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Fig. 15.7 Selection of bronchi to be marked using virtual bronchoscopy software
T. F. Chen-Yoshikawa
Fig. 15.8 The bronchoscopic spreading tube and preparation of dye (ICG+radiographic contrast agent) for injection
15 Lung Cancer (Marking theTumor Site)
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Fig. 15.9 X-ray uoroscopy after dye (ICG+ radiographic contrast agent) injection. Because ICG is injected with a mixture of radiographic
contrast material, the injection site can be clearly identied on radiography
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marking impossible. In other words, marking can be
completed with a smaller amount of dye than with conventional VAL-MAP.The injection is terminated when
the dye is visible on uoroscopy, followed by air injection with a 10cc syringe as with VAL-MAP.These procedures are repeated for the required number of
markings.
(ii) CT is taken to conrm the marked area. In some cases,
CT images are obtained in the same position as the
intraoperative position so that the 3D-CT reconstruction image is more consistent with the intraoperative
ndings. Figure 15.10 shows an example of how the
lung lesion with or without dye (ICG +radiographic
contrast agent or indigo carmine) is demonstrated in the
post-marking CT.
(iii) 3D-reconstructed CT images are created with a work-
station to understand the spatial positional relationships
between the marking site and the tumor before surgery
(Fig.15.11).
(iv) Surgical resection is performed based on the intraopera-
tive images of the surgical eld, guided by the
3D- reconstructed images (Movie 15.1).
In VAL-MAP, more than two markings have been performed in case of failure in identifying the target lesion. In
contrast, the success rate of ICG-VAL-MAP has been
improved, leading to reducing the total number of markings
required.
Point
• The amount of ICG injected should be minimum for
avoiding diffusion of uorescence signals.
• Thanks to the high sensitivity of ICG-VAL-MAP, the total
number of markings can be reduced as compared with
conventional VAL-MAP.
• The secret of successful marking is adequate planning
before the procedure, which is the same for both VAL-
MAP and ICG-VAL-MAP.
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Nodular peripheral lung lesion in right S1
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T. F. Chen-Yoshikawa
a
b
c
Fig. 15.10 CT images after marking in the case of a combination of VAL-MAP with indigo carmine and ICG-VAL-MAP with ICG and contrast
agent. (a) VAL-MAP (indigo carmine). (b) Plain CT identifying peripheral lung lesion in right S1. (c) ICG-VAL-MAP (ICG+contrast agent)
Indigocarmine
ICG
Fig. 15.11 Preoperative 3D-reconstructed CT images
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5 Expected Eects ofFluorescence
Imaging
ICG-VAL-MAP improves the visibility of pulmonary
lesions, which is a weak point of conventional VAL-MAP, by
using ICG for sensitive uorescence imaging (Fig.15.12 and
Movie 15.2). At present, ICG-VAL-MAP needs the bron-
abc
choscopy technique, but it will play a signicant role in
marking where surgeons want to mark in a less invasive manner in comparison with a conventional percutaneous marking. Future development of cancer-specic uorophores
enables intraoperative navigation of cancerous tissues in the
true sense.
Fig. 15.12 Visibility in ICG-VAL-MAP.Sufcient visibility of the lesion at the time of marking (a), CT after marking (b), and during surgery (c)
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T. F. Chen-Yoshikawa
6 Limitations andChallenges
ofICG-VAL-MAP
Although VAL-MAP is covered by the national insurance
system in Japan, it should be noted that the bronchial administration of ICG and radiographic contrast media is not
approved and should be performed as a clinical trial at present. It should also be noted that this technique is basically
contraindicated in patients who are allergic to ICG/contrast
media or asthmatic, although there have been no reports of
serious complications with ICG-VAL-MAP so far.
7 Conclusions
The ICG-VAL-MAP was developed as a tool for pulmonary
surgeons to perform diagnostic resections of peripheral
microlesions accurately. Currently, this technique can be used
not only for the identication of micropulmonary nodular
lesions but also to mark intersegmental boundaries of the lung
(Movie 15.3). In addition, by combining different dyes such
as indigo carmine and ICG in case of marking failures, more
accurate identication of the lesions can be performed.
References
1. Oikawa T, Nomoto Y, Kinoshita K. A case of residual left hemiparesis due to cerebral air embolization during CT-guided marking of a small peripheral lung cancer. J JPN Assoc Chest Surg.
2008;22:914–9.
2. Matsuura Y, Watari M. Two cases of intracardiac air emboli
after CT-guided pulmonary puncture. J JPN Assoc Chest Surg.
2010;24:967–71.
3. Chen F, Tatsumi A.Clinical study of preoperative CT-guided marking of peripheral mass lesions in the lung eld. J JPN Assoc Chest
Surg. 2001;15:87–91.
4. Sato M, Omasa M, Chen F, et al. Use of virtual assisted lung
mapping (VAL-MAP), a bronchoscopic multispot dye-marking
technique using virtual images, for precise navigation of thoracoscopic sublobar lung resection. J Thorac Cardiovasc Surg.
2014;147:1813–9.
5. Sato M, Yamada T, Menju T, et al. Virtual-assisted lung mapping: outcome of 100 consecutive cases in a single institute. Eur J
Cardiothorac Surg. 2015;47:e131–9.
6. Kasai Y, Tarumi S, Chang SS, etal. Clinical trial of new methods
for identifying lung intersegmental borders using infrared thoracoscopy with indocyanine green: comparative analysis of 2- and
1-wavelength methods. Eur J Cardiothorac Surg. 2013;44:1103–7.
7. Okusanya OT, Hess NR, Luketich JD, etal. Infrared intraoperative
uorescence imaging using indocyanine green in thoracic surgery.
Eur J Cardiothorac Surg. 2018;53:512–8.
8. Rho J, Lee JW, Quan YH, etal. Fluorescent and iodized emulsion
for preoperative localization of pulmonary nodules. Ann Surg.
2019. [Epub ahead of print].
9. Chen-Yoshikawa TF, Hatano E, Yoshizawa A, etal. Clinical application of projection mapping technology for surgical resection of
lung metastasis. Interact Cardiovasc Thorac Surg. 2017;25:1010–1.
10. Hamaji M, Chen-Yoshikawa TF, Minami M, etal. Near-infrared
imaging using intravenous indocyanine green at a conventional dose
to locate pulmonary metastases: a pilot study. Thorac Cardiovasc
Surg. 2019;67:688–91.
11. Sekine Y, Itoh T, Toyoda T, etal. Precise anatomical sublobar resection using a 3D medical image analyzer and uorescence-guided
surgery with transbronchial instillation of indocyanine green.
Semin Thorac Cardiovasc Surg. 2019;31:595–602.
Gastric Cancer (Primary Tumor,
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Peritoneal Dissemination)
TsuyoshiTakahashi, YukinoriKurokawa,
MakotoYamasaki, HidetoshiEguchi, andYuichiroDoki
16
Summary
• Photodynamic diagnosis using 5-aminolevulinic acid
(5-ALA), a natural amino acid, has been applied clinically in the case of brain tumors and bladder cancer.
• We are investigating the possibility of this technique for
intraoperative diagnosis of peritoneal dissemination of
gastric cancer.
1 Introduction
Peritoneal dissemination as well as hematogenous and lymphatic metastasis is an important clinical factor in the treatment of gastrointestinal cancers. In particular, tiny nodules of
peritoneal metastasis are difcult to detect with current diagnostic imaging modalities such as CT and MRI.Therefore,
staging laparoscopy is often indicated prior to making a decision for the treatment strategy in cases of advanced gastric
cancer and pancreatic cancer with a high risk of peritoneal
dissemination [1]. While staging laparoscopy is minimally
invasive and has a high positive diagnosis rate of 89–100%,
the insufcient false-negative rate (5–17.2%) [2–4] remains a
problem in this strategy. We need a higher sensitive diagnostic method for peritoneal dissemination.
2 Current Status ofPhotodynamic
Diagnosis Using
5-AminolevulinicAcid
5-aminolevulinic acid (5-ALA), a natural amino acid, plays
an important role in energy metabolism as a precursor of
heme. 5-ALA is taken up by cells and metabolized into protoporphyrin IX (Pp IX), which is translocated into mitochondria (Fig.16.1). In normal cells, Pp IX is rapidly metabolized
to heme. In cancer cells, however, Pp IX is not converted to
heme due to the lack of divalent iron, accumulating specically in the cells [5]. In cancer cells, the expression of PEPT1,
a transporter for 5-ALA uptake, is increased and the expression of ABCG2, a transporter for Pp IX efux, is decreased,
which would be the mechanistic background of Pp IX accumulation in cancer cells [6]. In addition, it has been reported
that the increased activity of porphobilinogen deaminase
promotes the synthesis of Pp IX [7] and the decreased activity of ferrochelatase inhibits the metabolism of Pp IX [8],
resulting in the accumulation of Pp IX in cancer cells. As a
photosensitizer, Pp IX is excited by blue light (400–410nm)
and emits red uorescence when it returns to the ground
state. These properties of 5-ALA enable photodynamic diagnosis of cancer cells [9].
T. Takahashi (*)
Medical Education Center, Osaka University School of Medicine,
Suita, Osaka, Japan
Department of Gastroenterological Surgery, Osaka University
Graduate School of Medicine, Suita, Osaka, Japan
e-mail: ttakahashi2@gesurg.med.osaka-u.ac.jp
Y. Kurokawa · M. Yamasaki · H. Eguchi · Y. Doki
Department of Gastroenterological Surgery, Osaka University
Graduate School of Medicine, Suita, Osaka, Japan
© 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_16
111
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T. Takahashi et al.
5-ALA
cancer cell
cell membrane
blue light
PEPT1
protoporphyrin IX
Porphobilinogen
deaminase
ABCG2
red fluorescence
2+
Fe
Ferrochelatase
heme
mitochondria
Fig. 16.1 Mechanism of photodynamic diagnosis using 5-ALA.Pp IX shows red uorescence under blue light illumination
3 Diagnosis ofPeritoneal
Dissemination ofGastric Cancer
5 Clinical Application inOur
Department
Using 5-Aminolevulinic Acid
In December 2013, we started a clinical trial of photodyAs an application of photodynamic diagnosis using 5-ALA
to gastric cancer, Kishi etal. conducted a clinical trial using
this technique for screening laparoscopy in 52 patients with
advanced gastric cancer. Among 24 cases in which peritoneal dissemination was not detected by white light, photodynamic diagnosis using 5-ALA detected peritoneal
dissemination in ve cases (20.8%). The authors concluded
that this diagnostic method was effective in increasing the
detection sensitivity of peritoneal dissemination from gastric cancer [9].
4 Safety of5-Aminolevulinic Acid
5-aminolevulinic acid is a naturally occurring amino acid
and is relatively safe. Possible adverse reactions include
photosensitivity, hypotension, gastrointestinal symptoms,
and hepatic dysfunction. Inoue et al. [10] reported
increases in LDH (16.2%), AST (16.2%), ALT (16.2%), γ
GTP (5.4%), blood bilirubin (2.7%), amylase (10.8%),
eosinophils (2.7%), nausea (10.8%), vomiting (8.1%),
treatment-induced vomiting (2.7%), and headache (2.7%),
and that the severity of these adverse events was mild in
all cases.
namic diagnosis for advanced gastric cancer patients under-
going screening laparoscopy with the following protocol.
Methods: 5-ALA (1g) is administered 3–5hours prior to
the start of the laparoscopy. After the administration of
5-ALA, long sleeves, long pants, and sunglasses should be
worn to prevent adverse effects due to photosensitivity, and
the patient should be shielded from strong light such as sunlight for 48hours. The examination equipment used is the
D-LIGHT system (KARL STORZ: D-LIGHT C PDD light
source, IMAGE1-S system camera control unit, IMAGE1S- FI camera head, HOPKINS® II telescope 30°). In this system, it is possible to easily switch between normal light and
blue light using a foot switch.
Laparoscopy procedures: Evaluation with white light is
followed by switching to blue light to search for areas with
red uorescence. The white nodule or the area with red uorescence under blue light is biopsied and conrmed by
pathology. If the observation time is prolonged, it becomes
difcult to evaluate red uorescence due to photo breaching;
therefore, priority should be given to lesions that cannot be
conrmed by white light.
Pathological examination: Pathological diagnosis was
made on formalin-xed specimens because foci of peritoneal
dissemination were often too small for intraoperative rapid
diagnosis.
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Case presentation: In the case of a 50-year-old man, upper
gastrointestinal endoscopy was indicated for anorexia and
revealed type 3 advanced gastric cancer in the anal part of the
gastric body. Abdominal CT identied extraserosal cancer
invasion, suggesting peritoneal dissemination. Therefore, we
decided to perform a staging laparoscopy. Nodules with red
uorescence on photodynamic diagnosis were found in the
pouch of Douglas and below the left diaphragm (Fig.16.2).
Biopsy specimens obtained from these lesions were pathologically diagnosed as peritoneal dissemination of gastric
cancer. Red uorescence was also observed in the primary
lesion of the stomach, where cancer tissues were exposed on
the gastric serosa (Fig.16.3).
a b
Point
• In photodynamic diagnosis during staging laparoscopy
for gastric cancer, 5-ALA (20 mg/kg) is administered
3–5hours before laparoscopy.
• Both white-light color imaging and blue light observation
shall be conducted.
• Observation of the abdominal cavity should be completed
quickly to avoid photo breaching of uorescence signal.
• 5-aminolevulinic acid photodynamic diagnosis may be
useful for the discrimination of malignancy in visible
peritoneal nodules and for the detection of new lesions
with cancer cells.
c d
Fig. 16.2 Images in staging laparoscopy. (a) White-light color imaging of the right subdiaphragmatic eld. (b) Fluorescence imaging of the right
subdiaphragmatic eld. (c) White-light color imaging of the pouch of Douglas. (d) Fluorescence imaging of the pouch of Douglas
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a b
Fig. 16.3 Images of primary lesion of gastric cancer. (a) White-light color imaging of the primary lesion. (b) Fluorescence imaging of the primary
lesion
T. Takahashi et al.
6 Clinical Signicance
of5-Aminolevulinic Acid-Positive
Peritoneal Dissemination
Ushimaru etal. reported that, among 113 patients undergoing staging laparoscopy for advanced gastric cancer, 13
patients had microscopic peritoneal dissemination, which
could be detected only by 5-ALA photodynamic diagnosis
[11]. They reported that the three-year survival rate of these
patients was equivalent to that of patients diagnosed with no
peritoneal dissemination, probably because of multidisciplinary treatments including chemotherapy enabled by
5-ALA photodynamic diagnosis.
As a result of recent advances in chemotherapy, there
have been many reports of successful conversion surgery
after conrmation of peritoneal dissemination and
chemotherapy. Kishi etal. reported the usefulness of 5-ALA
photodynamic diagnosis for the detection of peritoneal dissemination at the time when an indication of curative surgery
was evaluated after chemotherapy [12]. In our clinical study,
we also experienced a case in which the presence or absence
of viable cells after chemotherapy could be determined accurately by photodynamic diagnosis (Fig.16.4).
16 Gastric Cancer (Primary Tumor, Peritoneal Dissemination)
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a
b
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Fig. 16.4 Staging laparoscopy after chemotherapy. (a) White-light
color imaging (left) and uorescence imaging (right) of the left subdiaphragmatic eld. White nodules are identied without red uorescence
signals in photodynamic diagnosis. They were all negative for viable
cancer cells in postoperative pathological evaluations. (b) White-light
7 Toward theSpread ofClinical
Applications inGastric Cancer
Surgery
We have been conducting investigator-initiated clinical trials
to expand the insurance coverage of 5-ALA in Japan. In the
exploratory study, the safety, efcacy, and optimal dosage
were demonstrated. Furthermore, in 2017, we conducted a
multi-center phase III validation study consisting of 105
patients with gastric cancer, with “the number of subjects
who are negative for peritoneal dissemination by normal
light observation and can be diagnosed correctly by photodynamic diagnosis” as the primary endpoint, taking into
account the clinical signicance for patients. We are currently analyzing the outcomes.
color imaging (left) and uorescence imaging (right) of the left subdiaphragmatic eld. The visible white nodule has a partial red uorescence
signal of 5-ALA.Pathological examination of biopsied specimen was
positive for viable cancer cells
8 Conclusions
The combined use of photodynamic diagnosis using 5-ALA
may increase the sensitivity of detection of peritoneal dissemination of gastric cancer during staging laparoscopy and
enable the planning of an appropriate treatment strategy.
References
1. Stell DA, Carter CR, Stewart I, etal. Prospective comparison of
laparoscopy, ultrasonography and computed tomography in staging
gastric cancer. Br J Surg. 1996;83:1260–2.
2. Tsuchida K, Yoshikawa T, Tsuburaya A, etal. Indications for staging laparoscopy in clinical T4M0 gastric cancer. World J Surg.
2011;35:2703–9.
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