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      Extrahepatic cholangiography in near-infrared II window with the clinically approved fluorescence agent indocyanine green: a promising imaging technology for intraoperative diagnosis

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          Abstract

          Rationale: Biliary tract injury remains the most dreaded complication during laparoscopic cholecystectomy. New intraoperative guidance technologies, including near-infrared (NIR) fluorescence cholangiography with indocyanine green (ICG), are under comprehensive evaluation. Previous studies had shown the limitations of traditional NIR light (NIR-I, 700-900 nm) in visualizing the biliary tract structures in specific clinical situations. The aim of this study was to evaluate the feasibility of performing the extrahepatic cholangiography in the second NIR window (NIR-II, 900-1700 nm) and compare it to the conventional NIR-I imaging.

          Methods: The absorption and emission spectra, as well as fluorescence intensity and photostability of ICG-bile solution in the NIR-II window were recorded and measured. In vitro intralipid ® phantom imaging was performed to evaluate tissue penetrating depth in NIR-I and NIR-II window. Different clinical scenarios were modeled by broadening the penetration distance or generating bile duct injuries, and bile duct visualization and lesion site diagnosis in the NIR-II window were evaluated and compared with NIR-I imaging.

          Results: The fluorescence spectrum of ICG-bile solution extends well into the NIR-II region, exhibiting intense emission value and excellent photostability sufficient for NIR-II biliary tract imaging. Extrahepatic cholangiography using ICG in the NIR-II window obviously reduced background signal and enhanced penetration depth, providing more structural information and improved visualization of the bile duct or lesion location in simulated clinical scenarios, outperforming the NIR-I window imaging.

          Conclusions: The conventional clinically approved agent ICG is an excellent fluorophore for NIR-II bile duct imaging. Fluorescence cholangiography with ICG in the NIR-II window could provide adequate visualization of the biliary tract structures with increased resolution and penetration depth and might be a valid option to increase the safety of cholecystectomy in difficult cases.

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          Near‐Infrared‐II Molecular Dyes for Cancer Imaging and Surgery

          Fluorescence bioimaging affords a vital tool for both researchers and surgeons to molecularly target a variety of biological tissues and processes. This review focuses on summarizing organic dyes emitting at a biological transparency window termed the near-infrared-II (NIR-II) window, where minimal light interaction with the surrounding tissues allows photons to travel nearly unperturbed throughout the body. NIR-II fluorescence imaging overcomes the penetration/contrast bottleneck of imaging in the visible region, making it a remarkable modality for early diagnosis of cancer and highly sensitive tumor surgery. Due to their convenient bioconjugation with peptides/antibodies, NIR-II molecular dyes are desirable candidates for targeted cancer imaging, significantly overcoming the autofluorescence/scattering issues for deep tissue molecular imaging. To promote the clinical translation of NIR-II bioimaging, advancements in the high-performance small-molecule derived probes are critically important. We discuss here molecules with clinical potential for NIR-II imaging, summarizing the synthesis and chemical structures of NIR-II dyes, chemical and optical properties of NIR-II dyes, bioconjugation and biological behavior of NIR-II dyes, whole body imaging with NIR-II dyes for cancer detection and surgery, as well as NIR-II fluorescence microscopy imaging. We will also propose a key perspective on the direction of near-infrared-II molecular dyes for cancer imaging and surgery.
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            The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping.

            Invisible NIR fluorescent light can provide high sensitivity, high-resolution, and real-time image-guidance during oncologic surgery, but imaging systems that are presently available do not display this invisible light in the context of surgical anatomy. The FLARE imaging system overcomes this major obstacle. Color video was acquired simultaneously, and in real-time, along with two independent channels of NIR fluorescence. Grayscale NIR fluorescence images were converted to visible "pseudo-colors" and overlaid onto the color video image. Yorkshire pigs weighing 35 kg (n = 5) were used for final preclinical validation of the imaging system. A six-patient pilot study was conducted in women undergoing sentinel lymph node (SLN) mapping for breast cancer. Subjects received (99m)Tc-sulfur colloid lymphoscintigraphy. In addition, 12.5 microg of indocyanine green (ICG) diluted in human serum albumin (HSA) was used as an NIR fluorescent lymphatic tracer. The FLARE system permitted facile positioning in the operating room. NIR light did not change the look of the surgical field. Simultaneous pan-lymphatic and SLN mapping was demonstrated in swine using clinically available NIR fluorophores and the dual NIR capabilities of the system. In the pilot clinical trial, a total of nine SLNs were identified by (99m)Tc- lymphoscintigraphy and nine SLNs were identified by NIR fluorescence, although results differed in two patients. No adverse events were encountered. We describe the successful clinical translation of a new NIR fluorescence imaging system for image-guided oncologic surgery.
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              J-aggregates of Cyanine Dye for NIR-II In-vivo Dynamic Vascular Imaging Beyond 1500 nm

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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2020
                19 February 2020
                : 10
                : 8
                : 3636-3651
                Affiliations
                [1 ]Department of General Surgery, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
                [2 ]State Key Laboratory of Modern Optical Instrumentations, Centre for Optical and Electromagnetic Research, College of Optical Science and Engineering, Zhejiang University, Hangzhou, 310058, China.
                [3 ]Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou, 310016, China.
                [4 ]Department of Urology, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
                Author notes
                ✉ Corresponding authors: Dr. Xiujun Cai ( srrsh_cxj@ 123456zju.edu.cn ); Dr. Jun Qian ( qianjun@ 123456zju.edu.cn ); Dr. Hui Lin ( 369369@ 123456zju.edu.cn ).

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov10p3636
                10.7150/thno.41127
                7069080
                32206113
                fe0103ad-fef4-474c-9414-97fedce03cb7
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 13 October 2019
                : 31 January 2020
                Categories
                Research Paper

                Molecular medicine
                bile duct injury,diagnosis,near-infrared ii cholangiography,indocyanine green,fluorescence-guided surgery

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