ICG guided robotic liver surgery

Gian Luca Grazi
Hepato-Biliary-Pancreatic Surgery
National Cancer Institute Regina Elena
Rome
Future of robotic surgery
ICG guided robotic surgery
(20 minutes)

HCC
214
Intrahepatic
Cholangiocarcinoma
79
Metastases
402
Perihilar
Cholangiocarcinoma
36
Others
93
Gallbladder
29
892 Liver Resections
(June 2010 – September 2022)

5
7
10
11
19
23
1
0
5
10
15
20
25
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023
#
procedures
Years
Per Year # of 76 Robotic Hepatectomies

HCC
38%
Metastases
18%
Other Cancers
4%
CCA
12%
Benign
28%
Diagnosis
Left lateral
sectionectomy
12%
Minor resections
42%
1-2 Segments
34%
Left hepatectomy
5%
Right hepatectomy
7%
Type of Resection

 One major drawback of minimally-invasive
surgery is the lack of haptic feedback, since
palpation with laparoscopic or robotic forceps is
limited.
 The surgeon must rely on his/her own visual
impressions, making parenchymal dissections
particularly problematic

• Indocyanine green (ICG) was approved by the Food and Drug Administration (FDA) in
1957 and has been used in various medical fields.
• Since the 1980s, ICG has been used to test liver function prior to hepatobiliary surgery.
• In this indication (LiMON test), ICG is administered intravenously days before surgery
and the blood concentration and ICG plasma disappearance rates are measured
noninvasively.
• In healthy liver tissue, ICG is fully excreted after 72 h and no remnants should be
detectable.
• In 2009 it was noticed ICG accumulation in hepatocellular carcinoma (HCC) and hepatic
metastasis (HM) of colorectal cancer up to 14 days after ICG application for liver
function evaluation
Brief History of Indocyanine Green

 In open surgery, additional near-infrared (NIR) cameras and/or monitors are
needed for ICG visualization, theater lights need to be switched off, and the
operating surgeon must remove their focus from the operation field while
performing crucial parts of the operation.
 In laparoscopic surgery, the NIR camera is integrated into some systems.
 The Firefly™camera (Intuitive, Sunnyvale, CA, USA) is integrated in the da
Vinci Surgical Systems (Intuitive, Sunnyvale, CA, USA) and can easily be used
to intraoperatively visualize ICG accumulation.
Usage in Surgery

Indocyanine Green Fluorescence Navigation in Liver Surgery
A Systematic Review on Dose and Timing of Administration
Wakabayashi T, Ann Surg 2022;275:1025–1034

•Time of administration
•Dose to be given
•Impaired liver function (fibrosis or cirrhosis)
•Elderly patients with slower metabolism
Open Questions in the usage of Indocyanine Green

The reported depth penetration is
limited to a maximum of ≈ 8 mm

1.Study of the anatomy, mainly biliary
2.Detection of bile leaks
3.Guiding mini-invasive liver resections
4.Intra operative tumor staging

Wang X, Ann Surg 2021, 274: 97-106

On POD3, the bilirubin levels in the drainage fluid were
significantly lower in the IO-G than in the CO-G. Bars indicate
the median values and interquartile ranges.
Bilirubin levels in serum and drainage effluent on the third postoperative day (POD3).
Hanaki T, Anticancer Res 2022,42:4787-4793

Ishizawa T, Arch Surg 2012, 147: 393-394
Positive staining Negative staining
The portal branch of the segment to be resected is
punctured with a needle.
The ICG dye (0.025 mg in 10 mL of normal saline) is
injected without clamping the hepatic artery.
The liver surface of segment to be resected starts to
fluoresce following the injection of the ICG dye.
The intensity of the fluorescence on the surface of
segment to be resected is highest 10 minutes after
injection, which allows clear differentiation between
segment to be resected and adjacent.
The positive-staining technique with ICG dye does not
require hepatic artery clamping.
The root of the portal pedicle of the segment to be
resected had to be temporarily clamped and the ICG dye
(2.5 mg in 1 mL of normal saline) is intravenously
injected.
All hepatic segments, except segment to be resected,
are clearly fluorescent 1 minute after injection.
The hepatic segments with maintained portal and
arterial blood flow are illuminated with ICG demarcating
the area to be resected.
Positive and Negative Staining of Hepatic Segments by Use of Fluorescent
Imaging Techniques During Laparoscopic Hepatectomy

Chiow AKH, HPB 2021, 23: 475-482
Robotic ICG guided anatomical liver resection in a multicenter cohort: an
evolution from “positive staining” into “negative staining” method

• Robotic ICG guided hepatectomy technique for anatomical
liver resection is safe and feasible and has the potential
benefit for improving visualization of the demarcation line
especially in living donor liver graft harvest and cirrhotic
patients with minimal complications.
• The negative staining technique was easy to perform and
is recommended in major anatomical resections.
Chiow AKH, HPB 2021, 23: 475-482

ASSOCIATING INTRAOPERATIVE INDOCYANINE
GREEN FLUORESCENCE IMAGING AND
ULTRASOUND TO DETECT MICROSCOPIC CANCER
LESIONS DURING HEPATIC SURGERY
Scarinci A, Di Filippo S, Palmieri A, Police A, Marcelli ME,
Diodoro MG, Grazi GL
Abstract – Oral presentation
8 patients
Evaluated with CT/MR + IOUS
• 4 HCC
• 2 METS
• 2 CCA
Additional resection
6 patients
Planned resection
2 patients
11 more nodules
7
Tumoral
nodules
4
non tumoral nodules
2 regenerative nodule
1 fat containing cell
1 cirrhosis

Boogerd LSF, Surg Endosc 2017, 31: 952-961
Sensitivity of all imaging modalities employed.
Sensitivity and positive predictive value of computed tomography (CT), magnetic resonance imaging (MRI), visual
inspection, laparoscopic ultrasonography (LUS), near-infrared fluorescence imaging (NIRF), and combination of LUS and
NIRF.
Twenty-two patients planned
to undergo laparoscopic
staging (n = 4) or resection (n
= 19) of one or multiple
tumors confined to the liver
were included from April 2013
to November 2015.

Peyrat P, J Surg Oncol 2018;117:922-927

Fluorescence
patterns
Total all tumor tissue showed
uniform fluorescence
all well-differentiated
HCCs
the expression levels of portal uptake transporters of ICG were
well preserved, but functional or morphological biliary
excretion disorders were present, leading to retention of ICG in
cancerous tissues at the time of surgery, following
preoperative intravenous injection.
Partial some tumor tissues
showed fluorescence
Rim the cancer tissues were
negative for
fluorescence, but the
surrounding liver
parenchyma showed
fluorescence
poorly differentiated
HCCs
and CRLM
the portal uptake transporters were downregulated in
cancerous tissues but biliary excretion of ICG by surrounding
non-cancerous hepatic parenchyma was also disordered,
resulting in rim-type fluorescence.
The rim-type fluorescence signal in CRLM has been reported to
be caused by immature hepatocytes with decreased bile
excretion ability that surrounds the tumor
Ishizawa, HepatoBiliary Surg Nutr 2016, 5: 322-328

Liu T, Surgical Innovation 2022, 29:532–539
Fluorescent patterns of liver cancers on surgical specimens and their images and overlay
HCC
Fluorescent
Type
Overlay
Total fluorescent type, well-
differentiated HCC
Partial fluorescent type,
moderately differentiated
HCC with haemorrhagic
necrosis
Rim fluorescent type,
poorly differentiated HCC

Marino MV, HPB 2020, 22: 422-431

 Besides being highly user-dependent, IOUS has the
problem of not detecting lesions that are just below
the surface within the first cm of the liver.
 In contrast, NIR light can only penetrate up to 1 cm
into liver parenchyma and thereby fails to detect
deeper tumors.
 The combination of IOUS and ICG therefore seems to
increase the detection rate of hepatic metastasis

Handgraaf HJM, EJSO 2017, 43: 1463-1471

Additionally identified colorectal liver metastases

(Estimated) liver-specific recurrence-free interval and overall survival

Progress of NIR-II Fluorescence Technology
NIR-II (1000–1700 nm) fluorescence imaging technology has a longer
emission wavelength than NIR-I (750–900 nm) and can significantly
diminish photon scattering within biological tissues and reduce tissue
autofluorescence and light absorption, leading to significant benefits in
terms of
 deeper detection,
 higher resolution, and
 fidelity.
Liu T, Surgical Innovation 2022, 29:532–539

• Patients with liver cancer were enrolled in the study, and then received
preoperative imaging examinations, including enhanced CT, MRI,
ultrasonography and PET.
• Before surgery, the patients were injected with ICG intravenously at a
dose of 0.5 mg kg−1 body weight as a routine preoperative liver function
test.
• One to seven days later, on the day of surgery, the patients received a
laparotomy.
• The liver surface was examined by the integrated NIR-I/II and visible
multispectral imaging instrument and visible and NIR-I/II images were
obtained.
• Tumours were resected by the guidance of ultrasonography and NIR-I
imaging.
• During the resection, NIR-II images were also acquired. After the
operation, visible and NIR-I/II images of the resected specimens were
obtained.
• Pathological examination of the resected tissues was conducted.
First-in-human liver-tumour surgery guided by multispectral fluorescence imaging in the
visible and near-infrared-I/II windows
Hu Z, Nat Biomed Eng 2020;4:259-271

Intraoperative NIR-I/II fluorescence image-guided tumour resection
For a typical patient
with HCC, guided by
ultrasonography and
the visible light image,
the tumour was
resected and thought
to be completely
removed on the basis
of the experience of
the surgeons.
NIR-II imaging detected
fluorescence signals in
the remaining tissue
sections.
NIR-I imaging
did not reveal
any signals
The fluorescent residual
tissues were further
resected and received
histopathological
examination to verify that
the tissues were HCC.

Compared with the current preoperative imaging modalities (ultrasonography, MRI,
CT) and intraoperative imaging techniques (ultrasonography), intraoperative ICG-
based NIR-I/II fluorescence imaging can detect the tumour lesions with no obvious
imaging characteristics.
After laparotomy, intraoperative NIR-I/II fluorescence imaging was able to detect
the lesions missed by preoperative imaging modalities, which can substantially
promote the accuracy of patient staging and management.
During surgery, NIR-I/II imaging can also identify residual lesions that are difficult to
be recognized by surgeons or intraoperative ultrasonography.
Moreover, our imaging study revealed that ICG distributed quite uniformly in well-
differentiated or moderately differentiated tumours, but partial-type and rim-type
distributions were found in the poorly differentiated HCCs, which is consistent with
previously reported findings.

Molecular imaging is currently a hot research field in the world.
ICG fluorescence imaging technology can
• accurately identify liver tumors and enable real-time surgical navigation to ensure complete tumor resection;
• aid in the determination of tumor differentiation, creating a new target for accurate hepatobiliary surgery.
ICG technology combined with tumor-targeting nanoparticles and the emergence of novel targeted probes greatly
overcome the limitations of ICG.
With probe improvement, the fluorescence imaging system can be combined with other clinical treatment or examination
methods to improve the treatment efficiency of liver cancer.
The rapid development of NIR-II fluorescence imaging is conducive to achieving a more accurate intraoperative navigation
system.
With the advent of precision medicine and the progress of various biotechnology methods, fluorescence imaging technology
will be better developed and applied in the
• diagnosis,
• surgical navigation, and
• treatment of liver cancer.
TAKE HOME MESSAGE

As image-guided surgery solutions are quite often technically challenging.
Ethics and regulations provide a healthy translational hurdle to protect patients, while financial aspects
may also constrain development.
Lead compounds and detection device prototypes must be developed and refined in research setting and
often not within the domain of patient care.
While this helps preventing the patient exposure to potentially harmful technologies, it also means that
some approaches can become more ‘technology-driven’ than ‘clinical need-driven’. All developments
should be done with clinical translation in mind and based on real-life unmet surgical needs.
It is extremely challenging to translate laboratory findings to the clinic.
Most chemical and engineering efforts still find applications in multiple settings. The success stories in
the field of image-guided surgery are based on technologies that maximally align with innovations made
in other fields. For example, initial work on fluorescence laparoscopy presented in prostate cancer
surgery was later transferred to breast surgery and the technique is now also implemented during i.e.,
laparoscopic surgery.
FINAL CONSIDERATIONS

Gian Luca Grazi
Hepato Biliary Pancreatic Surgery
National Cancer Institute “Regina Elena”, Rome, Italy
gianluca.grazi@ifo.it
www.chirurgiadelfegato.it

ICG guided robotic liver surgery

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