Extreme precision is required to surgically remove a cancerous tumor without damaging the surrounding healthy tissue. Yet surgeons often must rely on their eyes and hands to determine where to cut. Fluorescence lifetime (FLT) imaging, developed at Mass General Brigham by researchers who collaborated with several other institutions to evaluate the technique, could improve the precision of cancer surgeries. FLT imaging, a visualization technique for targeting cancer, combines high-speed cameras and injectable fluorescent dye to distinguish tumor tissue from normal tissue with a high degree of accuracy. Instead of relying solely on dyes to identify cancer cells, the FLT technique also uses cameras to rapidly detect changes occurring in the properties of the light emitted by the tissue. In studies in preclinical models, the researchers found that in mice, malignant tumors injected with indocyanine green (ICG), a near-infrared dye, had a longer fluorescence lifetime compared to normal tissue injected with ICG. The researchers could accurately distinguish between tumor tissue and normal tissue by measuring the difference in their FLT. In the current study, the team applied this approach to tumor samples from patients with different cancers. The researchers began by analyzing samples from patients undergoing liver surgery at Massachusetts General Hospital (MGH) and head and neck surgery at Massachusetts Eye and Ear Hospital (Mass Eye and Ear). All the patients received an ICG injection at least one day before the surgery. The team then expanded its study to include several institutions. It evaluated tumor specimens from more than 60 patients with various types of cancer, including liver, brain, tongue, skin, bone, and soft tissue. In addition to MGH and Mass Eye and Ear, the study samples came from patients being treated at the University of Pennsylvania, the University of Newcastle, and Leiden University. FLT imaging revealed that after systemic injection of ICG dye in patients with different types of solid tumors, the fluorescence lifetime of the tumor tissue was longer than the fluorescence lifetime of the noncancerous tissue. The team was able to detect a fluorescence lifetime shift at the cellular level using microscopy and, in larger specimens, through wide-field imaging. This shift was consistent across tumor types and multiple patients. Using the FLT imaging technique, the team was also able to distinguish benign from metastatic lymph nodes. “Our lab has been studying fluorescence lifetime imaging since 2002, but this is the first time that anyone has combined it with tumor imaging and injectable dyes in humans,” said professor Anand Kumar, who led the research. “By doing so, we’ve developed a technique for accurately distinguishing tumor tissue from healthy tissue across cancer types.” The MGB research team achieved a greater than 97% accuracy when it used FLT imaging with IDC dye to differentiate between tumor tissue and healthy tissue in the 60 study participants. The results indicate that this technique could improve surgical precision in surgeries for different types of cancer. “This technology has taken us to the brink of a revolution in solid tumor surgery,” said Dr. Mark Varvares, chief of otolaryngology—head and neck surgery at Mass Eye and Ear. “By using the advanced imaging techniques combined with the dye, surgeons in the near future will have the ability to more completely remove all malignant cells during tumor surgery while at the same time, with confidence, spare normal tissue, enhancing postoperative function, and in some cases, the patient’s appearance.” The desire to improve tumor visualization during surgery has given rise to numerous techniques, including ones that use fluorescence imaging and advanced microscopy. However, these technologies have not been widely adopted, and most of them are restricted to specific types of cancer. Fluorescence-guided imaging alone can help make the surgical resection of solid tumors more precise, but variable tumor uptake and incomplete clearance of fluorescent dyes can reduce the accuracy of conventional fluorescence intensity-based imaging. Unlike fluorescence intensity, which depends on imaging-system parameters, tissue depth, and the amount of dye taken up by tumors, FLT is a photophysical property that is largely independent of these factors. The researchers said that although ICG is approved by the U.S. Food and Drug Administration for other indications, it is not yet approved for clinical use as a tumor-marking agent. The researchers’ next step will be to perform a larger-scale clinical trial to test the safety and efficacy of FLT imaging with ICG for tumor identification during surgeries. “Our work suggests that the combination of fluorescence lifetime imaging with ICG could improve surgical resections, thereby impacting patient lives,” Kumar said. “We’re excited to take these next steps to move our discoveries closer to clinical impact.” The research was published in Nature Biomedical Engineering (www.doi.org/10.1038/s41551-023-01105-2).
