Near‐infrared (NIR) fluorescence imaging is gaining clinical acceptance over the last years and has been used for detection of lymph nodes, several tumor types, vital structures and tissue perfusion. ...This review focuses on NIR fluorescence imaging with indocyanine green and methylene blue for different clinical applications in abdominal surgery with an emphasis on oncology, based on a systematic literature search. Furthermore, practical information on doses, injection times, and intraoperative use are provided.
In ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor ...lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting.
Ten patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions.
6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99).
This is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false-positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains.
ISRCTN Registry ISRCTN16945066.
Background
Operative management of pancreatic ductal adenocarcinoma (PDAC) is complicated by several key decisions during the procedure. Identification of metastatic disease at the outset and, when ...none is found, complete (R0) resection of primary tumor are key to optimizing clinical outcomes. The use of tumor-targeted molecular imaging, based on photoacoustic and fluorescence optical imaging, can provide crucial information to the surgeon. The first-in-human use of multimodality molecular imaging for intraoperative detection of pancreatic cancer is reported using cetuximab-IRDye800, a near-infrared fluorescent agent that binds to epidermal growth factor receptor.
Methods
A dose-escalation study was performed to assess safety and feasibility of targeting and identifying PDAC in a tumor-specific manner using cetuximab-IRDye800 in patients undergoing surgical resection for pancreatic cancer. Patients received a loading dose of 100 mg of unlabeled cetuximab before infusion of cetuximab-IRDye800 (50 mg or 100 mg). Multi-instrument fluorescence imaging was performed throughout the surgery in addition to fluorescence and photoacoustic imaging ex vivo.
Results
Seven patients with resectable pancreatic masses suspected to be PDAC were enrolled in this study. Fluorescence imaging successfully identified tumor with a significantly higher mean fluorescence intensity in the tumor (0.09 ± 0.06) versus surrounding normal pancreatic tissue (0.02 ± 0.01), and pancreatitis (0.04 ± 0.01;
p
< 0.001), with a sensitivity of 96.1% and specificity of 67.0%. The mean photoacoustic signal in the tumor site was 3.7-fold higher than surrounding tissue.
Conclusions
The safety and feasibilty of intraoperative, tumor-specific detection of PDAC using cetuximab-IRDye800 with multimodal molecular imaging of the primary tumor and metastases was demonstrated.
The typical method for creating targeted contrast agents requires covalent conjugation of separate targeting and fluorophore domains. In this study, we demonstrate that it is possible to create ...near-infrared (NIR) fluorophores with different tissue specificities driven by their inherent chemical structures. Thus, a single compact molecule performs both targeting and imaging. We use this strategy to solve a major problem in head and neck surgery: the identification and preservation of parathyroid and thyroid glands. We synthesized 700-nm and 800-nm halogenated fluorophores that show high uptake into these glands after a single intravenous (IV) injection of 0.06 mg kg(-1) in a pig. By using a dual-channel NIR imaging system, we observed-in real time and with high sensitivity-the unambiguous distinction of parathyroid and thyroid glands simultaneously in the context of blood and surrounding soft tissue. This novel technology lays a foundation for performing head and neck surgery with increased precision and efficiency along with potentially lower morbidity, and it provides a general strategy for developing targeted NIR fluorophores.
Fluorescence-guided surgery using tumour-targeted imaging agents has emerged over the past decade as a promising and effective method of intraoperative cancer detection. An impressive number of ...fluorescently labelled antibodies, peptides, particles and other molecules related to cancer hallmarks have been developed for the illumination of target lesions. New approaches are being implemented to translate these imaging agents into the clinic, although only a few have made it past early-phase clinical trials. For this translational process to succeed, target selection, imaging agents and their related detection systems and clinical implementation have to operate in perfect harmony to enable real-time intraoperative visualization that can benefit patients. Herein, we review key aspects of this imaging cascade and focus on imaging approaches and methods that have helped to shed new light onto the field of intraoperative fluorescence-guided cancer surgery with the singular goal of improving patient outcomes.
Background Identification of diseased and normal parathyroid glands during parathyroid surgery can be challenging. The aim of this study was to assess whether near-infrared (NIR) fluorescence imaging ...using administration of a low-dose Methylene Blue (MB) at the start of the operation could provide optical guidance during parathyroid surgery and assist in the detection of parathyroid adenomas. Methods Patients diagnosed with primary hyperparathyroidism planned for parathyroidectomy were included. Patients received 0.5 mg/kg MB intravenously directly after start of anesthesia. During the operation, NIR fluorescence imaging was performed to identify parathyroid adenomas. Imaging results were compared with a previous published feasibility study in which 12 patients received MB after intraoperative identification of the adenoma. Results A total of 13 patients were included in the current study. In 10 of 12 patients with a histologically proven adenoma, the adenoma was fluorescent. Mean signal to background ratio was 3.1 ± 2.8. Mean diameter of the resected lesions was 17 ± 9 mm (range 5–28 mm). Adenomas could be identified up to 145 minutes after administration, which was the longest timespan until resection. Interestingly, in 3 patients, a total of 6 normal parathyroid glands (median diameter 2.5 mm) with a signal to background ratio of 1.8 ± 0.4 were identified using NIR fluorescence imaging. Conclusion Early administration of low-dose MB provided guidance during parathyroidectomy by identifying both parathyroid adenomas and normal parathyroid glands. In patients in whom difficult identification of the parathyroid adenoma is expected or when normal glands have to be identified, the administration of MB may improve surgical outcome.
Paradigm shifts in surgery arise when surgeons are empowered to perform surgery faster, better and less expensively than current standards. Optical imaging that exploits invisible near-infrared (NIR) ...fluorescent light (700-900 nm) has the potential to improve cancer surgery outcomes, minimize the time patients are under anaesthesia and lower health-care costs largely by way of its improved contrast and depth of tissue penetration relative to visible light. Accordingly, the past few years have witnessed an explosion of proof-of-concept clinical trials in the field. In this Review, we introduce the concept of NIR fluorescence imaging for cancer surgery, examine the clinical trial literature to date and outline the key issues pertaining to imaging system and contrast agent optimization. Although NIR seems to be superior to many traditional imaging techniques, its incorporation into routine care of patients with cancer depends on rigorous clinical trials and validation studies.
Fluorescence-guided surgery is an intraoperative optical imaging method that provides surgeons with real-time guidance for the delineation of tumours. Currently, in phase 1 and 2 clinical trials, ...evaluation of fluorescence-guided surgery is primarily focused on its diagnostic performance, although the corresponding outcome variables do not inform about the added clinical benefit of fluorescence-guided surgery and are challenging to assess objectively. Nonetheless, the effect of fluorescence-guided surgery on intraoperative decision making is the most objective outcome measurement to assess the clinical value of this imaging method. In this Review, we explore the study designs of existing trials of fluorescence-guided surgery that allow us to extract information on potential changes in intraoperative decision making, such as additional or more conservative resections. On the basis of this analysis, we offer recommendations on how to report changes in intraoperative decision making that result from fluorescence imaging, which is of utmost importance for the widespread clinical implementation of fluorescence-guided surgery.
Background
Near-infrared (NIR) fluorescence is a promising novel imaging technique that can aid in intraoperative demarcation of pancreatic cancer (PDAC) and thus increase radical resection rates. ...This study investigated SGM-101, a novel, fluorescent-labeled anti-carcinoembryonic antigen (CEA) antibody. The phase 1 study aimed to assess the tolerability and feasibility of intraoperative fluorescence tumor imaging using SGM-101 in patients undergoing a surgical exploration for PDAC.
Methods
At least 48 h before undergoing surgery for PDAC, 12 patients were injected intravenously with 5, 7.5, or 10 mg of SGM-101. Tolerability assessments were performed at regular intervals after dosing. The surgical field was imaged using the Quest NIR imaging system. Concordance between fluorescence and tumor presence on histopathology was studied.
Results
In this study, SGM-101 specifically accumulated in CEA-expressing primary tumors and peritoneal and liver metastases, allowing real-time intraoperative fluorescence imaging. The mean tumor-to-background ratio (TBR) was 1.6 for primary tumors and 1.7 for metastatic lesions. One false-positive lesion was detected (CEA-expressing intraductal papillary mucinous neoplasm). False-negativity was seen twice as a consequence of overlying blood or tissue that blocked the fluorescent signal.
Conclusion
The use of a fluorescent-labeled anti-CEA antibody was safe and feasible for the intraoperative detection of both primary PDAC and metastases. These results warrant further research to determine the impact of this technique on clinical decision making and overall survival.
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