PurposeMetastasectomy is a common treatment option for patients with colorectal lung metastases (CLM). Challenges exist with margin assessment and identification of small nodules, especially during... Show morePurposeMetastasectomy is a common treatment option for patients with colorectal lung metastases (CLM). Challenges exist with margin assessment and identification of small nodules, especially during minimally invasive surgery. Intraoperative fluorescence imaging has the potential to overcome these challenges. The aim of this study was to assess feasibility of targeting CLM with the carcinoembryonic antigen (CEA) specific fluorescent tracer SGM-101.MethodsThis was a prospective, open-label feasibility study. The primary outcome was the number of CLM that showed a true positive fluorescence signal with SGM-101. Fluorescence positive signal was defined as a signal-to-background ratio (SBR) ≥ 1.5. A secondary endpoint was the CEA expression in the colorectal lung metastases, assessed with the immunohistochemistry, and scored by the total immunostaining score.ResultsThirteen patients were included in this study. Positive fluorescence signal with in vivo, back table, and closed-field bread loaf imaging was observed in 31%, 45%, and 94% of the tumors respectively. Median SBRs for the three imaging modalities were 1.00 (IQR: 1.00–1.53), 1.45 (IQR: 1.00–1.89), and 4.81 (IQR: 2.70–7.41). All tumor lesions had a maximum total immunostaining score for CEA expression of 12/12.ConclusionThis study demonstrated the potential of fluorescence imaging of CLM with SGM-101. CEA expression was observed in all tumors, and closed-field imaging showed excellent CEA specific targeting of the tracer to the tumor nodules. The full potential of SGM-101 for in vivo detection of the tracer can be achieved with improved minimal invasive imaging systems and optimal patient selection. Show less
Hoven, P. van den; Osterkamp, J.; Nerup, N.; Svendsen, M.B.S.; Vahrmeijer, A.; Vorst, J.R. van der; Achiam, M.P. 2023
PurposeIncorrect assessment of tissue perfusion carries a significant risk of complications in surgery. The use of near-infrared (NIR) fluorescence imaging with Indocyanine Green (ICG) presents a... Show morePurposeIncorrect assessment of tissue perfusion carries a significant risk of complications in surgery. The use of near-infrared (NIR) fluorescence imaging with Indocyanine Green (ICG) presents a possible solution. However, only through quantification of the fluorescence signal can an objective and reproducible evaluation of tissue perfusion be obtained. This narrative review aims to provide an overview of the available quantification methods for perfusion assessment using ICG NIR fluorescence imaging and to present an overview of current clinically utilized software implementations.MethodsPubMed was searched for clinical studies on the quantification of ICG NIR fluorescence imaging to assess tissue perfusion. Data on the utilized camera systems and performed methods of quantification were collected.ResultsEleven software programs for quantifying tissue perfusion using ICG NIR fluorescence imaging were identified. Five of the 11 programs have been described in three or more clinical studies, including Flow (R) 800, ROIs Software, IC Calc, SPY-Q (TM), and the Quest Research Framework (R). In addition, applying normalization to fluorescence intensity analysis was described for two software programs.ConclusionSeveral systems or software solutions provide a quantification of ICG fluorescence; however, intraoperative applications are scarce and quantification methods vary abundantly. In the widespread search for reliable quantification of perfusion with ICG NIR fluorescence imaging, standardization of quantification methods and data acquisition is essential. Show less
Purpose: Intraoperative identification of lung tumors can be challenging. Tumor-targeted fluorescence-guided surgery can provide surgeons with a tool for real-time intraoperative tumor detection.... Show morePurpose: Intraoperative identification of lung tumors can be challenging. Tumor-targeted fluorescence-guided surgery can provide surgeons with a tool for real-time intraoperative tumor detection. This study evaluated cell surface biomarkers, partially selected via data-driven selection software, as potential targets for fluorescence-guided surgery in non-small cell lung cancers: adenocarcinomas (ADC), adenocarcinomas in situ (AIS), and squamous cell carcinomas (SCC). Procedures: Formalin-fixed paraffin-embedded tissue slides of resection specimens from 15 patients with ADC and 15 patients with SCC were used and compared to healthy tissue. Molecular targets were selected based on two strategies: (1) a data-driven selection using > 275 multi-omics databases, literature, and experimental evidence; and (2) the availability of a fluorescent targeting ligand in advanced stages of clinical development. The selected targets were carbonic anhydrase 9 (CAIX), collagen type XVII alpha 1 chain (collagen XVII), glucose transporter 1 (GLUT1), G protein-coupled receptor 87 (GPR87), transmembrane protease serine 4 (TMPRSS4), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), folate receptor alpha (FR alpha), integrin alpha v beta 6 (alpha v beta 6), and urokinase-type plasminogen activator receptor (uPAR). Tumor expression of these targets was assessed by immunohistochemical staining. A total immunostaining score (TIS, range 0-12), combining the percentage and intensity of stained cells, was calculated. The most promising targets in ADC were explored in six AIS tissue slides to explore its potential in non-palpable lesions. Results: Statistically significant differences in TIS between healthy lung and tumor tissue for ADC samples were found for CEA, EpCAM, FR alpha, alpha v beta 6, CAIX, collagen XVII, GLUT-1, and TMPRSS4, and of these, CEA, CAIX, and collagen XVII were also found in AIS. For SCC, EpCAM, uPAR, CAIX, collagen XVII, and GLUT-1 were found to be overexpressed. Conclusions: EpCAM, CAIX, and Collagen XVII were identified using concomitant use of data-driven selection software and clinical evidence as promising targets for intraoperative fluorescence imaging for both major subtypes of non-small cell lung carcinomas. Show less
The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after... Show moreThe majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients. Show less
Hoven, P. van den; Verduijn, P.S.; Capelle, L. van; Tange, F.P.; Michi, M.; Corion, L.U.M.; ... ; Vorst, J.R. van der 2022
Background: One of the complications of free flap breast reconstruction is the oc-currence of skin and fat necrosis. Intra-operative use of near-infrared (NIR) fluorescence imag-ing with... Show moreBackground: One of the complications of free flap breast reconstruction is the oc-currence of skin and fat necrosis. Intra-operative use of near-infrared (NIR) fluorescence imag-ing with Indocyanine Green (ICG) has the potential to predict these complications. In this study, the quantification of the fluorescence intensity measured in free flap breast reconstruction was performed to gain insight into the perfusion patterns observed with ICG NIR fluorescence imag-ing.Methods: ICG NIR fluorescence imaging was performed in patients undergoing free flap breast reconstruction following mastectomy. After completion of the arterial and venous anastomosis, 7.5 mg ICG was administered intravenously. The fluorescence intensity over time was recorded using the Quest Spectrum Platform (R). Four regions of interest (ROI) were selected based on location and interpretation of the NIR fluorescence signal: (1) The perforator, (2) normal per -fusion, (3) questionable perfusion, and (4) low perfusion. Time-intensity curves were analyzed, and two parameters were extracted: Tmax and Tmax slopes.Results: Successful ICG NIR fluorescence imaging was performed in 13 patients undergoing 17 free flap procedures. Region selection included 16 perforators, 17 normal perfusions, 8 ques-tionable perfusions, and 5 low perfusion ROIs. Time-intensity curves of the perforator ROIs were comparable to the ROIs of normal perfusion and demonstrated a fast inflow. No outflow was observed for the ROIs with questionable and low perfusion.Conclusion: This study provides insight into the perfusion patterns observed with ICG NIR flu-orescence imaging in free flap breast reconstruction. Future studies should correlate quantita-tive parameters with clinical perfusion assessment and outcome.(c) 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Pub-lished by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ) Show less
Schie, P. van; Lelij, T.J.N. van der; Gerritsen, M.; Meijer, R.P.J.; Arkel, E.R.A. van; Fiocco, M.; ... ; Driel, P.B.A.A. van 2021
Purpose The purpose of this study was to assess whether the vascularisation of the meniscus could be visualised intra-operatively using near-infrared fluorescence (NIRF) imaging with indocyanine... Show morePurpose The purpose of this study was to assess whether the vascularisation of the meniscus could be visualised intra-operatively using near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) in patients undergoing total knee arthroplasty (TKA). Methods The anterior horn (i.e., Cooper classification: zones C and D) of the meniscus that was least affected (i.e., least degenerative) was removed during TKA surgery in ten patients to obtain a cross section of the inside of the meniscus. Thereafter, 10 mg of ICG was injected intravenously, and vascularisation of the cross section of the meniscus was assessed using the Quest spectrum NIRF camera system. We calculated the percentage of patients in whom vascularisation was observed intra-operatively using NIRF imaging compared to immunohistochemistry. Results Meniscal vascularisation using NIRF imaging was observed in six out of eight (75%) patients in whom vascularisation was demonstrated with immunohistochemistry. The median extent of vascularisation was 13% (interquartile range (IQR) 3-28%) using NIRF imaging and 15% (IQR 11-23%) using immunohistochemistry. Conclusion This study shows the potential of NIRF imaging to visualise vascularisation of the meniscus, as vascularisation was observed in six out of eight patients with histologically proven meniscal vascularisation. Show less
Objective. The aim of this study was to assess the superiority of ICG-Tc-99m-nanocolloid for the intraoperative visual detection of sentinel lymph nodes (SLNs) in vulvar squamous cell carcinoma ... Show moreObjective. The aim of this study was to assess the superiority of ICG-Tc-99m-nanocolloid for the intraoperative visual detection of sentinel lymph nodes (SLNs) in vulvar squamous cell carcinoma (VSCC) patients compared to standard SLN detection using Tc-99m-nanocolloid with blue dye.Methods. In this multicenter, randomized controlled trial, VSCC patients underwent either the standard SLN procedure or with the hybrid tracer ICG-Tc-99m-nanocolloid. The primary endpoint was the percentage of fluorescent SLNs compared to blue SLNs. Secondary endpoints were successful SLN procedures, surgical outcomes and postoperative complications.Results. Forty-eight patients were randomized to the standard (n = 24) or fluorescence imaging group (n = 24) using ICG-Tc-99m-nanocolloid. The percentage of blue SLNs was 65.3% compared to 92.5% fluorescent SLNs (p < 0.001). A successful SLN procedure was obtained in 92.1% of the groins in the standard group and 97.2% of the groins in the fluorescence imaging group (p = 0.33). Groups did not differ in surgical outcome, although more short-term postoperative complications were documented in the standard group (p = 0.041).Conclusions. Intraoperative visual detection of SLNs in patients with VSCC using ICG-Tc-99m-nanocolloid was superior compared to Tc-99m-nanocolloid and blue dye. The rate of successful SLN procedures between both groups was not significantly different. Fluorescence imaging has potential to be used routinely in the SLN procedure in VSCC patients to facilitate the search by direct visualization. Clinical Trial Registration: Netherlands Trial Register (Trial ID NL7443). (C) 2020 The Author(s). Published by Elsevier Inc. Show less
CONCLUSION: NIR fluorescence imaging can easily and safely be implemented in pituitary surgery. The timing of ICG administration is important for optimal results and warrants further study. It... Show moreCONCLUSION: NIR fluorescence imaging can easily and safely be implemented in pituitary surgery. The timing of ICG administration is important for optimal results and warrants further study. It appears that injection of ICG can best be postponed until some part of the normal pituitary gland is identified. Subsequent repeated low-dose ICG administrations improved the distinction between adenoma and gland. Show less
CONCLUSION: This study shows successful use of ICG: Nanocoll as lymphatic tracer for SLN detection in gastric cancer. Moreover, tumor-containing LNs outside the standard dissection planes were... Show moreCONCLUSION: This study shows successful use of ICG: Nanocoll as lymphatic tracer for SLN detection in gastric cancer. Moreover, tumor-containing LNs outside the standard dissection planes were identified. Show less
