ArticleNoninvasive quantification of bowel inflammation through positron emission tomography imaging of 2-deoxy-2-[18F]fluoro-D-glucose-labeled white blood cells
Introduction
Positron emission tomography (PET) used to noninvasively map the whole-body distribution of glucose metabolism with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has recently become widely available for routine clinical use. High-resolution FDG-PET can sensitively identify states of abnormal glucose metabolism in a variety of diseases. PET with FDG identifies areas of increased glucose metabolism due to the presence of malignant tissue, as well as increases that sometimes occur in inflammation or acute response to cancer treatments, and distinguishing among those situations can be problematic. Nevertheless, using PET with FDG has proven to be accurate and useful in the management of colorectal cancer, lung cancer, Hodgkin's and non-Hodgkin's lymphoma, head and neck cancers, melanoma, and other oncologic diseases.1 The use of PET imaging with other radiopharmaceuticals also holds promise for leading to improvements in medical management.2
Recent studies by our group3., 4., 5. and others6 have demonstrated clinically feasible methods of labeling autologous white blood cells (WBCs) with FDG. In a recent biodistribution/dosimetry study of FDG-WBC, uptake was found to occur predominantly in reticulo-endothelial tissue of healthy subjects. Whole-body and major organ dosimetry estimates for 225–250-MBq doses of FDG-labeled WBC were found to be comparable to those made with 111In-labeled leukocytes. Brain and urinary bladder radiation exposures were substantially lower than would be expected for free FDG, and no appreciable gastrointestinal uptake was found on FDG-WBC PET images.7., 8.
Taking advantage of the biodistribution patterns of FDG-WBC and the spatial resolution of PET, FDG-WBC may be especially useful for imaging inflammation and infection within the gastrointestinal region. In addition, the ability to readily achieve reliable quantification of regional tracer concentration in PET images that are corrected for photon attenuation by tissue, allows for the severity of inflammation to be assessed, and compared longitudinally at different time points. Scan sessions can begin within 40 minutes of injection, and the entire procedure completed within 70 minutes. Treatments for inflammatory bowel disease (IBD) often bring about substantial side effects, making it important to prescribe the minimal doses that are effective. There is, however, currently no noninvasive method for accurately quantifying disease severity in these patients.9., 10. Colorectal cancer can develop in the background of IBD, tending to progress in the setting of fields of flat dysplastic tissue (poorly visible neoplastic tissue that may have mutations in cancer-causing genes, but lack the full complement of genetic changes required for malignancy) instead of the typical polypto-invasive cancer pathway of sporadic colorectal cancer.11 Furthermore, colorectal cancer and IBD can produce similar symptoms—bloody diarrhea, abdominal cramping, and obstruction. In cancer surveillance, the identification of dysplasia often leads to surgical intervention, although one-fourth of patients with colorectal cancer have had no evidence of dysplasia in prior biopsies, and one-fourth of patients with dysplasia will not develop cancer.10 The lack of uniformity in dysplastic tissues thus results in unidentified cancers and unnecessary surgeries.
The aim of this study was to develop and test a method for noninvasively quantifying severity of bowel inflammation, which would be potentially useful for guiding IBD therapy. Coupled with PET imaging of glucose metabolism with FDG, the method could also prove more generally useful for differentiating between nonmalignant and malignant tissues, not only in patients with IBD but also in patients undergoing staging evaluations and therapeutic interventions for any of a wide variety of cancers, where inflammatory processes could compromise the interpretive accuracy of imaging studies.
Section snippets
Gene targeting
We used the previously described Gi2α-deficient mouse12 as a tool to develop a noninvasive method for the evaluation of the severity of bowel inflammation. Mice lacking this signal transducing G protein develop inflammatory bowel disease resembling very closely human ulcerative colitis, including development in its advanced stages of adenocarcinomas.13
Animal and human subjects
Three classes of mice were used (n = 27): (1) healthy wild-type mice, (2) mice with inflammatory bowel inflammation due to exogenous leukocyte
Distinct normal uptake patterns of FDG and FDG-WBC
Subjects were scanned with PET using both FDG and FDG-labeled WBCs (on two separate occasions). Normal distribution patterns of FDG and FDG-WBCs were distinct. Free FDG uptake in healthy mice was mainly seen in the brain, heart, ureters, and bladder (Figure 1A). FDG-WBCs accumulated at highest concentrations in the lungs, liver, spleen, and bone marrow (Figure 1B). There was little accumulation of FDG-WBCs in the normal genitourinary tract (Figure 2).
FDG-WBC uptake and kinetics in inflamed tissue
In mice with inflamed bowel tissue, %TBC of
Discussion
The physiologic patterns of distribution of FDG and FDG-WBC are distinct, as are the time courses of uptake of the two radiopharmaceuticals. PET studies using each of the radiopharmaceuticals provides complementary information in evaluation of inflammation. Measurements made with micro-PET scans of FDG-WBC uptake in the proximal colon of mice found close correlation between FDG-WBC activity and the degree of histopathologically graded inflammation in blinded analyses. Studies in three human
Acknowledgements
This study was supported by contract DE-FCO3-87ER60615 from the United States Department of Energy. Grant support for R. Aranda was provided by a VA Career Development Award.
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