Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Benson, J.R.

Leeuwen, F.W.B. van

Sugie, T.

Frontiers in Oncology

Leiden University Scholary Publications

Editorial: state-of-the-art fluorescence image-guided surgery: currentand future developmentsBenson, J.R.; Leeuwen, F.W.B. van; Sugie, T.CitationBenson, J. R., Leeuwen, F. W. B. van, & Sugie, T. (2021). Editorial: state-of-the-artfluorescence image-guided surgery: current and future developments. Frontiers InOncology, 11. doi:10.3389/fonc.2021.776832 Version: Publisher's VersionLicense: Creative Commons CC BY 4.0 licenseDownloaded from: https://hdl.handle.net/1887/3277675 Note: To cite this publication please use the final published version (if applicable).Frontiers in Oncology | www.frontiersin.orgEdited and reviewed by:Francesco Giovinazzo,Catholic University of the SacredHeart, Italy*Correspondence:John R. Bensonjohn.benson@addenbrookes.nhs.ukSpecialty section:This article was submitted toSurgical Oncology,a section of the journalFrontiers in OncologyReceived: 14 September 2021Accepted: 04 October 2021Published: 22 October 2021Citation:Benson JR, van Leeuwen FWB andSugie T (2021) Editorial: State-Of-The-Art Fluorescence Image-Guided Surgery: Current andFuture Developments.Front. Oncol. 11:776832.doi: 10.3389/fonc.2021.776832EDITORIALpublished: 22 October 2021doi: 10.3389/fonc.2021.776832Editorial: State-Of-The-ArtFluorescence Image-Guided Surgery:Current and Future DevelopmentsJohn R. Benson1*, Fijs W. B. van Leeuwen2 and Tomoharu Sugie31 Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge and School of Medicine, Anglia Ruskin University,Cambridge, United Kingdom, 2 Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden UniversityMedical Center, Leiden, Netherlands, 3 Breast Surgery, Kansai Medical University Hospital, Hirakata, JapanKeywords: fluorescence, indocyanine green, 5-aminolevulinic acid (5-ALA), fluorescent-guided surgery, sentinelnode mapping, angiography, image-guided surgeryEditorial on the Research TopicState-Of-The-Art Fluorescence Image-Guided Surgery: Current and Future DevelopmentsFluorescent-guided surgery (FGS) is an intra-operative imaging modality with a potentially broadapplication and range of clinical utility. It provides an additional visual dimension to white light andrepresents an extension of pre-operative radiological investigations with real-time imaging duringan operation (open or minimally invasive procedure). The main clinical usage relates to lymphaticmapping or evaluation of blood flow in the context of tissue perfusion (1). In addition, FGS hasshown promise as a method for more accurately localizing and delineating solid tumors anddetecting smaller impalpable tumor foci not evident pre-operatively or visualized with conventionalwhite light-based technologies at the time of surgery.Indocyanine green (ICG) is the most commonly used fluorophore that is considered clinicallysafe and has exclusive FDA approval (1). These near-infrared fluorescence properties initially led todevelopment of dedicated intra-operative imaging systems that allow blood flow measurementsduring cardiac and transplantation surgery. These perfusion applications have been successfullyextended to parathyroid surgery, partial nephrectomies, and anastomosis. Clinical usage hassubsequently expanded with notable applications that rely on local dye accumulation. Examplesare identification of hepatic lesions and sentinel lymph node (SLN) biopsy where ICG appears safeand of low toxicity (2, 3). With for example SLN biopsy, fluorescence guidance permits visualizationof lymphatic channels and nodes, yielding high levels of concordance (>90%) for SLN detection byICG in relation to blue dye or radioisotope (RI) (4–8). It remains unclear if ICG as a sole tracer canreplace standard tracers (RI and blue dye) and whether a combination of ICG with either RI or bluedye optimizes performance parameters (6, 7). Hybrid approaches using shared tracer platforms mayoffer a convenient alternative to combinations of individual techniques (Figure 1A) (9).Notwithstanding potential advantages, there are drawbacks of fluorescent imaging that includesignificant signal attenuation by overlaying tissue and interference from ambient white light(surgical lights) during open surgery. Fluorescent imaging of tumors can be challenging wheredistinction between malignant and benign tissues relies on differential sensitivity. Development oftumor-targeting strategies for FGS can improve the chance of achieving radical resection of tumorswith clear surgical margins and inclusion of occult foci of disease. Such approaches have beendescribed using antibodies, peptides, and small molecules (10–12) which all offer excitingopportunities for refining the field of FGS.October 2021 | Volume 11 | Article 7768321Benson et al. Editorial: Image-Guided Surgery Using FluorescenceThis series of research papers discusses current applicationsof FGS surgery and strategies for widening clinical usage of thistechnology during both conventional and minimally invasivesurgery. A shared principle is the visual augmentation ofmolecular feedback that provides an adjunct to tactile feedbackin open surgery and compensates for lack of this withlaparoscopic or robotic procedures.Nakamura and colleagues report on a medical imagingprojection system (MIPS) that provides a continuous real-timeprojection of fluorescence mapping onto the surgical field andovercomes the problem of periodic dimming of theatre lights.This novel system avoids the need to shift visual focus fromdirect viewing of the surgical field under white light to the TVmonitor. Initial studies revealed comparable nodal identificationrates to standard NIR methodology but relatively low nodeFrontiers in Oncology | www.frontiersin.org 2positivity rate (13) that have also been observed in this follow-on study (7%). Further work with larger numbers of patients isrequired to clarify the accuracy of MIPS in terms of false negativerates and for SLN biopsy following neoadjuvant chemotherapyfor clinically node negative patients.Utility for lymphatic mapping and detection of nodalmetastases in breast and other cancers has dominated FGSliterature in the field of surgical oncology. However, animportant translational challenge is use of this technology toenhance the visualization of solid tumors in real-time duringsurgery; surgical extirpation remains the primary managementoption for most solid tumors and is potentially curative whencomplete removal of the index lesion and any satellite foci oftumor is achieved with clear surgical margins. In addition totheir therapeutic role, monoclonal antibodies can be re-purposedFIGURE 1 | (A) The hybrid tracer ICG-99mTc-nanocolloid helps allying intraoperative fluorescence imaging with preoperative SPECT/CT data. This example showsSLN-biopsy in the head-and-neck region that was performed with the ambient lights on in the operation room (9). (B) Multi-color fluorescence imaging using thehybrid tracer ICG-99mTc-nanocolloid (preoperative SPECT/CT and blue) and fluorescein (yellow). This example shows robot-assisted SLN-biopsy in prostate cancer.October 2021 | Volume 11 | Article 776832Benson et al. Editorial: Image-Guided Surgery Using Fluorescenceand used to image tumors after being linked to a fluorophore in abioconjugate structure. Vargas and colleagues describe howclinical studies with immunoconjugates provide ‘proof ofprinciple’ for the concept of selective receptor binding andclinical feasibility of tumor-specific FGS for cancer treatment.However, these agents have limited specificity and it may benecessary to wait up to 7 days from injection before there issufficient tumor contrast to proceed with FGS. This isattributable to slow clearance of these large molecules fromnon-target tissues and distinction between tumor and normaltissues may be further hindered by interactions between thesemonoclonal antibodies and immune-effector cells that produceconfounding fluorescent signals. A possible solution to thisproblem is use of low molecular weight (LMW) agents, such aspeptides or small molecules that retain a high receptor affinitybut possess an improved pharmacokinetic profile. Six LMWagents are discussed that can potentially improve intra-operative visualization and identify foci of tumor that wouldotherwise have been undetected (PPV 90 – 95%) (14). Apartfrom promoting accurate tumor staging and margin negativeresections, this FGS study suggests there is also a potential todetect widespread malignancy prior to cytoreductive surgerywith adoption of a palliative approach rather than any radicaland potentially morbid surgical procedure.There are some important challenges for receptor-targetedFGS before adoption into routine clinical practice; these includeuncertainties in optimum quantitative evaluation of drugperformance parameters along with confounding imagingfactors. Furthermore, most commercial FGS devices have beenoptimized for ICG imaging in terms of spectral and sensitivityrequirements and these may differ for tumor-specific probes andother fluorescent bio-conjugates. Development of newer cancermarkers must ensure the presence of high affinity targeting motifsto guarantee high tumor selectivity and minimize non-specificinteractions within normal tissues. This may be facilitated by anet-neutral charge that will promote elimination from non-malignant tissue (15).Ultimately FGS techniques should improve clinical outcomesby reducing local recurrence through more precise surgery withnegative resection margins. Kaibori and colleagues review theclinical application of NIR fluorescence imaging for hepaticresection in liver surgery. These authors have developed anovel nanoparticle incorporating ICG as a signaling agent thatis biocompatible and can potentially assess hepatic anatomy andfunction as well as acting as a therapeutic agent for drug delivery(so-called ‘theranostics’). The ICG lactosome relies on increasedvascular permeability of cancerous tissues that retain theseparticles to permit FGS with tumor demarcation or anti-tumoreffect of a therapeutic molecule that uses the lactosome as acarrier. Fluorescence imaging with either ICG or the porphyrinFrontiers in Oncology | www.frontiersin.org 3precursor (5-aminolevulinic acid (5-ALA) can improve accuracythrough real-time visualization of hepatic tissue during surgery.Furthermore, ICG fluorescence can detect fibrosis within non-cancerous liver parenchyma and indicate severity. ICG has ahigher sensitivity for detection of smaller tumors near the surfaceof the liver, although is associated with lower levels of specificity;by contrast, 5-ALA imaging showed a lower sensitivity but ahigher specificity. Optimum imaging of superficial liver tumorsmight eventually be achieved through use of a combination ofICG and 5-ALA that employs the concept of multi-wavelengthfluorescence imaging; the latter can be applied to other scenariosincluding imaging for SLN biopsy (Figure 1B) (16).Formal anatomical liver resection is greatly assisted withtechniques of FGS that can accurately (>90%) delineatesegments and sub-segments during laparoscopic surgery inboth cirrhotic and non-fibrotic livers, but careful planning isessential with appropriate simulation and selection of fluorescentimaging method (17).There are several important applications of fluorescenceimaging in surgical oncology not directly related to tumorlocation and adequacy of resection, but nonetheless canimprove clinical outcomes for patients. Luo and colleagues haveexamined the role of ICG fluorescence angiography (ICG-FA) inprevention of major anastomotic leakage after minimally invasivesurgery (MIS) for a range of esophageal malignancies. This relieson use of intra-operative fluorescent imaging to assess perfusionof the gastric conduit prior to definitive anastomosis. ICG-FAmight allow more accurate and objective evaluation of blood flowin the anastomotic zone without reliance on visual inspectionand detection of vascular pulsation or peristalsis. Larger studieswith standardized surgical techniques are required to confirmthese benefits of ICG-FA in terms of reducing anastomoticleakage (18, 19).A number of vendors now supply laparoscopic systems thatincorporate an NIR imaging options an example beingintegration of the firefly camera in the da Vinci roboticplatform. Moreover, technologies for dynamic visualization ofthe gastric conduit are now available and provide more reliableinformation on adequacy of perfusion. Hence employment ofreal time intra-operative evaluation may reduce the frequencyand severity of surgical complications, although the majority ofanastomotic leaks do not lead to secondary surgery.AUTHOR CONTRIBUTIONSOriginal draft preparation: JB. Review and editing: FL and TS.All authors contributed to the article and approved thesubmitted version.REFERENCES1. Alander JT, Kaartinen I , Laakso A, Pätilä T, Spillmann T, Tuchin VV, et al. AReview of Indocyanine Green Fluorescent Imaging in Surgery. In J BioMedImaging (2012) 2012:940585. doi: 10.1155/2012/9405852. Kitai T, Inomoto T, Miwa M, Shikayama T. Fluorescence Navigation WithIndocyanine Green for Detecting Sentinel Lymph Nodes in Breast Cancer.Breast Cancer (2005) 12:211–5. doi: 10.2325/jbcs.12.2113. Tajima Y, Yamazaki K, Masuda Y, Kato M, Yasuda D, Aoki T, et al. SentinelNode Mapping Guided by Indocyanine Green Fluorescence Imaging inOctober 2021 | Volume 11 | Article 776832Benson et al. Editorial: Image-Guided Surgery Using FluorescenceGastric Cancer. Ann Surg (2009) 249:58–62. doi: 10.1097/SLA.0b013e31819272674. Wishart GC, Jones LC, Loh S-W, Benson JR. A Feasibility Study (ICG-10) ofIndocyanine Green (ICG) Fluorescence Mapping for Sentinel Lymph NodeDetection in Early Breast Cancer. Eur J Surg Oncol (2012) 38:651–6. doi:10.1016/j.ejso.2012.05.0075. Sugie T, Kassim KA, Takeuchi M, Hashimoto T, Yamagami K, Masai Y, et al.A Novel Method for Sentinel Lymph Node Biopsy by Indocyanine GreenFluorescence Technique in Breast Cancer. Cancers (2010) 2:713–20. doi:10.3390/cancers20207136. Ballardini B, Santoro L, Sangalli C, Gentilini O, Renne G, Lissidini G, et al.The Indocyanine Green Method is Equivalent to the Tc-Labelled RadiotracerMethod for Identifying the Sentinel Lymph Node in Breast Cancer: AConcordance and Validation Study. Eur J Surg Oncol (2013) 39:1332–36.doi: 10.1016/j.ejso.2013.10.0047. Sugie T, Kinoshita T, Masuda N, Sawada T, Yamauchi A, Kuroi K, et al.Evaluation of the Clinical Utility of the ICG Fluorescence Method ComparedWith the Radioisotope Method for Sentinel Lymph Node Biopsy in BreastCancer. Ann Surg Oncol (2016) 23:44–50. doi: 10.1245/s10434-015-4809-48. Pitsinis V, Provenzano E, Wishart GC, Benson JR. Indocyanine GreenFluorescence Mapping for Sentinel Lymph Node Biopsy in Early BreastCancer. Surg Oncol (2015) 24:375–9. doi: 10.1016/j.suronc.2015.10.0029. van den Berg NS, Miwa M, KleinJan GH, Sato T, Maeda Y, van Akkooi AC,et al. (Near-Infrared) Fluorescence-Guided Surgery Under Ambient LightConditions: A Next Step to Amendment of the Technology in ClinicalRoutine. Ann Surg Oncol (2016) 23:2586–95. doi: 10.1245/s10434-016-5186-310. Koller M, Qiu SQ, Linssen MD, Jansen L, Kelder W, de Vries J, et al.Implementation and Benchmarking of a Novel Analytical Framework toClinically Evaluate Tumor-Specific Fluorescent Tracers. Nat Commun(2018) 9:3739. doi: 10.1038/s41467-018-05727-y11. Rosenthal EL, Warram JM, de Boer E, Chung TK, Korb ML, Brandwein-Gensler M, et al. Safety and Tumor Specificity of Cetuximab-IRDye800 forSurgical Navigation in Head and Neck Cancer. Clin Cancer Res (2015)21:3658–68. doi: 10.1158/1078-0432.CCR-14-328412. Gao RW, Terphongphom NT, van den Berg NS, Martin BA, Oberhelman NJ,Divi V, et al. Determination of Tumor Margins With Surgical SpecimenMapping Using Near-Infrared Fluorescence. Cancer Res (2018) 78:5144–54.doi: 10.1158/0008-5472.CAN-18-087813. Takada M, Takeuchi M, Suzuki E, Sato F, Matsumoto Y, Torii M, et al. Real-Time Navigation System for Sentinel Lymph Node Biopsy in Breast CancerUsing Projection Mapping With Indocyanine Green Fluorescence. BreastCancer (2018) 25:650–5. doi: 10.1007/s12282-018-0868-2Frontiers in Oncology | www.frontiersin.org 414. Randall LM, Wenham RM, Low PS, Dowdy SC, Tanyi JL. A Phase IIMulticenter, Open-Label Trial of OTL38 Injection for the Intra-OperativeImaging of Folate Receptor-Alpha Positive Ovarian Cancer. Gynaecol Oncol(2019) 155:63–8. doi: 10.1016/j.ygyno.2019.07.01015. Koch M, Symvoulidis P, Ntziachristos V. Tackling Standardization inFluorescence Molecular Imaging. Nat Photonics (2018) 12:505–15. doi:10.1038/s41566-018-0221-516. van Beurden F, van Willigen DM, Vojnovic B, van Beurden F, Heimburger N,van der Wal JE, et al. Multi-Wavelength Fluorescence Image-Guided Surgery.Clinical Feasibility and Future Perspectives. Mol Imaging (2020)19:1536012120962333. doi: 10.1177/153601212096233317. Aoki T, Murakami M, Yasuda D, Shimizu Y, Kusano T, Matsuda K, et al.Intraoperative Fluorescent Imaging Using Indocyanine Green for LiverMapping and Cholangiography. J Hepatobiliary Pancreat Sci (2010) 17:590–4. doi: 10.1007/s00534-009-0197-018. Koyanagi K, Ozawa S, Oguma J, Kazuno A, Yamazaki Y, Ninomiya Y, et al. BloodFlow Speed of the Gastric Conduit Assessed by Indocyanine Green Fluorescence:New Predictive Evaluation of Anastomotic Leakage After Esophagectomy.Medicine (2016) 95:e4386. doi: 10.1097/MD.000000000000438619. Ohi M, Toiyama Y, Mohri Y, Saigusa S, Ichikawa T, Shimura T, et al.Prevalence of Anastomotic Leak and the Impact of Indocyanine GreenFluorescein Imaging for Evaluating Blood Flow in the Gastric ConduitFollowing Esophageal Cancer Surgery. Esophagus (2017) 14:351–9. doi:10.1007/s10388-017-0585-5Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2021 Benson, van Leeuwen and Sugie. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice. Nouse, distribution or reproduction is permitted which does not comply with these terms.October 2021 | Volume 11 | Article 776832

Editorial: state-of-the-art fluorescence image-guided surgery: current and future developments

John R. Benson

Fijs W. B. van Leeuwen

Tomoharu Sugie

Directory of Open Access Journals

Frontiers in Oncology | www.frontiersin.org
Edited and reviewed by:
Francesco Giovinazzo,
Catholic University of the Sacred
Heart, Italy
*Correspondence:
John R. Benson
john.benson@addenbrookes.nhs.uk
Specialty section:
This article was submitted to
Surgical Oncology,
a section of the journal
Frontiers in Oncology
Received: 14 September 2021
Accepted: 04 October 2021
Published: 22 October 2021
Citation:
Benson JR, van Leeuwen FWB and
Sugie T (2021) Editorial: State-Of-The-
Art Fluorescence Image-
Guided Surgery: Current and
Future Developments.
Front. Oncol. 11:776832.
doi: 10.3389/fonc.2021.776832
EDITORIAL
published: 22 October 2021
doi: 10.3389/fonc.2021.776832Editorial: State-Of-The-Art
Fluorescence Image-Guided Surgery:
Current and Future Developments
John R. Benson1*, Fijs W. B. van Leeuwen2 and Tomoharu Sugie3
1 Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge and School of Medicine, Anglia Ruskin University,
Cambridge, United Kingdom, 2 Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University
Medical Center, Leiden, Netherlands, 3 Breast Surgery, Kansai Medical University Hospital, Hirakata, Japan
Keywords: fluorescence, indocyanine green, 5-aminolevulinic acid (5-ALA), fluorescent-guided surgery, sentinel
node mapping, angiography, image-guided surgery
Editorial on the Research Topic
State-Of-The-Art Fluorescence Image-Guided Surgery: Current and Future Developments
Fluorescent-guided surgery (FGS) is an intra-operative imaging modality with a potentially broad
application and range of clinical utility. It provides an additional visual dimension to white light and
represents an extension of pre-operative radiological investigations with real-time imaging during
an operation (open or minimally invasive procedure). The main clinical usage relates to lymphatic
mapping or evaluation of blood flow in the context of tissue perfusion (1). In addition, FGS has
shown promise as a method for more accurately localizing and delineating solid tumors and
detecting smaller impalpable tumor foci not evident pre-operatively or visualized with conventional
white light-based technologies at the time of surgery.
Indocyanine green (ICG) is the most commonly used fluorophore that is considered clinically
safe and has exclusive FDA approval (1). These near-infrared fluorescence properties initially led to
development of dedicated intra-operative imaging systems that allow blood flow measurements
during cardiac and transplantation surgery. These perfusion applications have been successfully
extended to parathyroid surgery, partial nephrectomies, and anastomosis. Clinical usage has
subsequently expanded with notable applications that rely on local dye accumulation. Examples
are identification of hepatic lesions and sentinel lymph node (SLN) biopsy where ICG appears safe
and of low toxicity (2, 3). With for example SLN biopsy, fluorescence guidance permits visualization
of lymphatic channels and nodes, yielding high levels of concordance (>90%) for SLN detection by
ICG in relation to blue dye or radioisotope (RI) (4–8). It remains unclear if ICG as a sole tracer can
replace standard tracers (RI and blue dye) and whether a combination of ICG with either RI or blue
dye optimizes performance parameters (6, 7). Hybrid approaches using shared tracer platforms may
offer a convenient alternative to combinations of individual techniques (Figure 1A) (9).
Notwithstanding potential advantages, there are drawbacks of fluorescent imaging that include
significant signal attenuation by overlaying tissue and interference from ambient white light
(surgical lights) during open surgery. Fluorescent imaging of tumors can be challenging where
distinction between malignant and benign tissues relies on differential sensitivity. Development of
tumor-targeting strategies for FGS can improve the chance of achieving radical resection of tumors
with clear surgical margins and inclusion of occult foci of disease. Such approaches have been
described using antibodies, peptides, and small molecules (10–12) which all offer exciting
opportunities for refining the field of FGS.October 2021 | Volume 11 | Article 7768321
Benson et al. Editorial: Image-Guided Surgery Using FluorescenceThis series of research papers discusses current applications
of FGS surgery and strategies for widening clinical usage of this
technology during both conventional and minimally invasive
surgery. A shared principle is the visual augmentation of
molecular feedback that provides an adjunct to tactile feedback
in open surgery and compensates for lack of this with
laparoscopic or robotic procedures.
Nakamura and colleagues report on a medical imaging
projection system (MIPS) that provides a continuous real-time
projection of fluorescence mapping onto the surgical field and
overcomes the problem of periodic dimming of theatre lights.
This novel system avoids the need to shift visual focus from
direct viewing of the surgical field under white light to the TV
monitor. Initial studies revealed comparable nodal identification
rates to standard NIR methodology but relatively low nodeFrontiers in Oncology | www.frontiersin.org 2positivity rate (13) that have also been observed in this follow-
on study (7%). Further work with larger numbers of patients is
required to clarify the accuracy of MIPS in terms of false negative
rates and for SLN biopsy following neoadjuvant chemotherapy
for clinically node negative patients.
Utility for lymphatic mapping and detection of nodal
metastases in breast and other cancers has dominated FGS
literature in the field of surgical oncology. However, an
important translational challenge is use of this technology to
enhance the visualization of solid tumors in real-time during
surgery; surgical extirpation remains the primary management
option for most solid tumors and is potentially curative when
complete removal of the index lesion and any satellite foci of
tumor is achieved with clear surgical margins. In addition to
their therapeutic role, monoclonal antibodies can be re-purposedFIGURE 1 | (A) The hybrid tracer ICG-99mTc-nanocolloid helps allying intraoperative fluorescence imaging with preoperative SPECT/CT data. This example shows
SLN-biopsy in the head-and-neck region that was performed with the ambient lights on in the operation room (9). (B) Multi-color fluorescence imaging using the
hybrid tracer ICG-99mTc-nanocolloid (preoperative SPECT/CT and blue) and fluorescein (yellow). This example shows robot-assisted SLN-biopsy in prostate cancer.October 2021 | Volume 11 | Article 776832
Benson et al. Editorial: Image-Guided Surgery Using Fluorescenceand used to image tumors after being linked to a fluorophore in a
bioconjugate structure. Vargas and colleagues describe how
clinical studies with immunoconjugates provide ‘proof of
principle’ for the concept of selective receptor binding and
clinical feasibility of tumor-specific FGS for cancer treatment.
However, these agents have limited specificity and it may be
necessary to wait up to 7 days from injection before there is
sufficient tumor contrast to proceed with FGS. This is
attributable to slow clearance of these large molecules from
non-target tissues and distinction between tumor and normal
tissues may be further hindered by interactions between these
monoclonal antibodies and immune-effector cells that produce
confounding fluorescent signals. A possible solution to this
problem is use of low molecular weight (LMW) agents, such as
peptides or small molecules that retain a high receptor affinity
but possess an improved pharmacokinetic profile. Six LMW
agents are discussed that can potentially improve intra-
operative visualization and identify foci of tumor that would
otherwise have been undetected (PPV 90 – 95%) (14). Apart
from promoting accurate tumor staging and margin negative
resections, this FGS study suggests there is also a potential to
detect widespread malignancy prior to cytoreductive surgery
with adoption of a palliative approach rather than any radical
and potentially morbid surgical procedure.
There are some important challenges for receptor-targeted
FGS before adoption into routine clinical practice; these include
uncertainties in optimum quantitative evaluation of drug
performance parameters along with confounding imaging
factors. Furthermore, most commercial FGS devices have been
optimized for ICG imaging in terms of spectral and sensitivity
requirements and these may differ for tumor-specific probes and
other fluorescent bio-conjugates. Development of newer cancer
markers must ensure the presence of high affinity targeting motifs
to guarantee high tumor selectivity and minimize non-specific
interactions within normal tissues. This may be facilitated by a
net-neutral charge that will promote elimination from non-
malignant tissue (15).
Ultimately FGS techniques should improve clinical outcomes
by reducing local recurrence through more precise surgery with
negative resection margins. Kaibori and colleagues review the
clinical application of NIR fluorescence imaging for hepatic
resection in liver surgery. These authors have developed a
novel nanoparticle incorporating ICG as a signaling agent that
is biocompatible and can potentially assess hepatic anatomy and
function as well as acting as a therapeutic agent for drug delivery
(so-called ‘theranostics’). The ICG lactosome relies on increased
vascular permeability of cancerous tissues that retain these
particles to permit FGS with tumor demarcation or anti-tumor
effect of a therapeutic molecule that uses the lactosome as a
carrier. Fluorescence imaging with either ICG or the porphyrinFrontiers in Oncology | www.frontiersin.org 3precursor (5-aminolevulinic acid (5-ALA) can improve accuracy
through real-time visualization of hepatic tissue during surgery.
Furthermore, ICG fluorescence can detect fibrosis within non-
cancerous liver parenchyma and indicate severity. ICG has a
higher sensitivity for detection of smaller tumors near the surface
of the liver, although is associated with lower levels of specificity;
by contrast, 5-ALA imaging showed a lower sensitivity but a
higher specificity. Optimum imaging of superficial liver tumors
might eventually be achieved through use of a combination of
ICG and 5-ALA that employs the concept of multi-wavelength
fluorescence imaging; the latter can be applied to other scenarios
including imaging for SLN biopsy (Figure 1B) (16).
Formal anatomical liver resection is greatly assisted with
techniques of FGS that can accurately (>90%) delineate
segments and sub-segments during laparoscopic surgery in
both cirrhotic and non-fibrotic livers, but careful planning is
essential with appropriate simulation and selection of fluorescent
imaging method (17).
There are several important applications of fluorescence
imaging in surgical oncology not directly related to tumor
location and adequacy of resection, but nonetheless can
improve clinical outcomes for patients. Luo and colleagues have
examined the role of ICG fluorescence angiography (ICG-FA) in
prevention of major anastomotic leakage after minimally invasive
surgery (MIS) for a range of esophageal malignancies. This relies
on use of intra-operative fluorescent imaging to assess perfusion
of the gastric conduit prior to definitive anastomosis. ICG-FA
might allow more accurate and objective evaluation of blood flow
in the anastomotic zone without reliance on visual inspection
and detection of vascular pulsation or peristalsis. Larger studies
with standardized surgical techniques are required to confirm
these benefits of ICG-FA in terms of reducing anastomotic
leakage (18, 19).
A number of vendors now supply laparoscopic systems that
incorporate an NIR imaging options an example being
integration of the firefly camera in the da Vinci robotic
platform. Moreover, technologies for dynamic visualization of
the gastric conduit are now available and provide more reliable
information on adequacy of perfusion. Hence employment of
real time intra-operative evaluation may reduce the frequency
and severity of surgical complications, although the majority of
anastomotic leaks do not lead to secondary surgery.AUTHOR CONTRIBUTIONS
Original draft preparation: JB. Review and editing: FL and TS.
All authors contributed to the article and approved the
submitted version.REFERENCES
1. Alander JT, Kaartinen I , Laakso A, Pätilä T, Spillmann T, Tuchin VV, et al. A
Review of Indocyanine Green Fluorescent Imaging in Surgery. In J BioMed
Imaging (2012) 2012:940585. doi: 10.1155/2012/9405852. Kitai T, Inomoto T, Miwa M, Shikayama T. Fluorescence Navigation With
Indocyanine Green for Detecting Sentinel Lymph Nodes in Breast Cancer.
Breast Cancer (2005) 12:211–5. doi: 10.2325/jbcs.12.211
3. Tajima Y, Yamazaki K, Masuda Y, Kato M, Yasuda D, Aoki T, et al. Sentinel
Node Mapping Guided by Indocyanine Green Fluorescence Imaging inOctober 2021 | Volume 11 | Article 776832
Benson et al. Editorial: Image-Guided Surgery Using FluorescenceGastric Cancer. Ann Surg (2009) 249:58–62. doi: 10.1097/SLA.
0b013e3181927267
4. Wishart GC, Jones LC, Loh S-W, Benson JR. A Feasibility Study (ICG-10) of
Indocyanine Green (ICG) Fluorescence Mapping for Sentinel Lymph Node
Detection in Early Breast Cancer. Eur J Surg Oncol (2012) 38:651–6. doi:
10.1016/j.ejso.2012.05.007
5. Sugie T, Kassim KA, Takeuchi M, Hashimoto T, Yamagami K, Masai Y, et al.
A Novel Method for Sentinel Lymph Node Biopsy by Indocyanine Green
Fluorescence Technique in Breast Cancer. Cancers (2010) 2:713–20. doi:
10.3390/cancers2020713
6. Ballardini B, Santoro L, Sangalli C, Gentilini O, Renne G, Lissidini G, et al.
The Indocyanine Green Method is Equivalent to the Tc-Labelled Radiotracer
Method for Identifying the Sentinel Lymph Node in Breast Cancer: A
Concordance and Validation Study. Eur J Surg Oncol (2013) 39:1332–36.
doi: 10.1016/j.ejso.2013.10.004
7. Sugie T, Kinoshita T, Masuda N, Sawada T, Yamauchi A, Kuroi K, et al.
Evaluation of the Clinical Utility of the ICG Fluorescence Method Compared
With the Radioisotope Method for Sentinel Lymph Node Biopsy in Breast
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10.1007/s10388-017-0585-5Conflict of Interest: The authors declare that the research was conducted in the
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potential conflict of interest.
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use, distribution or reproduction is permitted which does not comply with these terms.October 2021 | Volume 11 | Article 776832


Editorial: State-Of-The-Art Fluorescence Image-Guided Surgery: Current and Future Developments

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Editorial: state-of-the-art fluorescence image-guided surgery: current and future developments

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