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a
b
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b
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T. Nishidate et al.
: Before light emission
Fig. 28.3 Luminescent ber placement during robot-assisted surgery. (a) Before light emission. (b) During light emission
: During light emission
: Before light emission
Fig. 28.4 Ureter identication with placement of luminescent ureteral
catheter into the right ureter and uorescence imaging using the Stryker
1588 system during surgical treatment for diverticulitis. (a) Before light
: Fluorescence imaging visualizing the ureter
through the mesentery
emission. (b) Fluorescence imaging visualizing the ureter through the
mesentery
a
retroperitoneum due to sigmoid colon diverticulitis.
b
c
a
b
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207
: Adhesions around the abdominal wall and
: After dissection around the ureter (cranial aspect)
: Adhesions between abscess and the ureter
d : After dissection around the ureter (caudal aspect)
Fig. 28.5 Ureter identication by uorescence imaging during surgical treatment for diverticulitis. (a) Adhesions around the abdominal
wall and retroperitoneum due to sigmoid colon diverticulitis. (b)
: Before light emission
Adhesions between the abscess and the ureter. (c) After dissection
around the ureter (cranial aspect). (d) After dissection around the ureter
(caudal aspect)
: Identification of the ureter by fluorescence imaging
Fig. 28.6 Dissection of adhesions after sigmoidectomy. (a) Before light emission. (b) Identication of the ureter by uorescence imaging
208
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T. Nishidate et al.
: Taping of the ureter
Fig. 28.7 Ureter identication by uorescence imaging using the Stryker 1688 and luminescent ureteral catheter during lateral lymph dissection
for recurrent lymph node metastasis. (a) Taping of the ureter. (b) The ureterohypogastric nerve fascia is dissected
5 Pitfalls
: Ureterohypogastric nerve fascia is dissected
developed and evaluated in clinical studies (Table28.2)
[4–11]. For example, Tanaka etal. [12] reported that intra-
The use of a cystoscope requires the cooperation of a urologist. There can be cases of difcult stent placement, difculty in deep reinsertion during surgery, and inability to
advance the inner tube. Forcible manipulation may lead to
ureteral injury during stent placement.
venous injection of near-infrared uorescent dye
CW800-CA enables real-time visualization of the ureter
in the animal model. The CW800-CA is excreted into the
kidney and thus accumulates in high concentrations in the
ureter, resulting in selective identication of the urinary
system. Other uorophores under development include
CW800-BK, cRGD-ZW800-1, uorescein, liposomal
6 Future Perspective
ICG, Genhance 750, UL-766, and UreterGlow (Table28.3)
[4, 12–23]. In the future, the intraoperative ureteral iden-
In order to visualize the ureter without catheter placement, uorescence imaging techniques using various uorescent agents in the near-infrared region have been
tication technique will become widely used, enhancing
the accuracy and safety of surgical treatments in the pelvic cavity.
28 Visualization oftheUreter
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Ureters
identied Complications References
[6]
a
All None [5]
All Yes, in one
ureter
25mg in 10mL/
209
patient
ureter
Number of
patients Administration Dose
Laparoscopic/
open
Gynecologic Laparoscopic >10 Ureteral catheter 25mg in 10mL/
Surgical
specialism
Siddighi etal.
(2014)
Article
PNT
Colorectal Laparoscopic 9 Intravenous 0.125–1.0mg/kg 6/9 None [9]
Colorectal Both 8 Intravenous 0.25–1mg/kg 10/11 None [8]
Abdominal Open 12 Intravenous 0.25–1mg/kg 24/24 None [7]
Al-Taher etal.
(2016)
(2016)
Yeung etal.
Lee etal. (2015) Urologic Laparoscopic 25 Ureteral catheter and/or
(2013)
Abdominal Laparoscopic 44 Intravenous 3.9mg/kg None [11]
Colorectal Both 40 Intravenous 0.25–1mg/kg 63/69 None [10]
(2018)
(2019)
Barnes etal.
Indocyanine
Table 28.2 Previous reports on the use of ICG, MB, and ZW800-1
green
Methylene blue Verbeek etal.
ZW800-1 de Valk etal.
From Slooter etal. [4]
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T. Nishidate et al.
Table 28.3
Dye Article
CW800-CA Tanaka etal.
Previous studies of intraoperative visualization of the ureter
(2007)
Number of
animals
12 rats, 6
pigs
Duration of
visualization
120min 0.0015–0.015 >20 NCT03387410
Doses (IV
kg)
a
, mg/
Toxicity in rats
(mg/kg)
Ongoing clinical
trials References
c
[12]
NCT03106038
c
Schols etal. (2014) 2 pigs 0.007–0.086 [13]
Korb etal. (2015) 6 pigs 0.030–0.12 [14]
CW800-BK Al-Taher etal.
3 pigs 0.08–0.3 [15]
(2018)
cRGD-ZW800-1 Verbeek etal.
3 rats <7.5h 0.25–30nmol > 24.5 2017-001954-32
e
[16]
(2014)
Fluorescein Dip etal. (2014) 9 rats <12h 7 LD
Meershoek etal.
(2018)
Liposomal ICG Portnoy etal.
3 pigs 5ml, 100mg/
ml SC/IM
b
25 mice >90min 8 Liposomes: 10
(2015)
Friedman-Levi
etal. (2018)
> 12 mice, 2
pigs
4–16 [20]
=600 Unknown [17]
50
Unknown [19]
ICG: LD
=87
50
[18]
Genhance 750 Rowe etal. (2012) 10 swine >20min 0.5 NR Unknown [21]
UL-766 Cha etal. (2018) 8 rats >60min 0.09 NR Unknown [22]
UreterGlow Mahalingam etal.
5 pigs <6h 0.1 NR Unknown [
(2018)
From Slooter etal. [4]
References
1. Matsui A, Tanaka E, Choi HS, et al. Real-time, near-infrared,
uorescence- guided identication of the ureters using methylene
blue. Surgery. 2010;148:78–86.
2. Selzman AA, Spirnak JP. Iatrogenic ureteral injuries: a 20-year
experience in treating 165 injuries. J Urol. 1996;155:878–81.
3. Burks FN, Santucci RA.Management of iatrogenic ureteral injury.
Ther Adv Urol. 2014;6:115–24.
4. Slooter MD, Jansen A, Bemelman WA, et al. Tech Coloproctol.
2019;23:305–13.
5. Siddighi S, Yune JJ, Hardesty J.Indocyanine green for intraoperative localization of ureter. Am J Obstet Gynecol. 2014;211:436.
e1–2.
6. Lee Z, Moore B, Giusto L, etal. Use of indocyanine green during
robot-assisted ureteral reconstructions. Eur Urol. 2015;67:291–8.
7. Verbeek FP, Vorst JR, Schaafsma BE, et al. Intraoperative nearinfrared uorescence guided identication of ureters using
low dose methylene blue: a rst in human experience. J Urol.
2013;190:574–9.
8. Yeung TM, Volpi D, Tullis ID, etal. Identifying ureters in situ under
uorescence during laparoscopic and open colorectal surgery. Ann
Surg. 2016;263:e1–2.
9. Al-Taher M, van den Bos J, Schols RM.Fluorescence ureteral visualization in human laparoscopic colorectal surgery using methylene
blue. J Laparoendosc Adv Surg Tech A. 2016;26:870–5.
10. Barnes TG, Hompes R, Birks J, et al. Methylene blue uorescence of the ureter during colorectal surgery. Surg Endosc.
2018;32:4036–43.
11. de Valk KS, Handgraaf HJ, Deken MM, etal. A zwitterionic nearinfrared uorophore for real-time ureter identication during laparoscopic abdominopelvic surgery. Nat Commun. 2019;10:3118.
12. Tanaka E, Ohnishi S, Laurence RG, etal. Real-time intraoperative
ureteral guidance using invisible near-infrared uorescence. J Urol.
13. Schols RM, Lodewick TM, Bouvy ND, etal. Application of a new
dye for near-infrared uorescence laparoscopy of ureters: demonstration in a pig model. Dis Colon Rectum. 2014;57:407–11.
14. Korb ML, Huh WK, Boone JD, et al. Laparoscopic uorescent
visualization of the ureter with intravenous IRDye800CW.J Minim
Invasive Gynecol. 2015;22:799–806.
15. Al-Taher M, van den Bos J, Schols RM, etal. Evaluation of a novel
dye for near-infrared uorescence delineation of ureters during
laparoscopy. BJS Open. 2018;2:254–61.
16. Verbeek FP, van der Vorst JR, Tummers QR, etal. Near-infrared uorescence imaging of both colorectal cancer and ureters using a lowdose integrin targeted probe. Ann Surg Oncol. 2014;21:S528–37.
17. Dip FD, Nahmod M, Anzorena FS, et al. Novel technique for
identication of ureters using sodium uorescein. Surg Endosc.
2014;28:2730–3.
18. Meershoek P, KleinJan GH, van Oosterom MN, etal. Multispectral
uorescence imaging as a tool to separate healthy and diseaserelated lymphatic anatomies during robot-assisted laparoscopic
procedures. J Nucl Med. 2018;59:1757–60.
19. Portnoy E, Nizri E, Golenser J, et al. Imaging the urinary pathways in mice by liposomal indocyanine green. Nanomedicine.
2015;11:1057–64.
20. Friedman-Levi Y, Larush L, Diana M, etal. Optimization of liposomal indocyanine green for imaging of urinary pathways and a proof
of concept in a pig model. Surg Endosc. 2018;32:963–70.
21. Rowe CK, Franco FB, Barbosa JA, etal. A novel method of evaluating ureteropelvic junction obstruction: dynamic near infrared uorescence imaging compared to standard modalities to assess urinary
obstruction in a swine model.
22. Cha J, Nani RR, Luciano MP, etal. A chemically stable uorescent
marker of the ureter. Bioorg Med Chem Lett. 2018;28:2741–5.
23. Mahalingam SM, Dip F, Castillo M, et al. Intraoperative ureter
visualization using a novel near-infrared uorescent dye. Mol
Pharm. 2018;15:3442–7.
2007;178:2197–202.
23]
Imaging oftheParathyroid Gland
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AkihiroNakajo andYoshiakiShinden
29
Summary
• ICG uorescence imaging is useful for intraoperative
identication of small biological structures like parathyroid glands, although it can be interfered by nonspecic
uorescence signals.
• Since the discovery of autouorescence in parathyroid
glands in 2008, the usefulness of autouorescence imaging without using specic uorescent agents has been
widely reported.
• Autouorescence imaging of the parathyroid glands is a
highly sensitive technique that can be easily performed
using commercially available near-infrared imaging systems, and its widespread use is expected in the future.
1 Introduction
The parathyroid glands are endocrine organs that surround
the thyroid and usually consist of four glands. Each gland is
about the size of a grain of rice and secretes parathyroid hormones. Parathyroid hormones increase the calcium concentration in the blood by indirectly increasing calcium
absorption from the digestive tract and kidneys, in addition to
transferring calcium stored in the bones to the bloodstream.
Calcium metabolism is important for the human body,
and abnormalities in parathyroid gland function can cause a
variety of symptoms. For example, hyperparathyroidism is
associated with symptoms such as thirst, fatigue, and nausea
due to hypercalcemia and urinary tract stone disease. On the
other hand, if all of the parathyroid glands are removed dur-
Supplementary Information The online version contains supplementary
material available at
https://doi.org/10.1007/978- 981- 19- 7372- 7_29.
ing thyroid surgery or if they become dysfunctional due to
decreased blood ow, hypoparathyroidism occurs.
Hypoparathyroidism is characterized by numbness in the ngertips and lips due to hypocalcemia and tetany, a spasm of
the limbs. On the other hand, the function of the parathyroid
glands can often be restored by intramuscular autotransplantation of the removed parathyroid glands. In this sense, accurate intraoperative identication of parathyroid tissues is
very important for assuring the safety of thyroid and parathyroid surgery. For example, normal parathyroid glands must
be preserved in surgery for benign thyroid disease. In malignant thyroid disease, intramuscular autotransplantation of
parathyroid glands removed during lymph node dissection is
indicated whenever possible to avoid permanent postoperative hypoparathyroidism. In addition, in surgery for hyperparathyroidism, it is essential but often difcult to identify
relatively small parathyroid tissues for preservation.
Conventionally, the identication of parathyroid glands has
relied on the surgeon’s eye. Although experienced endocrine
surgeons have been able to identify most of the normal parathyroid glands and perform parathyroid preservation or autotransplantation, inexperienced surgeons often fail to detect
parathyroid glands. Even experienced surgeons may overlook
parathyroid glands buried in fatty tissue. In recent years, uorescence imaging has been clinically applied to accurately
identify parathyroid glands using uorescently labeled agents,
but there were some problems such as difculty in obtaining
sufcient contrast between the glands and surrounding tissues.
In 2008, the discovery that parathyroid glands have autouorescence led to the focus of attention on autouorescence
imaging, which could be a simple method to identify parathyroid glands without the use of uorescent labeling agents.
A. Nakajo (*) · Y. Shinden
Department of Digestive Surgery, Breast and Thyroid Surgery,
Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
e-mail: anakajo@m.kufm.kagoshima-u.ac.jp
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
T. Ishizawa (ed.), Fluorescence-Guided Surgery, https://doi.org/10.1007/978-981-19-7372-7_29
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2 Conventional Methods ofIdentifying
theParathyroid Glands
For intraoperative identication of parathyroid glands, uorescence imaging using uorescent dyes such as methylene
blue, 5-ALA, and ICG has been reported [1–5]. Although
methylene blue retains in adenomas and hyperplasia, it does
not accumulate in normal parathyroid glands, and its use has
been limited due to toxicity issues [6, 7]. Optical coherence
tomography, confocal reectance microscopy, and Raman
spectroscopy have been clinically applied to identify parathyroid glands without using uorescent dyes. Although these
methods showed some usefulness, they were not widely used
because of the complexity of imaging procedures [8–10].
3 Development History
ofAutouorescence Imaging
oftheParathyroid Glands
Around 2008, researchers at Vanderbilt University in the
USA discovered that parathyroid glands have endogenous
autouorescence in the near-infrared region [11]
Autouorescence refers to the spontaneous emission of
light that occurs when biological structures such as mitochondria and lysosomes absorb light and is distinct from
light emitted from articially added uorophores. They
found that the intensity of autouorescence of excited
parathyroid glands peaks at a wavelength in the infrared
region around 822 nm (Fig.29.1, upper left graph) and
succeeded in identifying parathyroid glands intraoperatively using a dedicated excitation device and an infrared
observation camera [12–14] This method is safe because it
does not require the administration of specic uorescent
dyes or contrast agents. In addition, autouorescence
imaging is innovative in that it is not susceptible to nonspecic accumulation, which remains a problem with uorescence imaging using uorescent dyes. Furthermore,
since the peak wavelength of parathyroid glands is similar
to that of ICG (around 810–830nm), autouorescence of
parathyroid glands can be easily detected with high sensitivity using near-infrared camera systems that are already
commercially available for ICG uorescence imaging
[15–17]. Thus, autouorescence imaging of parathyroid
glands has attracted wide attention and has been applied
clinically.
a
Fig. 29.1 (a–c) Discovery of autouorescence in parathyroid glands.
Intraoperative uorescence images of the parathyroid gland. (a) Brighteld image of parathyroid and thyroid from patient undergoing thyroid-
ectomy. (b) NIR uorescence image shows parathyroid in red. (c)
Bright-eld and uorescence images overlaid show parathyroid uorescence. (Adapted from McWade etal [12, 13])
1234
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4 Clinical Practice ofAutouorescence
Imaging ofParathyroid Glands
Since the autouorescence of parathyroid glands and the
uorescence spectrum of ICG are similar, a commercially
available near-infrared camera system that detects ICG uorescence can be used for this method without any modication. In this article, we introduce autouorescent imaging
using the PDE-neo®, a near-infrared imaging system for
open surgery.
First, the imaging parameters of PDE-neo® were set to the
following values: brightness, minimum; contrast, maximum;
excitation light, maximum; and imaging mode, uorescence
mapping mode.
a
For intraoperative real-time identication of the parathyroid
glands (in vivo imaging), a camera unit with a special sterile
cover is xed at a distance of 5–30cm from the observation
position, focused, all lights in the operating room are turned
off, and autouorescence is observed on a monitor. The location of the uorescing parathyroid gland is identied by turning
the surgical lights on and off several times to integrate uorescence images and visual inspection of surgical elds (Fig.29.2).
To identify the parathyroid glands in the removed thyroid
gland or fat tissues including lymph nodes (ex vivo imaging),
observation is performed using a shielding box on the operating table. When autotransplanting parathyroid glands in
thyroid cancer surgery, the removed tissue is observed in a
sterilized condition.
b
c
d
Fig. 29.2 (a–d) In vivo identication of the parathyroid gland using
the intrinsic uorescence method. Four parathyroid glands; upper right
(a), lower right (b), upper left (c) and lower left (d) from one patient are
shown. The rst column shows high-resolution pictures, and the second
column shows pictures taken with the PDE system under white light.
White arrows indicate the parathyroid glands. Under white light, some
tissues were difcult to identify as parathyroid tissue. In the third column, uorescent pictures are shown. Here, image qualities were
adjusted for printing. In the fourth column, merged images from the
second column and the third column are shown. All of these glands
were identied as parathyroid tissue pathologically. (Adapted from
Shinden etal. [16])
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A. Nakajo and Y. Shinden
Point
• Identication of parathyroid glands using autouorescence detected with PDE-neo®.
1. Intraoperative real-time identication (in vivo
imaging)
(i) Fluorescence mapping mode is used under the
following condition (brightness, minimum value;
contrast, maximum value; excitation light, maximum value).
(ii) Attach the sterile cover to the camera head, hold
the camera at a distance of approximately 5cm
from the observation position of the surgical
eld, and focus the camera.
(iii) Turn off all lights in the operating room, and
observe autouorescence on a monitor. The location of the parathyroid gland is determined by
integrating autouorescent images and visual
inspection of the operation eld.
(iv) Remove the identied parathyroid gland, turn off
the light, and conrm autouorescence signals.
2. Identication of parathyroid glands in the removed tis-
sues (ex vivo imaging)
(i) Observe uorescence signals on the resected
specimen, using a shielding box on the table outside the surgical eld.
(ii) When autotransplanting parathyroid glands in
thyroid cancer surgery, the removed tissue should
be kept sterilized.
Table 29.1 Autouorescence intensity and detection rate for each
tissue
Tissue
Parathyroid 3.53 (0.17~15.3) 100% (34/34)
Lymph
node
Fat 0.15 (0~2.1) 12% (2/17)
Thyroid 0.45 (0~3.71) 27% (3/11)
Adapted from Shinden etal. [16]
Mean value of uorescence
intensity
0.01 (0~2.0) 0.5% (1/198)
Fluorescent positive
rate
We measured the uorescence intensity of autouorescence in surgically removed parathyroid glands (n=34), thyroid glands (n = 11), lymph nodes (n= 198), and adipose
®
tissue (n=17) using PDE-neo
in our department. When the
cutoff value was set at a uorescence intensity that could
detect all of the excised parathyroid tissue, it was possible to
differentiate most lymph nodes and fat tissues (Table 29.1
and Fig. 29.3). Autouorescence was also found in about
30% of the thyroid glands, but in the setting of invivo imaging, autouorescence of parathyroid could be discriminated
from that of the thyroid. This demonstrates that PDE-neo
autouorescence imaging is clinically applicable, simple,
and extremely useful for intraoperative parathyroid identication (Movie 29.1).
®
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215
a
b
c
Fig. 29.3 (a–c) Autouorescence intensity of parathyroid glands and
neighboring tissue (ex vivo imaging by PDE-neo
vivo measurement of the resected parathyroid gland. Pictures of parathyroid glands and other tissues with the PDE system taken under
white light (a) and excitation light (c) are shown. Fluorescence of the
parathyroid gland can be seen as green light (c, white arrow), and it
®
). An example of ex
5 Expected Eects ofAutouorescence
Imaging oftheParathyroid Glands
Autouorescence imaging of the parathyroid glands is most
valuable in identifying small, difcult-to-detect parathyroid
glands. Specically, autouorescence imaging of the parathyroid glands is useful in the search for small responsible
lesions in primary hyperparathyroidism, ectopic parathyroid
lesions, and normal parathyroid glands in thyroid cancer surgery (autotransplantation). In particular, if the detection rate
of small normal parathyroid glands is increased, the frequency of postoperative permanent hypoparathyroidism may
be signicantly reduced. Autouorescence imaging does not
require any specic uorescence labeling agent or contrast
medium and is therefore nontoxic and easy to perform. The
detection rate of parathyroid by autouorescence imaging
was reported to be higher than that by ICG uorescence
imaging [18].
was identied as normal parathyroid tissue pathologically. The scheme
of each tissue was shown in (b). The dotted white arrow in a indicated
fat tissue which was identied as parathyroid by surgeon. However, it
had no uorescence and it was revealed to be fat tissue after peeling
surrounding tissue. (Adapted from Shinden etal. [16])
6 Pitfalls andLimitations
This method is characterized by low nonspecic background
uorescence and contrast with surrounding tissues such as
the thyroid gland, but there are some points to be noted. First
of all, it may be difcult to identify the parathyroid glands in
patients with strong autouorescence in the thyroid gland.
Fluorescence signals are rarely detected in fat tissues, but it
may lead to misidentication. Some surgical sutures (e.g.,
Vicryl®) also show strong autouorescence signals.
Application to endoscopic surgery remains a problem.
Although it has been reported that autouorescence imaging
could be used with the KARL STORZ endoscopic surgery
system [19], our experience is that the current surgical endoscopic systems available for near-infrared uorescence
imaging do not have the high detection rate as achieved in
the use of open surgical imaging systems. In the future, it
will be necessary to optimize the imaging conditions (excita-
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