| Near-infrared fluorescence guided cancer surgery(NIRFGCS)offers better distinction between cancerous and normal tissues compared to surgeries relying on a surgeon’s senses of sight and touch.Due to the greater accuracy in determining tumor tissue margins,NIRFGCS within clinics continues to grow.NIRFGCS mostly utilizes indocyanine green(ICG)as contrast,the only FDA approved near-infrared dye for clinical use.The tumor-to-background ratio(TBR)is dependent on the ICG dosage and timing of surgery,but NIRFGCS lacks standardization of the Indocyanine Green(ICG)dose and the preoperative period allowed after ICG administration.In spite of the long history of its clinical use since 1955,there was no approach to real-time noninvasive quantification of ICG in tissue due to its complicated characteristics of fluorescence dependent on the microenvironment around it and its ultralow concentration in tissue.In an aim to find optimal doses and times allowed prior to surgery for NIRFGCS standardization,we developed a method that quantitatively determines ICG levels within tissues in real-time,with skin signal interference removed via mathematical models.We find that not only do the dose and the preoperative periods influence tumor-to-background ratios(TBRs),but both also heavily influence subject-to-subject variances of these ratios.Optimal detection conditions are observed when larger than typical ICG doses are administered and longer preoperative periods are allowed.Larger doses lead to increased TBRs,but longer preoperative periods are necessary to reduce variances to those observed when using smaller doses.Our results suggest that a clinical investigation into maximum tolerable ICG doses and prolonging preoperative periods in NIRFGCS is warranted.Most of all,by looking through the time-dependent fluorescence of liver,tumor and adjacent muscle,we found that hepatic metabolic capability played a key role in optimizing the dosage and timing to get higher and more reliable TBR.When dosage was comparable with hepatic metabolic capability,individual difference in hepatic metabolic capability led to individual difference in ICG clearance rate in normal tissue.Whereas ICG concentration in tumor increased with the increase of dosage by the large,and showed no correlations with hepatic metabolic capability when saturated.TBR,as a key factor in NIRFGCS,is related to ICG accumulation in tumor,ICG clearance in normal tissue,and individual difference of tissue physiological or pathological factors.Considering all these limits,we found two appropriate combinations of dosage and operation time for mice and we believe such a balance point for human with a certain cancer also exist.Therefore,we have further verified the balance points and influence of hepatic metabolic capability on ICG concentration in different tissue types in human oral cancer and esophageal cancer.And before that,as a verification of effectiveness and safety of self-developed equipment,we carried out fluorescent navigations of sentinel lymph node localization in human breast cancer surgery. |
