Surgical resection continues to function as the primary treatment option for most solid tumors. However, the detection of cancerous tissue remains predominantly subjective and reliant on the expertise of the surgeon. Surgery that is guided by fluorescence imaging has shown clinical relevance as a new approach to detecting the primary tumor, tumor margins, and metastatic lymph nodes. It is a technique to reduce recurrence and increase the possibility of a curative resection. While significant progress has been made in developing this emerging technology as a tool to assist the surgeon, further improvements are still necessary. Refining imaging agents and tumor targeting strategies to be a precise and reliable surgical strategy is essential in order to translate this technology into patient care settings. This review seeks to provide a comprehensive update on the most recent progress of fluorescence-guided surgery and its translation into the clinic. By highlighting the current status and recent developments of fluorescence image-guided surgery in the field of surgical oncology, we aim to offer insight into the challenges and opportunities that require further investigation.
Surgical resection is currently the only potentially curative option for patients with pancreatic cancer. However, the 5-year survival rate after resection is only 25%, due in part to high rates of R1 resections, in which cells are left behind at the surgical margin, resulting in disease recurrence. Fluorescence-guided surgery (FGS) has emerged as a method to reduce incomplete resections and improve intraoperative assessment of cancer. Mucin-16 (MUC16), a protein biomarker highly overexpressed in pancreatic cancer, is a potential target for FGS. In this study, we developed a fluorescent MUC16-targeted antibody probe, AR9.6-IRDye800, for imageguided resection of pancreatic cancer. We demonstrated the efficacy of this probe to bind human pancreatic cancer cell lines in vitro and in vivo. In an orthotopic xenograft model, AR9.6-IRDye800 exhibited superior fluorescence enhancement of tumors and lower signal in critical background organs in comparison to a nonspecific IgG control. The results of this study suggest that AR9.6-IRDye800 has potential for success as a probe for FGS in pancreatic cancer patients, and MUC16 is a feasible target for intraoperative imaging.
Surgery remains the only potentially
curative treatment option
for pancreatic cancer, but resections are made more difficult by infiltrative
disease, proximity of critical vasculature, peritumoral inflammation,
and dense stroma. Surgeons are limited to tactile and visual cues
to differentiate cancerous tissue from normal tissue. Furthermore,
translating preoperative images to the intraoperative setting poses
additional challenges for tumor detection, and can result in undetected
and unresected lesions. Thus, pancreatic ductal adenocarcinoma (PDAC)
has high rates of incomplete resections, and subsequently, disease
recurrence. Fluorescence-guided surgery (FGS) has emerged as a method
to improve intraoperative detection of cancer and ultimately improve
surgical outcomes. Initial clinical trials have demonstrated feasibility
of FGS for PDAC, but there are limited targeted probes under investigation
for this disease, highlighting the need for development of additional
novel biomarkers to reflect the PDAC heterogeneity. MUCIN16 (MUC16)
is a glycoprotein that is overexpressed in 60–80% of PDAC.
In our previous work, we developed a MUC16-targeted murine antibody
near-infrared conjugate, termed AR9.6–IRDye800, that showed
efficacy in detecting pancreatic cancer. To build on the translational
potential of this imaging probe, a humanized variant of the AR9.6
fluorescent conjugate was developed and investigated herein. This
conjugate, termed huAR9.6–IRDye800, showed equivalent binding
properties to its murine counterpart. Using an optimized dye:protein
ratio of 1:1, in vivo studies demonstrated high tumor
to background ratios in MUC16-expressing tumor models, and delineation
of tumors in a patient-derived xenograft model. Safety, biodistribution,
and toxicity studies were conducted. These studies demonstrated that
huAR9.6–IRDye800 was safe, did not yield evidence of histological
toxicity, and was well tolerated in vivo. The results
from this work suggest that AR9.6-IRDye800 is an efficacious and safe
imaging agent for identifying pancreatic cancer intraoperatively through
fluorescence-guided surgery.
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