Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3721_Библиотеки_им_академика_М_И_Перельмана
.pdf
Aryl or alkyl compounds
a
b
Wavelength (nm)
+-
a
30 Development of Novel Fluorescent Probes: Rapid Intraoperative Visualization of Microcarcinoma by Local Application…
https://t.me/medicina_free
Carboxy
peptidase
Azoformyl
-
e
PSMA
R =Glutamate
227
Fig. 30.5 Development of activatable PSMA activity detection uorescent probe based on photoinduced electron transfer. (a) Hydrolysis
of azoformyl derivatives by PSMA and subsequent decarboxylation and
4000
3500
).u.a(ytisnetniecnecseroulF
3000
2500
2000
1500
1000
500
0
Fig. 30.6
human specimen by a topical spray of the developed PSMA probe. (a)
Reactivity of the successfully developed uorescent probe for PSMA
About 400-fold
5-GluAFflu
5-fluAFGlu
5-GluAFflu+inhibitor
5-fluAFGlu+ inhibitor
6-fluAFGlu
6-GluAFflu
6-fluAFGlu+ inhibitor
6-GluAFflu+inhibitor
450 500 550 600 650 700
Fluorescent detection of prostate cancer site in a fresh
denitration reactions to form allyl and alkyl compounds. (b) Principle
of operation of an activatable PSMA activity-detecting uorescent
probe based on photoinduced electron transfer
PSMA ++Inhibitor-
6-fluAFGlu
10 µM Probes were incubatedwith PSMA
at 37 °Cfor 15 hr. Measured in pH 7.4, 0.2
M Na-PiBuffer
activity detection with PSMA. (b) Microprostate cancer imaging in a
fresh specimen by dropping a transmembrane PSMA activity-detecting
uorescent probe
228
and the other 4 sites were not cancer (-).
b
https://t.me/medicina_free
Before dripping probes
Prostate cancer fresh specimen
Y. Urano
30 minutes after dripping probes
Strong probe fluorescence response
Fig. 30.6 (continued)
Pathology: 2 sites with strong
fluorescence were cancer (+)
30 Development of Novel Fluorescent Probes: Rapid Intraoperative Visualization of Microcarcinoma by Local Application…
https://t.me/medicina_free
229
when the probe was applied to resected specimens from
prostate cancer patients, it was found that even small cancers
of several mm in diameter could be detected, and the world’s
rst rapid uorescence visualization of microscopic prostate
cancer sites was achieved by targeting the carboxypeptidase
activity of PSMA [7].
Point
• We have succeeded in developing the world’s rst uorescent probe for detecting PSMA activity.
• The use of this probe is expected to enable intraoperative
detection of prostate cancer, which is difcult to detect by
conventional imaging modalities.
7 Future Perspectives
In this paper, we have introduced a number of examples of
the development of activatable-type rapid uorescent
probes whose uorescence characteristics are signicantly
altered based on cancer-specic enzymatic activities, utilizing our original uorescent probe precision design methods. Previous studies have indicated that novel uorophores
designed by our technologies are sufciently effective for
cancer localization in actual patients beyond the level of
experiments using animal models, and are practical enough
to be used in clinical settings. Following expectations from
many surgeons and endoscopists, we have started preclinical trials of several probes in cooperation with a domestic
chemical venture, an invitro uorescent imager manufacturer, and an endoscope manufacturer, with investment
from venture capitalists. Among them, uorescent probes
for exvivo breast cancer imaging and endoscopic identication of esophageal cancer have recently passed nonclinical studies such as toxicity tests after face-to-face advice
with the Japanese FDA, and the rst-in-human study is
about to start after the review by the hospital ethics committee. I am very much looking forward to the day when
surgeons will be able to clearly determine the location of
cancer to be removed with the use of novel uorescence
imaging techniques.
References
1. Urano Y, Sakabe M, Kosaka N, et al. Rapid cancer detection by
topically spraying a γ-glutamyltranspeptidase-activated uorescent
probe. Sci Transl Med. 2011;3:110ra119.
2. Sakabe M, Asanuma D, Kamiya M, etal. Rational design of highly
sensitive uorescence probes for protease and glycosidase based on
precisely. J Am Chem Soc. 2013;135:409–14.
3. Ueo H, Shinden Y, Tobo T, etal. Rapid intraoperative visualization
of breast lesions with γ -glutamyl hydroxymethyl rhodamine green.
Sci Rep. 2015;5:12080.
4. Shinden Y, Ueo H, Tobo T, etal. Rapid diagnosis of lymph node
metastasis in breast cancer using a new uorescent method with γ glutamyl hydroxymethyl rhodamine green. Sci Rep. 2016;6:27525.
5. Onoyama H, Kamiya M, Kuriki Y, etal. Rapid and sensitive detection of early esophageal squamous cell carcinoma with uorescence
probe targeting Dipeptidylpeptidase IV.Sci Rep. 2016;6:26399.
6. Kuriki Y, Kamiya M, Kubo H, etal. Establishment of a molecular
design strategy to obtain activatable uorescent probes for carboxypeptidases. J Am Chem Soc. 2018;140:1767–73.
7. Kawatani M, Yamamoto K, Yamada D, etal. Fluorescence detection
of prostate cancer by an activatable uorescence probe for PSMA
carboxypeptidase activity. J Am Chem Soc. 2019;141:10409–16.
Development ofaNew Imaging System
https://t.me/medicina_free
SatoruSeo andEtsuroHatano
31
Summary
• Although preoperative simulation has become essential
for hepatectomy, it cannot follow intraoperative movement and deformation of the liver. That’s why intraoperative navigation has to be developed.
• ICG uorescence imaging is useful for real-time visualization of hepatic segments and tumor locations, but it is
not practical to use conventional handheld devices
throughout surgical procedures.
• We developed the Medical Imaging Projection System
(MIPS) using an industry-academia collaboration framework, which projects ICG uorescence images directly
onto the patient’s organs by applying the projection mapping technology that has been used in the eld of
entertainment.
• The system has recently been launched in Japan with
pharmaceutical approval.
1 Introduction
In recent years, the development of intraoperative navigation
using uorescent dyes has progressed. Among the intraoperative navigation techniques, uorescence imaging using
ICG and a near-infrared camera system has attracted particular attention. This technique is based on a mechanism in
which ICG bound to plasma proteins emits uorescence signals in the near-infrared range, which is outside of the
absorption wavelengths of hemoglobin and water [1]. In the
eld of liver surgery, it has been reported to be useful for the
visualization of hepatic segments [2], liver tumors [3], and
bile ducts [4].
Since the development of near-infrared camera systems
for open surgery, ICG uorescence imaging has also been
incorporated into imaging systems for laparoscopic or
robot- assisted surgery. In the setting of laparoscopic or
robot- assisted surgery where surgeons are always watching a monitor, it has become possible to continue surgical
procedures while checking ICG uorescence images overlayed on the full-color images in real time. In contrast, the
use of a hand-held camera during open surgery has other
problems: frequent eye movement between the operative
eld and the monitor is required to see the uorescence
images displayed on the monitor, the camera needs to be
held by a surgeon, the image can be blurred by the movement of the hand-held device, and the surgical lights need
to be turned off during uorescence imaging to remove the
light interference (Fig.31.1). Because of these problems,
continuous real-time navigation using ICG uorescence
imaging is difcult to perform in the setting of open surgery, and in reality, only intermittent navigation is usually
applied.
Supplementary Information The online version contains supplementary
material available at
S. Seo (*) · E. Hatano
Department of Surgery, Kochi Medical School, Nankoku,
Kochi, Japan
e-mail: rutosa@kuhp.kyoto-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_31
https://doi.org/10.1007/978- 981- 19- 7372- 7_31.
231
232
https://t.me/medicina_free
Fig. 31.1 Problems of the
conventional uorescence
imaging
S. Seo and E. Hatano
Heavy handheld camera
2 Motivation toDevelop aNovel ICG
Fluorescence Imaging System
forOpen Abdominal Surgery
Using software such as Synapse Vincent (Fujilm), the shape
of the liver, vasculature, and tumor are reconstructed in 3D
based on preoperative CT images. In clinical settings, a preoperative simulation is becoming an indispensable tool for
determining the resection line with consideration of the balance between curability and safety. However, simulation
images cannot reect real-time information because they do
not correspond to intraoperative positional movement and
organ deformation. Technological innovation in preoperative
simulation images has enabled detailed surgical procedure
planning, but in order to complete surgery as simulated, it is
necessary to establish real-time navigation that follows intraoperative positional movement and deformation.
The technology we focused on is the projection mapping
technique, which has been widely used in the eld of entertainment. By applying this technology, we have started to
develop a system that can project ICG uorescence images
directly onto a patient’s organs during surgery.
Shifting the vision
Dark operative field
3 Launch oftheMIPS Project
We started joint development with Panasonic Corporation
as an industry-academia collaboration project and rst
made a prototype of the principle (Fig.31.2). In experiments using this prototype, we conrmed that ICG
injected into the pig’s liver could be projection-mapped
without any positional shift, and we then developed a pro-
totype for clinical use (Fig.31.3). We named the prototype the Medical Imaging Projection System (MIPS), and
the project was named the MIPS Project. In animal experiments using the prototype, we conrmed that the system
could be used invivo without misalignment and could follow movement. At the same time, we identied the problem that the excitation light illumination was close to the
surgical eld and interfered with surgical operations.
Then, we improved the design to incorporate the projector
and excitation light illumination into the imaging head
(Fig.31.4a). We have used this updated system in clinical
trials for breast cancer and liver cancer surgery, achieving
the <2mm misalignment and the <0.2 s time difference
between projections. In addition, by using an algorithm
31 Development ofaNew Imaging System
https://t.me/medicina_free
Projector
Fluorescent
imaging camera
Excitation light
illumination
Animal liver
233
Fig. 31.2 Principle of the prototype imaging system
Excitation light illumination
Fig. 31.3 Animal experiments using the prototype imaging system
that converts uorescent areas to specic colors and nonuorescent areas to white, we were able to provide a sufciently bright surgical eld even in the circumstance
where the surgical lights were turned off. With these
improvements, we were able to overcome all of the aforementioned problems (Fig.31.5).
234
ab
Conventional System
Shadowless
Shadowless lamp
New System
https://t.me/medicina_free
S. Seo and E. Hatano
Based on the results of interviews
with physicians, the device
conguration was designed with
the highest priority on feasibility.
Fig. 31.4 Updates of the MIPS system. (a) First machine. (b) Final machine. Based on the results of interviews with physicians, the device con-
guration was designed with the highest priority on feasibility
Shadowless
lamp
Lights off
Operative field
Developed
Head
Liver
Effects
①
②
③
Lights off
No shifting the vision
Well-lit operative field
No image blurring
lamp
Lights off
ICG imaging
Infrared
camera
Monitor
Infrared
camera
Monitor
Shadowless lamp
Lights off
Liver
Limitations
Shifting the vision
①
Dark operative field
②
③
Heavy handheld camera
Fig. 31.5 Advantages of MIPS
31 Development ofaNew Imaging System
https://t.me/medicina_free
235
4 Challenges inMIPS Development
One of the challenges the project faced at the time of its
inception was that Japanese insurance coverage for the intraoperative use of ICG was limited to sentinel node identication (breast cancer and malignant melanoma). Although ICG
was subsequently approved for use in the “evaluation of
blood ow in blood vessels and tissues,” the companies
acknowledged concerns about potential complications and
liability for inaccurate MIPS navigation. This concern was
also an issue with ICG uorescence imaging itself. These
were discussed within the project and resolved by emphasizing at subsequent conferences and in publicity that MIPS is
a medical device to be used by specialists to perform more
precise surgery. In order to perform accurate ICG uorescence imaging during surgery, it was necessary to adjust the
ICG dose and uorescence gain based on individual patient
information. For this reason, we added an image superimposing function to the monitor and improved it so that we
can always check whether the settings are appropriate.
Another issue was how to raise the costs for research and
development. Fortunately, we were selected for research
support by the Japan Agency for Medical Development
(AMED), which has offered various advantages to our project. For example, the academia side was able to bear the
medical expenses for expensive clinical trials using unapproved medical devices, and we were able to actively present
the obtained data at domestic and international conferences.
The results of the initial clinical trials were published in the
Annals of Surgery, and this provided an opportunity to raise
awareness of MIPS [5]. The company was not only able to
bear the cost of developing and fabricating an expensive prototype, but the fact that the project was selected encouraged
the company to obtain internal development funds, which
enabled the project to be transferred from the research
department to the business department. By holding progress
meetings every 2months for AMED site visits and annual
reports, academia and the company were able to work closely
together and establish a clear goal and roadmap. This was
one of the factors that enabled the project to be successful.
5 Key Factors forSuccessful Medical-
Industrial Collaboration
The key to success in medical-engineering collaboration is
the matching of seeds and needs, and in our case, we had two
successful matches: the rst was between the seeds of
Panasonic Corporation’s optical technology and image processing technology, and our need to perform ICG uorescence imaging in open surgery in the same way as in
endoscopic surgery. We also matched the need for doctors to
move the projection head freely, which arose in the MIPS
project, with the seeds of arm control technology that Mitaka
Koki had already commercialized (Fig.31.4b, Movie 31.1).
Through this matching, MIPS has grown into a medical
device that enables surgeon-friendly and continuous colorcoded surgery (Movie 31.2).
6 Unexpected Diculties andSolutions
Industry-academia framework is a collaboration between a
company and an academia for the purpose of R&D of new
technology and creation of new business. However, there are
often cases where communication fails due to differences in
position and culture, even if the members share the same purpose. At Kyoto University, the Integrated Center for Clinical
Research (iACT) acted as a bridge between the two parties,
supporting the preparation of communication tools (e.g.,
internet conference, teleconference, opening of a shared
server) and the holding of progress conrmation meetings at
Kyoto University every 2 months. In addition, we received
support for condentiality agreements, joint research agreements, and advice for regulatory approval and were able to
deal with all steps quickly.
Initially we were aiming to obtain Class 2 regulatory
approval in March 2019, but the schedule has been signicantly delayed. One of the reasons is the recent tightening of
the laws and regulations for clinical research in Japan. In our
case, it took 8months for the ethical review after the amendment, and we could not conduct the clinical study using the
actual device during that period, which delayed the schedule
signicantly. Even with these unexpected difculties, we
were able to share information and consider solutions within
the project and successfully obtain Class 2 regulatory
approval.
7 Future Perspectives
The number of laparoscopic liver resections has been increasing in Japan since the insurance coverage was introduced in
2010. In the course of the MIPS project, we sometimes heard
the opinion, “What is the point of developing a medical
device for open surgery in the era of endoscopic surgery?”.
Especially in the eld of hepatobiliary surgery, however,
there remain many cases that can only be treated by open
surgery, such as complicated repeated liver resections and
hepatectomy for huge tumors. In addition, the ICG uorescence method has many problems such as administration
route and dosage. Therefore, we believe that it is time to
overcome the problems of ICG uorescence imaging by consolidating the knowledge of both surgical approaches.
236
https://t.me/medicina_free
S. Seo and E. Hatano
We hope to accumulate experience in using MIPS at many
institutions in the future to realize safe and precise hepatectomy. In the future, we expect that real-time navigation using
MIPS will be expanded to areas other than liver resection, as
we have already reported on the usefulness of ICG uorescence in sentinel lymph node identication in breast surgery
[6] and in lung metastasis identication in hepatoblastoma [7].
Point
We have applied projection mapping technology to ICG uorescence imaging, enabling truly real-time navigation during
open surgery.
The development of new medical devices will be accelerated by obtaining research funding and reporting the results
of clinical trials.
The key to success in medical-industrial collaboration is
the matching of seeds and needs.
Acknowledgement This research was supported by the IndustryAcademia Collaboration Medical Innovation Creation Program (ACTM) of the Japan Agency for Medical Research and Development
(AMED).
References
1. Landsman ML, Kwant G, Mook GA, etal. Light-absorbing properties, stability, and spectral stabilization of indocyanine green. J Appl
Physiol. 1976;40:575–83.
2. Aoki T, Yasuda D, Shimizu Y, et al. Image-guided liver mapping
using uorescence navigation system with indocyanine green for
anatomical hepatic. World J Surg. 2008;32:1763–7.
3. Ishizawa T, Fukushima N, Shibahara J, et al. Real-time identication of liver cancers by using indocyanine green uorescent imaging. Cancer. 2009;115:2491–504.
4. Ishizawa T, Bandai Y, Ijichi M, etal. Fluorescent cholangiography
illuminating the biliary tree during laparoscopic cholecystectomy.
Br J Surg. 2010;97:1369–77.
5. Nishino H, Hatano E, Seo S, etal. Real-time navigation for liver
surgery using projection mapping with indocyanine green uorescence: development of the novel Medical Imaging Projection
System. Ann Surg. 2018;267:1134–40.
6. Takada M, Takeuchi M, Suzuki E, etal. Real-time navigation system for sentinel lymph node biopsy in breast cancer patients using
projection mapping with indocyanine green uorescence. Breast
Cancer. 2018;25:650–5.
7. 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.
Development ofaNew Operating Room
https://t.me/medicina_free
That Integrates Imaging Information
ShunsukeTsuzuki, JunOkamoto, ManabuTamura,
KenMasamune, andYoshihiroMuragaki
32
Summary
• The operating room is at the potential risk of incidents
and accidents due to the mixture of various old and new
medical equipment.
• Attempts are being made to integrate augmented reality
(AR) image processing technology with new medical
technology to help with surgical planning and strategies.
• To achieve a high curative resection rate and a low complication rate, we are developing a new operating room
that integrates imaging information from preoperative
simulations and novel image processing techniques to
reect surgical strategies.
1 Introduction
The operating room is a “place” that provides a space to perform sterilized procedures, and specialized equipment as
well as basic surgical instruments are brought in according to
surgical procedures. A wide variety of surgical devices are
usually stocked and used, as different surgeons may use different models even if they have the same function. In addition, new intraoperative diagnostic and therapeutic devices
are introduced one after another. Therefore, we are in a situation where new and old devices are mixed together and
there is a potential risk of medical incidents and accidents
occurring.
S. 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
e-mail: tsuzuki.shunsuke@twmu.ac.jp
J. Okamoto · M. Tamura · K. Masamune · Y. Muragaki
Faculty of Advanced Techno Surgery (FATS), Institute of
Advanced Biomedical Engineering and Science, Tokyo Women’s
Medical University, Tokyo, Japan
We believe that the potential risk of mixing old and new
equipment is the main cause of errors. In order to reduce this
risk and improve the effectiveness of surgery and procedures,
we have developed SCOT
Theater
Research and Development (AMED) and introduced it into
clinical practice. In this treatment room, we aim to achieve a
high level of safety and tumor removal rate by not only synchronizing devices that have been used as stand-alone
devices but also integrating new medical technologies with
image processing technologies such as simulation from various preoperative images and AR.
achieve both a high survival rate and prevention of surgical
complications, making decisions on the extent of removal
based on information measured by various medical devices.
Specically, intraoperative MRI, surgical navigation systems, neuromonitoring devices, and intraoperative rapid
diagnostic devices (intraoperative ow cytometry) are used.
However, the use of these stand-alone devices without data
sharing makes it difcult for surgeons to integrate information for selecting appropriate surgical procedures. In order to
solve this problem, we developed the “Smart Cyber Operation
Theater” project in 2014 and devised OPeLiNK® enabling
connection to various surgical equipment. In February 2019,
Tokyo Women’s Medical University Hospital installed the
agship version of Hyper SCOT®, which is the world’s most
advanced treatment room that aims to be linked with robotic
operating tables and articial intelligence (AI). In this paper,
we describe the simulation technology to enhance the safety
of surgery and the integration with the latest medical technology and detail the history and outline of the development
of this operating room.
®
) with the support of the Japan Agency for Medical
In the removal of malignant brain tumors, we aim to
®
(Smart Cyber Operating
© 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_32
237
Соседние файлы в папке Библиотека им академика М.И. Перельмана