Detecting Metastatic Cancer Lesions… Before it is Too Late!March 2009
By Julius Goepp, MD
Seeing Beyond Cancer
The promise of improved tissue visualization using Combidex® is not limited to assessment of cancer and metastases. The remarkable ability of the USPIO particles in Combidex® to target macrophages means that they can, in principle, be used to identify any tissue in which these important inflammatory cells gather. That opens the door to a whole new world of functional diagnostic imaging, in which we look at how a tissue is performing in addition to simply what it looks like.
We’ve learned that much of the damage caused by ischemia (lack of blood flow) during strokes and heart attacks is related to inflammation in the tissue following the return of blood flow to the area.33-35 That idea, coupled with the inflammation-sensing abilities of Combidex® scanning, caught the imagination of a team of radiologists and neurologists at Heinrich-Heine-University in Dusseldorf. Finding that even high-resolution standard MRI did not allow them to discriminate between healthy and damaged tissue in rat brains following experimentally induced strokes,36 the team went on to study a small group of humans who had undergone naturally occurring strokes.37 Using Combidex® as a “cell-specific” contrast agent, the scientists went in search of the macrophages they knew must be infiltrating damaged tissue in the stroke victims. The patients received the Combidex® infusion at the end of the first week after the stroke, and had scans done twice over the next three days. Remarkably, the researchers found that they could identify changes in both blood vessels and in surrounding brain tissue. In this way they could actually watch as the inflammation-sensing macrophages made their way from the bloodstream into the damaged tissue, accurately tracking the location and the progress of the destructive inflammatory process. This landmark study marks the first time that physicians have been able to actually watch a stroke unfold before their eyes, with unprecedented detail, and to see precisely where and how much damage was occurring!
These researchers have now extended their work to pinpoint regions of developing inflammation in patients very early in an evolving stroke.13,15 These creative scientists concluded that “[Combidex®-] enhanced MRI may help to more specifically target anti-inflammatory therapy in patients with stroke,” potentially ushering in a new age of functional treatment as well as diagnosis for this widespread condition.
A less common but equally destructive condition, multiple sclerosis (MS) is also a result of inflammation in the brain, and the presence of macrophages in affected brain regions suggested the use of Combidex®-enhanced scans to French researchers in Bordeaux.11 They studied 10 patients with MS in acute relapses, conducting MR scans 24 hours after Combidex® injections. Thirty-three regions of brain inflammation were seen in nine patients, while similar regions showed up in only seven patients using conventional gadolinium-enhanced scans. The researchers concluded that Combidex® uniquely revealed cellular inflammatory events that were unfolding as the MS lesions were forming. As with the stroke studies described above, this offers a previously unheard-of ability to watch disease drama unfold—and perhaps ultimately, to administer targeted therapy.
Neurologists in Amsterdam have now extended that work in patients with MS, demonstrating that they can detect more brain lesions, earlier, with a USPIO-containing contrast agent than with standard scans.38 Studying 19 patients with fluctuating levels of disease activity, they identified 188 regions of brain inflammation, 144 of which were not identified on the standard scans. Areas of enhancement with the USPIO particles were evident earlier, and lasted longer, than lesions detected on the standard scans; this behavior suggests that the USPIO-enhanced scan is much more sensitive at demonstrating activity associated with inflammation in brain tissue—the researchers even speculated that they could see signs of tissue repair on some images!
Combidex®—At Risk of Becoming an “Orphan Technology?
Despite this extensive body of evidence favoring Combidex® in terms of effectiveness and safety, it is still not approved by the FDA or its counterpart in the EU. We asked Dr. Barentsz to comment on this situation. “This is an uphill battle,” he replies, “But one that I believe we can win. Physicians are notoriously slow to adopt new technologies, and frankly egos sometimes get in the way of progress. We need to get better-prepared and organized data in front of these regulatory agencies, and unfortunately they are becoming more, not less, bureaucratic over time.” Fortunately, because of his convincing studies, Barentsz himself is authorized to use Combidex® in scans at his facility in the Netherlands, and he continues to publish extensively on his successes.1,2,5,26,39
Can patients seek care voluntarily at Barentsz institution? “Yes, of course they can,” he says. “And in general I’ve found that, except for a few ‘dinosaurs,’ most surgeons and oncologists who’ve read the literature are willing to act on the results of our scans, which are read both by me and by an independent radiologist who’s familiar with the method.”
The discovery of the remarkable properties of ultra-microscopic iron particles, and their appeal to the inflammation-seeking macrophages, has opened new vistas for making functional diagnoses—diagnoses that show physicians not only the structures that comprise our bodies, but also their activities at an extraordinarily detailed level. Combidex®, the commercially produced MRI contrast-enhancing agent that contains these space-age particles, has proven its effectiveness and safety in numerous studies. The ability of oncologists to find and react to metastatic lesions previously too small or too isolated for detection will change the roadmap of cancer therapy, while neurologists and cardiologists can look forward to new ways of visualizing the destructive inflammatory changes that accompany cardiovascular disease, stroke, and other chronic conditions. There is still work to be done to achieve the widespread recognition that Combidex® deserves—the work of devoted clinician-researchers such as Dr. Jelle Barentsz is sure to achieve this in the near future.
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