ORIGINAL ARTICLE

Intraoperative Near-infrared Imaging Can Identify Neoplasms

and Aid in Real-time Margin Assessment During
Pancreatic Resection
Andrew D. Newton, MD,  Jarrod D. Predina, MD,  Michael H. Shin, BA,  Lydia G. Frenzel-Sulyok, BA, 
Charles M. Vollmer, MD,  Jeffrey A. Drebin, MD, PhD,y Sunil Singhal, MD,  and Major K. Lee IV, MD, PhD 

are hindered by high rates of local and distant recurrence due to

Objective: To determine if intraoperative near-infrared (NIR) imaging car-
positive surgical margins and occult metastatic disease. The R1/R2
ries benefit in resection of pancreatic neoplasms.
resection rate ranges from 24% to 42% in several large series but may
Background: Resection of pancreatic malignancies is hindered by high rates
be as high as 76% with stringent pathologic analysis.5– 9 Further-
of local and distant recurrence from positive margins and unrecognized
more, early distant recurrences following margin-negative resection
metastases. Improved tumor visualization could improve outcomes. We
highlight the likelihood of unrecognized metastases at the time of
hypothesized that intraoperative NIR imaging with a clinically approved
surgery.8,10
optical contrast agent could serve as a useful adjunct in assessing margins and
Neoadjuvant therapy is an attractive strategy in the manage-
extent of disease during pancreatic resections.
ment of PDAC as it may allow for better patient selection. Patients
Methods: Twenty patients were enrolled in an open-label clinical trial from
who progress on neoadjuvant therapy are less likely to benefit from
July 2016 to May 2018. Subjects received second window indocyanine green
resection and may therefore be spared from a morbid procedure.
(ICG) (2.5–5 mg/kg) 24 hours prior to pancreatic resection. NIR imaging was
However, neoadjuvant therapy can create confusion in borderline
performed during staging laparoscopy and after pancreas mobilization in situ
resectable or locally advanced patients who do not progress. Recent
and following resection ex vivo. Tumor fluorescence was quantified using
data indicate that preoperative imaging in these patients becomes
tumor-to-background ratio (TBR). Fluorescence at the specimen margin was
unreliable in predicting resectability.11–13
compared to pathology evaluation.
Adjunctive measures that improve intraoperative assessment
Results: Procedures included 9 pancreaticoduodenectomies, 10 distal pan-
of the extent of disease are needed. Intraoperative near-infrared
createctomies, and 1 total pancreatectomy; 21 total specimens were obtained.
(NIR) imaging is an emerging technology that can improve real-
Three out of 8 noninvasive tumors were fluorescent (mean TBR 2.59  2.57).
time identification of tumor margins and small nodules during an
Twelve out of 13 invasive malignancies (n ¼ 12 pancreatic adenocarcinoma, n
operation. Indocyanine green (ICG) is the only US Food and Drug
¼ 1 cholangiocarcinoma) were fluorescent (mean TBR 4.42  2.91). Fluo-
Administration (FDA)-approved intraoperative NIR imaging fluo-
rescence at the transection margin correlated with final pathologic assessment
rophore. Intraoperative NIR imaging with ICG has traditionally been
in 12 of 13 patients. Following neoadjuvant therapy, 4 of 5 tumors were
used to assess vascular perfusion.14,15 However, an alternative
fluorescent; these 4 tumors showed no treatment response on pathology
method of ICG administration—the second window ICG tech-
assessment. One tumor had a significant treatment response and showed
nique—has recently demonstrated benefit in tumor imaging.16 Spe-
no fluorescence.
cifically, high-dose ICG (5 mg/kg) will accumulate in nonhepatic
Conclusions: Second window ICG reliably accumulates in invasive pancre-
solid tumors over 24 hours via the enhanced permeability and
atic malignancies and provides real-time feedback during pancreatectomy.
retention (EPR) effect.17 This technique has demonstrated benefit
NIR imaging may help to assess the response to neoadjuvant therapy.
in identifying pulmonary nodules and gliomas.18,19
Keywords: indocyanine green, intraoperative imaging, near-infrared We hypothesized that intraoperative NIR imaging with second
imaging, pancreatic cancer, pancreatic ductal adenocarinoma window ICG could serve as a useful adjunct in identifying pancreatic
neoplasms and assessing margins intraoperatively. The primary
(Ann Surg 2019;270:12–20) outcome was the presence of fluorescence in malignant and prema-
lignant neoplasms (TBR  2.0). Secondary outcomes were the
D espite improved adjuvant therapy, median survival for patients
with resected pancreatic ductal adenocarcinoma (PDAC) is
only 20 to 28 months.1– 4 Outcomes following surgical resection
correlation of fluorescence at the resection margin with pathologic
margin assessment and correlation of fluorescence with response to
neoadjuvant treatment. Here, we report on the feasibility and utility
of NIR imaging in 20 patients with suspected malignant or prema-
From the Department of Surgery, University of Pennsylvania Perelman School of lignant pancreatic lesions.
Medicine, Philadelphia, PA; and yDepartment of Surgery, Memorial Sloan
Kettering Cancer Center, New York, NY.
S.S. was supported by the NIH (R01 CA193556).
METHODS
The authors report no conflicts of interest.
Supplemental digital content is available for this article. Direct URL citations Study Design
appear in the printed text and are provided in the HTML and PDF versions of A prospective open-label intraoperative NIR imaging clinical
this article on the journal’s Web site (www.annalsofsurgery.com).
Reprints: Major K. Lee IV, MD, PhD, Andrew D. Newton, MD, Department of trial was approved by the University of Pennsylvania Institutional
Surgery, Hospital of the University of Pennsylvania, 3400 Spruce St., 4 Review Board. The primary objective of this study was to determine
Silverstein, Philadelphia, PA 19104. the feasibility of NIR imaging with second window ICG for pancre-
E-mails: Major.Lee@uphs.upenn.edu, Andrew.Newton@uphs.upenn.edu. atic neoplasms. Twenty patients provided written informed consent
Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0003-4932/19/27001-0012 and were recruited between July 2016 and May 2018. Included
DOI: 10.1097/SLA.0000000000003201 subjects were scheduled for pancreatectomy based on suspicion of a

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Annals of Surgery  Volume 270, Number 1, July 2019 Pancreatic Cancer Near-infrared Imaging

malignant or premalignant lesion by preoperative imaging and with TBR was assessed using the Pearson correlation coefficient for
endoscopic evaluation. continuous variables and the Wilcoxon rank-sum test for
categorical variables.
Study Drug
Indocyanine green (ICG) was purchased from the manufac- RESULTS
turer (Akorn, Lake Forest, IL). ICG is a water-soluble anionic,
amphiphilic NIR fluorophore with a peak excitation wavelength Patient Characteristics
of 805 nm, a peak emission wavelength of 830 nm, and a molecular Twenty patients (10 females, mean age 65.0  15.2 yrs) were
weight of 775 Da. A 2.5 to 5 mg/kg ICG dose was given as an enrolled in the trial. One patient had multifocal PDAC; she presented
intravenous infusion 1 day prior to pancreatectomy. with jaundice but the dominant mass was in the pancreatic tail. This
patient had a total pancreatectomy in which the pancreas was divided
Near-infrared Imaging at the neck. For analysis purposes, this was treated as a distal
Macroscopic surgical fluorescent imaging in situ was per- pancreatectomy and a pancreaticoduodenectomy. As a result, there
formed using the Iridium system (Visionsense Corps, Philadelphia, are 21 specimens for 20 patients. Fifteen of the 20 patients underwent
PA) or the Stryker 1588AIM (Kalamazoo, MI). All ex vivo imaging either a laparoscopic resection or a staging laparoscopy prior to
was performed using the Iridium. NIR imaging in situ was per- open resection.
formed a minimum of 3 times during each case. First, the abdomen Patient characteristics are shown in Table 1. Eighteen patients
was triaged by white light and NIR imaging. Any lesions that were received 5 mg/kg ICG 1 day before surgery, and 2 patients received
suspicious for malignancy on white light imaging were examined 2.5 mg/kg ICG 1 day before surgery. Mean time from drug infusion to
for fluorescence and were biopsied. Second, following pancreas imaging was 23.9  3.0 hours. ICG infusion was safe with no serious
mobilization, the primary tumor was analyzed for fluorescence. adverse events.
Third, after pancreas resection, the wound bed was evaluated for
residual fluorescence. In each case, the resected pancreatic speci- NIR Imaging for Benign or Low-grade Malignant
men was imaged on the back-table ex vivo. The pancreatic neck and Pancreatic Lesions
retroperitoneal margins were assessed for fluorescence. The pres- Eight patients had benign tumors or low-grade malignancies
ence or absence of fluorescence was then compared to both frozen (intraductal papillary mucinous neoplasm [IPMN], serous cystade-
section and final histopathologic analysis. The bile duct and duo- noma, neurofibroma, or well-differentiated neuroendocrine tumor)
denal margins were not assessed for fluorescence because ICG is on final pathology. Characteristics of these patients are included in
hepatically excreted which could create background fluorescence at Table 2. Five of the 8 lesions were nonfluorescent. Three of these
these margins. Importantly, as this was primarily a feasibility trial, lesions were fluorescent: a main duct IPMN with high-grade dys-
the operative approach was not altered based on fluorescence. The plasia, a microcystic serous cystadenoma, and a mixed-type IPMN
use of frozen section, the site of transection, and the decision with low-grade dysplasia. The first 2 tumors had modest fluorescence
to resect further were at the surgeon’s discretion based on standard (mean fluorescence intensities [MFI] of 63.4 and 85.0 arbitrary units
white light imaging and manual palpation, not based on fluores- [AU], respectively) but background fluorescence in the normal
cence. pancreas was very low (MFI 29.8 and 16.0). Fluorescence was
particularly strong in the mixed-type IPMN with low-grade dysplasia
Fluorescence Microscopy (MFI 205.3 AU) (Supplemental Figure 1, http://links.lww.com/SLA/
All resected specimens were examined by a gastrointestinal B559). In this case, there was evidence of ICG pooling around
pathologist. Tumors were formalin fixed and paraffin embedded. intrapancreatic blood vessels on fluorescence microscopy.
Serial sections of tumor and normal tissue were cut for pathology
slides. Slides were stained with 4, 6’-diamidino-2-phenylindole
(DAPI), and fluorescence microscopy for ICG and DAPI was
performed. ICG was pseudo-colored green, and DAPI was
pseudo-colored blue. Fluorescence was compared to the correspond- TABLE 1. Characteristics of the Study Patients
ing area on hematoxylin and eosin (H&E) stained slides. Positive and N (%) or Mean  SD
negative controls were used for all images. In patients who received
neoadjuvant treatment, the entire pancreas was submitted for histo- Age (yrs) 65.0  15.2
logic examination. A treatment response score was given which is an Sex
Male 10 (50.0)
estimated metric reflecting how much tumor was felt to be viable.
Female 10 (50.0)
Poor treatment response was defined as  90% remaining viable Neoadjuvant treatment 4 (20.0)
tumor, moderate tumor response was defined as >10 and <90% Laparoscopy performed 15 (75.0)
remaining viable tumor, and good treatment response was defined as Procedure
 10% remaining viable tumor. Open pancreaticoduodenectomy 10 (47.6)
Laparoscopic distal pancreatectomy 3 (14.3)
Statistical Analysis Open distal pancreatectomy 8 (38.1)
Descriptive statistics are presented as mean  standard devi- Final pathology
ation. Post hoc image analysis was performed using region-of- Pancreatic ductal adenocarcinoma 12 (57.1)
Cholangiocarcinoma 1 (4.8)
interest software and HeatMap plugin within ImageJ (National
IPMN 3 (14.3)
Institutes of Health; http://rsb.info.nih.gov/ij/). The fluorescence in Neuroendocrine tumor 2 (9.5)
the tumor and in adjacent uninvolved pancreas was quantified using Serous cystadenoma 2 (9.5)
this technology, and a tumor-to-background fluorescence ratio Neurofibroma 1 (4.8)
(TBR) was calculated for each case. A TBR  2.0 was considered Mean hours from infusion to imaging 23.9  3.0
positive for fluorescence based on previous clinical studies using this IPMN indicates intraductal papillary mucinous neoplasm; SD, standard deviation.
imaging system.20–22 The association of clinicopathologic features

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Newton et al Annals of Surgery  Volume 270, Number 1, July 2019

TABLE 2. Clinicopathologic Characteristics of Patients With Benign or Low-grade Malignant Tumors

Patient Age Procedure Final Pathology TBR
6 75 DP Mixed-type IPMN with low-grade dysplasia 7.82
8 71 PD Well-differentiated pancreatic neuroendocrine tumor 1.06
9 44 DP Microcystic serous cystadenoma 5.31
12 83 DP Main duct IPMN with high grade dysplasia 2.13
14 22 DP Neurofibroma 1.00
15 61 PD Mixed-type IPMN with high grade dysplasia 1.43
18 72 PD Serous cystadenoma 0.98
20 47 DP Well-differentiated pancreatic neuroendocrine tumor 0.99
DP indicates distal pancreatectomy; IPMN, intraductal papillary mucinous neoplasm; PD, pancreaticoduodenectomy; TBR, tumor-to-background ratio.

NIR Imaging for Invasive Malignancies with final pathology analysis for 12/13 specimens. The fluorescence
Thirteen specimens were obtained from the 12 patients with status, frozen section diagnosis, and final margin status for malignant
invasive malignancies (n ¼ 12 PDAC, n ¼ 1 cholangiocarcinoma). tumors are summarized in Table 3.
Twelve out of 13 specimens were fluorescent (mean TBR
4.42  2.91). All fluorescent tumors were fluorescent both in situ Correlation Between Fluorescence and Response to
and ex vivo. In patients with PDAC, 91.7% (11/12) were fluorescent Neoadjuvant Treatment
(mean TBR 4.62  2.95). The 1 patient with PDAC and a nonfluo- Four patients had neoadjuvant treatment prior to pancreatic
rescent tumor (TBR 1.25) had preoperative chemoradiotherapy and resection (Table 3). Two patients (patients 10 and 16) had neo-
only 10% remaining viable tumor. Representative images from 2 adjuvant chemoradiation, while 2 patients (patients 13 and 19) had
patients with PDAC are shown in Figure 1. For patients with PDAC, neoadjuvant chemotherapy only. One was the patient who under-
there was no correlation between TBR and age, BMI, time from went total pancreatectomy; thus, there were 5 specimens from these
infusion to imaging, total ICG dose, tumor size, or procedure 4 patients. Four specimens from 3 of these patients were fluorescent
(Supplemental Table 1, http://links.lww.com/SLA/B559). (mean TBR 4.29  1.74) and demonstrated poor treatment response
Ten of the 12 patients with invasive malignancies underwent (>90% viable tumor) on pathology. Both specimens were fluores-
either a laparoscopic resection or a staging laparoscopy prior to open cent in the patient who had a total pancreatectomy (TBR 4.63 and
resection. In every case, the liver had background fluorescence. 2.76). One patient had no tumor fluorescence (TBR 1.25) and had a
There were no patients with a liver lesion that was suspicious visually good treatment response with only 10% remaining viable tumor.
(ie, on white light imaging) and also suspicious by fluorescence. Two Representative images from 2 of these patients are shown in
liver lesions that were suspicious on white light imaging but non- Figure 3.
fluorescent were biopsied and sent for frozen section analysis.
Pathology showed a benign biliary cyst and a bile duct adenoma. DISCUSSION
In this prospective open-label clinical trial, we demonstrate
Correlation Between Fluorescence and Pathologic that intraoperative NIR imaging with a clinically approved fluoro-
Assessment of Surgical Margins phore and imaging system can identify invasive pancreatic malig-
Pancreatic transection margins were sent for frozen section in nancies including PDAC. This is the largest clinical trial of
5 cases. Four of these cases were pancreaticoduodenectomies, and intraoperative NIR imaging of PDAC. Intraoperative NIR imaging
the frozen section that was sent in each case was from the pancreatic with second window ICG had 100% sensitivity for viable invasive
neck margin. Frozen sections were not routinely sent in distal malignancies. Fluorescence at the resection margin correlated with
pancreatectomies when the transection margin was well away from final pathology in 12 of 13 cases. Following neoadjuvant therapy,
the mass. Frozen section was also not sent in pancreaticoduodenec- tumor fluorescence correlated with treatment response, suggesting
tomies when the outcome would not change management. this may be a valuable new tool to assess the response to neoadjuvant
The frozen section was read as adenocarcinoma in 1 of 5 cases. treatment.
There was fluorescence at the transection margin in 2 of 5 cases. In Although several different fluorescent tracers for intraopera-
the 1 instance where both fluorescence and frozen section suggested tive NIR imaging of PDAC have been studied in preclinical animal
carcinoma at the margin (Patient 3), the surgeon cut back further to models,23–25 successful translation to human clinical trial has been
achieve a negative margin (Fig. 2A). In the 1 instance where frozen challenging. In a previous clinical trial of NIR imaging with ICG for
section was negative but there was fluorescence at the margin, pancreatic tumors, Hutteman et al26 performed NIR imaging imme-
nothing was done. This patient had a negative final margin. Thus, diately after intraoperative infusion of 5 to 10 mg of ICG in patients
frozen section was 100% accurate in this series. undergoing pancreaticoduodenectomy. They concluded that ICG
There were an additional 4 cases where fluorescence was provided no useful tumor demarcation. However, the use of perfusion
identified at the transection margin but no frozen section was sent. In dosing (a small ICG dose given during surgery) rather than the
each of these 4 cases, the surgeon felt that the frozen section outcome second window ICG technique (a high ICG dose given a day prior to
would not change management, and in each case, the transection surgery) did not allow for ICG accumulation in tumor via the
margin was positive for adenocarcinoma on final pathologic assess- enhanced permeability and retention (EPR) effect. The EPR effect
ment. A representative case with fluorescence at the resection margin was first described by Matsumura et al and suggests that tumor
and carcinoma at the margin on final pathology is shown in angiogenesis creates excess but leaky capillaries.27 Macromolecules
Figure 2B. In total, fluorescence at the resection margin correlated leak out of this defective vasculature and become trapped in tumors

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Annals of Surgery  Volume 270, Number 1, July 2019 Pancreatic Cancer Near-infrared Imaging

FIGURE 1. Intraoperative near-infrared (NIR) imaging from 2 patients with pancreatic adenocarcinoma. Patient 4 underwent a
distal pancreatectomy for a pancreatic tail cyst with at least high-grade dysplasia on FNA. Final pathology demonstrated pancreatic
ductal adenocarcinoma (PDAC). Patient 13 underwent a total pancreatectomy for multifocal PDAC. Pathology demonstrated a
3.5 cm PDAC in the pancreatic tail (arrows) and multifocal PDAC involving the entire portion of the resected pancreatic head
(arrowheads). A, Preoperative CT scan, in situ white light, and NIR images. B, Back table white light, NIR, and overlay images. C,
H&E microscopy, ICG fluorescence microscopy, DAPI fluorescence microscopy, and ICG and DAPI overlay fluorescence microscopy.

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Newton et al Annals of Surgery  Volume 270, Number 1, July 2019

FIGURE 2. Intraoperative near-infrared (NIR) imaging from 2 patients with fluorescence at the initial resection margin. A, In situ
intraoperative white light, near infrared, and overlay images after pancreas transection and prior to specimen removal for Patient 3.
The patient underwent a pancreaticoduodenectomy and had both fluorescence at the margin and a positive frozen section. The
specimen was cut back further to achieve a negative margin. B, Preoperative CT, in situ intraoperative white light, near infrared, and
overlay images after pancreas resection for Patient 2. The patient initially underwent a distal pancreatectomy for duct dilation
without a clear tumor. Intraoperative imaging showed diffuse fluorescence throughout the pancreas including in the pancreatic
head and at the transection margin. The patient had a positive margin on final pathology and eventually underwent a completion
pancreatectomy at which time adenocarcinoma was found throughout the pancreatic head.

due to properties including size, shape, charge, and polarity.28 In this was fluorescence at the margin in the 1 patient where fluorescence
study, the second window technique allowed for reliable ICG accu- and pathologic assessment were discordant. This was an advanced
mulation in pancreatic malignancies. These data add to the growing tumor requiring a complete portal/superior mesenteric vein resec-
body of evidence that NIR imaging with second window ICG can tion, but the discordance remains unexplained. Interestingly, fluo-
localize a diverse array of solid tumors.18,19,29 rescence was seen at the transection margin in 4 cases where a frozen
This technique could be criticized because 3 of 8 (37.5%) section was not sent. In one case, the surgeon identified residual
benign or low-grade malignant tumors were fluorescent. Fluores- tumor in other areas (around the hepatic artery) and knew that this
cence in benign lesions was certainly multifactorial. Intense fluo- was a margin positive resection. Thus, no frozen section was sent at
rescence in 1 benign IPMN was associated with small pockets of ICG the transection margin. In a second case (Appleby procedure), the
pooling around intrapancreatic vasculature on fluorescence micros- surgeon was at the anatomic limit of resection and thus sent no
copy. This may indicate that there was microvascular extravasation frozen section. In the 2 other cases, the preoperative imaging vastly
from the IPMN as is seen in malignant tumors. Regardless, perhaps underestimated the extent of the tumor, and the surgeon felt that a
the most critical finding here is that the negative predictive value for positive transection margin would be a marker of advanced disease
fluorescence was 100%—tumors with no fluorescence were benign, that was unlikely to be solved by further resection. In each of these 4
low grade, or nonviable. Further, for the noninvasive lesions that did cases the final transection margin was positive for adenocarcinoma.
fluoresce, intraoperative imaging assisted in visualization, especially ICG fluorescence predicted the positive margin in each of these 4
in laparoscopic procedures. cases, and in 3 of the 4 it suggested extensive disease that was
The presence or absence of fluorescence at the margin underestimated by preoperative imaging. Importantly, gross inspec-
correlated with margin status on final pathology in 12 of 13 speci- tion by the surgeon clearly identified a positive margin in only
mens with invasive malignancy. Positive predictive value for fluo- the first case. The latter 2 cases were infiltrative tumors in
rescence at the pancreatic neck margin was 83.3% (5/6) while which a positive margin was suggested by ICG but was otherwise
negative predictive value was 100% (7/7). It is unclear why there uncertain until formal pathologic assessment. This is one potential

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Annals of Surgery  Volume 270, Number 1, July 2019 Pancreatic Cancer Near-infrared Imaging

(þ) neck, () uncinate

(þ) neck, () uncinate

(þ) neck, () uncinate

Margin Status
benefit to NIR imaging—each of these patients might have
been spared an extensive, margin-positive resection and instead
directed toward neoadjuvant therapy or definitive chemotherapy/
Final

chemoradiotherapy.
There are currently no ideal options to assess the response of
(þ) neck

(þ) neck
pancreatic cancer to neoadjuvant therapy. Imaging often does not
(þ) adenocarcinoma ()

()
()

()
()
()

()
()
correlate with response to neoadjuvant treatment or the ability to
perform an R0 or R1 resection.12,13,30 Tumor markers are useful but
cannot be used in isolation to decide upon high-risk resections. In
Frozen Section

our series, 4 patients received neoadjuvant therapy. Two of the 4

Diagnosis

patients had evidence of tumor regression on imaging, and 3 of the 4

CO indicates chemotherapy only; CRT, chemoradiotherapy; DP, distal pancreatectomy; HGD, high-grade dysplasia; PD, pancreaticoduodenectomy; TBR, tumor-to-background ratio.
had a significant tumor marker response. However, only 1 patient
(þ) HGD had a significant pathologic response. Fluorescence correlated
with pathology in all cases. In the patient with good treatment
N/A
N/A

N/A

N/A
N/A

N/A
N/A
N/A
()

()

()
response, the tumor could not be distinguished from surrounding
TABLE 3. Comparison of Fluorescence at Resection Margin and Margin Pathology for Patients With Invasive Malignancies

fibrosis intraoperatively with white light and palpation. The surgeon

Fluorescence Margin Fluorescence

was highly suspicious of a positive margin. However, NIR

Retroperitoneal

imaging showed no tumor fluorescence, and in fact the patient

had a negative margin. The other 3 patients required extensive
No
No
No

No
No
No
No
No
No
No
No
No
No

pancreatic resections after neoadjuvant therapy—a total pancrea-

tectomy, an Appleby procedure, and a pancreaticoduodenectomy
with portal vein reconstruction. These patients all had highly
fluorescent tumors and poor treatment response. In such cases,
the ability to confirm poor treatment response prior to resection
Neck Margin

may have affected the decision to proceed. NIR imaging could

Yes
Yes
Yes

Yes

Yes
Yes

Yes
No
No

No
No
No

No

therefore be integrated into intraoperative decision-making for

borderline resectable or locally advanced PDAC following neo-
adjuvant therapy.
The results of this study suggest 5 potential clinical appli-
7.71
3.77
2.08

2.13
3.29
1.25
4.20
4.63
2.76
4.83
3.38
5.06
12.43
TBR

cations for this technology: 1) as an adjunct to intraoperative

ultrasound during distal pancreatectomy, 2) for margin assessment,
100% viable tumor
100% viable tumor
100% viable tumor

100% viable tumor

3) to assess extent of disease, 4) to assess the response to neo-

PDAC, 10% viable tumor
cholangiocarcinoma

adjuvant therapy, and 5) to predict benign disease. When each case

was retrospectively assessed using these 5 criteria, NIR imaging
Pathology

provided valuable information in 18 of 20 cases (Table 4). The only

Final

Intrapancreatic

cases where imaging had no value were for pancreatic neuroendo-

crine tumors.
There are several limitations to our study. The first is that
PDAC,
PDAC,
PDAC,

PDAC,
PDAC
PDAC

PDAC
PDAC
PDAC

PDAC

intraoperative imaging was somewhat limited for pancreaticoduo-

denectomies due to background fluorescence. ICG is cleared hepati-
cally which creates more fluorescence in the area of the pancreatic
Procedure Treatment Response Cross Sectional Imaging
Following Neoadjuvant Treatment
Tumor Regression on

head. In an attempt to decrease the background signal, we did

decrease the ICG dose to 2.5 mg/kg for 2 pancreaticoduodenecto-
mies. A pancreatic adenocarcinoma fluoresced at this dose while a
Yes

Yes

cystadenoma did not, but there was no appreciable difference in

No
No

No
—
—
—

—
—
—

background fluorescence. We therefore continued with a dose of

>50% reduction in CA19-9 immediately prior to surgery.

5 mg/kg in the remainder of the patients. Background fluorescence

was not a limitation during distal pancreatectomy which allowed for
more precise tumor localization in this setting. It was especially
helpful in laparoscopic procedures, and some minimally invasive
Neoadjuvant CA19-9

platforms including the da Vinci Firefly fluorescence imaging system

Yes

Yes
Yes
Yes

No
—
—
—

—
—
—

readily incorporate technology capable of ICG imaging.31,32 A

–

second limitation is that we retrospectively reviewed the results of

imaging and did not use them to change decision making regarding
the extent of pancreatic resection. Reviewing what might have been
done differently is obviously much different than using the informa-
tion gained to make real-time intraoperative decisions. Nevertheless,
None
None
None

None
None
None
CRT

CRT
CO
CO

CO
No

No

this trial suggested multiple clinical applications that can serve as a

foundation when considering relevant clinical endpoints of phase II
and III clinical trials. Third, the number of patients who received
PD
DP
PD

DP
PD
PD
DP
DP
DP
PD
DP
PD
PD

neoadjuvant treatment was small. Neoadjuvant therapy was

used selectively among surgeons in this study and it was therefore
difficult to enroll large numbers of treated patients. However,

10
11
13
13
16
17
19

this was one of the more promising findings of the study, and we
#
1
2
3

4
5
7

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Newton et al Annals of Surgery  Volume 270, Number 1, July 2019

FIGURE 3. Intraoperative near-infrared (NIR) imaging from 2 patients following neoadjuvant treatment. Patient 16 underwent an
Appleby procedure and had no treatment response on final pathology. Patient 10 underwent a distal pancreatectomy and had good
treatment response with only 10% remaining viable tumor. A, Preoperative CT scan, in situ white light, and NIR images. B, Back
table white light, near-infrared, and overlay images.

plan to evaluate the ability of NIR imaging with second window ICG In conclusion, this work demonstrates that intraoperative NIR
to assess neoadjuvant treatment response in a more sizable imaging with second window ICG for pancreatic neoplasms is
future study. Lastly, there were no patients in this series with feasible and provides meaningful tumor demarcation that correlates
suspicious liver lesions identified solely by NIR imaging. Another with tumor margins. This technology may also be a promising way to
potential benefit to this technology is identification of subclinical assess the response to neoadjuvant treatment. This study sets a
metastatic disease not seen with white light. Unfortunately, this could foundation for future intraoperative NIR imaging clinical trials for
not be evaluated here as there was no patient who presented such pancreatic malignancies including the use of targeted fluorescent
a scenario. dyes as they become available.

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Annals of Surgery  Volume 270, Number 1, July 2019 Pancreatic Cancer Near-infrared Imaging

TABLE 4. Clinical Value of Intraoperative Near-infrared Imaging

Potential Operative Changes Based
Patient Procedure Final Pathology Benefit of Imaging on NIR Imaging
1 PD PDAC Identified positive margin Abort resection
Consider preoperative therapy
2 ODP PDAC Identified positive margin Abort resection
Consider preoperative therapy
3 PD Intrapancreatic cholangiocarcinoma Identified positive margin —
4 LDP PDAC Tumor localization —
Margin assessment
5 PD PDAC Margin assessment —
6 ODP IPMN Tumor localization —
7 PD PDAC Identified positive margin Abort resection
Consider preoperative therapy
8 PD Neuroendocrine tumor — —
9 LDP Microcystic serous cystadenoma Tumor localization —
10 ODP PDAC, 10% viable tumor Predicted good response to neoadjuvant therapy —
11 ODP PDAC Margin assessment —
12 ODP IPMN Tumor localization —
13 TP PDAC, 100% viable tumor Predicted poor response to neoadjuvant therapy Abort high-risk resection entirely
14 LDP Neurofibroma Predicted benign pathology —
15 PD IPMN Predicted benign pathology —
16 Appleby PDAC, 100% viable tumor Predicted poor response to neoadjuvant therapy Abort high-risk resection entirely
Identified positive margin
17 PD PDAC Margin assessment —
18 PD Serous cystadenoma Predicted benign pathology —
19 PD PDAC, 100% viable tumor Predicted poor response to neoadjuvant therapy Abort high-risk resection entirely
20 ODP Neuroendocrine tumor — —
IPMN indicates intraductal papillary mucinous neoplasm; LDP, laparoscopic distal pancreatectomy; ODP, open distal pancreatectomy; PD, pancreaticoduodenectomy; TP, total
pancreatectomy.

ACKNOWLEDGMENT 11. Xia BT, Fu B, Wang J, et al. Does radiologic response correlate to pathologic
response in patients undergoing neoadjuvant therapy for borderline resectable
The authors acknowledge Ronald P. DeMatteo, MD for his pancreatic malignancy? J Surg Oncol. 2017;115:376–383.
assistance in reviewing the manuscript. 12. Katz MH, Fleming JB, Bhosale P, et al. Response of borderline resectable
pancreatic cancer to neoadjuvant therapy is not reflected by radiographic
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