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Imaging based on the EPR e ect in ovarian cancer 125
undetected metastatic disease could be found, but did result in the resection of non-malignant lesions.
The intended e ect of NIR uorescence imaging with ICG was based on the EPR e ect. Due to tumor-induced angiogenesis, solid tumors exhibit leaky and immature vessels. Because of this macromolecules are able to permeate through the vessels and into tumor tissue where they are retained due to impaired lymph drainage16. ICG is not a macromolecule, but behaves like one after binding to serum proteins. This, combined with the rapid clearance from the circulation, makes ICG a potentially good probe for NIR uorescence imaging of solid tumors. This theory has proven to be true for gastric and breast cancer18-23. But it should be noted that all the trials in breast cancer patients were conducted in a pre-operative diagnostic setting and results may di er from intraoperative usage of ICG.
The large number of false-positives found in this study may be due to the lack of speci city of the EPR e ect. It is known that the EPR e ect is in uenced by multiple factors, such as size, presence of necrosis, tumor type, presence of vascular mediators such as bradykinin or prostaglandins, and location (including primary tumor vs metastatic lesion) of the lesion. Moreover, reactive processes and cancer have parallels in pathophysiological pathways and in vascular mediators. It has been shown that the EPR e ect also occurs in in ammatory lesions25;28;29. This is in agreement with part of the false-positive lesions identi ed in the current study. Especially since the EPR e ect in reactive tissue is more prominently present hours after injection (coinciding with our imaging window) versus days to weeks after injection in tumor tissue26.
Several studies describe the intraoperative identi cation of solid tumors using clinically available, non-targeted uorescent probes as ICG and methylene blue (MB). These studies report higher TBRs than found in the current study. For example, imaging of colorectal liver metastases using ICG (TBR 7.0)30, parathyroid adenomas using MB (6.1)31 and breast cancer using MB (2.4)32 all showed higher TBRs than the observed 2.0. A possible explanation for this is that in these studies other mechanisms causing accumulation of the uorescent probe in or around tumor tissue played a role in addition to the possible EPR e ect. The EPR e ect on its own may not be su cient in providing high enough TBRs for tumor imaging. Finally, the average TBR of false-positive, benign lesions was just as high as the average TBR of true positive malignant lesions, while the average TBR of reactive benign lesions was even higher