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Received: 6 July 2017 Revised: 13 October 2017 Accepted: 3 November 2017
DOI: 10.1002/wsbm.1412
OVERVIEW
Image-guided surgery in cancer: A strategy to reduce incidence

of positive surgical margins
Kathryn R. Tringale1 | John Pang1 | Quyen T. Nguyen1,2,3
1
Division of Otolaryngology, Head and Neck
Surgery, University of California, San Diego, Primary treatment for many solid cancers includes surgical excision or radiation ther-
La Jolla, California apy, with or without the use of adjuvant therapy. This can include the addition of radi-
2
Department of Pharmacology, University of ation and chemotherapy after primary surgical therapy, or the addition of
California, San Diego, La Jolla, California
chemotherapy and salvage surgery to primary radiation therapy. Both primary thera-
3
Moores Cancer Center, University of California,
pies, surgery and radiation, require precise anatomic localization of tumor. If tumor is
San Diego, La Jolla, California
not targeted adequately with initial treatment, disease recurrence may ensue, and if tar-
Correspondence
Quyen T. Nguyen, Surgery and Pharmacology, geting is too broad, unnecessary morbidity may occur to nearby structures or remain-
University of California, San Diego, 9500 Gilman ing normal tissue. Fluorescence imaging using intraoperative contrast agents is a
Drive, MC 0647, La Jolla, CA 92093. rapidly growing field for improving visualization in cancer surgery to facilitate resec-
Email: q1nguyen@ucsd.edu
tion in order to obtain negative margins. There are multiple strategies for tumor visu-
Funding information
NIH, Grant/Award numbers: 1TL1TR001443,
alization based on antibodies against surface markers or ligands for receptors
EB014929 preferentially expressed in cancer. In this article, we review the incidence and clinical
implications of positive surgical margins for some of the most common solid tumors.
Within this context, we present the ongoing clinical and preclinical studies focused on
the use of intraoperative contrast agents to improve surgical margins.
This article is categorized under:
Laboratory Methods and Technologies > Imaging
KEYWORDS
cancer surgery, fluorescence imaging, image-guided surgery, intraoperative

contrast agents, surgical margins
1 | INTRODUCTION
The American Cancer Society (ACS) estimates that one in four deaths in the United States is due to cancer (Siegel, Miller, &
Jemal, 2016). Technological advances in cancer diagnostics and therapeutics have been made to mitigate this high percent-
age, leading to recent efforts such as the Precision Medicine Initiative in January 2017. By using a targeted approach to med-
icine, we can tailor disease diagnosis and management at the cellular level. This revolutionary approach has provided new
opportunities in oncology, as historically cancer detection has involved nonspecific contrast agents and systemic chemothera-
peutics damaging off-target healthy tissue. Thus, cancer cell-specific targeted therapy is the “holy grail” of cancer
treatment—targeting cancerous cells will not only guide systemic treatments but will also enable visualization for more pre-
cise diagnostics and surgical excision.
Although modern surgical advancements have improved surgical oncology, adequate tumor visualization remains a limita-
tion preventing total removal of cancerous tissue. Surgeons rely primarily on white light reflectance, which limits the differenti-
ation between healthy tissue and tumor and can lead to residual cancer cells inadvertently left behind at the resection border.
Defined as positive surgical margins (PSMs, Figure 1), these remaining cells generally have poor prognostic implications across
different tumor types and typically require adjuvant treatments that confer significant increased costs and burden to the patient
and healthcare system (National Comprehensive Cancer Network, 2017). Advances in fluorescent intraoperative imaging offer
pseudo-color distinction between tumor and adjacent normal tissue to improve accuracy of resection and potentially reduce
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https://doi.org/10.1002/wsbm.1412
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2 of 18 TRINGALE ET AL.
Positive margins Negative margins
Normal tissue Normal tissue
Cancer Cancer
Edge of surgical
resection Edge of surgical
resection
Positive margin:
residual cancer
present at edge of
surgical resection
FIGURE 1 Schematic of surgical margins showing tumor present at the edge of the resection (positive margins) or absence of tumor at the edge of the
resection (negative margins)
PSMs. Fluorescence imaging also has the potential to distinguish different anatomic structures to reduce inadvertent injury to
healthy tissue. Improved real-time, intraoperative visualization can decrease the rate of PSMs across tumor types to facilitate
cancer treatment while decreasing adjuvant therapy costs and improving prognosis. This review provides a background of fluo-
rescent visual enhancers and targeted probes for surgery, presents a background of the clinical need and applications by tumor
site, and provides an overview of preclinical and clinical trials in fluorescent imaging techniques for cancer identification.
2 | OV ER VIEW OF FL UORE SCE NT VISU AL ENHA NC ER S AN D SMA RT PROBE S FOR

SURGERY
Chemical imaging agents can be administered either intravenously or applied topically for intraoperative use either in vivo or
ex vivo to evaluate biopsies. Fluorescence-guided surgery (FGS) has already used nontargeted fluorescent dyes or “visual
enhancers,” namely indocyanine green (ICG) and fluorescein. These dyes improve the identification of vital anatomic struc-
tures, such as blood vessels and ducts. Smart probes provide a more targeted approach to intraoperative visualization. Specif-
ically, conjugation of tumor-targeting ligands to near-infrared (NIR) fluorophores (700–900 nm) allows for penetration
through 8 mm into tissue, allowing for identification of unexposed targets (Handgraaf et al., 2017; Ishizawa et al., 2009).
There are two main types of probes based on their recognition element: affinity-based and activity-based probes. Affinity-
based probes bind to target-specific tissue markers such as receptors or ion channels using antibodies or peptides that have
high affinity for certain cell surface antigens (Kaushal et al., 2008; Whitney et al., 2011; Wu et al., 2011). Alternatively,
activity-based probes give off fluorescent signal upon enzymatic localization and amplification by proteases or peptidases
(Nguyen et al., 2010; Olson et al., 2012; Orosco, Tsien, & Nguyen, 2013; Shu et al., 2011) (Figure 2).
There are currently a variety of U.S. Food and Drug Administration (FDA)-approved surgical camera systems to image
these agents intraoperatively in human subjects, including the Firefly system in the da Vinci Surgical System (Buchs et al.,
2012), the Pinpoint camera (Sherwinter, 2012), the Fluorescence-Assisted Resection and Exploration (FLARE) and Mini-
FLARE image-guided surgery systems (Tummers et al., 2015; Verbeek et al., 2013), the Photo Dynamic Eye (PDE) and
PDE-neo (Aoki et al., 2010), the Hyper Eye Medical System (HEMS) (Yoshida et al., 2012), and the IMAGE1 SPIES NIR/
ICG system (Garland, Yim, & Bogyo, 2016; Schols et al., 2013). In addition, there are devices used for basic science and
animal model applications, including IVIS, Maestro, Fluobeam, MiroSurg, Lab-FLARE Model R1 Open Space Imaging Sys-
tem, and a range of confocal microscopes (Garland et al., 2016). 5-ALA (Gleolan) is the only molecularly targeted optical
contrasts agent that is FDA-approved for human use.
These probes and devices have been extensively reviewed previously (Garland et al., 2016; Orosco et al., 2016); thus,
this review will focus on the latest clinical and preclinical studies of intraoperative visualization of site-specific cancers.
3 | PSMs BY TUMOR S IT E
Without adequate intraoperative visualization, residual cancer cells can remain along the excision border. Rates of PSMs
and implications of these residual tumors vary across tumor sites (Table 1); in general, the goal in surgical treatment of
TRINGALE ET AL. 3 of 18
(a)
Real-Time Post-Resection
Clinic Operating O.R Back Table Surgical
room Pathology
Closed-Field Fluorescent Scanner

Wide-Field
(b) (c)
A
A B
C
80 Median
Minimum
Number of tumor spots detected
Maximum
P < .001
60
B White light Overlay

40
20
0
Color FLI
FIGURE 2 Images reprinted with permission from published reports of fluorescence-guided surgery in patients with head and neck cancer (a), ovarian
cancer (b), or breast cancer (C). (a) Trial imaging workflow. Real-time imaging was performed with a wide-field near-infrared (NIR) imaging system in the
clinic on (1) day 0, 1, and in the (2) operating room on day 3 post-cetuximab-IRDye800 infusion. (3) During postresection processing, resected tissues were
imaged with a closed-field NIR imaging system. (4) Following histologic preparation, a corresponding slide was imaged in surgical pathology using a
fluorescence scanning system (Rosenthal et al., 2015). (b) Quantification of tumor deposits ex vivo. (A, B) Color image (A) with the corresponding tumor-
specific fluorescence image (B) of a representative area in the abdominal cavity. (C) Scoring was based on three different color images (median 7, range
4–22) and their corresponding fluorescence images (FLI) (median 34, range 8–81); P < .001 by five independent surgeons (van Dam et al., 2011). (c)
Primary tumor image. Red, green, blue (RGB) color images with putative malignant tissue region-of-interest (ROI) were produced by adding the ROI area
as a solid green color blended into the color image. (A) Two specimens including primary tumor at the surface of the specimens before and after the
application of the overlay. (B) Positive lymph node before and after application of the overlay (Unkart et al., 2017)
cancer is total tumor removal. Efforts have been made to develop targeted visualization of different tumor cells. Implica-
tions of PSMs and current efforts to better target cancer cells intraoperatively are presented below by the most common
cancers with the highest rate of PSMs in women and men. In this review, we aim to discuss the incidence of PSMs for
the most common solid tumors amenable to surgical resection. We will also discuss the clinical relevance of PSMs and
highlight preclinical and clinical studies aimed at mitigating PSMs for each individual cancer sites.
TABLE 1 Positive surgical margin rates for specific tumor sites and implications
Site Range Oncologic implications Cost implications per patient

Breast 23–38% (Marinovich et al., 2016; Morrow et al., 2× Increased local recurrence rate (Correa et al., 2010; $22,000–$93,300 (Greenup et al.,
2009, 2016) Donker et al., 2013; Houssami, Macaskill, 2012; Smith et al., 2017)
Marinovich, & Morrow, 2014; Marinovich et al., 2016;
Moran et al., 2014)
Lung 6–18% (Little et al., 2005; Osarogiagbon et al., 2× Increased risk of death (Hancock et al., 2015; $6000–$129,000 (Deen et al., 2014;
2017; Predina, Keating, Patel, Nims, & Singhal, Osarogiagbon et al., 2017) Wang et al., 2016)
2016; Wakeam et al., 2017)
Colon and 6–13% (Gravante et al., 2016; Homan et al., 2015) 2–7.8× Increased local recurrence rate (Adam et al., 1994; $1400–$32,000 (Carvalho, Leal, &
rectum Marijnen et al., 2003; Nagtegaal, Marijnen, Kranenbarg, Sasse, 2017; Gehrman et al., 2017;
van de Velde, & van Krieken, 2002) Hanly, Ceilleachair, Skally,
O'Neill, & Sharp, 2015)
Pancreas 20–43% (Allema et al., 1995; Bassi et al., 2005; 1.3 – 4× Increased risk of death (Allema et al., 1995; $42,000–$69,500 (Murphy et al.,
Neoptolemos et al., 2001) Howard et al., 2006) 2012)
Prostate 4–48% (Cookson & Chang, 2010; Silberstein & 2× Increased risk of biochemical recurrence (Mithal et al., $27,145–$54,706 (Halpern et al.,
Eastham, 2014) 2016) 2016)
Ovary 25–55% (Seagle et al., 2016) 0.5–3.5× Increased risk of death (May et al., 2017; Rosen $25,849–$57,000 (Rowland, Lesnock,
et al., 2014; Seagle et al., 2016) Farris, Kelley, & Krivak, 2015)
4 | BREAST CANCER
4.1 | Background
Breast cancer is the most common solid organ cancer among women and is the second leading cause of cancer death among
women after lung cancer (DeSantis et al., 2016). Breast conservation surgery followed by whole breast irradiation yields
oncologic outcomes equivalent to mastectomy for stage I and II breast cancer, with long-term cancer-specific survival rates
approaching 65–85% (Darby et al., 2011; Fisher et al., 2002). Patients with ductal carcinoma in situ (DCIS) undergoing
breast-conserving therapy followed by whole breast irradiation have long-term cancer-specific survival greater than 95% and
approaching 99% (Narod, Iqbal, Giannakeas, Sopik, & Sun, 2015; Worni et al., 2015). Overall, the breast cancer death rate
has declined by 38% from 1989 to 2014 (Siegel, Miller, & Jemal, 2017).
4.2 | Relevance of PSMs

Obtaining negative surgical margins is essential in oncologic breast surgery. Currently, one in three women undergoing breast-
conserving therapy for DCIS or invasive stage I or II cancer undergo re-excision or mastectomy (Morrow et al., 2009). In a
recent task force meeting formed by the Society of Surgical Oncology, American Society for Radiation Oncology, and Ameri-
can Society of Clinical Oncology analyzing 20 studies of DCIS, there was 100% consensus that a positive margin, defined as
ink on tumor, is associated with a significant increase in ipsilateral breast tumor recurrence (Morrow et al., 2016). PSMs after
lumpectomy for DCIS is associated with an approximately two-fold higher risk of ipsilateral breast tumor recurrence, and the
increased recurrence risk is not fully mitigated with radiation therapy (Correa et al., 2010; Donker et al., 2013). For this reason,
a surgical margin of ≥2 mm should be obtained in the management of DCIS (Morrow et al., 2016).
Current guidelines for treating stage I and II invasive breast cancer emphasize obtaining negative margins as well. A
2014 task force meeting found that PSMs, defined as ink on tumor, were associated with a greater than two-fold increase in
ipsilateral breast tumor recurrence rate. This relationship is true even for patients with favorable tumor biology (i.e., estrogen
receptor positive; Moran et al., 2014). Administration of whole breast irradiation only mitigates the recurrence risk by half
(Jones et al., 2009).
In the event of a PSM, the National Comprehensive Cancer Network (NCCN) recommends re-excision, mastectomy, or
radiotherapy boost (National Comprehensive Cancer Network, 2017). Additional costs of subsequent surgery range from
$22,000 to $88,000 (Smith et al., 2017) and subsequent radiation costs $5,300 to $13,300 (Greenup et al., 2012).
4.3 | Intraoperative imaging techniques

4.3.1 | Clinical trials
Breast as a cancer site has the largest number of clinical trials in imaging techniques for intraoperative cancer visualization
(Table 2). Nontargeted techniques include intraoperative magnetic resonance imaging (MRI) and polarization subtracting
imaging to visualize methylene blue. Smart probe imaging techniques include molecules that target vascular endothelial
TRINGALE ET AL.
TABLE 2 Probes in preclinical and clinical trials for breast cancer
Clinical trials
Name Target Type Recognition Dye Trial Phase Status
Tumor Paint (BLZ-100) Unsure Chemically derived, affinity-based target probe Peptidic probe derived Cy5.5 NIR fluorophore NCT02496065 I Active, not recruiting
from chlorotoxin (CTX)
venom
LUM015 Pan-cathepsin Substrate and activity-based PEGylated pan-cathepsin Cy5 fluorophore with NCT01626066 I Complete
Gly-Gly-Arg QSY21 quencher
LUM015 Pan-cathepsin Substrate and activity-based PEGylated pan-cathepsin Cy5 fluorophore with NCT02438358 Feasibility trial Recruiting
Gly-Gly-Arg QSY21 quencher
AVP-620 (RACPP) Elastase-specific Substrate and activity-based Cell-penetrating poly-D- Cy5, Cy7 NCT02391194 I Complete
arginine and poly-D-
glutamate sequences
EC17 FRA Chemically derived, affinity-based target probe Folate FITC NCT01994369 Pilot and feasibility trial Recruiting
VEGF-targeted VEGF-A Monoclonal antibody Bevacizumab IRDye800CW NCT01508572 I Complete
fluorescent tracer
VEGF-targeted VEGF-A Monoclonal antibody Bevacizumab IRDye800CW NCT00991978 I Complete
fluorescent tracer
Smart Goggles Sentinal lymph Stereoscopic fluorescence imaging - Indocyanine green NCT02802553 Pilot study Not yet recruiting
nodes
Magnetic resonance Nontargeted Intraoperative MRI - - NCT02057432 I Complete
imaging-guided therapy
Methylene Blue Nontargeted Polarization subtraction imaging - Methylene Blue NCT02207179 I Unknown
Preclinical trials
Associated
Name Target Type Recognition Dye publication
BMV109 Cathepsin Substrate and activity- PMK electrophile Cy5.5 (Verdoes et al., 2013)
based
6QCNIR Cathepsin Substrate and activity- Latent lysosomotropic effect (LLE) to quench Compatible with FDA-approved da Vinci imaging system with Firefly (Ofori et al., 2015)
based detection
OBP-401 Adenovirus Telomerase-dependent adenovirus with selective GFP GFP (Yano et al., 2016)
expression
FRA = folate receptor alpha; HMRG = hydroxymethyl rhodamine green; VEGF = vascular endothelial growth factor.
5 of 18
growth factor (VEGF), folate receptor alpha (FRA), cathepsin, or cell-penetrating peptides. The NIR fluorescently labeled
humanized monoclonal antibody, bevacizumab, has been used as an affinity-based probe to target VEGF, a protein shown
to be important in angiogenesis and therefore highly expressed in breast cancer cells (Lamberts et al., 2017; Yavuz, Pay-
das, Disel, Zorludemir, & Erdogan, 2005). Similarly, folate receptors have shown to be expressed in up to 33% of all breast
cancers, thus folate-fluorescein isothiocyanate (folate-FITC or EC17) has been used to target and fluorescently label folate
receptors overexpressed in breast tumors (Boogerd et al., 2016). LUM015 is an activatable probe that targets cathepsins,
proteins that alter tumor microenvironment to facilitate metastasis and are expressed in activated macrophages, thus are
highly expressed in cancer and inflammation. Similarly, ratiometric activatable cell-penetrating peptides (RACPPs) enter
cells and are retained intracellularly after tumor-specific protease cleavage. AVB-620 (Avelas Biosciences, Inc, La Jolla,
CA) is a matrix metalloproteinase cleavable probe used in a phase I clinical trial for breast cancer, which uses the ratio-
metric read-out between two fluorescent dyes to increase signal specificity and eliminate bias of differential probe
accumulation.
4.3.2 | Preclinical trials

Preclinical trials have investigated activity-based probes that target cathepsin, specifically with a phenoxymethyl ketone
(PMK) electrophile for improved reactivity with the cathepsin target and smaller size for increased range of possible cathep-
sins to bind, along with a quencher with improved water solubility (QSY21) (Verdoes et al., 2013). Another preclinical trial
used the technique of a latent lysotromotopic effect to improve signal intensity and duration by promoting cellular retention
(Ofori et al., 2015). OBP-401 is a GFP-expressing adenovirus that selectively illuminates cancer cells, including invasive
triple-negative breast cancer (Yano et al., 2016). Yano et al. demonstrated that FGS using OBP-401 resulted in improved sur-
vival at 150 days in a mouse model (80% vs. 10%) and even surgical cures (Yano et al., 2016).
5 | L U NG C AN CE R
5.1 | Background
Lung cancer is the most common cause of cancer death in men and women (Siegel et al., 2017). For patients with stage I or
II non-small cell lung carcinoma or stage I small cell lung carcinoma, surgical therapy is the standard treatment as it offers
the best change for cure (Dziedzic et al., 2017; Molina, Yang, Cassivi, Schild, & Adjei, 2008). Although the lung cancer
death rate has declined over time, it still remains unacceptably high as 5-year relative survival remains at 18% (Siegel
et al., 2017).

Numerous groups recommend obtaining negative margins for surgical resection of lung cancer, including the International
Association for the Study of Lung Cancer (IASLC) (Rami-Porta, Wittekind, & Goldstraw, 2005) and the NCCN (National
Comprehensive Cancer Network, 2017). However, compliance with surgical guidelines is poor, as 6–18% of patients
undergoing surgery for lung cancer have positive margins, and a further 74% do not undergo sampling of stations, poten-
tially leaving residual disease (Little et al., 2005; Osarogiagbon et al., 2017; Predina et al., 2016; Wakeam et al., 2017).
Patients with PSMs have worse overall survival (OS) by about 50% across all stages (Hancock et al., 2015; Osarogiagbon
et al., 2017).
In the event of a PSM, the NCCN recommends re-resection, radiotherapy, chemotherapy, or a combination of these modalities
(National Comprehensive Cancer Network, 2017). Re-resection costs range from $6000 to $17,000 while radiation costs $18,000
to $33,000 (Deen et al., 2014; Wang et al., 2016). Additional chemotherapy costs $62,000 to $89,000 (Gilden et al., 2017).

Similar to breast cancer, the FRA target, EC17, has been evaluated for use in lung cancer (Table 3). One study evaluating
high-density tissue microarrays from 188 non-small cell lung cancers found that FRA protein was expressed in most lung
cancers and a minority of lung squamous cell carcinomas (Driver et al., 2016). Interestingly, FRA expression correlated with
histologic grade, with poorly differentiated tumors showing less protein expression, which may indicate resistance to FRA-
targeting drugs or in this case, tumor visualization from fluorescently labeled smart probes. The nontargeted probe, ICG, is
also being evaluated for use in lung cancer. In China, one clinical trial is evaluating ICG NIR fluorescence 3–5 min after
injection into normal lung tissue surrounding the tumor before systematic lymphadenectomy for both tumor and sentinel
TABLE 3 Probes in preclinical and clinical trials for lung tumors
Clinical trials
EC17 FRA Chemically derived, affinity-based target probe Folate FITC NCT01778920 I Complete
ICG - Nontargeted, systemic - ICG fluorescent dye NCT02611245 I Enrolling by invitation
ICG - Nontargeted, systemic - ICG fluorescent dye NCT02851368 I Recruiting
Preclinical trials
Name Target Type Recognition Dye Associated publication
ICG - Nontargeted, systemic Metastases ICG fluorescent dye (Keating, Newton, et al.,
2017)
OTL0038 Folate Chemically derived, affinity-based Folate receptor Folate analog ligand conjugated with (Keating, Runge, et al.,
receptor indole cyanine-like green dye 2017)
6QCNIR Cathepsin Substrate and activity-based Latent lysosomotropic effect Compatible with FDA-approved da (Ofori et al., 2015)
(LLE) to quench Vinci imaging system with Firefly
detection
OBP-401 Substrate and activity-based Telomerase-dependent GFP (Yano et al., 2016)
adenovirus with selective
GFP expression
lymph node visualization (NCT02611245). Similarly, at the University of Pittsburg, Sarkaria and Luketich (2016) are admin-
istering ICG on the day prior to surgery to identify regional lymph nodes in esophageal cancer. Both groups have the shared
aim of achieving negative surgical margins given complete tumor resection is the most important predictor of survival for
patients with non-small cell lung cancer (Keating, Runge, et al., 2017).

Srinivasarao et al. further optimized a folate analog compound to develop OTL38, which is comprised of a folate analog conju-
gated to IR-783 (Garland et al., 2016; Srinivasarao, Galliford, & Low, 2015). While On Target Laboratories evaluated OTL38
in phase II clinical trials for ovarian cancer (Hoogstins et al., 2016), Keating et al. also evaluated OTL38 preclinically for visu-
alization of lung cancer in dog models and in three human patients for a proof-of-principle study (Keating, Runge, et al., 2017).
They found that NIR imaging could discriminate lymph nodes with cancer cells and identify PSMs both in dog models and in
human participants. Keating et al. also evaluated the use of ICG preclinically for intraoperative visualization of lung metastases
in both murine models and eight human subjects during pulmonary metastectomy (Keating, Runge, et al., 2017). Similar to
breast cancer, the cathepsin-targeting probe, 6QCNIR, was evaluated preclinically for lung cancer and found to be compatible
with the FDA-approved da Vinci imaging system (Ofori et al., 2015). OBP-401 has also been used to fluorescently label lung
tumors and allow for complete lung tumor resection (Yano, Zhang, et al., 2015).
6 | COLOR ECT AL CA NC ER
6.1 | Background
Colorectal cancer is the third most common cancer among men and women in the United States and second leading cause of
cancer-related death in Western countries (Monson et al., 2013; Siegel et al., 2017). In the past decade, the incidence has
decreased by 1.4–4% annually (Siegel et al., 2017). Five-year survival rates are 64–66% (Siegel et al., 2017). In patients with
nonmetastatic colorectal cancer, surgery is the cornerstone of curative therapy.

Obtaining negative surgical margins is critical. The Standards Practice Task Force of the American Society of Colon and
Rectal Surgeons recommends, depending on anatomic factors, a 1–5 cm surgical margin (strong recommendation, level 1A
evidence) (Monson et al., 2013). The NCCN states that for an adequate excision for tumors in the upper rectum, a distal rec-
tal margin of at least 5 cm below the distal edge of the tumor is necessary. For tumors in the distal rectum, a distal margin of
1–2 cm may be acceptable (National Comprehensive Cancer Network, 2017). Despite these best practices, PSMs still occur
in 6–13% of colorectal cases (Gravante et al., 2016; Homan et al., 2015). Local recurrence rates with a negative margin range
from 6 to 13% but are 16–78% with a positive circumferential margin (Adam et al., 1994; Bernstein, Endreseth, Romund-
stad, & Wibe, 2012; Nagtegaal et al., 2002; Nash et al., 2010; Vernava, Moran, Rothenberger, & Wong, 1992; Wheeler
et al., 2004). Although adjuvant radiation is indicated for PSMs, it does not compensate in terms of recurrence (Marijnen
TABLE 4 Probes in preclinical and clinical trials for colorectal tumors
Clinical trials
LUM015 Pan-cathepsin PEGylated pan-cathepsin Cy5 fluorophore with Cy5 fluorophore NCT02584244 Feasibility Recruiting
Gly-Gly-Arg QSY21 quencher study
RAPIDO-TRACT VEGF Monoclonal antibody Bevacizumab IRDye800CW NCT01972373 I Recruiting
Fluorescent lectin Integrins Affinity-based Fluorescent lectin ? NCT03070613 I Not yet
recruiting
Preclinical trials
cRGD-ZW800-1 Integrins Affinity-based Cyclic RGD peptides NIR zwitterionic dye (Handgraaf et al., 2017)
(avB3)
BMV109 Cathepsin - PMK electrophile Cy5.5 (Segal et al., 2015)
6QCNIR Cathepsin Substrate and Latent lysosomotropic effect (LLE) to Compatible with FDA- (Ofori et al., 2015)
activity-based quench approved da Vinci imaging
system with Firefly detection
OBP-401 Substrate and Telomerase-dependent adenovrirus GFP (Kishimoto et al., 2011)
activity-based with selective GFP expression
Anti-CEA CEA Monoclonal Anti-CEA conjugated AlexaFlour 488 (Hiroshima, Maawy, Metildi, et al.,
antibody antibody 2014; Metildi et al., 2015)
et al., 2003; Mukkai Krishnamurty & Wise, 2016). Positive margins are also correlated with worse survival in colorectal can-
cer (Leo et al., 2009; Lin et al., 2013).
The NCCN recommends further surgery, chemotherapy, and/or radiation in the event of a PSM (National Comprehensive
Cancer Network, 2017). Chemotherapy for colorectal cancer costs $11,800–$13,000 (Carvalho et al., 2017), and radiation therapy
costs range from $1400 to $3800 (Hanly et al., 2015). Surgery costs range from $14,000 to $16,000 (Gehrman et al., 2017).

The cathepsin-targeting molecule, LUM015, is being assessed clinically in a feasibility study for ex vivo far-red imaging of
colorectal (as well as pancreatic and esophageal) cancer (NCT02584244) (Table 4). Another clinical trial is evaluating the
fluorescent monoclonal antibody tracer, Bevacizumab-IRDye800CW (RAPIDO-TRACT), targeting VEGF in patients with
colorectal cancer (NCT01972373). Ultimately, the aim of this work is to identify which patients respond to VEGF-targeted
chemotherapy using newly developed NIR fluorescence endoscopes. A recently approved early phase I clinical trial will
evaluate the use of fluorescently conjugated lectins to intraoperatively identify colorectal cancer as well as visualize dysplasia
during colonoscopy (NCT03070613). Lectins have shown to have specific binding to altered cell-surface glycans in gastroin-
testinal cancer (Bird-Lieberman et al., 2012), thus fluorescein-conjugated lectin, Wisteria floribunda, will be sprayed topi-
cally on the colonic surface during surgery.

FGS on mice with GFP-expressing colon cancer cells resulted in 100% R0 resection compared to 58% in the bright light sur-
gery group, and curative resection in 67% versus 38% (Metildi, Kaushal, Snyder, Hoffman, & Bouvet, 2013).
The cathepsin-binding molecules, BMV109 and 6QCNIR, were also evaluated preclinically for use in colorectal cancer
(Ofori et al., 2015; Segal et al., 2015). Binding of the tumor-targeted zwitterionic NIR fluorescent peptide cRGD-ZW800-1
was evaluated by Handgraaf et al. (2017) for use with the colorectal cell line (HT-29) in vitro and in vivo, along with a vari-
ety of other cancer cell types. This probe is a conjugated cyclic pentapeptide known to bind to various overexpressed integ-
rins found on tumor cells and tumor-associated vascular endothelium (Desgrosellier & Cheresh, 2010). Specific probe
accumulation was found in colorectal cancer cells, and cRGD-ZW800-1 was visualized at a window 2–24 h postinjection
and had the benefit of renal as opposed to hepatic clearance for visualization of most solid tumors and metastases.
Injection of OBP-401, a fluorophore utilizing GFP, identified incompletely resected tumor in a mouse model of colonic
carcinomatosis (Kishimoto et al., 2011).
Anti-CEA antibody in a mouse model of FGS for colon cancer demonstrated accurate tumor labeling and subsequently
higher R0 resection rates compared to bright light surgery alone (Hiroshima, Maawy, Metildi et al., 2014; Metildi et al.,
2014). Anti-CEA antibody was also used in a mouse model of colorectal liver metastasis, and facilitated more complete
removal of tumor and improved OS and disease-free survival (DFS) (Hiroshima et al., 2016).
7 | PA NC RE ATIC CA NC ER
7.1 | Background
Pancreatic cancer is the fourth leading cause of cancer death in the United States (Siegel et al., 2017). Overall 5-year survival
is very poor at just 8%, mainly due to the majority of cases having distant metastasis at stage of presentation (Siegel et al.,
2017) Surgery is the mainstay of curative-intent therapy for patients with local or locally advanced pancreatic cancer,
although adjuvant or neo-adjuvant therapies are often administered (Khorana, Mangu, & Katz, 2017). Survival time after sur-
gery ranges from 10 to 20 months (Vera et al., 2016). Still, the majority of recurrences are within 2 years after surgery
(Castellanos & Merchant, 2014).

Achieving negative margins is the goal for curative pancreatic surgery. Approximately 20–25% of resections result in posi-
tive margins (Bassi et al., 2005; Neoptolemos et al., 2001). Although negative margins have been associated with decreased
risk of cancer death (Allema et al., 1995; Howard et al., 2006), patients typically succumb to recurrent or metastatic disease
eventually (Conlon, Klimstra, & Brennan, 1996). Some studies have found that resection margin independent of tumor grade
is not correlated with worse survival, suggesting that grade and local invasiveness are interacting factors (Neoptolemos et al.,
2001). Furthermore, a recent large systematic review of secondary re-resections to negative margins in patients with an ini-
tially PSM failed to demonstrate a survival benefit (Petrucciani et al., 2016). Varying definitions of PSM and heterogeneity
of clinical studies have contributed to the controversy over the prognostic important of negative margins, yet the consensus
is that negative margins with surgical therapy should be the goal (Ethun & Kooby, 2016). Negative surgical margins are
advocated by NCCN (National Comprehensive Cancer Network, 2017).
The NCCN recommends consideration of chemotherapy and/or radiation for positive resection margins in pancreatic car-
cinoma. Chemotherapy for pancreatic cancer with or without radiation costs $42,000–$69,500 (Murphy et al., 2012).

As mentioned previously for colorectal cancer, binding of the tumor-targeted zwitterionic NIR fluorescent peptide cRGD-
ZW800-1 was evaluated by Handgraaf et al. (2017) also for use with pancreatic cancer (BxPC-3). This probe enabled
in vivo visualization of pancreatic tumor xenografts in mice. McElroy et al. (2008) designed a monoclonal antibody with
CA19-9 specificity capable of specific fluorescence of pancreatic cancer cells in a mouse model. This probe, in conjunction
with neoadjuvant chemotherapy, reduced metastatic recurrences in mice with CA19-9 positive pancreatic tumors (13% vs.
75%) (Hiroshima, Maawy, Zhang, et al., 2014).
An injectable anti-CEA fluorophore has been developed for FGS in a mouse model of pancreatic cancer (Kaushal et al.,
2008; Metildi et al., 2012), and improves rates of complete resection (92% vs. 46%), cure (40% vs. 4.5%), and 1-year sur-
vival (28% vs. 0%) (Metildi et al., 2014). Furthermore, this agent reduced local recurrence rates in mice with pancreatic can-
cer resistant to chemotherapy and can be used with laparoscopic methods (Hiroshima et al., 2015; Metildi, Hoffman, &
Bouvet, 2013).
OBP-401, a GFP-containing virus that replicates in cancer cells, has been used in a mouse model of pancreatic cancer
(Yano, Hiroshima, et al., 2015). FGS using OBP-401 yielded lower local recurrence rates (36% vs. 83%), and the addition of
dual-color FGS completely prevented recurrences.
8 | PR OS T AT E C AN CE R
8.1 | Background
Prostate cancer is the most common solid organ cancer in men, affecting one in six men, and the third leading cause of can-
cer death (Siegel et al., 2017). Approximately half of prostate cancer diagnoses are detected at a localized stage (Seikkula
et al., 2017), and these patients are offered either active surveillance, radical prostatectomy, or definitive radiation, depending
on risk stratification and expected life expectancy (Heidenreich et al., 2014). In the past two decades, survival for prostate
cancer has improved by 51% (Siegel et al., 2017).
TABLE 5 Probes in preclinical and clinical trials for prostate cancer
Clinical trials
MDX1201-A488 PSMA Affinity-based, monoclonal antibody MDX1201-A488 Alexa Fluor (A488) NCT02048150 Pilot Recruiting
Preclinical trials
YC-27 PSMA Affinity-based Urea inhibitors IRDye800CW (Neuman et al., 2015)
(111)In-DTPA-D2B- PSMA Affinity-based Dual-labeled monoclonal antibody IRDye800CW + (111) (Lutje et al., 2014)
IRDye800CW In
PSMA-1-IR800 PSMA Affinity-based D-Glutamic acid residues attached to cysteine- IR800 (Wang et al., 2014)
glutamate urea targeting element
Cy5-cDb PSCA Affinity-based Antibody fragment (Cys-diabody [cDb]) Cy5 (Sonn et al., 2016)
PSCA = prostate stem cell antigen; PSMA = prostate-specific membrane antigen.

Radical prostatectomy is one of the most common surgeries performed in the United States and reduces disease-specific mor-
tality, overall mortality, and the risks of metastasis and local progression (Bill-Axelson et al., 2011). The goal is eradication
of cancer, however there is debate regarding the oncologic effect of positive margins for prostatectomy. A recently published
large-scale study found that PSMs occurred in 40% of prostatectomies, although this number can vary from 4 to 48%
(Cookson & Chang, 2010; Silberstein & Eastham, 2014). However, after adjusting for Gleason score, stage, or PSA level,
positive margin was only predictive of biochemical recurrence but not metastasis or OS (Mithal et al., 2016).
Patients with positive margins after radical prostatectomy should be offered adjuvant radiation according to guidelines
published by NCCN, the American Urological Association (AUA), and the American Society for Therapeutic Radiology
Organization (ASTRO) (Thompson et al., 2013). Cost of adjuvant radiation can range from $27,145 to $54,706 (Halpern
et al., 2016).

A pilot clinical trial is currently investigating the optimal dose of anti-prostate-specific membrane antigen (PSMA) monoclo-
nal antibody (MDX1201) conjugated to Alexa Flour (A488) (Table 5). This probe is administered intravenously 5 days
before robotic-assisted laparoscopic prostatectomy to patients with moderate- to high-risk prostate cancers (NCT02048150).

Miwa et al. (2014) showed that mice with GFP-expressing prostate cancer bone metastases treated by FGS had slower tumor
regrowth and superior DFS compared to mice undergoing bright light surgery. Given its abundant expression in prostate cancer,
PSMA is a common target for prostate cancer fluorescent probes and several have been evaluated preclinically. Previously, dual-
labeled anti-PSMA monoclonal antibody (D2B) was evaluated in mouse models and was found to have sensitive and specific
detection of prostate cancer lesions in vivo via micro-SPECT/CT and NIRF imaging (Lutje et al., 2014). Wang et al. (2014)
found that a high-affinity PSMA ligand (PSMA-1) of low molecular weight demonstrated selective in vitro and in vivo binding
and uptake by prostate cancer cells. Sonn et al. (2016) targeted prostate stem cell antigen for real-time intraoperative imaging of
prostate cancer in mouse xenografts using an antibody fragment (cys-Diabody) conjugated to a far-red fluorophore (Cy5). In their
prospective, randomized study comparing surgical resection with and without Cy5-cDb-mediated fluorescent guidance, they
found that targeted fluorescence reduced the incidence of PSMs (0/8) compared to white light surgery alone (7/7).
9 | OV A RI AN CA N CE R
9.1 | Background
Ovarian cancer is the fifth leading cause of cancer death among women in the United States (Siegel et al., 2017). Five-year rel-
ative survival is ~50% for all stages, but in patients with local disease the survival rate is 90% (Siegel et al., 2017). However,
~15% of patients are diagnosed at early stage with cancer localized to the ovary. Depending on extent of disease at presenta-
tion, patients may undergo salpingo-oophorectomy or laparotomy/total abdominal hysterectomy/bilateral salpingo-
oophorectomy with staging and/or debulking. Poor surgical candidates or those with bulky disease may receive neoadjuvant
chemotherapy.
TABLE 6 Probes in preclinical and clinical trials for ovarian cancer
Clinical trials
OTL38 FRA Chemically derived, affinity-based Folate analog IR-783 NCT02317705 II Complete
EC17 FRA Chemically derived, affinity-based Folate FITC NCT02000778 Pilot and feasibility Active, not recruiting
Preclinical trials
Associated
Name Target Type Recognition Dye publication
Z-Phe-Arg-HMRG Cathepsin Substrate and activity-based Leucine aminopeptidase, fibroblast HMRG (caged fluorophore) (Fujii et al., 2014)
activation protein, B-galactosidase,
g-glutamyltransferase, cathepsins
ProSense 750 Cathepsin B Protease activatable Prosense 750 - (Sheth et al., 2009)

Surgical margins have not played a significant role in the management of ovarian carcinoma. However, primary surgical
debulking, aimed at removal of gross visible tumor, has demonstrated superior oncologic outcomes over neoadjuvant chemo-
therapy. Specifically, patients without residual disease exhibited better OS than patients with residual disease (47–74% vs.
21–26%) (May et al., 2017; Rosen et al., 2014; Seagle et al., 2016). The greatest possible effort to remove all visible pelvic
disease and to evaluate for occult disease is recommended by NCCN. If residual disease remains after initial surgical debulk-
ing, the NCCN recommends completion surgery or adjuvant chemotherapy. The cost for primary debulking is estimated at
$31,465 and the cost for neoadjuvant chemotherapy is $25,849 (Rowland, Lesnock, Farris, Kelley, & Krivak, 2015).

Two clinical trials investigating methods for intraoperative visualization of ovarian tumors used affinity-based probes target-
ing FRA, which is frequently overexpressed in ovarian tumors and has been used in both imaging and targeted therapies
(Lutz, 2015) (Table 6). The pilot clinical trial assessing the use of folate-FITC (EC17) in visualizing breast and lung cancer
is also evaluating the use of EC17 in ovarian cancer (NCT02000778). On Target Laboratories’ FRA-targeting probe,
OTL38, which was evaluated preclinically in lung cancer (see section 5), is a folate analog conjugated to a NIR fluorescent
agent (796 nm) used in a clinical trial for patients with FRA-positive ovarian cancer (NCT02317705; results not yet avail-
able). Results from a clinical trial in the Netherlands (European Clinical Trials Database 2014-002352-12) evaluating this
agent in 12 patients with ovarian cancer showed OTL38 accumulation in all FRA-positive ovarian tumors and metastases
(Hoogstins et al., 2016). This specific fluorescent signal facilitated the resection of 29% of malignant lesions that were not
identified previously, thus improving the completeness of cytoreductive surgery.

Preclinical trials of fluorescently labeling ovarian cancer cells have focused on targeting cathepsin with activity-based probes.
Fujii, Kamiya, and Urano (2014) assessed an affinity-based probe that has hydroxymethylrhodamine green (HMRG)-based
fluorescence and is hydrolyzed upon reaction with cathepsin from a colorless probe at pH of 7.4 to fluorescent HMRG. Simi-
larly, Sheth et al. (2009) targeted ovarian cancer metastases by using an activatable probe targeting upregulated cathepsins,
specifically cathepsin B, using the commercially available NIR fluorescent probe, ProSense 750 (VisEn Medical, Woburn,
MA). They achieved a sensitivity of 100% in detecting cancerous cells during laparoscopic procedures for peritoneal carcino-
matosis in murine models with metastatic ovarian cancer (Sheth et al., 2009).
1 0 | CN S CA N CE R
10.1 | Background
Brain and nervous system tumors are rare but deadly, although over the past three decades the incidence and death rate from
brain tumors have decreased by 1% yearly (Kohler et al., 2011). Although survival varies depending on patient factors and
tumor type, altogether 5-year survival is 35% (Jemal et al., 2017).
Surgical treatment is indicated if resection is feasible based on tumor size and location. The goal for such patients is safe
maximal resection of tumor. For meningioma, complete surgical resection may be curative, but hinges upon intraoperative
TABLE 7 Probes in preclinical and clinical trials for CNS tumors
Clinical trials
Tumor Paint (BLZ-100) Unsure (pediatric Chemically derived, Peptidic probe derived from Cy5.5 NIR NCT02462629 I Recruiting
CNS) affinity-based target chlorotoxin (CTX) venom fluorophore
probe
Tumor Paint (BLZ-100) Unsure (adult Chemically derived, Peptidic probe derived from Cy5.5 NIR NCT02234297 I Complete
glioma) affinity-based target CTX venom fluorophore
probe
Confocal microscopy Nontargeted Nontargeted Oral demeclocycline - NCT02740933 I Not yet
post recruiting
PO demeclocycline
IRDye800CW-BBN Gastrin-releasing Affinity-based probe 68Ga-BBN IRDye800CW NCT02910804 I Recruiting
peptide receptor
(GRPR)
5-ALA Malignant cells Endogenous 5-Aminolevulinic acid invokes - NCT01128218 I, II Recruiting
photosensitizer synthesis of protoporphyrin
IX
Preclinical trials
CLR1501 and CLR1502 Cellular membrane Affinity-based probe APC derivative BODIPY and ICG (Swanson et al., 2015)
CNS = central nervous system.
detection of dural tails and residual tumor (Lee et al., 2017). Extent of resection is an important prognostic factor for glio-
blastoma as well (Neira et al., 2016).

Several fluorescent agents are currently used in clinical practice in neurosurgery, including fluorescein sodium, ICG, and 5-
aminolevulinic acid (5-ALA) (Table 7). A current phase I and II clinical trial is assessing the sensitivity and specificity of
oral 5-ALA for intraoperative identification of the indistinct borders of malignant gliomas (NCT01128218). This substance
induces fluorescence due to accumulation of protoporphyrin IX in glioma cells and has shown to have sensitivity (82.6%)
and specificity (88.9%) for fluorescence image-guided surgical resection (Eljamel & Mahboob, 2016). A randomized con-
trolled trial of FGS using 5-ALA has previously demonstrated superior complete removal (65% vs. 36%) and resulting in
higher 6-month progression-free survival than bright light surgery (41% vs. 21%) (Stummer et al., 2006).
An open-label clinical trial for visualization of glioblastoma is investigating the affinity-based probe 68Ga-BBN-
IRDye800CW. BBN is an amino acid sequence that targets the G protein-coupled receptor family of bombesin receptors,
which is overexpressed in glioblastoma. Patients are assessed by positron emission tomograph (PET) scan 30 min after injec-
tion with 68Ga-BBN-IRDye800CW using PET imaging preoperatively and then BBN-IRDye800CW intraoperatively for
NIR fluorescent-guided imaging surgery (NCT02910804). A phase I clinical trial is examining the use of FDA-approved oral
demeclocycline to visualize excised glioma specimens using confocal microscopy (NCT02740933).
A phase I dose escalation/expansion study of the affinity-based imaging agent Tumor Paint (BLZ-100) administered
intravenously was conducted in adults with glioma (NCT02234297). This probe has also been evaluated clinically for adult
skin cancer and sarcoma and is derived from chlorotoxoin venum (CTX) of the Leiurus quinquestriatus scorpion, which was
found to bind specifically to tumors of neuroectodermal origin (Garland et al., 2016; Lyons, O'Neal, & Sontheimer, 2002).
This probe is also currently being assessed in a phase I dose escalation study for pediatric patients with central nervous sys-
tem tumors (NCT02462629).

Momiyama et al. (2013) demonstrated that FGS on mice with gliomas expressing red-fluorescent protein results in lower
residual tumor volume and longer survival than bright light surgery. Mice with gliomas treated with OBP-401 and FGS had
dramatically fewer recurrences (36% vs. 86%) and significantly longer DFS and OS (Yano, Miwa, Kishimoto, Toneri, et al.,
2015). Two cancer-selective alkylphosphocholine analogs, CLR1501 (green) and CLR1402 (NIR), were evaluated in a pre-
clinical proof-of-principle study intraoperative fluorescence of glioma in mouse models (Swanson et al., 2015). This study
found that CLR1501 exhibits a tumor-to-brain fluorescence ratio similar to that of the currently FDA-approved 5-ALA probe,
whereas CLR1502 has an improved tumor-to-brain fluorescence ratio.
TABLE 8 Probes in preclinical and clinical trials for skin and soft tissue cancer
Clinical trials
Name Target Type Recognition Dye Cancer Trial Phase Status
Tumor Paint Unsure Chemically derived, Peptidic probe derived Cy5.5 NIR fluorophore Skin NCT02097875 I Complete
(BLZ-100) affinity-based target probe from chlorotoxin
(CTX) venom
LUM015 Pan-cathepsin Substrate and activity-based PEGylated pan-cathepsin Cy5 fluorophore with Soft tissue NCT01626066 I Complete
Gly-Gly-Arg QSY21 quencher sarcoma
Preclinical trials
Name Target Type Recognition Dye Cancer Associated publication
Fluorocoxib A COX-2 Affinity-based Nonselective COX-2 inhibitor (indomethacin) 5-ROX Nonmelanoma skin (Ra et al., 2015)
1 1 | SKIN AN D S OF T T ISSU E S AR COMA S
11.1 | Background
Skin cancer, both melanomatous and nonmelanomatous, is the most common malignancy among Caucasians, with increasing
incidence over recent decades (Apalla, Nashan, Weller, & Castellsague, 2017). Surgical excision of both low- and high-risk
skin cancers plays a fundamental role in treatment. Mohs surgery highlights the importance of negative surgical margins, as
histologic assessment of the entire excised tumor margin is done in tandem with the procedure.
Sarcomas account for ~1% of all adult and 15% of all pediatric malignancies, the most frequent of which are soft tissue
sarcomas (Demetri et al., 2010). For most sarcomas, surgery is the standard primary treatment. The risk for failed complete
removal of tissue is high, thus surgery is commonly augmented with either pre- or postoperative radiation therapy and che-
motherapy (Dileo & Demetri, 2005; Mocellin, Rossi, Brandes, & Nitti, 2006). Negative surgical margins are recommended
given the higher rate of local recurrence and lower rate of DFS in patients with extremity sarcomas (Fleming et al., 1999;
Pisters, Leung, Woodruff, Shi, & Brennan, 1996) although close margins may be adequate for patients undergoing postoper-
ative radiation therapy (Kim et al., 2010). In some cases, amputation may even be considered for soft tissue sarcoma
(Williard, Hajdu, Casper, & Brennan, 1992).

Molecules previously described for targeting other cancer sites have also been evaluated in clinical trials for visualization of
skin cancer and soft tissue sarcoma (Table 8). Specifically, Tumor Paint (the peptidic probe derived from CTX) was evalu-
ated in patients with nonmetastatic skin cancer (NCT02097875) and LUM015 (the activatable cathepsin-targeting probe) was
evaluated in both patients with soft tissue sarcoma as well as breast cancer (NCT01626066).

Mice with retroperitoneal sarcomas expressing GFP had significantly less residual tumor (0.4 0.4 mm2 and
10.5 2.4 mm2), smaller recurrences (11.7 6.9 mm2 vs. 379 147 mm2), and superior DFS at 5 weeks (82% vs. 9%)
than mice undergoing bright light surgery (Uehara et al., 2015). Similarly, mice with fibrosarcomas expressing GFP treated
with FGS had no residual tumor postoperatively, lower local recurrence rates (0% vs. 80%), and lower lung metastases rates
(0% vs. 10%) (Yano, Miwa, Kishimoto, Uehara, et al., 2015). DFS and OS at 120 days were both 100% in the FGS group
compared to 20% in the bright light surgery group. Fluorocoxib A was evaluated as a molecular probe targeting
cyclooxygenase-2 (COX-2), an enzyme expressed highly in both tumor and inflamed tissues (Ra et al., 2015). This study
investigated the sensitivity of fluorocoxib A in a mouse model, finding a detection sensitivity of 88% and specificity of
100% in macroscopic tumors.
1 2 | CONC LU SION S
Surgeons have the unique opportunity to dramatically influence the course of a patient’s cancer by completely removing the
tumor. Given the generally poor prognostic implications and financial burden of adjuvant treatments driven by the presence
of PSMs, identifying their presence intraoperatively to aid in complete tumor removal will provide a unique opportunity to
individual patients and the healthcare system as a whole. Fluorescence-guided imaging and intraoperative guidance will
enable surgeons to better navigate the surgical field for complete tumor removal and avoidance of critical structures.
ACKNOWLEDGMENTS
This study was supported by NIH-EB014929 to Q.T.N. and NIH-1TL1TR001443 training grant to K.T.
CONFLICT OF INTEREST
The authors have declared no conflicts of interest for this article.
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How to cite this article: Tringale KR, Pang J, Nguyen QT. Image-guided surgery in cancer: A strategy to reduce
incidence of positive surgical margins. WIREs Syst Biol Med. 2018;10:e1412. https://doi.org/10.1002/wsbm.1412

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Image-guided surgery in cancer: A strategy to reduce incidence

cancer surgery, fluorescence imaging, image-guided surgery, intraoperative

Positive margins Negative margins

Normal tissue Normal tissue

2 | OV ER VIEW OF FL UORE SCE NT VISU AL ENHA NC ER S AN D SMA RT PROBE S FOR

Closed-Field Fluorescent Scanner

B White light Overlay

Site Range Oncologic implications Cost implications per patient

4.2 | Relevance of PSMs

4.3 | Intraoperative imaging techniques

TABLE 2 Probes in preclinical and clinical trials for breast cancer

4.3.2 | Preclinical trials

5.2 | Relevance of PSMs

5.3 | Intraoperative imaging techniques

TABLE 3 Probes in preclinical and clinical trials for lung tumors

5.3.2 | Preclinical trials

6.2 | Relevance of PSMs

TABLE 4 Probes in preclinical and clinical trials for colorectal tumors

6.3 | Intraoperative imaging techniques

6.3.2 | Preclinical trials

7.2 | Relevance of PSMs

7.3 | Intraoperative imaging techniques

TABLE 5 Probes in preclinical and clinical trials for prostate cancer

PSCA = prostate stem cell antigen; PSMA = prostate-specific membrane antigen.

8.2 | Relevance of PSMs

8.3 | Intraoperative imaging techniques

8.3.2 | Preclinical trials

TABLE 6 Probes in preclinical and clinical trials for ovarian cancer

9.2 | Relevance of PSMs

9.3 | Intraoperative imaging techniques

9.3.2 | Preclinical trials

TABLE 7 Probes in preclinical and clinical trials for CNS tumors

CNS = central nervous system.

10.2 | Intraoperative imaging techniques

10.2.2 | Preclinical trials

1 1 | SKIN AN D S OF T T ISSU E S AR COMA S

11.2 | Intraoperative imaging techniques

11.2.2 | Preclinical trials

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