Page 52 - Fluorescence-guided cancer surgery

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Chapter 3
that the high dose (7.5 mg/kg) used in these prior studies, which was needed for visualization of the blue colored dye the human eye, brings substantial risk of serious adverse events, such as toxic metabolic encephalopathy19.
NIR uorescence imaging permits visualization of MB at low concentration because MB uoresces at 700 nm. In transgenic mice, Winer et al.20 showed intraoperative identi cation of insulinoma, a pancreatic neuroendocrine tumor, using NIR uorescence imaging and MB. In a clinical setting, this technique has been used for the intraoperative identi cation of parathyroid adenomas and a solitary brous tumor of the pancreas21;22. In these prior studies, a dose of only 0.5 - 0.1 mg/kg MB was used, which resulted in clear uorescent signal in the identi ed lesions. Although we did not explore dose in this feasibility study, our results suggest that a formal study of dose, which includes higher doses than 1.0 mg/kg, is warranted. Such a study could answer de nitively if the 17% of tumors that were not identi ed using MB were because the dose was too low.
The exact mechanism of tracer uptake in these tumors is unclear. The physicochemical similarities of MB and 99mTc-MIBI, both lipophilic and cationic, suggest a possible common mechanism. Lipophilic captions were originally developed as myocardial perfusion agents, and subsequently used as tumor- seeking agents in a variety of tumors23. They emerged as suitable tools to explore speci c cellular processes and functions in malignant tumors. In several studies, it was shown that lipophilic cations show passive in ux into cells with large negative plasma membrane and mitochondrial membrane potentials23;24, with in ux being reversible. Cellular processes that are associated with uptake of these tracers are apoptosis, proliferation, P-glycoprotein expression, and neoangiogenesis. However, it has to be further explored whether any of these mechanisms result in MB accumulation in breast cancer tissue.
Using 99mTc-MIBI, a breast tumor identi cation rate of 83-90% has been reported. Although our present study was small (N = 24 subjects), our identi cation rate is in agreement with the sensitivity of 99mTc-MIBI described in the literature. Based on clinical experience with 99mTc-MIBI in breast cancer, early and delayed imaging is used to discriminate between malignant and benign lesions, as tracer accumulation is prolonged in malignant lesions. This is in contrary to MR imaging of breast malignancies, where malignant lesions tend to enhance but also washout quicker than benign lesions25. This is caused by endothelial fenestration in microvasculature, which leads to increased capillary leakage, and connections between the arteriolar and venular systems