Glioblastomas are among the most common malignancies of the brain, with a median survival time of <18 months after initial diagnosis. These tumors are highly invasive in nature and typically infiltrate along the white matter tracts. Anatomic imaging modalities including contrast-enhanced computed tomography and magnetic resonance imaging (MRI) are used extensively for the diagnosis of intracranial neoplasms. However, infiltrative tumor cells (beyond the areas of contrast enhancement) and certain pediatric brain tumors grow in a diffused pattern and do not exhibit contrast enhancement, thereby limiting the use of these imaging modalities. Over the past several years, advanced imaging methods that probe tumor metabolism (magnetic resonance spectroscopy ) or neovascularity (cerebral blood volume ) have been added to clinical imaging routines for increasing the diagnostic efficacy. However, these methods suffer from relatively poor sensitivity and lack the specificity of detecting changes at cellular level. Molecular MRI techniques using targeted contrast agents have recently been proposed to specifically target the tumor cells (see Delikatny and Poptani and references therein). However, these methods are still in their infancy and are limited to poor sensitivity inherent to MRI methods.
Optical imaging with molecularly targeted imaging agents, on the other hand, promises to have very high degrees of sensitivity and specificity in detection of smaller tumors . The technique is minimally invasive, easy to use, and cost effective and can thus be incorporated at any clinical research institution. The two essential components of optical imaging are the presence of a molecular-specific signal and a system that can detect this signal. The molecular-specific signal is typically generated by the activation of cell-specific proteins, peptides, or genes using an activable contrast agent that can enhance the optical signal from disease-specific molecular markers . Epidermal growth factor (EGF) is one such candidate marker that has been extensively used for the development of targeted contrast agents. Several tumors overexpress the EGF receptor (EGFR), and thus EGF agents that bind to EGFR are commonly used for cancer detection in preclinical tumor models . It has been reported that about 40% to 50% of glioblastomas overexpress EGFR , and thus fluorescence imaging methods can be devised for detection of these tumors. Inhibition of the EGFR pathways has also emerged as a primary mode of anticancer treatment . Currently, four EGFR tyrosine kinase inhibitors are in different stages of clinical development . Among these inhibitors, the monoclonal antibody cetuximab is currently approved for the treatment of head and neck cancer, and early phase clinical trials are in progress for its use in the treatment of brain tumors.
The work by Gibbs-Strauss et al in this issue of Academic Radiology describes the use of EGFR-targeted fluorescent transmission spectroscopy for the detection of EGFR overexpressing U251 tumors implanted intracranially in the mouse brain. Because of the diffused growth pattern and smaller size of the U251 tumors, the authors were unable to detect these tumors using MRI. However, with EGF-targeted fluorescence imaging, these tumors were detected with 100% sensitivity and specificity. These findings are of particular interest because optical imaging methods could then be used to detect small clusters of metastatic tumor cells or invasive tumor cells beyond the contrast-enhanced area seen on magnetic resonance images. These findings further justify the use of intraoperative fluorescence in the detection of accurate tumor margins, as reported earlier . Gibbs-Strauss et al further report a significant decrease in fluorescence uptake in EGFR-positive U251 tumors after treatment with cetuximab in comparison to untreated controls or EGFR-negative 9L tumors. Glioblastomas in general respond poorly to conventional radiation and chemotherapeutic regimens, and a positive response to cetuximab in tumors overexpressing EGFR may further help in better selection of patients for immunotherapy with cetuximab.
One of the drawbacks of optical imaging techniques is the poor spatial resolution and limitation to the depth to which the tissue of interest can be observed. Gibbs-Strauss et al used a multichannel transmission fluorescence spectroscopy system and the commercially available EGF-IRDye (LI-COR Biosciences, Lincoln, NE) for detection of the EGF signal from the tumors. It was previously reported by these investigators that the eight–fiber optic probe configuration was better than the two–fiber optic probe configuration in the detection of EGFR-positive tumors . Although technical challenges remain in acquiring better spatial resolution images with optical imaging techniques, the higher specificity to molecular events and the low cost of these techniques make them suitable as complementary tools in the diagnosis and treatment monitoring of brain tumors.
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