Can You See It? Optical Imaging in the OR

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Source: MethBlue.jpg - Indocyanine
Indocyanine green and methylene blue are among some old dyes that have found new enthusiasts with the advance of near-infrared fluorescence imaging. They’re far less fluorescent than new optical molecular probes now in development, but they are FDA-approved—and their effectiveness at fine-targeting tissue for precise resection points to possible things to come in optical molecular imaging.

What nuclear medicine is now to presurgical planning, optical molecular imaging may soon become to intraoperative tumor removal. Using near-infrared light to excite fluorescence in new contrast agents coming down the pike, and imaging the reactions in diseased tissue with specially sensitive imaging systems, surgeons would see tumor margins and molecular targets in real time. Tiny clusters of as few as 10 precancerous cells would give themselves up to the molecular searchlight. Fully formed tumors would be thoroughly resected. Across the board, healthy surrounding tissue would routinely remain untouched and unharmed.

The technology’s potential for improving care while reducing costs—early and thorough cancer treatments accomplish both—would explain why numerous attendees of June’s annual meeting of the Society of Nuclear Medicine and Molecular Imaging reported much buzz around optical imaging. It surely helped that the optical sessions were split into two tracks to showcase the field’s reach and scope. One dealt with the use of contrast agents (a.k.a. molecular probes), the other with basic optical properties inherent in all animal and human tissue. 

Meanwhile, to keep optical moving from the lab toward the OR, more than a few accomplished scientists are becoming energetic entrepreneurs. In the molecular-probe arena, where the hopes for the greatest advancements seem to be most concentrated, several researchers are working with old contrast agents that have relatively poor fluorescence but long histories of safe use in humans. 

Eva Sevick, PhD, is among them. Director of the Center for Molecular Imaging at the University of Texas Health Science Center in Houston, she is working with indocyanine green—a dye that’s been used in humans since the 1950s—and applying it to optical lymphatic imaging. 

“It’s a terrible fluorophore, but it works well with a device that we qualified under IND (Investigational New Drug) studies with NIH support,” says Sevick. “With a microdose of indocyanine green,” for example, “it takes only a couple of minutes to assess a patient’s lymph system. After cancer patients have been treated, you can quickly check to see if they have any phenotypes for lymphedema. It’s a great screening tool.” 

Sevick, who has launched a company to eventually commercialize the technology—she’s calling her firm NIRFImaging, for near-infrared fluorescence—adds that the application is not just for demonstration. “We are meeting an unmet clinical need and, at the same time, working with the National Institute of Standards and Technology to get these standards certified so that we can share with industry.”

Not incidentally, standardization is high on Sevick’s list of professional priorities. The FDA will only issue combinational approvals for optical advances, one particular contrast agent with one particular imaging device, which does little to fast-track a burgeoning technology as a broad category. So Sevick has become something of a standards evangelist, writing and speaking on the field’s need to progress from one-device, one-probe development to device platforms à la, for example, MRI scanners’ compatibility with any number of contrast agents regardless of scanner manufacturer. 

Sevick says that, absent such standardization, “the need for investment is going to be too great and we’re not going to be able to get this through to the clinic.” In the meantime, she adds, “There are things we can do to lower the translational barriers and show clinical utility. Clearly, resecting more disease is going to be a great thing to do. We’ll see where we go from there.” 

Adoptable options 

Among the attributes of light that make it uniquely promising for intraoperative imaging is its versatility, as every wavelength can be used to define a particular imaging parameter. Add in the variety of ways light interacts with tissues—whether “as is,” injected with contrast or both—and the means multiply for observing and measuring not only fluorescence but also scattering and absorption. That kind of versatility slows standardization and, thus, FDA approval, but it also drives innovation. 

At Stanford University School of Medicine, Christopher Contag, director of that institution’s Center for Innovation in In Vivo Imaging, is using micro-optics to develop miniaturized microscopes—3 millimeters by 5—that can work with a wide range of wavelengths and reach inside the body for point-of-care pathology. 

“The process of taking a tissue sample for biopsy somewhat blindly, then sending it to pathology and waiting for the results, is a technology we’ve had around for the last 100 years,” says Contag. “We think we can put the pathologist’s eyes right on the tissue right there in the patient. That visual can guide the biopsy so you select only the tissue that looks like it has a signature characteristic of disease.”  

Since every wavelength can isolate a different molecular marker, Contag’s microscopes would image from 400 nanometer wavelength to 800 nanometer wavelength at a couple of micron resolution. Precision imaging doesn’t get much more precise than that.  

Contag says his group has received two large NIH grants to develop the invention, and they’re funded by a grant from the Network for Translational Research (as is Sevick for her work in wide-field fluorescence). “It’s largely an academic pursuit; I don’t have a company in this area,” says Contag. “But it’s been sitting there waiting for the right time, and we’ve been really pushing the technology at Stanford. They’re kind of waiting for us to develop the tools so that then there would be a market.” 

Clinically, optical’s only major limitation is that light, no matter the type or wavelength, does not deeply penetrate tissue. Nuclear medicine has nothing to worry about for many of the deep-tissue cancer applications for which it is now the gold standard. But optical may become the intraoperative imaging tool of choice not only for dermatologic resections but also resections of tumors on superficial layers of the stomach, colon, esophagus and wherever else an endoscope can go. 

Potential awaiting proof  

On the funding front, optical faces a hurdle: a lack of capital to prove that the most promising new agent-imaging combinations can be made, approved and adequately reimbursed. 

And a formidable obstacle it is. A half dozen or so companies are making FDA-approved, optical-specific imaging devices, points out John Frangioni, MD, PhD, co-director of the Center for Molecular Imaging at Beth Israel Deaconess Medical Center in Boston. “But the contrast agents are a big problem,” he explains. “They’re difficult small molecules to synthesize and they’re expensive to develop.” At the same time, the FDA “has been very clear that they’re going to treat these new contrast agents as drugs, and we all know what it costs to develop new drugs.” Frangioni estimates the lab-to-market cost at $30 million to $50 million per agent. 

Contrast agents are far less lucrative than drugs, so Big Pharma has no interest in developing them. The deep-pocketed companies that could inject sufficient capital into optical research and development and might wring a profit from it in the long run are taking a “wait and see” stance, according to an industry observer who spoke off the record. Industry’s reticence might reverse if an optical startup were to raise the money, test the technology and prove that the demand will eventually justify creating the supply.

Frangioni, one of the field’s pioneers and the inventor of the Flare image-guided surgery system—the word is an acronym for Fluorescence-Assisted Resection and Exploration—says he’s frustrated with the slow pace of progress. In 2010, he launched the Flare Foundation, hoping to build a worldwide community to accelerate lab-to-clinic translations while sacrificing on royalties for himself and his employer, Harvard Medical School. “We’ve tried really hard,” he says, “but we’re kind of a typical nonprofit barely staying alive, and we’re talking about massive investments to bring a single one of these contrast agents to the clinic.” The field has immense potential to improve patient care while reducing costs, he adds, yet it’s “stuck in a state of unproven hope.”

“Given the limited resources we have, the most important thing we can do for the field right now is to conduct well-designed, longitudinal trials on outcomes using the old contrast agents,” says Frangioni. Such studies have never been done, he points out, adding that “they wouldn’t be sexy and they wouldn’t catapult anybody’s career—but, ultimately, that’s what will drive reimbursement, help the field and it’s what we can do while we’re waiting for everything else to come down the line.”

And if such studies were to come back with negative results? “That would give us proper pause,” says Frangioni. “Negative results would tell us that maybe improved visualization by way of optical molecular imaging doesn’t improve outcomes, economics or morbidity after all. As a scientist, I have to say those are unanswered questions. So there it is again: We have hope but not proof.” 

The Basis of Optical's Boosterism

 - John Frangioni, MD, PhD
John Frangioni, MD, PhD, Co-Director of the Center for Molecular Imaging, Beth Israel Deaconess Medical Center, Boston
John Frangioni, MD, PhD, co-director of the Center for Molecular Imaging at Beth Israel Deaconess Medical Center in Boston, itemizes the performance points that have lately been driving a wave of expressed enthusiasm and high expectations over optical molecular imaging:
  • Sensitive, real-time, high-resolution tumor margin detection in deposits as small as 10 cells wide
  • Avoidance of blood vessels, nerves, ureters, bile ducts and other vital structures during tumor resection
  • Rapid identification of sentinel lymph nodes and other sub-surface structures without the need for ionizing radiation
  • Reduced anesthesia time
  • Lower patient morbidity from damage to vital structures
  • Increased surgeon and operating-room throughput
  • Improved surgical outcomes lead to lower healthcare costs
  • Proof of principal in more than 500 patients worldwide