Lighting Up Tumors

Many cancer patients leave surgery still harboring dangerous tumor cells, while others suffer painful aftereffects because a surgeon has removed too much healthy tissue or nicked a nerve. A new imaging system that highlights cancerous tissue in lurid colors should help surgeons remove every last trace of cancer without harming the surrounding tissue. The system, currently in early clinical trials, uses a new class of contrast agents that emit near-infrared light and can attach to virtually any kind of tissue, cancerous or a healthy–showing surgeons just where to cut.

“During surgery, we cannot see small collections of tumor cells we know are being left behind,” says John Frangioni, a physician at Beth Israel Deaconess Medical Center in Boston. Frangioni, also an associate professor of medicine and radiology at Harvard Medical School, will present details of his new imaging system and imaging agents at the annual meeting of the American Chemical Society in Philadelphia today.

The imager, which is being licensed by GE Healthcare, augments a normal video feed with near-infrared imagery to show the location of targeted contrast agents–microscopic particles made up mostly of fluorescent proteins administered to the patient before surgery. During a surgical procedure, a boom carrying one visible-light camera and two for different bands of the near-infrared spectrum is suspended above the patient, sending live video and infrared footage to a computer that displays a combined picture on a screen next to the operating table.

The imager is designed to work with any contrast agent that emits near-infrared light, no matter what type of tissues it binds to. Its boom carries a light-emitting diode that illuminates the surgical area with near-infrared light, causing the fluorescent proteins within the contrast agents to also emit near-infrared light. The core proteins may be coupled to any of a large range of targeting molecules that bind to cells within particular tissue types–for example, antibodies that bind to the proteins on the surface of breast cancer cells.

Since near-infrared light is invisible to the naked eye, the imaging system converts it into bright neon colors laid over a visible-light image. By using multiple imaging agents that bind to different tissues and emit different wavelengths of light, a surgeon can see different types of tissue at the same time: blood vessels can be colored bright blue, while tumor cells are shown in bright green.

Cancer surgery is currently “a guessing game,” admits Bernard Lee, a surgeon at Beth Israel Deaconess. To identify tumor borders, surgeons rely on their own senses (cancerous tissue looks and feels different from healthy tissue) and on medical scans taken before the surgery. Surgeons can send tissue samples to the pathology lab during surgery for a quick examination, but a proper analysis takes between five and seven days. So the best strategy is often to cut a broad margin around the tumor, sacrificing some healthy tissue in the process.

Frangioni’s imaging system is the first to allow real-time imaging of this kind in the operating room, says Lee, who has used it to distinguish between blood vessels and other tissue during experimental surgery on animals.

Near-infrared light can also penetrate through a few millimeters of tissue, allowing surgeons to see different layers. “It gives you the ability to see things that would otherwise be invisible,” says Frangioni.

Other researchers are working on making cancer cells visible during surgery, and targeted fluorescent proteins similar to Frangioni’s have helped surgeons achieve increased survival rates in other animal studies involving tumor removal. But the imaging systems used show a tumor only as a white spot on a black background. It’s difficult for a surgeon to relate this to the real anatomy, says Lee: “You get a black-and-white, low-resolution image, and you can’t tell where the [tumor] is in relation to the rest of the surgical field.”

Frangioni’s lab is also testing a less toxic fluorescent protein in animals. It is surrounded by biofriendly polymers but can still be attached to different types of targeting molecules.

James Olson, an oncologist at the Fred Hutchinson Cancer Research Center in Seattle, says fluorescent imaging agents have shown great promise in animal testing, but he notes that none has yet entered clinical trials in the United States. Frangioni believes that a good imaging system, integrated into surgical practice, will help research on fluorescent agents progress further.