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      Intraoperative Imaging-Guided Cancer Surgery: From Current Fluorescence Molecular Imaging Methods to Future Multi-Modality Imaging Technology

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          Abstract

          Cancer is a major threat to human health. Diagnosis and treatment using precision medicine is expected to be an effective method for preventing the initiation and progression of cancer. Although anatomical and functional imaging techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role for accurate preoperative diagnostics, for the most part these techniques cannot be applied intraoperatively. Optical molecular imaging is a promising technique that provides a high degree of sensitivity and specificity in tumor margin detection. Furthermore, existing clinical applications have proven that optical molecular imaging is a powerful intraoperative tool for guiding surgeons performing precision procedures, thus enabling radical resection and improved survival rates. However, detection depth limitation exists in optical molecular imaging methods and further breakthroughs from optical to multi-modality intraoperative imaging methods are needed to develop more extensive and comprehensive intraoperative applications. Here, we review the current intraoperative optical molecular imaging technologies, focusing on contrast agents and surgical navigation systems, and then discuss the future prospects of multi-modality imaging technology for intraoperative imaging-guided cancer surgery.

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          Most cited references165

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          A Brain Tumor Molecular Imaging Strategy Using A New Triple-Modality MRI-Photoacoustic-Raman Nanoparticle

          The vexing difficulty in delineating brain tumor margins represents a major obstacle toward better outcome of brain tumor patients. Current imaging methods are often limited by inadequate sensitivity, specificity, and spatial resolution. Here we show that a unique triple-modality Magnetic resonance imaging - Photoacoustic imaging – surface enhanced Raman scattering (SERS) nanoparticle (MPR) can accurately help delineate the margins of brain tumors in living mice both pre- and intra-operatively. The MPRs were detected by all three modalities with at least picomolar sensitivity both in vitro and in living mice. Intravenous injection of MPRs into glioblastoma-bearing mice led to specific MPR accumulation and retention by the tumors, allowing for non-invasive tumor delineation by all three modalities through the intact skull. Raman imaging allowed guidance of intra-operative tumor resection, and histological correlation validated that Raman imaging is accurately delineating brain tumor margins. This novel triple-modality nanoparticle approach holds promise to enable more accurate brain tumor imaging and resection.
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            In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.

            We have developed a method to image tumor-associated lysosomal protease activity in a xenograft mouse model in vivo using autoquenched near-infrared fluorescence (NIRF) probes. NIRF probes were bound to a long circulating graft copolymer consisting of poly-L-lysine and methoxypolyethylene glycol succinate. Following intravenous injection, the NIRF probe carrier accumulated in solid tumors due to its long circulation time and leakage through tumor neovasculature. Intratumoral NIRF signal was generated by lysosomal proteases in tumor cells that cleave the macromolecule, thereby releasing previously quenched fluorochrome. In vivo imaging showed a 12-fold increase in NIRF signal, allowing the detection of tumors with submillimeter-sized diameters. This strategy can be used to detect such early stage tumors in vivo and to probe for specific enzyme activity.
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              Real-time identification of liver cancers by using indocyanine green fluorescent imaging.

              We have often encountered difficulties in identifying small liver cancers during surgery. Fluorescent imaging using indocyanine green (ICG) has the potential to detect liver cancers through the visualization of the disordered biliary excretion of ICG in cancer tissues and noncancerous liver tissues compressed by the tumor. ICG had been intravenously injected for a routine liver function test in 37 patients with hepatocellular carcinoma (HCC) and 12 patients with metastasis of colorectal carcinoma (CRC) before liver resection. Surgical specimens were investigated using a near-infrared light camera system. Among the 49 subjects, the 26 patients examined during the latter period of the study (20 with HCC and 6 with metastasis) underwent ICG-fluorescent imaging of the liver surfaces before resection. ICG-fluorescent imaging identified all of the microscopically confirmed HCCs (n = 63) and CRC metastases (n = 28) in surgical specimens. Among the 63 HCCs, 8 tumors (13%, including 5 early HCCs) were not evident grossly unless observed by ICG-fluorescent imaging. Five false-positive nodules (4 large regenerative nodules and 1 bile duct proliferation) were identified among the fluorescent lesions. Well-differentiated HCCs appeared as uniformly fluorescing lesions with higher lesion-to-liver contrast than that of moderately or poorly differentiated HCCs (162.6 [71.1-218.2] per pixel vs 67.7 [-6.3-211.2] per pixel, P < .001), while CRC metastases were delineated as rim-fluorescing lesions. Fluorescent microscopy confirmed that fluorescence originated in the cytoplasm and pseudoglands of HCC cells and in the noncancerous liver parenchyma surrounding metastases. ICG-fluorescent imaging before resection identified 21 of the 41 HCCs (51%) and all of the 16 metastases that were examined. ICG-fluorescent imaging enables the highly sensitive identification of small and grossly unidentifiable liver cancers in real time, enhancing the accuracy of liver resection and operative staging. (c) 2009 American Cancer Society.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2014
                15 August 2014
                : 4
                : 11
                : 1072-1084
                Affiliations
                1. Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China.
                2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institute of Health (NIH), Bethesda, MD, 20892, USA.
                3. Department of General Surgery, General Hospital of People's Liberation Army, Beijing 100853, China.
                Author notes
                ✉ Corresponding author: Dr. Xiaoyuan Chen, Email: shawn.chen@ 123456nih.gov Or Dr. Jie Tian, E-mail: tian@ 123456ieee.org ; jie.tian@ 123456ia.ac.cn .

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

                Article
                thnov04p1072
                10.7150/thno.9899
                4165775
                25250092
                844480e1-19eb-4e49-8a42-718fe5a598e1
                © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                History
                : 13 June 2014
                : 31 July 2014
                Categories
                Review

                Molecular medicine
                optical molecular imaging,intraoperative imaging-guided cancer surgery,near-infrared fluorescence,multi-modality imaging,indocyanine green.

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