title: Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results.
abstract: Fluorescence-guided surgery (FGS) is a technique used to enhance visualization of tumor margins in order to increase the extent of tumor resection in glioma surgery. In this paper, we systematically review all clinically tested fluorescent agents for application in FGS for glioma and all preclinically tested agents with the potential for FGS for glioma.
  
  
  
  We searched the PubMed and Embase databases for all potentially relevant studies through March 2016. We assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression-free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.
  
  
  
  The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5-aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.
  
  
  
  5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives.
authors.affiliation: Department of Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Joeky T
authors.initials: JT
authors.lastname: Senders
authors.affiliation: Department of Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Ivo S
authors.initials: IS
authors.lastname: Muskens
authors.affiliation: Department of Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Schnoor
authors.affiliation: Department of Neurosurgery, Cushing Neurosurgery Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, 15 Francis Street, Boston, MA, 02115, USA.
authors.forename: Aditya V
authors.initials: AV
authors.lastname: Karhade
authors.affiliation: Department of Neurosurgery, Cushing Neurosurgery Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, 15 Francis Street, Boston, MA, 02115, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cote
authors.affiliation: Department of Neurosurgery, Cushing Neurosurgery Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, 15 Francis Street, Boston, MA, 02115, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Smith
authors.affiliation: Department of Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. m.l.d.broekman-4@umcutrecht.nl.
authors.forename: Marike L D
authors.initials: ML
authors.lastname: Broekman
mesh_terms: D000622:Aminolevulinic Acid; D000818:Animals; D001932:Brain Neoplasms / Q000601:surgery*; D005456:Fluorescent Dyes; D005910:Glioma / Q000601:surgery*; D006801:Humans; D019635:Neurosurgical Procedures / Q000379:methods*; D017319:Photosensitizing Agents
chemical_list: D005456:Fluorescent Dyes; D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid
keywords: 5-ALA, Fluorescein; Fluorescence-guided surgery; Glioma; Neurosurgery