**8. Future perspectives**

IOUS is still characterized by several drawbacks: it cannot detect lesions smaller than 3 mm, its accuracy is dependent on the surgeon's skill and experience, the images are 2D and there is a "blind area "of about 1 cm below the surface of the liver, which is particularly problematic in the case of small hepatic metastases due to colorectal cancer that are mainly located on the surface of the liver. Of course, associating contrast agents has greatly improved IOUS accuracy; however, the disadvantage of visualization of the lesions for a too short period of time makes this technique to be of limited applicability in guiding hepatic resections that may last between 2 and 6 h [112].

Recently, a new fluorescent approach, using indocyanine green (ICG), has been proposed to improve the intraoperative detection of neoplastic lesions [113, 114]. ICG is a non-specific molecule that allows detection of tumor tissue, but with limited specificity. The main advantage of its use is its safety and its commercial availability as a contrast substance. The imaging technique of intraoperative fluorescence using ICG was initially used for the detection of sentinel lymph nodes in patients with gastric, colon, and breast cancer [115, 116]. Several studies have shown that malign liver tumors show strong fluorescence when preoperative ICG administration is made [117, 118]. This technique is based on the fact that ICG binds to plasma proteins and together emit light with a peak wavelength of approximately 830 nm when illuminated with infrared light [119].

Initially, ICG-fluorescence imaging was limited to open surgery alone. After year 2010, as laparoscopic and robotic imaging systems with fluorescence have developed, ICG-fluorescence imaging has been extended to minimally invasive abdominal surgery, especially for the visualization of extrahepatic biliary tract anatomy (during laparoscopic/robotic cholecystectomies) [120], an approach known as fluorescence cholangiography [121]. In 2014, the use of ICG-fluorescence imaging was reported for the identification of subcapsular hepatic tumors before liver transection [122]. A new laparoscopic imaging system is starting to be used, this system overlapping pseudo-color fluorescence images with white color-light images in real-time (fusion ICG-fluorescence imaging) with the proposal to identify segmental hepatic margins and localization of liver tumors [123]. Thus, ICG has the ability to "label" bile ducts [121, 124–126], hepatic tumors [118, 127–130], edges of liver segments [117, 131–133], this being due both to ICG fluorescence [134], and to its property to be excreted into the bile [135]. Due to the property of being eliminated for more than 6 h after intravenous injection [126, 135], ICG-fluorescence imaging can also be used to identify small biliary fistulas after hepatectomy [136].

As for ICG-fluorescence imaging sensitivity in detecting liver metastases, it varies between 69 and 100%. However, sensitivity is limited because the examination does not have the ability to detect hepatic lesions at a depth greater than 8 mm in the hepatic parenchyma. It has also been shown that this method can detect new metastatic lesions in up to 43% of cases [137]. In fact, it has been reported that ICG-fluorescence imaging can detect superficial lesions of up to 2 mm in both HCC and metastases liver disease due to colorectal cancers [127, 129].

Currently, a combination of a fluorophore, such as ICG, with an anti-tumor antibody is evaluated in preclinical studies. These new molecules could present a major advantage in the future for clinical applications that would allow the detection of tumor lesions with a higher TBR (tumor-to-background ratio between the intensity of fluorescence in tumor tissue and normal surrounding tissue). Recently, Harlaar et al. reported the first clinical trial using IRD-800CW-labeled bevacizumab for the detection of peritoneal metastases of colorectal origin [138].
