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Column 2: Establishment and Activities of the International Society for Fluorescence Guided Surgery (ISFGS)

Part III Intraoperative Fluorescence Imaging [Practice] – Imaging of Cancer

14 Liver Cancer (Primary Liver Cancer, Metastatic Liver Cancer) . . . . . . . . . . . . . . 93

Yoshiharu Kono, Takeaki Ishizawa, and Kiyoshi Hasegawa

15 Lung Cancer (Marking the Tumor Site) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Toyofumi Fengshi Chen-Yoshikawa

16 Gastric Cancer (Primary Tumor, Peritoneal Dissemination) . . . . . . . . . . . . . . . . . 111

Tsuyoshi Takahashi, Yukinori Kurokawa, Makoto Yamasaki, Hidetoshi Eguchi, and Yuichiro Doki

17 Brain Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Toshihiko Kuroiwa

18 Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Keiji Inoue, Hideo Fukuhara, and Shinkuro Yamamoto

Part IV Intraoperative Fluorescence Imaging [Practice] –

Imaging of Lymph Nodes and Lymph Vessels

Contents

19 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

Masashi Yoshida

20 Identification of Sentinel Lymph Nodes in Breast Cancer Surgery . . . . . . . . . . . . 139

Manami Tada and Tomoharu Sugie

21 Identification of Sentinel Lymph Nodes in Gastric Cancer Surgery . . . . . . . . . . . 145

Shinichi Kinami

22 Identification of Sentinel Lymph Nodes in Colorectal Cancer Surgery. . . . . . . . . 153

Hironori Odaira, Masashi Yoshida, and Yutaka Suzuki

23 Identification of Sentinel Lymph Nodes in Gynecologic Surgery . . . . . . . . . . . . . . 159

Kensuke Sakai, Wataru Yamagami, Nobuyuki Susumu, and Daisuke Aoki

24 Lymphography and Evaluation of Lymphedema . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Takumi Yamamoto

Part V Intraoperative Fluorescence Imaging [Practice] – Imaging of Anatomical

Structures

25 Imaging of the Bile Ducts (Fluorescence Cholangiography) . . . . . . . . . . . . . . . . . . 175

Kazuhiro Matsuda, Takeshi Aoki, and Tomokazu Kusano

26 Hepatic Segmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Takeshi Aoki and Kazuhiro Matsuda

27 Lung Segmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .195

Yasuo Sekine

28 Visualization of the Ureter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Toshihiko Nishidate, Koichi Okuya, Kenji Okita, and Ichiro Takemasa

29 Imaging of the Parathyroid Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .211

Akihiro Nakajo and Yoshiaki Shinden

Contents

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Part VI Intraoperative Fluorescence Imaging in Practice [Development]

30 Development of Novel Fluorescent Probes: Rapid Intraoperative

Visualization of Microcarcinoma by Local Application of

Chemical Fluorescence Probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219

Yasuteru Urano

31 Development of a New Imaging System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Satoru Seo and Etsuro Hatano

32 Development of a New Operating Room That Integrates Imaging

Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

Shunsuke Tsuzuki, Jun Okamoto, Manabu Tamura, Ken Masamune, and Yoshihiro Muragaki

33 Therapeutic Applications: Photodynamic Therapy Using

Porphyrin Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

Takeomi Hamada and Atsushi Nanashima

34 Application to Therapy (2): Photoimmunotherapy Using a Near- Infrared

Fluorescent Probe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .253

Yutaka Tamura, Akiko Suganami, and Yoshiharu Okamoto

Afterword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

Editors and Contributors

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Supervised

Japanese Society for Fluorescence Guided Surgery, Tokyo, Japan

Editor

Takeaki Ishizawa Department of Hepatobiliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan

Japanese Society for Fluorescence Guided Surgery (JSFGS), Tokyo, Japan

Contributors

DaisukeAoki Department of Obstetrics & Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

TakeshiAoki Division of Gastroenterological and General Surgery, Department of Surgery, School of Medicine, Showa University, Tokyo, Japan

TohruAsai Department of Cardiovascular Surgery, Juntendo University, Bunkyo-ku, Tokyo, Japan

Hironobu Baba Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

Toyofumi Fengshi Chen-Yoshikawa Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

Yuichiro Doki

School of Medicine, Suita, Osaka, Japan

Hidetoshi Eguchi Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

HideoFukuhara Department of Urology, Kochi Medical School, Nankoku-shi, Kochi, Japan

Center for Photodynamic Medicine, Kochi Medical School, Nankoku-shi, Kochi, Japan

Takeomi Hamada Division of Hepato-biliary-pancreas Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

Kazuhiro Hanazaki Department of Surgery, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

Center for Photodynamic Medicine, Kochi Medical School, Nankoku, Kochi, Japan

Department of Gastroenterological Surgery, Osaka University Graduate

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HiroHasegawa Department of Colorectal Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

KiyoshiHasegawa Department of Hepatobiliary and Pancreatic Surgery, Articial Organ and Transplantation Surgery, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

Etsuro Hatano Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

Itaru Higuchi Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan

KeijiInoue Department of Urology, Kochi Medical School, Nankoku-shi, Kochi, Japan

Center for Photodynamic Medicine, Kochi Medical School, Nankoku-shi, Kochi, Japan

Masaaki Ito Department of Colorectal Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

MasakiKaibori Department of Surgery, Kansai Medical University, Hirakata, Osaka, Japan

ShinichiKinami Department of Surgical Oncology, Kanazawa Medical University, Kahoku,

Ishikawa, Japan

Yusuke Kinugasa Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

Editors and Contributors

KazuoKishi Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan

NorihiroKokudo National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan

Japanese Society for Fluorescence Guided Surgery (JSFGS), Tokyo, Japan

YoshiharuKono Department of Hepatobiliary and Pancreatic Surgery, Articial Organ and Transplantation Surgery, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

Kazuo Koyanagi Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan

Koshi Kumagai Division of Gastric Surgery, Department of Gastroenterological Surgery, The Cancer Institute Hospital of JFCR, Koto, Tokyo, Japan

ToshihikoKuroiwa Tesseikai Neurosurgical Hospital, Shijonawate, Osaka, Japan

YukinoriKurokawa Department of Gastroenterological Surgery, Osaka University Graduate

School of Medicine, Suita, Osaka, Japan

MitsuoKusano Yoichi Hospital, Hokkaido Social Work Association, Yoichi, Japan

Kushiro Rosai Hospital, Kushiro, Hokkaido, Japan

Tomokazu Kusano Division of Gastroenterological and General Surgery, Department of Surgery, School of Medicine, Showa University, Tokyo, Japan

Ken Masamune Faculty of Advanced Techno Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan

FumihiroMatano Department of Neurological Surgery, Nippon Medical School, Bunkyo, Tokyo, Japan

Kazuhiro Matsuda Division of Gastroenterological and General Surgery, Department of Surgery, School of Medicine, Showa University, Tokyo, Japan

KosukeMatsui Department of Surgery, Kansai Medical University, Hirakata, Osaka, Japan

Editors and Contributors

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AkioMorita Department of Neurological Surgery, Nippon Medical School, Bunkyo, Tokyo, Japan

Yoshihiro Muragaki Faculty of Advanced Techno Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan

YasuoMurai Department of Neurological Surgery, Nippon Medical School, Bunkyo, Tokyo, Japan

AkihiroNakajo Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

Tsutomu Namikawa Department of Surgery, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

Center for Photodynamic Medicine, Kochi Medical School, Nankoku, Kochi, Japan

Atsushi Nanashima Division of Hepato-biliary-pancreas Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

Yamato Ninomiya Department of Gastroenterological Surgery, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan

ToshihikoNishidate Department of Surgery and Gastroenterological surgery, Muroran City General Hospital, Muroran, Hokkaido, Japan

Hironori Odaira Department of Gastroenterological Surgery, International University of Health and Welfare Hospital, Nasushiobara-Shi, Tochigi-Ken, Japan

Toshiro Ogura Department of Gastrointestinal Surgery, Saitama Cancer Center, Ina, Kitaadachi District, Saitama, Japan

KeisukeOkabe Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan

JunOkamoto Faculty of Advanced Techno Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan

Yoshiharu Okamoto Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, Tottori, Japan

Kenji Okita Department of Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido, Japan

KoichiOkuya Department of Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido, Japan

SojiOzawa Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan

KensukeSakai Department of Obstetrics & Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

YasuoSekine Department of General Thoracic Surgery, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan

SatoruSeo Department of Surgery, Kochi Medical School, Nankoku, Kochi, Japan

YoshiakiShinden Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima

University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

Akiko Suganami Department of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba, Japan

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Tomoharu Sugie Department of Breast Surgery, Kansai Medical University Hospital, Hirakata, Osaka, Japan

NobuyukiSusumu Department of Obstetrics and Gynecology, International University of Health and Welfare, Narita, Chiba, Japan

Yutaka Suzuki Department of Gastroenterological Surgery, International University of Health and Welfare Hospital, Nasushiobara-Shi, Tochigi-Ken, Japan

ManamiTada Department of Breast Surgery, Kansai Medical University Hospital, Hirakata, Osaka, Japan

Tsuyoshi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

IchiroTakemasa Department of Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido, Japan

Editors and Contributors

NobuyukiTakemura

Hepato-Biliary Pancreatic Surgery Division, Department of Surgery,

National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan

Manabu Tamura Faculty of Advanced Techno Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan

Yutaka Tamura Department of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba, Japan

MinoruTanabe Department of Surgery, Kochi Medical School, Nankoku, Kochi, Japan

Center for Photodynamic Medicine, Kochi Medical School, Nankoku, Kochi, Japan

MasakazuToi Professor, Breast Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

Japanese Society for Fluorescence Guided Surgery (JSFGS), Tokyo, Japan

YuichiroTsukada Department of Colorectal Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

ShunsukeTsuzuki Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan

Faculty of Advanced Techno Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan

SunaoUemura Department of Surgery, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

Yasuteru Urano Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

ShuichiWatanabe Department of Hepatobiliary and Pancreatic Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

Wataru Yamagami Department of Obstetrics & Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

Miho Yamamoto Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan

ShinkuroYamamoto Department of Urology, Kochi Medical School, Nankoku-shi, Kochi, Japan

Editors and Contributors

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TakumiYamamoto Department of Plastic and Reconstructive Surgery, National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan

MakotoYamasaki Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Kentaro Yatabe Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan

Masashi Yoshida Department of Surgery, International University of Health and Welfare Hospital, Nasushiobara, Tochigi, Japan

Part I

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Basics of Intraoperative Fluorescence Imaging

[Introduction]

Takeak iIshizawa

Intraoperative uorescence imaging requires a “uorescent reagent” and an “imaging device (light source and camera)” that matches the wavelength of the reagent. In the current clinical settings, indocyanine green (ICG) and 5-aminolevulinic acid (5-ALA) are mainly used as the uorescent reagents for various applications of intraoperative uorescence imaging. Imaging devices are broadly classied into those for open surgery, those for endoscopic surgery (laparoscopy and thoracoscopy), and those for microscopic surgery, and the method of displaying uorescent images and image resolution differ depending on the product. In order to utilize uorescence imaging in the operating room, it is necessary to fully understand the features of uorescent reagents and imaging devices. In addition, it will be increasingly important to create appropriate operative records and to store them with the videos in order to evaluate and report the efcacy of uorescence imaging after surgery.

Clinically Available Fluorescent

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Reagents

KosukeMatsui andMasakiKaibori

Summary

1 Introduction

• Indocyanine green (ICG) and 5-aminolevulinic acid

(5-ALA) are typical uorescent reagents approved by the

pharmaceutical affairs bodies in Japan.

• Fluorescence imaging can be used for (1) angiography

and evaluation of blood ow, (2) lymph node mapping

and lymphography, (3) visualization of anatomical struc-

tures, and (4) cancer localization.

In recent years, intraoperative uorescence imaging has been clinically applied to identify the extent of cancer spread and anatomical structures in real time using uorescent probes. In Japan, indocyanine green (ICG), 5-aminolevulinic acid (5-ALA, a precursor of porphyrin), and uorescein have been approved by the pharmaceutical affairs bodies for clinical use, although their indications are still limited (Table1.1). In this chapter, we will focus on the characteristics of ICG and 5-ALA for practical use in clinical situations.

Table 1.1

Product Indocyanine green(ICG) Dosage form Lyophilized products Lyophilized products or granule Aqueous injection Maximum (maximal)

Absorption wavelength, excitation wavelength Maximum (maximal) wavelength of uorescence Characteristics of uorescent Excited by infrared light

Characteristics of uorescent agents approved in Japan

805nm 375~445nm

835nm (near-infrared uorescence)

(maximum absorption wavelength is around 805nm) and emits uorescence (maximum uorescence wavelength is around 835nm)

5-aminolevulinic acid (5-ALA) Fluorescein

(blue light)

600~740nm (red uorescence) Exogenously administered 5-ALA is synthesized from glycine and succinyl CoA invivo, metabolized to protoporphyrin IX (PP IX) in the process of biosynthesis from 5-ALA to heme, and selectively accumulated in tumor cells. PP IX is a photosensitizer and emits red uorescence when excited by blue light (400–410nm).

494nm

521nm (visible light region: Green) Represents strong green uorescence under alkaline conditions

K. Matsui (*) · M. Kaibori Department of Surgery, Kansai Medical University, Hirakata, Osaka, Japan e-mail: matsuik@hirakata.kmu.ac.jp

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K. Matsui and M. Kaibori

2 Indocyanine Green

2.1 Indications (Insurance Coverage)

The insurance coverage of ICG in Japan has been limited to (1) liver function tests (plasma loss rate, blood stagnation rate, and hepatic blood ow measurement); (2) circulatory function tests (cardiac output, mean circulatory time, or abnormal blood ow measurement); (3) cerebral angiography during neurosurgery (by uorescence measurement during infrared irradiation); and (4) identication of sentinel lymph nodes in breast cancer and malignant melanoma. In the 2018 revision of the medical fee system, intraoperative monitoring of blood ow (by measuring uorescence during infrared irradiation) was approved. In the revision of medical fees in 2020, an additional fee can be calculated when intraoperative uorescence imaging is used for the identication of tumors, blood vessels, and gastrointestinal perfusion with ICG or aminolevulinic acid hydrochloride.

2.2 Dosage andAdministration

2.2.1 Liver Function Test

• For plasma disappearance rate measurement and blood

stagnation rate measurement

In the case of cerebral angiography during neurosurgery, 25mg of ICG is dissolved in 5mL of water for injection, and the usual dose is 0.1–0.3mg/kg administered intravenously.

2.2.4 Identication ofSentinel Lymph Node

In the identication of sentinel lymph nodes in breast cancer, 25mg of ICG is dissolved in 5mL of water for injection, and 5 mL or less is usually administered in the vicinity of the malignant tumor or subcutaneously in the nipple area in divided doses as appropriate. In the identication of sentinel lymph nodes in malignant melanoma, 25mg of ICG is dissolved in 5mL of water for injection, and 1mL is usually administered in several intradermal locations near the malignant tumor in divided doses as appropriate.

Point

• Fluorescence imaging using indocyanine green for identication of liver cancer

In our center, the ICG retention rate at 15minutes (ICG

R15) is routinely measured by injecting ICG at a dose of

0.5 mg/kg for the estimation of liver function [1, 2]. For

intraoperative identication of liver cancer, the ICG that was administered for measurement of ICGR15 can also be used as a uorescent source, if patients underwent the liver function test within 14days before surgery.

A dose equivalent to 0.5mg of ICG per kilogram of body weight is diluted to about 5mg/mL with water for injection and gradually administered intravenously through the elbow vein within 30seconds while paying attention to symptoms.

• For hepatic blood ow measurement

Dissolve 25mg of ICG in as little water as possible for injection, dilute to a concentration of 2.5–5 mg/mL with saline solution, and administer the above solution equivalent to 3mg of ICG intravenously. Thereafter, the drug is administered intravenously at a constant rate of 0.27–0.49mg/min for about 50minutes until blood sampling is completed.

2.2.2 Circulatory Function Test

Depending on the purpose, ICG is injected into various vascular sites from the intracardiac cavity to the peripheral veins, usually through the forearm vein. The dose per adult is 5–10mg of ICG, or about 1–2mL, and the dose for children is reduced according to their body weight.

2.2.3 Evaluation ofBlood Flow inBlood Vessels

andTissues

Indocyanine green is dissolved in 5–10 mL of water for injection at a dose of 25mg and administered intravenously at a dose of 0.04–0.3mg/kg, depending on the intended use.

3 5-Aminolevulinic Acid

3.1 Indications (Insurance Coverage)

5-aminolevulinic acid, a precursor of porphyrin, is a naturally occurring amino acid in the body and a precursor of heme. In cancer cells, an increase in porphobilinogen deaminase activity and a decrease in ferrochelatase activity cause intracellular accumulation of protoporphyrin IX (PpIX), which emits red uorescence with a peak at 635nm upon excitation with 405nm blue-violet light (Table1.1). 5-ALA has been clinically applied as a photosensitizer in photodynamic diagnosis using this mechanism, and is covered by insurance in Japan for “visualization of tumor tissue during tumor resection of malignant glioma” in neurosurgery and “visualization of non-muscle layer invasive bladder cancer during transurethral resection of bladder tumor” in urological surgery.

3.2 Dosage andAdministration

The usual adult dose of 20 mg/kg of aminolevulinic acid hydrochloride dissolved in water is orally administered 3 hours (range: 2–4hours) before induction of anesthesia during surgery.

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