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IMAGING Technique Tracks Tumor Escape into Lymph Nodes These days, Mukesh Harisinghani can barely make his way down the hospital halls without being pulled aside by excited colleagues. Two years ago, he began testing a new method for detecting lymph node metastases in patients with prostate cancer. In the June 19 New England Journal of Medicine, Harisinghani, Ralph Weissleder, who invented the method, and colleagues announced that the technique--which employs a fleet of tiny magnetic particles--revealed lymph node metastases that were invisible to other approaches. And it did so without requiring surgery. Magnetic resonance imaging of magnetic nanoparticles distinguishes a normal lymph node (green) from a metastatic one (red). (Image courtesy of Mukesh Harisinghani) "You have to understand that the importance of this is tremendous. It is going to change the way we do clinical practice," said Weissleder, HMS professor of radiology at Massachusetts General Hospital. It is the new technique's noninvasiveness, as much as its accuracy, that is stopping traffic. "I cross surgeons in the corridor and they say if we could have something like this right now, it would save them a tremendous amount of effort," said Harisinghani, HMS instructor in radiology at MGH. "You have to understand that the importance of this is tremendous. It is going to change the way we do clinical practice." --Ralph Weissleder For doctors as well as patients, detecting metastases can be a notoriously burdensome affair. Often, the only way to see whether a patient's lymph nodes are invaded by cancer cells is to surgically remove and inspect them. In some cases, such as gastric cancer, this can mean several hours of sorting through the nodes in the abdominal cavity before even tackling the primary tumor. Even then surgeons are not sure they are looking in the right place. In the case of metastatic prostate cancer, surgical removal of the primary tumor is not the best treatment option and, like all surgeries, can be dangerous--which only adds to the surgeon's burden. And there is the additional worry that patients with apparently clean lymph nodes could still be harboring metastatic tumor cells. "They would bend over backwards to have somebody take this load off their mind so they could concentrate on the surgery that they want to do," Harisinghani explained. A Sugar-coated Approach The tiny magnetic particles at the center of the excitement are surprisingly ordinary in composition. "If you took your refrigerator magnet and ground it up into real fine powder and put a sugar coat around each particle, that is what they are," said Weissleder. Yet these nanoagents work in counterintuitive ways. Rather than home to tumor cells, they target normal tissue, in particular, the macrophages, a class of immune cells that swarm through healthy lymph nodes. Once taken up by the macrophages, the particles interfere with the cells' magnetic properties, causing a reduction in signal, and hence, a dimming of the lymph node when viewed by magnetic resonance imaging techniques. During metastasis, tumor cells fill the lymphatic ducts, essentially preventing the flow of macrophages--and of image-dimming particles--into and out of the lymph nodes. "When the particles do not get to the lymph nodes, or the lymph node is replaced by tumor, there is no decrease in signal intensity and the lymph nodes stand out as bright spots," said Weissleder. Ahead of the Nanocurve Nanoparticles were barely a glint in the eye of most imagers when the magnetic agents were first invented in the late 1980s. "This was before the whole nanoparticle, nanotechnology craze," said Weissleder. Along with his colleague Lee Josephson, HMS assistant professor of radiology at MGH, he had been using larger iron particles to image organs such as the liver and spleen, but they wanted to find a way to target the lymph nodes. By shrinking the particles down to essentially two thousand iron oxide atoms each and coating them with dextran for added buoyancy, they were able to keep the agents in circulation long enough to be picked up by the lymph node-homing macrophages. "The response to our findings has been overwhelming. I recruited 12 patients in a year for our first phase III trials. Now, I can do 12 patients in three days if I want to," said Mukesh Harisinghani (left), shown with Ralph Weissleder. (Photo by Steve Gilbert) Demonstrating that they actually work in a mouse model of metastatic disease was difficult, owing in part to the lack of magnetic resonance imaging strong enough to pick up the signals generated by the diminutive creatures. It was only in 1998, when imaging methods improved, that the researchers actually got the method to work in the mice. Clinical trials were launched the same year by Advanced Magnetics, the pharmaceutical company where Josephson had been director of research, with patients exhibiting a wide variety of cancers. Harisinghani, who had participated in those initial trials, decided to focus on a narrower group, namely patients with genito-urinary and breast cancers. He and colleagues at the University Medical Center, Nijmegen, the Netherlands, enrolled 40 prostate patients each. The patients, who had highly aggressive tumors, had all opted for surgery. Beforehand, they received an intravenous drip containing the magnetic particles mixed in saline. Magnetic resonance imaging was performed on their pelvic lymph nodes 24 to 36 hours later. Having recorded the bright spots, or purported metastases, Harisinghani and his colleagues sat in on the patients' nodal dissections. Not only were their diagnoses confirmed, that is, the bright spots actually did harbor metastatic cells, they were able to direct the surgeons to nodes they would otherwise have missed. Of the 334 nodes that were removed from the 80 patients in the study, 63 were metastatic. Forty-five of these, or 71 percent, were too small to be detected by normal histopathological means. "If we had just scanned those patients with CT, we would have missed 71 percent of nodes with metastases," said Harisinghani. Nine patients whose lymph nodes had appeared to be clean were found to harbor tumor cells using the new method. "We would have otherwise removed their prostates, despite the metastases. They would have come back with recurrence in a few months time," said Harisinghani. Prostate cancer patients may not be the only ones who stand to benefit. Preliminary results from Harisanghani's other clinical trials suggest the particles can detect metastases in breast, bladder, and kidney cancer. Yet as a cancer-spotting agent, the new method is limited. "It is really about metastases to the lymph nodes, period. It is not the solution to finding small primary tumors," said Weissleder. To carry out those critical tasks, he and his colleagues have been developing a variety of optical probes (Focus, April 30, 1999). They are also souping up their iron oxide nanoparticles. "The next generation of these particles will be targeted magnetic particles that are decorated with certain affinity ligands that recognize specific molecules on targets, including cancer cells," Weissleder said. --Misia Landau