title: Fluorescence guided surgery and tracer-dose, fact or fiction?
abstract: BACKGROUND
  Fluorescence guidance is an upcoming methodology to improve surgical accuracy. Challenging herein is the identification of the minimum dose at which the tracer can be detected with a clinical-grade fluorescence camera. Using a hybrid tracer such as indocyanine green (ICG)-(99m)Tc-nanocolloid, it has become possible to determine the accumulation of tracer and correlate this to intraoperative fluorescence-based identification rates. In the current study, we determined the lower detection limit of tracer at which intraoperative fluorescence guidance was still feasible.
  
  
  METHODS
  Size exclusion chromatography (SEC) provided a laboratory set-up to analyze the chemical content and to simulate the migratory behavior of ICG-nanocolloid in tissue. Tracer accumulation and intraoperative fluorescence detection findings were derived from a retrospective analysis of 20 head-and-neck melanoma patients, 40 penile and 20 prostate cancer patients scheduled for sentinel node (SN) biopsy using ICG-(99m)Tc-nanocolloid. In these patients, following tracer injection, single photon emission computed tomography fused with computed tomography (SPECT/CT) was used to identify the SN(s). The percentage injected dose (% ID), the amount of ICG (in nmol), and the concentration of ICG in the SNs (in μM) was assessed for SNs detected on SPECT/CT and correlated with the intraoperative fluorescence imaging findings.
  
  
  RESULTS
  SEC determined that in the hybrid tracer formulation, 41 % (standard deviation: 12 %) of ICG was present in nanocolloid-bound form. In the SNs detected using fluorescence guidance a median of 0.88 % ID was present, compared to a median of 0.25 % ID in the non-fluorescent SNs (p-value < 0.001). The % ID values could be correlated to the amount ICG in a SN (range: 0.003-10.8 nmol) and the concentration of ICG in a SN (range: 0.006-64.6 μM).
  
  
  CONCLUSIONS
  The ability to provide intraoperative fluorescence guidance is dependent on the amount and concentration of the fluorescent dye accumulated in the lesion(s) of interest. Our findings indicate that intraoperative fluorescence detection with ICG is possible above a μM concentration.
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, C2-S zone, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.|Department of Nuclear Medicine, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Gijs H
authors.initials: GH
authors.lastname: KleinJan
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, C2-S zone, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.
authors.forename: Anton
authors.initials: A
authors.lastname: Bunschoten
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, C2-S zone, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.|Department of Urology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Nynke S
authors.initials: NS
authors.lastname: van den Berg
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, C2-S zone, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.|Department of Nuclear Medicine, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Renato A Valdès
authors.initials: RA
authors.lastname: Olmos
authors.affiliation: Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: W Martin C
authors.initials: WM
authors.lastname: Klop
authors.affiliation: Department of Urology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Simon
authors.initials: S
authors.lastname: Horenblas
authors.affiliation: Department of Urology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Henk G
authors.initials: HG
authors.lastname: van der Poel
authors.affiliation: Pharmaceutical Radiochemistry, Technical University Munich, Walther-Meißner-Str. 3, 85748, Garching, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.affiliation: Interventional Molecular Imaging Laboratory, Department of Radiology, C2-S zone, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands. F.W.B.van_Leeuwen@lumc.nl.|Department of Urology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. F.W.B.van_Leeuwen@lumc.nl.|Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. F.W.B.van_Leeuwen@lumc.nl.
authors.forename: Fijs W B
authors.initials: FW
authors.lastname: van Leeuwen
mesh_terms: D006801:Humans; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000601:surgery*; D061848:Optical Imaging / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000071036:Sentinel Lymph Node / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000601:surgery; D025321:Surgery, Computer-Assisted / Q000379:methods*; D013668:Technetium Tc 99m Aggregated Albumin / Q000493:pharmacokinetics*
chemical_list: D019275:Radiopharmaceuticals; D013668:Technetium Tc 99m Aggregated Albumin; C083602:technetium Tc 99m nanocolloid
keywords: Fluorescence-guided surgery; Microdosing; Multimodal; SPECT/CT; Sentinel node