Preclinical Study Digest
 | |
| A: Reconstructed 18F-FDG PET images fused with micro-CT (left). Coronal and transverse slices at level of tumor. Threshold was applied to PET images to show biodistribution despite high activity in bladder. Corresponding slices from 3D FOT reconstruction fused with micro-CT (right). B: Cryosection image of fluorescence from 2-DG at approximately same level as in vivo transverse slices. Image source: J Nucl Med 2011;5:1268-1275 |
Imaging blood perfusion in pig livers
J Nucl Med 2011;52:1119-1124A simplified method for quantification of hepatic blood perfusion was developed, using three-minute dynamic 18F-FDG PET or 11C-MG PET with blood sampling from only a peripheral artery, based on a porcine study in the Journal of Nuclear Medicine. The parametric K1 images were constructed and showed homogeneous blood perfusion in these normal livers.
According to the authors, there is an unmet clinical need for an imaging method for quantification of hepatic blood perfusion. Thus, in this study, Susanne Keiding, MD, from the PET Centre at Aarhus University Hospital in Aarhus, Denmark, and colleagues sought to develop and validate a PET method using blood-to-cell clearance (K1) of 18F-FDG, 11C-MG, or 18F-FDGal as a measure of hepatic blood perfusion without the need for portal venous blood samples.
Researchers noted that they aimed to “make the method as simple as possible with the prospect of future application to clinical studies.” For this purpose, they examined the possibility of using a three-minute data acquisition and a model-derived dual input calculated from measurements of radioactivity concentrations in a peripheral artery.
Pigs (40 kg) underwent dynamic PET of the liver with 18F-FDG, 11C-MG or 18F-FDGal with simultaneous measurements of time–activity curves in blood sampled from a femoral artery and the portal vein (PV); blood flow rates were measured in the hepatic artery (HA) and PV by transit-time flow meters.
Agreement between K1 estimated using the measured and the model-derived dual input was “good for all three tracers,” the authors wrote. For 18F-FDG and 11C-MG, K1 (three-minute data acquisition, model-derived dual input and one-tissue compartmental model) correlated to the measured blood perfusion. For 18F-FDGal, the correlation was not significant, they reported.
When regarding 18F-FDG and 11C-MG as double determinations in the six pigs that underwent PET with both tracers, the researchers found a “highly significant correlation” between changes in hepatic blood perfusion, Q and changes in K1.
Based on their results, Keiding and colleagues concluded that they had developed and validated a simplified method to quantify and image blood perfusion in normal pig livers using a three-minute dynamic PET acquisition after intravenous injection of 11C-MG or 18F-FDG, the latter being a commonly available PET tracer.
A molecular theranostics primer
AJR August 2011;197:318-324Molecular theranostics holds promise, according to a review published in the American Journal of Roentgenology.
The article detailed methods and hurdles to the clinical implementation of molecular theranostics, which uses a diagnostic test to determine whether a patient may benefit from a specific therapy, explained Daniel Y. Lee, MD, and King C. P. Li, MD, of the department of radiology, nuclear medicine division at the Methodist Hospital Research Institute in Houston. Molecular theranostics, they continued, integrates a diagnostic test with a therapeutic intervention targeting a molecular feature of disease.
“The main reason for the tremendous excitement of theranostics is its revolutionary approach that promises improved therapy selection on the basis of specific molecular features of disease, greater predictive power for adverse effects and new ways to objectively monitor therapy response. These properties are fundamental elements of personalized medicine,” Lee and Li wrote.
One of the newest avenues is nanomedicines, nanoparticle-based therapeutics composed of organic and inorganic materials, which offer multiple advantages. These include: the ability to carry targeting agents, imaging moieties and drugs in configurations not readily possible with conventional small organic molecules. In addition, they may reinvigorate drug candidates shelved because of solubility or pharmokinetic issues.
Despite the promise of molecular theranostics, significant barriers remain. Cost, which stretches to $200 million to introduce a diagnostic imaging agent and more than $800 million for a therapeutic drug, tops the list, partially because the payoff for theranostics may not provide the same level of return as blockbuster drugs.
The authors also identified the potential need for further specialization within diagnostic radiology and possible development of a new subspecialty of medicine, and concluded, “the landscape of medicine will likely change because future theranosticians will inevitably share or fully adopt the care of patients with disease that will be molecularly characterized, a requisite step toward individualized medicine.
Mice provide a biomarker roadmap for human approach
Nature Biotechnology 2011;29:625–634Researchers at Fred Hutchinson Cancer Research Center in Seattle have demonstrated in mice that the performance of a novel biomarker-development pipeline using targeted mass spectrometry is robust enough to support the use of an analogous approach in humans, based on findings published in Nature Biotechnology. Amanda Paulovich, MD, PhD, an associate member at Hutchinson, and colleagues demonstrated that a staged, targeted pipeline approach using mass spectrometry to prioritize and validate proteins of interest enabled them to test a far larger number of biomarker candidates than would have been possible using conventional technologies, making a substantial improvement over the current state of biomarker evaluation.
“If, as we hope, this approach enables more efficient translation of novel biomarkers into use as diagnostic tests, the effect will be an improved ability to personalize medicine by optimizing our treatment of individual patients, thus improving patient outcomes and also helping to contain healthcare costs,” Paulovich says.
The researchers undertook this proof-of-concept study in an attempt to accelerate and streamline the process of biomarker candidate testing because, over nearly a decade, hundreds of millions of dollars have been spent on the discovery of promising protein biomarkers of human diseases, particularly biomarkers found in the blood. Despite this significant investment, the number of new FDA-approved blood-based biomarkers has remained very low.
For this study, the researchers tested 80 blood samples from healthy control mice and mice harboring preclinical or clinically apparent breast cancers. They also studied a group of mice that experience conditions that commonly affect the results of cancer screening tests. The researchers found 36 blood biomarkers of breast cancer in this mouse model. Of these, two were elevated in the blood of tumor-bearing mice before the tumors could be seen or felt, indicating that they enabled early detection of the cancers.
The purpose of the study was not to find biomarkers for breast cancer that would be of use in humans, but rather to develop and test technologies in a preclinical model before embarking on human studies.
“It remains to be tested whether any of the specific biomarkers identified in the mouse will be of use in humans, where disease and biological variation will be much greater than in a mouse model. It is more likely that we have developed a road map for conducting more effective biomarker studies in humans,” Paulovich says.
Simultaneous PET/3D FOT is feasible
J Nucl Med 2011;52:1268-1275Phantom and in vivo experiments have demonstrated the feasibility of simultaneous PET and 3D fluorescence optical tomography (FOT) imaging, according to research published in the Journal of Nuclear Medicine.
“A perfect biomedical imaging modality would provide anatomic, functional, physiologic and molecular information,” the study authors wrote. “Integrated PET and 3D FOT imaging has unique and attractive features for in vivo molecular imaging applications.”
In the phantom experiment, the distribution of the radionuclide and fluorophore were “accurately reconstructed” for location, wrote the authors, who added that several enhancements are planned. These enhancements include more excitation locations across multiple surfaces of the phantoms, excitation and detection at multiple wavelengths, increased cooling of the EMCCD camera to reduce the noise and improved rejection of ambient light.