A Glimpse of the Future With Intraoperative Molecular Imaging

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In reading the article by Predina et al entitled “Intraoperative Molecular Imaging: The Surgical Oncologist's North Star ” in the Annals of Surgery, it becomes evident that surgery is embarking on a new era. The concept of intraoperative molecular imaging (IMI) has been of greatest interest to the surgical oncologist as it leverages the unique characteristics and molecular behaviors of tumors to preferentially take up or concentrate optical contrast agents, allowing improved intraoperative visualization of malignant disease versus normal surrounding tissues. This is particularly appealing with the recognition that several systemically administered optical contrast agents are able to accumulate in a wide variety of tumors throughout the body including lung, gastrointestinal, thymic, neurologic, and genitourinary malignancies.
The ability to accurately delineate diseased from normal tissue, particularly in terms of the surgical resection of cancer, has been the holy grail for surgical oncology, and the authors of this manuscript have 1 of the largest, if not the largest, clinical experience with IMI, having just enrolled their 500th patient. Their success has come from critical advances in both the imaging technology itself and the tumor specificity of the contrast agents. The development of near-infrared (NIR) imaging systems with improved depth of penetration, enhanced detection, and intrinsically lower biologic background interference due to lower light absorption and scattering and a higher signal-to-noise ratio, has fueled the growing interest in this technology to improve intraoperative assessment for a variety of clinical needs. Although initially filling the footprint of a refrigerator, NIR imaging systems are now readily mobile, offering improved imaging functionality and both video-assisted and robotic minimally invasive capabilities. Applications for NIR imaging during surgical resection of cancers are of particular interest, with significant efforts being focused on tumor localization and prediction of malignant histology as demonstrated in this paper, examination of surgical margins,1 identification of sentinel lymph nodes and lymphatic mapping,2 and assessment of conduit or reconstructive flap perfusion3 among others. Recognition that the already US Food and Drug Administration (FDA)-approved intravenous optical contrast agent indocyanine green (ICG), previously used for neurovascular and cardiac angiography as early as the 1960s and 1970s,4 was also an excellent NIR contrast agent coupled with the subsequent discovery and clinical implementation by Singhal that systemically administered ICG preferentially accumulates in tumor tissues has proved critically important to facilitating the development of the field of IMI.
The authors have included excellent examples of their work in tumor localization in pancreatic cancer, thymomas, and prostate cancer that have leveraged this powerful technology in the setting of systemically administered ICG-based agents. As the field has evolved, additional applications and agents have been developed to increase tumor-specificity by targeting tumor-specific molecular differences or the tumor microenvironment, such as with intraoperative imaging of glioblastoma multiforme with 5-aminoleuvolinic acid (5-ALA),5 and, as shown in this report, the use of a folate-targeted NIR agent in nonsmall cell lung cancer, which is being pioneered in collaboration with the current authors of this study. It is of note that earlier work with a folate-fluorescein isothiocyanate conjugate were less successful, thereby highlighting the importance of both advances in NIR imaging and contrast agents.6
Overall, this article highlights the rapid advances and exciting future of IMI as a means to improve intraoperative visualization and thus surgical accuracy in the operating room by allowing surgeons to see what was previously invisible to the surgeon's eye. Specificities, sensitivities, and positive and negative predictive values have been impressive in the published studies.
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