Intraoperative molecular imaging of colorectal lung metastases with SGM-101: a feasibility study.

PURPOSE: Metastasectomy 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. METHODS: This 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. RESULTS: Thirteen 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. CONCLUSION: This 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. TRIAL REGISTRATION: The study was registered in ClinicalTrial.gov under identifier NCT04737213 at February 2021.

Quantification of indocyanine green near-infrared fluorescence bowel perfusion assessment in colorectal surgery.

BACKGROUND: Indocyanine green near-infrared fluorescence bowel perfusion assessment has shown its potential benefit in preventing anastomotic leakage. However, the surgeon's subjective visual interpretation of the fluorescence signal limits the validity and reproducibility of the technique. Therefore, this study aimed to identify objective quantified bowel perfusion patterns in patients undergoing colorectal surgery using a standardized imaging protocol. METHOD: A standardized fluorescence video was recorded. Postoperatively, the fluorescence videos were quantified by drawing contiguous region of interests (ROIs) on the bowel. For each ROI, a time-intensity curve was plotted from which perfusion parameters (n = 10) were derived and analyzed. Furthermore, the inter-observer agreement of the surgeon's subjective interpretation of the fluorescence signal was assessed. RESULTS: Twenty patients who underwent colorectal surgery were included in the study. Based on the quantified time-intensity curves, three different perfusion patterns were identified. Similar for both the ileum and colon, perfusion pattern 1 had a steep inflow that reached its peak fluorescence intensity rapidly, followed by a steep outflow. Perfusion pattern 2 had a relatively flat outflow slope immediately followed by its plateau phase. Perfusion pattern 3 only reached its peak fluorescence intensity after 3 min with a slow inflow gradient preceding it. The inter-observer agreement was poor-moderate (Intraclass Correlation Coefficient (ICC): 0.378, 95% CI 0.210-0.579). CONCLUSION: This study showed that quantification of bowel perfusion is a feasible method to differentiate between different perfusion patterns. In addition, the poor-moderate inter-observer agreement of the subjective interpretation of the fluorescence signal between surgeons emphasizes the need for objective quantification.

Semi-automatic standardized analysis method to objectively evaluate near-infrared fluorescent dyes in image-guided surgery.

Significance: Near-infrared fluorescence imaging still lacks a standardized, objective method to evaluate fluorescent dye efficacy in oncological surgical applications. This results in difficulties in translation between preclinical to clinical studies with fluorescent dyes and in the reproduction of results between studies, which in turn hampers further clinical translation of novel fluorescent dyes. Aim: Our aim is to develop and evaluate a semi-automatic standardized method to objectively assess fluorescent signals in resected tissue. Approach: A standardized imaging procedure was designed and quantitative analysis methods were developed to evaluate non-targeted and tumor-targeted fluorescent dyes. The developed analysis methods included manual selection of region of interest (ROI) on white light images, automated fluorescence signal ROI selection, and automatic quantitative image analysis. The proposed analysis method was then compared with a conventional analysis method, where fluorescence signal ROIs were manually selected on fluorescence images. Dice similarity coefficients and intraclass correlation coefficients were calculated to determine the inter- and intraobserver variabilities of the ROI selections and the determined signal- and tumor-to-background ratios. Results: The proposed non-targeted fluorescent dyes analysis method showed statistically significantly improved variabilities after application on indocyanine green specimens. For specimens with the targeted dye SGM-101, the variability of the background ROI selection was statistically significantly improved by implementing the proposed method. Conclusion: Semi-automatic methods for standardized quantitative analysis of fluorescence images were successfully developed and showed promising results to further improve the reproducibility and standardization of clinical studies evaluating fluorescent dyes.

A quantitative assessment of perfusion of the gastric conduit after oesophagectomy using near-infrared fluorescence with indocyanine green.

INTRODUCTION: Anastomotic leakage is a severe complication after oesophageal resection with gastric conduit reconstruction. Poor perfusion of the gastric conduit plays an important role in the development of anastomotic leakage. Quantitative near-infrared (NIR) fluorescence angiography with indocyanine green (ICG-FA) is an objective technique that can be used for perfusion assessment. This study aims to assess perfusion patterns of the gastric conduit with quantitative ICG-FA. METHODS: In this exploratory study, 20 patients undergoing oesophagectomy with gastric conduit reconstruction were included. A standardized NIR ICG-FA video of the gastric conduit was recorded. Postoperatively, the videos were quantified. Primary outcomes were the time-intensity curves and nine perfusion parameters from contiguous regions of interest on the gastric conduit. A secondary outcome was the inter-observer agreement of subjective interpretation of the ICG-FA videos between six surgeons. The inter-observer agreement was tested with an intraclass correlation coefficient (ICC). RESULTS: In a total of 427 curves, three distinct perfusion patterns were recognized: pattern 1 (steep inflow, steep outflow); pattern 2 (steep inflow, minor outflow); and pattern 3 (slow inflow, no outflow). All perfusion parameters were significantly different between the perfusion patterns. The inter-observer agreement was poor - moderate (ICC:0.345,95%CI:0.164-0.584). DISCUSSION: This was the first study to describe perfusion patterns of the complete gastric conduit after oesophagectomy. Three distinct perfusion patterns were observed. The poor inter-observer agreement of the subjective assessment underlines the need for quantification of ICG-FA of the gastric conduit. Further studies should evaluate the predictive value of perfusion patterns and parameters on anastomotic leakage.

Integration of Three-Dimensional Liver Models in a Multimodal Image-Guided Robotic Liver Surgery Cockpit.

Background: Robotic liver surgery represents the most recent evolution in the field of minimally-invasive liver surgery. For planning and guidance of liver resections, surgeons currently rely on preoperative 2-dimensional (2D) CT and/or MR imaging and intraoperative ultrasonography. Translating 2D images into digital 3-dimensional (3D) models may improve both preoperative planning and surgical guidance. The da Vinci® robotic surgical system is a platform suitable for the integration of multiple imaging modalities into one single view. In this study, we describe multimodal imaging options and introduce the Robotic Liver Surgery Cockpit; Methods: in-house developed software was used and validated for segmentation and registration to create a virtual reality 3D model of the liver based on preoperative imaging. The accuracy of the 3D models in the clinical setting was objectively assessed in 15 patients by measuring tumor diameters and subjectively with a postoperative conducted questionnaire; Results: Implementation and applicability of the 3D model in the surgical cockpit was feasible in all patients and the quality of the 3D reconstructions was high in 14 (93%) of cases. Tumor diameters measured on CT and/or MR imaging were comparable to automated measurements using the segmentation software and 3D models; Conclusions: the 3D model was successfully incorporated in the robotic surgery console as part of a multimodality imaging platform and aided the surgeon in planning and guidance of the resection. Future studies should focus on further automation of 3D rendering and progress into augmented reality.

AVOID; a phase III, randomised controlled trial using indocyanine green for the prevention of anastomotic leakage in colorectal surgery.

INTRODUCTION: Anastomotic leakage (AL) is one of the major complications after colorectal surgery. Compromised tissue perfusion at the anastomosis site increases the risk of AL. Several cohort studies have shown that indocyanine green (ICG) combined with fluorescent near-infrared imaging is a feasible and reproducible technique for real-time intraoperative imaging of tissue perfusion, leading to reduced leakage rates after colorectal resection. Unfortunately, these studies were not randomised. Therefore, we propose a randomised controlled trial to assess the value of ICG-guided surgery in reducing AL after colorectal surgery. METHODS AND ANALYSIS: A multicentre, randomised controlled clinical trial will be conducted to assess the benefit of ICG-guided surgery in preventing AL. A total of 978 patients scheduled for colorectal surgery will be included. Patients will be randomised between the Fluorescence Guided Bowel Anastomosis group and the Conventional Bowel Anastomosis group. The primary endpoint is clinically relevant AL (defined as requiring active therapeutic intervention or reoperation) within 90 days after surgery. Among the secondary endpoints are 30-day clinically relevant AL, all-cause postoperative complications, all-cause and AL-related mortality, surgical and non-surgical reinterventions, total surgical time, length of hospital stay and all-cause and AL-related readmittance. ETHICS AND DISSEMINATION: This protocol has been approved by the Medical Ethical Committee Leiden-Den Haag-Delft (METC-LDD) and is registered at ClinicalTrials.gov and trialregister.nl. The results of this study will be reported through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04712032; NL7502.

Three-dimensional quantitative margin assessment in patients with colorectal liver metastases treated with percutaneous thermal ablation using semi-automatic rigid MRI/CECT-CECT co-registration.

PURPOSE: To assess the quantitative minimal ablation margin (MAM) in patients with colorectal liver metastases (CRLM) treated with percutaneous thermal ablation (TA) and correlate the quantitative MAM with local tumour recurrence (LTR). METHOD: Thirty-nine of 143 patients with solitary or multiple CRLM who underwent a first percutaneous TA procedure between January 2011 and May 2020 were considered eligible for study enrolment. Image fusion of pre- and post-ablation scans and 3D quantitative MAM assessment was performed using the in-house developed semi-automatic rigid MRI/CECT-CECT co-registration software deLIVERed. The quantitative MAM was analysed and correlated with LTR. RESULTS: Eighteen (46 %) patients were additionally excluded from further analyses due to suboptimal co-registration (quality co-registration score ≤ 3). The quality of co-registration was considered sufficient in 21 (54 %) patients with a total of 29 CRLM. LTR was found in 5 of 29 (17 %) TA-treated CRLM. In total, 12 (41 %) negative MAMs were measured (mean MAM -4.7 ± 2.7 mm). Negative MAMs were significantly more frequently seen in patients who developed LTR (100 %) compared to those without LTR (29 %; p = 0.003). The median MAM of patients who developed LTR (-6.6 mm (IQR -9.5 to -4.6)) was significantly smaller compared to the median MAM of patients without LTR (0.5 mm (IQR -1.8 to 3.0); p < 0.001). The ROC curve showed high accuracy in predicting LTR for the quantitative MAM (area under the curve of 0.975 ± 0.029). CONCLUSION: This study demonstrated the feasibility of 3D quantitative MAM assessment, using deLIVERed co-registration software, to assess technical success of TA in patients with CRLM and to predict LTR.