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Journal ArticleDOI

A clinical trial of intraoperative near-infrared imaging to assess tumor extent and identify residual disease during anterior mediastinal tumor resection.

TL;DR: This clinical trial explored intraoperative near‐infrared (NIR) imaging as an approach to improving tumor delineation during mediastinal tumor resection.
Abstract: Background The management of most solid tumors of the anterior mediastinum involves complete resection. Because of their location near mediastinal structures, wide resection is not possible; therefore, surgeons must use subjective visual and tactile cues to determine disease extent. This clinical trial explored intraoperative near-infrared (NIR) imaging as an approach to improving tumor delineation during mediastinal tumor resection. Methods Twenty-five subjects with anterior mediastinal lesions suspicious for malignancy were enrolled in an open-label feasibility trial. Subjects were administered indocyanine green (ICG) at a dose of 5 mg/kg, 24 hours before resection (via a technique called TumorGlow). The NIR imaging systems included Artemis (Quest, Middenmeer, the Netherlands) and Iridium (VisionSense Corp, Philadelphia, Pennsylvania). Intratumoral ICG uptake was evaluated. The clinical value was determined via an assessment of the ability of NIR imaging to detect phrenic nerve involvement or incomplete resection. Clinical and histopathologic variables were analyzed to determine predictors of tumor fluorescence. Results No drug-related toxicity was observed. Optical imaging added a mean of 10 minutes to case duration. Among the subjects with solid tumors, 19 of 20 accumulated ICG. Fluorescent tumors included thymomas (n = 13), thymic carcinomas (n = 4), and liposarcomas (n = 2). NIR feedback improved phrenic nerve dissection (n = 4) and identified residual disease (n = 2). There were no false-positives or false-negatives. ICG preferentially accumulated in solid tumors; this was independent of clinical and pathologic variables. Conclusions NIR imaging for anterior mediastinal neoplasms is safe and feasible. This technology may provide a real-time tool capable of determining tumor extent and specifically identify phrenic nerve involvement and residual disease.

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Citations
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Journal ArticleDOI
TL;DR: In this paper, the authors explore the study designs of existing trials of fluorescence-guided surgery that allow us to extract information on potential changes in intraoperative decision making, such as additional or more conservative resections.
Abstract: Fluorescence-guided surgery is an intraoperative optical imaging method that provides surgeons with real-time guidance for the delineation of tumours. Currently, in phase 1 and 2 clinical trials, evaluation of fluorescence-guided surgery is primarily focused on its diagnostic performance, although the corresponding outcome variables do not inform about the added clinical benefit of fluorescence-guided surgery and are challenging to assess objectively. Nonetheless, the effect of fluorescence-guided surgery on intraoperative decision making is the most objective outcome measurement to assess the clinical value of this imaging method. In this Review, we explore the study designs of existing trials of fluorescence-guided surgery that allow us to extract information on potential changes in intraoperative decision making, such as additional or more conservative resections. On the basis of this analysis, we offer recommendations on how to report changes in intraoperative decision making that result from fluorescence imaging, which is of utmost importance for the widespread clinical implementation of fluorescence-guided surgery.

89 citations

Journal ArticleDOI
TL;DR: In this Phase 2 clinical trial, IMI improved outcomes for 26% of patients and benefits of IMI were pronounced in patients undergoing sublobar pulmonary resections and in those with ground-glass opacities.

26 citations

Journal ArticleDOI
Yifan Wu1, Fan Zhang1
01 Dec 2020
TL;DR: It is convinced that NIR fluorescence‐guided surgery has the potential to improve current surgical resection and ameliorate the postoperative outcomes of diverse diseases.
Abstract: Near‐infrared (NIR) fluorescence imaging can provide real‐time navigation for surgeons to discriminate boundaries between lesions and healthy tissue, which serves as a promising tool to enhance precise diagnosis and accurate excision during surgery. Molecular probes with NIR fluorescence can visualize diseased tissue in deep penetration with improved signal‐to‐noise ratio, which considerably encourages the active participation of NIR fluorescence‐guided surgery in the operating room. Although a great quantity of fluorescent probes has been employed in clinical trials, the U.S. Food and Drug Administration only approves an extremely narrow number of contrast agents for clinical use so far. Currently, there remain two significant problems to be addressed in surgical resection: accurate identification of diseased tissue and the preservation of adjacent vital structures. Here, molecular probes with NIR fluorescence are systematically reviewed to offer possible solutions to these two problems. Targeting strategies of fluorescent probes are introduced, where the strengths and weaknesses of each strategy are presented. Advances in fluorescent probes for the imaging of vital structures, such as nerve and ureter, are also summarized in this review. It is convinced that NIR fluorescence‐guided surgery has the potential to improve current surgical resection and ameliorate the postoperative outcomes of diverse diseases.

21 citations

Journal ArticleDOI
TL;DR: Near infra-red (NIR) fluorescence guided surgery offers an intra-operative modality through which complete tumour resection with adequate tumour-free margins may be achieved, while simultaneously minimising surgical morbidity.

11 citations

Journal ArticleDOI
TL;DR: In this paper , a novel homodimer-directed near-infrared (NIR) probe (TMTP1-PEG4)2-ICG was successfully constructed and synthesized.
Abstract: TMTP1 is a polypeptide independently screened in our laboratory, which can target tumors in situ and metastases. In previous work, we have successfully developed a near-infrared (NIR) probe TMTP1-PEG4-ICG for tumor imaging. However, the limited ability to target tumor micrometastases hinders its further clinical application. Multimerization of peptides has been extensively demonstrated as an effective strategy to increase receptor binding affinity due to "multivalent effect" or "apparent cooperative affinity". In this study, a novel TMTP1 homodimer-directed NIR probe (TMTP1-PEG4)2-ICG was successfully constructed and synthesized. The cyclic TMTP1 peptides were bridged by two PEG4 linkers and then labeled with ICG-NHS for tumor imaging and photothermal therapy. In vivo biodistribution were assessed in normal BALB/c mice, and tumor targeting abilities of (TMTP1-PEG4)2-ICG and its monomer were evaluated and compared in 4T1-bearing subcutaneous tumor and lymph node metastasis model mice. Biodistribution analysis in vivo revealed that (TMTP1-PEG4)2-ICG was cleared mainly in both liver and kidney dependent way. Comparing with free ICG dye or TMTP1-PEG4-ICG probe, this improved (TMTP1-PEG4)2-ICG dimer showed more sensitive tumor imaging and could clearly identify tumors at a minimum volume of 10 mm3. Additionally, when compared to its monomer, lymph node (LN) metastases could also be apparently visualized and easily distinguished from normal LN by the novel dimer at 24 h post-injection. The blocking study revealed that the tumor accumulation of this probe was specifically medicated by receptor-ligand interaction. Furthermore, with the increase in stability and tumor targeting ability of ICG in vivo, the probe could also be an attractive photothermal agent to significantly inhibit tumor growth under 808 nm NIR laser irradiation. In conclusion, our work revealed that the novel (TMTP1-PEG4)2-ICG dimer could be a promising theranostic agent for sensitive tumor imaging and imaging-guided photothermal therapy, indicating its broad prospects for further clinical transformation.

7 citations

References
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Journal ArticleDOI
TL;DR: An overview of the recent surgical intraoperational applications of indocyanine green fluorescence imaging methods, the basics of the technology, and instrumentation used is given.
Abstract: The purpose of this paper is to give an overview of the recent surgical intraoperational applications of indocyanine green fluorescence imaging methods, the basics of the technology, and instrumentation used. Well over 200 papers describing this technique in clinical setting are reviewed. In addition to the surgical applications, other recent medical applications of ICG are briefly examined.

1,000 citations


"A clinical trial of intraoperative ..." refers methods in this paper

  • ...ICG has commonly been used in the clinic as a tool for evaluating perfusion by NIR angiography.(20,21) As a perfusion agent, ICG is delivered at a dose of 0....

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  • ...4 mg/kg, with fluorescence imaging occurring in the first window after the intravenous infusion (within 10-20 minutes).(15,20,21)...

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Journal ArticleDOI
TL;DR: In the experience, the ICG fluorescence imaging system seems to be simple, safe, and useful, and may well become a standard in the near future in view of its different diagnostic and oncological capabilities.
Abstract: Background Recently major developments in video imaging have been achieved: among these, the use of high definition and 3D imaging systems, and more recently indocyanine green (ICG) fluorescence imaging are emerging as major contributions to intraoperative decision making during surgical procedures. The aim of this study was to present our experience with different laparoscopic procedures using ICG fluorescence imaging.

367 citations


"A clinical trial of intraoperative ..." refers methods in this paper

  • ...ICG has commonly been used in the clinic as a tool for evaluating perfusion by NIR angiography.(20,21) As a perfusion agent, ICG is delivered at a dose of 0....

    [...]

  • ...4 mg/kg, with fluorescence imaging occurring in the first window after the intravenous infusion (within 10-20 minutes).(15,20,21)...

    [...]

Journal ArticleDOI
TL;DR: This is the first-in-human demonstration of identifying pulmonary nodules during thoracic surgery with NIR imaging without a priori knowledge of their location or existence.

139 citations


"A clinical trial of intraoperative ..." refers background or methods or result in this paper

  • ...This approach has been successful in the context of central nervous system tumors,(15) pulmonary metastases,(9) and primary lung neoplasms.(12) In this trial, we found ICG-based NIR imaging safe, with no patients experiencing drug-related toxicity....

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  • ...Our group initially explored this approach in clinical trials involving patients with pulmonary metastases(9) and non–small cell lung cancer.(12) In these feasibility studies, NIR imaging was capable of identifying both subcentimeter malignant lesions and positive margins....

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  • ...Mechanistically, intratumoral accumulation appears to be driven by the presence of abnormal endothelial cells and the high vascularity of these lesions; this suggests a role for EPR, as has been described by our group.(9,12,18)...

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  • ...The low toxicity further authenticates the safety profile that we observed in experiences with second-window ICG for neurologic malignancies and thoracic malignancies.(9,12,15)...

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  • ...Notably, dosing parameters were determined on the basis of preclinical data involving thymoma models(14) and previous human data involving other pleural-based and intrapulmonary neoplasms.(9,12,18)...

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Journal ArticleDOI
TL;DR: With the use of Second Window ICG, gadolinium-enhancing tumors can be localized through brain parenchyma intraoperatively and its utility for margin detection is promising but limited by lower specificity.
Abstract: Background Although real-time localization of gliomas has improved with intraoperative image guidance systems, these tools are limited by brain shift, surgical cavity deformation, and expense. Objective To propose a novel method to perform near-infrared (NIR) imaging during glioma resections based on preclinical and clinical investigations, in order to localize tumors and to potentially identify residual disease. Methods Fifteen patients were identified and administered a Food and Drug Administration-approved, NIR contrast agent (Second Window indocyanine green [ICG], 5 mg/kg) before surgical resection. An NIR camera was utilized to localize the tumor before resection and to visualize surgical margins following resection. Neuropathology and magnetic resonance imaging data were used to assess the accuracy and precision of NIR fluorescence in identifying tumor tissue. Results NIR visualization of 15 gliomas (10 glioblastoma multiforme, 1 anaplastic astrocytoma, 2 low-grade astrocytoma, 1 juvenile pilocytic astrocytoma, and 1 ganglioglioma) was performed 22.7 hours (mean) after intravenous injection of ICG. During surgery, 12 of 15 tumors were visualized with the NIR camera. The mean signal-to-background ratio was 9.5 ± 0.8 and fluorescence was noted through the dura to a maximum parenchymal depth of 13 mm. The best predictor of positive fluorescence was enhancement on T1-weighted imaging; this correlated with signal-to-background ratio (P = .03). Nonenhancing tumors did not demonstrate NIR fluorescence. Using pathology as the gold standard, the technique demonstrated a sensitivity of 98% and specificity of 45% to identify tumor in gadolinium-enhancing specimens (n = 71). Conclusion With the use of Second Window ICG, gadolinium-enhancing tumors can be localized through brain parenchyma intraoperatively. Its utility for margin detection is promising but limited by lower specificity. Abbreviations 5-ALA, 5-aminolevulinic acidEPR, enhanced permeability and retentionFDA, Food and Drug AdministrationGBM, glioblastomaICG, indocyanine greenNIR, near-infraredNPV, negative predictive valuePPV, positive predictive valueROC, receiver operating characteristicROI, region of interestSBR, signal-to-background ratioWHO, World Health Organization.

109 citations


"A clinical trial of intraoperative ..." refers methods or result in this paper

  • ...4 mg/kg, with fluorescence imaging occurring in the first window after the intravenous infusion (within 10-20 minutes).(15,20,21)...

    [...]

  • ...The low toxicity further authenticates the safety profile that we observed in experiences with second-window ICG for neurologic malignancies and thoracic malignancies.(9,12,15)...

    [...]

  • ...In situ, real-time fluorescence imaging was performed using 2 systems optimized for the detection of ICG, Artemis Handheld Fluorescence Imaging System (Quest Medical Imaging, Middenmeer, the Netherlands) and Visionsense VS3 Iridium (VisionSense Corp, Philadelphia, Pennsylvania), as previously described.(9,15,16) The Artemis imaging system was used for subjects 1 to 10, whereas Iridium was used for subjects 11 to 25....

    [...]

  • ...Twenty-four hours before resection, all subjects received intravenous ICG (5 mg/kg) at the University of Pennsylvania Health System’s Clinical Translational Research Center.9,15 Patients were monitored for 30 minutes and then discharged....

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  • ...Twenty-four hours before resection, all subjects received intravenous ICG (5 mg/kg) at the University of Pennsylvania Health System’s Clinical Translational Research Center.(9,15) Patients were monitored for 30 minutes and then discharged....

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Journal Article
TL;DR: For non-hepatic solid tumors, ICG was optimal when dosed at 5 mg/kg and 24 hours before surgery, and these findings were applicable to lung cancer patients, and tumor was clearly delineated from surrounding normal tissue by NIR imaging.
Abstract: Surgery is the most effective method to cure patients with solid tumors. New techniques in near-infrared (NIR) cancer imaging are being used to identify surgical margins and residual tumor cells in the wound. Our goal was to determine the optimal time and dose for imaging solid tumors using Indocyanine Green. Syngeneic murine flank tumor models were used to test NIR imaging of ICG at various doses ranging from 0 to 10 mg/kg. Imaging was performed immediately after injection and up to 72 hours later. Biodistribution in the blood and murine organs were quantified by spectroscopy and fluorescence microscopy. Based on these results, a six patient dose titration study was performed. In murine flank tumors, the tumor-to-background ratio (TBR) for ICG at doses less than 5 mg/kg were less than 2 fold at all time points, and the surgeons could not subjectively identify tissue contrast. However, for doses ranging from 5 mg/kg to 10 mg/kg, the TBR ranged from 2.1 to 8.0. The tumor signal was best appreciated at 24 hours and the background was least pronounced after 24 hours. Biodistribution studies in the blood and murine organs revealed excretion through the biliary tree and gastrointestinal tract, with minimal blood fluorescence at the higher doses. A follow up pilot study confirmed that these findings were applicable to lung cancer patients, and tumor was clearly delineated from surrounding normal tissue by NIR imaging. For non-hepatic solid tumors, we found ICG was optimal when dosed at 5 mg/kg and 24 hours before surgery.

96 citations


"A clinical trial of intraoperative ..." refers background in this paper

  • ...When these delivery parameters are implemented, ICG functions by exploiting abnormally leaky capillaries and increased pressure gradients (also known as the EPR effect), which are found in most solid malignancies.(13)...

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  • ...EPR permits nanostructures (between 10 nm and 100 nm) to accumulate in solid malignancies as a result of leaky vasculature and the lack of lymphatics.(13) Our group initially explored this approach in clinical trials involving patients with pulmonary metastases(9) and non–small cell lung cancer....

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