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[If you cannot see the flash video below, you can click here for a high quality mp4 video.]

"Invisible Light"

In a darkened operating room, Joan Hunt is receiving the standard of care for her breast cancer treatment. Her surgeon, Susan Troyan, performs a lymph node biopsy to see whether Hunt’s cancer has spread. That means Hunt had to arrive several hours before the surgery and receive eight shots of a radioactive material to help surgeons locate and remove the sentinel lymph node.

But in this OR, the lights are off, because in addition to the standard of care, Hunt is also one of eight women with breast cancer participating in the first clinical trial testing a new type of imaging system that uses a single shot of a safe dye to precisely highlight tissues. She calls it "a bright light" in her ordeal— the opportunity to benefit others.

"It lifted my spirits immensely," says Hunt. "In all the grungies of finding out about the breast cancer and the whole routine of what is ahead of me, this was a bright light to think that if this works, then the next people that come along will just have to have this dye shot in the operating room."

John Frangioni and his colleagues at Beth Israel Deaconess Medical Center in Boston invented a camera that shows a part of the light spectrum that people can’t see. The dye gives off near infrared light, or what Frangioni dubs "invisible light."

In this the trial, the researchers hope to confirm that using the invisible light system doesn’t interfere with surgeons’ workflow during breast cancer surgery, as well as its potential to be a better tracer of lymph fluid. Even though both the dye and the radioactive tracer are injected into the same area, doctors can evaluate them independently because they don’t interfere with each other. Frangioni hopes that ultimately, the new system will prove to have many other advantages, especially in cancer surgery, by better showing surgeons what to cut, and what to avoid.

"We all have personal experiences with surgery, ourselves or our loved ones, and we know there can be possible complications," Frangioni says. "We also know that in cancer surgery, although surgeons try very hard, they don’t always get all the tumor. We know that leaving tumor behind is– in the case of breast cancer, statistics suggest that across the country, one in five woman have breast cancer left behind during cancer surgery through no fault of the surgeon. It’s a difficult surgery and right now we can’t see the cancer during the surgery.

"So over the last seven years we developed an imaging system that actually uses two independent channels of near infrared light, and sees those channels in addition to color video light," Frangioni explains.

"It just makes sense that if we’re able to give the surgeon an advantage… give the surgeon the ability to see the tumor during surgery, we may improve success rates. And if we simultaneously give the surgeon the ability to avoid vessels and nerves… it makes sense that this may improve outcomes," he says. "But these are hypotheses that need to be proven by careful clinical studies. But we’ve hit a milestone where this idea has turned into actual testing on patients, and we’re very proud."

Fluorophore Flexibility

The special dyes that give off the near infrared (NIR) light are called NIR fluorophores, and can be designed to target many different types of tissues. "It converts light of one wavelength to a different wavelength," explains Frangioni. "And that gives us the ability, optically, to separate fluorophores from other things in the body. So the fluorophores, these chemicals, are injected into the body and permit us to see things that would otherwise be invisible."

Because incandescent lights also give off NIR, and the camera is very sensitive, the researchers substituted the regular operating room lights with a light that cuts out NIR wavelengths.

As Frangioni recently described at an industry meeting, a computer converts the NIR images to easy-to-see colors of the surgeon’s choice. "Colors like lime green don’t exist in the body naturally, so we give very sensitive and easy to see landmarks to the surgeon," he says.

The fluorophore shot that Hunt received during surgery as part of the clinical trial was indocyanine green (ICG). "It has been FDA approved since 1958 for other indications and has a remarkably good safety record," says Frangioni.

New fluorophores that can greatly expand the system’s abilities would need to go through FDA testing and approval in order to be used in people. The system was extensively tested in animals before proceeding to human trials.

"We have very high specificity by using these chemicals, these fluorophores, targeted to different structures in the body," Frangioni says. "So, by designing the imaging system the way we did, with two independent channels, we really let the surgeon– and the chemist, who’s suddenly become very important in this process– use their imagination and ask very important questions, such as, ‘I need to see a nerve during surgery, how do I do it? I need to see a particular tumor cell during surgery, how do we do it?’

"So one can use a targeting agent, light it up with one fluorophore, and use a different targeting agent and light it up with the other fluorophore," he says "And it’s going to be very surgery-specific. We envision over the next decade, we and many other groups around the world [will develop] fluorophores that are specific to particular surgeries."

"Rate-Limiting Step"

"This clinical trial is important because it gives us the opportunity to test the imaging system in a real patient setting and, of course, to improve it– to find what it does well, what it doesn’t do well, and to fine-tune it to be perfect for the future," Frangioni says.

But he points out, a great deal of effort has already gone into making the system easy for surgeons to use. It’s carried by a small cart, the camera can move in any direction and be locked down for safety. The camera is kept 18 inches away from the patient, so it’s not intrusive, and the surgeon can control it with a foot pedal.

Indeed, the researchers are now partnering with two major medical device manufacturers, General Electric and Siemens, to develop the system further. With such strong corporate partners, Frangioni says, "we are hopeful the technology– if validated, again, if the hypothesis is correct– that it could be commercialized in relatively rapid fashion… meaning possibly within a couple of years.

"The big ‘but’ here is, the imaging system is only half the problem," he says. "All new NIR fluorophores would be subjected to the same rigorous approval process for any new diagnostic agent… every one of them will have to go through independent FDA approval. Each and every one of them will cost somewhere in the vicinity of 50 to 100 million dollars" to go through that process, which he says currently takes five years on average.

Hunt realizes it’s likely the next generations who will benefit from her participation in the research. Since breast cancer runs in her family, "Of course I especially thought of my daughters and granddaughters. And all other women too, of course," she adds.

Following the biopsy, Hunt learned that her lymph nodes were clear, but she still faces a series of hurdles. "This will be a bright light that I’ll keep reminding myself of," she says.

The trial is still recruiting participants.
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This research was presented at the American Chemical Society and World Molecular Imaging Congress, 2008, and has been published in Annals of Surgical Oncology 2007 and 2006, and Chest, 2005. All initial funding was by the National Institutes of Health.

Elsewhere on the Web:
October is National Breast Cancer Awareness Month
Frangioni Lab

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Responses

1. Hemlock says:
   

   October 15th, 2008 at 6:32 am (#)

   Great new tool to target tissues for surgery, but how do the fluorophores actually target specific cells/tissues? Anybody have an answer?

2. rypitch says:
   

   October 15th, 2008 at 9:27 am (#)

   Wow! What an amazing breakthrough. I want the trials to go well so that the number of successful surgeries proves this technique to be a preferred treatment for cancer surgery.

3. Lincoln says:
   

   October 15th, 2008 at 12:24 pm (#)

   A flourescent highlighter to help docs get everything without having to go back for follow up surgery—very cool.

4. Joyce_Gramza says:
   

   October 17th, 2008 at 11:03 am (#)

   Hey Hemlock, thanks for the question. Here's the answer in “English”: They use “modular” fluorophores that consist of a NIR fluorescing part linked to a targeting part that attaches to a certain molecule or structure specific to the cell or tissue. Both parts can be modified. Frangioni and others are designing families of modular fluorophores in which all the family members are tuned to the same NIR wavelength, but each member targets a different type of cell or tissue. Hope that makes sense!

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