Fluorescence grid analysis for the evaluation of piecemeal surgery in sinonasal inverted papilloma: a proof-of-concept study

Abstract

Purpose Local recurrence occurs in ~ 19% of sinonasal inverted papilloma (SNIP) surgeries and is strongly associated with incomplete resection. During surgery, it is technically challenging to visualize and resect all SNIP tissue in this anatomically complex area. Proteins that are overexpressed in SNIP, such as vascular endothelial growth factor (VEGF), may serve as a target for fluorescence molecular imaging to guide surgical removal of SNIP. A proof-of-concept study was performed to investigate if the VEGF-targeted near-infrared fluorescent tracer bevacizumab-800CW specifically localizes in SNIP and whether it could be used as a clinical tool to guide SNIP surgery. Methods In five patients diagnosed with SNIP, 10 mg of bevacizumab-800CW was intravenously administered 3 days prior to surgery. Fluorescence molecular imaging was performed in vivo during surgery and ex vivo during the processing of the surgical specimen. Fluorescence signals were correlated with final histopathology and VEGF-A immunohistochemistry. We introduced a fluorescence grid analysis to assess the fluorescence signal in individual tissue fragments, due to the nature of the surgical procedure (i.e., piecemeal resection) allowing the detection of small SNIP residues and location of the tracer ex vivo. Results In all patients, fluorescence signal was detected in vivo during endoscopic SNIP surgery. Using ex vivo fluorescence grid analysis, we were able to correlate bevacizumab-800CW fluorescence of individual tissue fragments with final histopathology. Fluorescence grid analysis showed substantial variability in mean fluorescence intensity (FImean), with SNIP tissue showing a median FImean of 77.54 (IQR 50.47–112.30) compared to 35.99 (IQR 21.48–57.81) in uninvolved tissue (p < 0.0001), although the diagnostic ability was limited with an area under the curve of 0.78. Conclusions A fluorescence grid analysis could serve as a valid method to evaluate fluorescence molecular imaging in piecemeal surgeries. As such, although substantial differences were observed in fluorescence intensities, VEGF-A may not be the ideal target for SNIP surgery. Trial registration NCT03925285.

Detection of Tumour-Targeted IRDye800CW Tracer with Commercially Available Laparoscopic Surgical Systems

“…A high sensitivity of laparoscopic NIRF systems for a tracer is one of the six key features described by Dsouza et al and is especially important for tracers in microdosages [14]. However, micro-dosages of tumour-targeted bevacizumab-800CW have already been used for a broad range of indications with (experimental) open-air and endoscopic systems [18,19,21,24,57,59,[73][74][75][76]. Thus, translation to optimised laparoscopes should be achievable.…”

“…Multiple commercially available open-air NIRF camera systems can detect IRDye800CW (absorption: ~780 nm, excitation: ~800 nm [11,12]), but are primarily intended for ICG (absorption: ~800 nm, excitation: ~830 nm [13]) and cannot be used for minimally invasive surgery [14]. Bevacizumab-800CW is a tumour-targeted tracer, aimed at vascular endothelial growth factor α (VEGFα), which has been used in multiple clinical studies [9,[15][16][17][18][19][20][21][22]. Likewise, cetuximab-800CW, aimed at endothelial growth factor, is used in multiple clinical trials [23,24], and various other antibodies conjugated to IRDye800CW are currently investigated [25][26][27] since the process of developing these tracers is relatively simple compared to developing a new investigational drug or tracer [27,28].…”