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Science to Practice |
1 Cancer Imaging Program, National Cancer Institute, NCI/DCTD/CIP, 6130 Executive Blvd, EPN/6070, Bethesda, MD 20892-7412 jhoffman@mail.nih.gov.
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The ability to image basic molecular processes such as gene expression, enzyme activity, and disease-specific molecular interactions with catheter-based optical imaging techniques holds promise for practical applications. In this issue of Radiology, Funovics et al (1) show that a miniaturized fiberoptic sensor system used in conjunction with a molecular sensitive fluorescent probe can be of value in the detection of very small intraperitoneal malignant tumor foci in mice.
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Molecular imaging has already shown its potential importance in the practice of radiology (2). Implicit in the development of molecular imaging techniques and methods are improved methods of detection and development of probes and ligands that will allow the in vivo elucidation of the important and key molecular and metabolic alterations in disease. Optical imaging techniques have developed from a purely morphologic modality to one that can now aid detection of disease-specific molecular markers and interactions in vivo. This application was a result of the development of targeted probes and enzyme-cleavable and activatable "smart" probes, which are typically optically silent at injection and fluoresce after target interaction.
Funovics et al (1) developed a miniaturized fiberoptic sensor for use in a mouse model of human malignancy. This 2.7-F fiberoptic catheter can simultaneously record white-light and fluorescent images. When the authors coupled the use of the catheter with endogenous green fluorescent protein gene expression, they were able to image peritoneal tumor nodules smaller than 1 mm. They also were able to use a near-infrared probe construct based on cathepsin B, a lysosomal protease overexpressed in a variety of malignant tumors (3), and were able to detect peritoneal tumor seeds from ovarian cancer in a mouse model, with marked sensitivity.
The current description of a catheter-based system is a logical extension of work performed in the same laboratory in experimental studies published previously (4) in which the researchers showed that it was possible to detect overexpression of cathepsin B in an animal model of dysplastic colonic adenomatous polyps. In that study, lesions as small as 50 µm in diameter were detected by using a standard optical imaging system.
The Practice
Clinical use.—The catheter-based system described by Funovics et al (1) is potentially directly transferable to human studies. Such a catheter-based optical fluorescent imaging system, in conjunction with an activatable smart optical probe used at concentrations similar to those used in ex vivo surface imaging studies, would allow endoscopic intraluminal imaging of vessel walls directly through the bloodstream and imaging of the stomach, intestines, and bowel. An intraperitoneal approach could be used to image lymph nodes, intraabdominal organs, and mesenteric tumor deposits; numerous other possibilities also exist. The device, with both visible and near-infrared capabilities, would allow precise anatomic orientation with acquisition of the standard real-time white-light video image coupled with the optical fluorescent or activatable smart probe image of the target of interest.
In the colon, for example, such a system could potentially improve detection of precancerous lesions by providing improved sensitivity for detection of dysplasia in polyps due to alteration of molecular processes such as increased protease activity (5). There is certainly a need for such a method, as conventional colonoscopy has a rate of missed lesions for adenomatous polyps (6). Rex et al (6) showed this rate of missed lesions to be 24% overall, with a rate of missed lesions of 27% for adenomas 5 mm or smaller, 13% for adenomas 6–9 mm, and 6% for adenomas 10 mm or larger. Improved sensitivity for detection of small dysplastic adenomas during standard colonoscopy performed in conjunction with an optical molecular imaging technique could ultimately lead to improved survival after colon cancer.
It will also be important to confirm the recent encouraging results of three-dimensional display computed tomographic (CT) colonography (7). The catheter-based system with an optical smart probe may eventually be a complementary procedure to standard colonoscopy performed after CT colonography. The appealing aspect of the catheter-based approach with a smart probe is that a basic biologic alteration and/or function of early malignancy is assessed rather than simply lesion size.
Future opportunities and challenges.—Thorough validation of catheter-based techniques will be required in humans. Before researchers conduct clinical trials, it will be necessary to ensure Food and Drug Administration approval of both the device and the investigational new drug, the smart optical probe. The other challenge will be the training of imaging specialists adept at optical interventional techniques and at understanding molecular biology. As often happens, competing imaging procedures evolve. CT colonography will undoubtedly become a widely used procedure once confirmatory findings of studies are obtained and medical insurance reimbursement occurs. Its appeal is its minimal invasiveness as an alternative for screening for colon cancer. It is possible that once optimal size thresholds have been defined for CT colonography to trigger subsequent conventional colonoscopy, the catheter-based approach will serve as a complementary procedure for the improved detection of colonic neoplasia.
Summary
Funovics et al have shown that the potential use of a fiberoptic sensor system in conjunction with molecular fluorescent smart probes can be of value in the detection of very small malignant tumor foci.
FOOTNOTES
See also the article by Funovics et al in this issue.
REFERENCES
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  J. T. Heverhagen Smart Near-Infrared Imaging Probes--A Quantum Leap for Early Detection of Colorectal Cancer? Radiology, July 1, 2007; 244(1): 1 - 2. [Full Text] [PDF]
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H. Alencar, M. A. Funovics, J. Figueiredo, H. Sawaya, R. Weissleder, and U. Mahmood Colonic Adenocarcinomas: Near-Infrared Microcatheter Imaging of Smart Probes for Early Detection--Study in Mice Radiology, July 1, 2007; 244(1): 232 - 238. [Abstract] [Full Text] [PDF]
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