.
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