Imaging Innovation Helps Surgeons "Cut by Color"

John V. Frangioni, M.D., Ph.D.

Radiologists are poised to contribute a new tool to the surgical arsenal, creating a fluorescent roadmap of sorts to light the way for more favorable surgical results.

Researchers from Beth Israel Deaconess Medical Center (BIDMC) in Boston report the development and early clinical trials of a new imaging system that will essentially light up and color cancerous tumors, enabling surgeons to evaluate whether they've resected an entire diseased area. The team presented their work on fluorescence-assisted resection and exploration—or FLARE—at the 236th National Meeting of the American Chemical Society in Philadelphia earlier this year.

FLARE is portable and consists of a near infrared (NIR) imaging system, a video monitor and a computer. "We don't require the surgeon to relearn anything," said project director John V. Frangioni, M.D., Ph.D., an attending physician at BIDMC and associate professor of radiology and medicine at Harvard Medical School.

"We're embellishing the surgery with additional information they otherwise wouldn't have," added Dr. Frangioni.

The additional information comes from the use of chemical dyes called near-infrared (NIR) fluorophores designed to target specific structures when injected into patients. When exposed to NIR light, which is invisible to the human eye, the contrast agents light up targeted cells and are viewed on a video monitor during surgery. If, for instance, cancer cells are targeted, the image of the lit-up cancer cells can be superimposed over the surgical field, allowing surgeons to cut away the fluorescent "glowing" cells and sparing nerves and other healthy structures in the area.

Dr. Frangioni described the scene. "If you imagine a surgical field where suddenly the tumor is glowing bright green, you teach the surgeon to cut out the bright green," he said. "When you don't see any more bright green, you know the tumor's gone. It is cutting by color."

"Chicken and Egg" Dilemma Posed by Contrast Agent

Cutting by Color John V. Frangioni, M.D., Ph.D., and colleagues are developing fluorescence-assisted resection and exploration (FLARE) to guide physicians during tumor resection. Chemical dyes called near-infrared (NIR) fluorophores are designed to target specific structures when injected into patients. When exposed to NIR light, which is invisible to the human eye, the contrast agents light up targeted cells and are viewed on a video monitor. Here the technique has been used to map lymph nodes in a swine limb. Image courtesy of John V. Frangioni, M.D., Ph.D.

FLARE came together slowly after years of struggle to develop and utilize the right imaging system and to find the proper contrast agent, said Dr. Frangioni. The agent currently being tested is an already available fluorophore being used off-label.

"We've been faced in the last few years with a chicken and egg problem," he said. "In order to perform this task, you need an imaging system to see the contrast agents. But without an imaging system, why would anyone develop the contrast agents? Without both, there's no justification for either. The milestone we're proud of is being able to translate the imaging system into the clinic using an already available fluorophore."

As they fine-tune the new method, BIDMC team members devote much of their efforts to finding ways to give surgeons real-time information. "The system we developed has two independent channels of near-infrared fluorescence," said Dr. Frangioni. "You can highlight two different things on the surgical field, and those things are only limited by one's imagination and the chemistry.

"You might want to see tumor with one channel and nerves with another," continued Dr. Frangioni. "You might want to see blood vessels with one channel and tumor with the other. Whatever that particular surgery calls for, that is how you would design the contrast agents." He further described the surgical field: "They're invisible to our eye, but the imaging system and computer translate those wavelengths into a visible color of the surgeon's choice. We always recommend unnatural colors like lime green or fluorescent orange, things that wouldn't normally be in the surgical field, so they're obvious."

When using the FLARE system, the surgeon sees a screen with four windows—one for color video, one for each of the two independent channels of NIR fluorescence and a fourth called the "merge" window. "It can be any arithmetic combination of windows, so we can get very fancy and overlay one or both windows on top of the color video," said Dr. Frangioni. "We can subtract one from another, multiply, divide. It gives us a lot of flexibility. The surgeon really has quite a bit of additional information they otherwise wouldn't see."

Breast Cancer is Focus

The BIDMC team is currently focusing human trials on sentinel lymph node mapping in patients with breast cancer. A study launched last summer was conducted on six patients, while another 50-patient study will get under way later this year comparing standard compounds against the new fluorescent compound utilized in the FLARE studies.

Focusing efforts on breast cancer patients made sense from both treatment and surgical perspectives, said Dr. Frangioni, noting that in one-fifth of breast cancer surgeries, the surgeon is not able to remove all of the cancerous tissue. "When the tumor is sent to the pathologist for analysis, 20 percent of the reports come back saying you cut through the tumor, meaning there's a fraction of it left behind," he said.

"When we have breast cancer-specific agents we will study whether the FLARE system results in removal of more cancerous tumor," he continued. "That process will probably be relatively straightforward because we're starting with a population where we know we're leaving tumor behind. If we're able to improve those results, it should become obvious in the numbers."

Dr. Frangioni said he looks forward to feedback from other centers now testing the FLARE and the smaller, portable FLARE system. Physicians at Leiden University in The Netherlands and Brigham and Women's Hospital in Boston are involved. "Part of the milestone and why we're very proud of this achievement is that the imaging system with its two channels can be used for any surgery for any application," Dr. Frangioni said. "The fact we've got it in the clinic and it's available for research means that now you can let your imagination go on the contrast agents themselves.

"It's very easy to mislead oneself by getting excited about the technology," Dr. Frangioni continued. "It's really up to unbiased observers to tell us whether it's useful or not."