title: Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery.
abstract: OBJECTIVE
  Previous studies in high-grade gliomas (HGGs) have indicated that protoporphyrin IX (PpIX) accumulates in higher concentrations in tumor tissue, and, when used to guide surgery, it has enabled improved resection leading to increased progression-free survival. Despite the benefits of complete resection and the advances in fluorescence-guided surgery, few studies have investigated the use of PpIX in low-grade gliomas (LGGs). Here, the authors describe their initial experience with 5-aminolevulinic acid (ALA)-induced PpIX fluorescence in a series of patients with LGG.
  
  
  METHODS
  Twelve patients with presumed LGGs underwent resection of their tumors after receiving 20 mg/kg of ALA approximately 3 hours prior to surgery under an institutional review board-approved protocol. Intraoperative assessments of the resulting PpIX emissions using both qualitative, visible fluorescence and quantitative measurements of PpIX concentration were obtained from tissue locations that were subsequently biopsied and evaluated histopathologically. Mixed models for random effects and receiver operating characteristic curve analysis for diagnostic performance were performed on the fluorescence data relative to the gold-standard histopathology.
  
  
  RESULTS
  Five of the 12 LGGs (1 ganglioglioma, 1 oligoastrocytoma, 1 pleomorphic xanthoastrocytoma, 1 oligodendroglioma, and 1 ependymoma) demonstrated at least 1 instance of visible fluorescence during surgery. Visible fluorescence evaluated on a specimen-by-specimen basis yielded a diagnostic accuracy of 38.0% (cutoff threshold: visible fluorescence score ≥ 1, area under the curve = 0.514). Quantitative fluorescence yielded a diagnostic accuracy of 67% (for a cutoff threshold of the concentration of PpIX [CPpIX] > 0.0056 μg/ml, area under the curve = 0.66). The authors found that 45% (9/20) of nonvisibly fluorescent tumor specimens, which would have otherwise gone undetected, accumulated diagnostically significant levels of CPpIX that were detected quantitatively.
  
  
  CONCLUSIONS
  The authors' initial experience with ALA-induced PpIX fluorescence in LGGs concurs with other literature reports that the resulting visual fluorescence has poor diagnostic accuracy. However, the authors also found that diagnostically significant levels of CPpIX do accumulate in LGGs, and the resulting fluorescence emissions are very often below the detection threshold of current visual fluorescence imaging methods. Indeed, at least in the authors' initial experience reported here, if quantitative detection methods are deployed, the diagnostic performance of ALA-induced PpIX fluorescence in LGGs approaches the accuracy associated with visual fluorescence in HGGs.
authors.affiliation: Department of Neurosurgery, Brigham and Women's/Boston Children's Hospitals, Harvard Medical School;|Geisel School of Medicine at Dartmouth, Hanover;|Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon;|Thayer School of Engineering, Hanover, New Hampshire;
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Valdés
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts;|Geisel School of Medicine at Dartmouth, Hanover;
authors.forename: Valerie
authors.initials: V
authors.lastname: Jacobs
authors.affiliation: Georgetown University Medical Center, Washington, DC;
authors.forename: Brent T
authors.initials: BT
authors.lastname: Harris
authors.affiliation: Ontario Cancer Institute, University of Toronto, Ontario; and.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
authors.affiliation: Department of Engineering Physics, Polytechnique Montreal, Quebec, Canada.
authors.forename: Frederic
authors.initials: F
authors.lastname: Leblond
authors.affiliation: Thayer School of Engineering, Hanover, New Hampshire;
authors.forename: Keith D
authors.initials: KD
authors.lastname: Paulsen
authors.affiliation: Geisel School of Medicine at Dartmouth, Hanover;|Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon;
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000622:Aminolevulinic Acid; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000601:surgery*; D005260:Female; D005453:Fluorescence; D005910:Glioma / Q000378:metabolism / Q000601:surgery*; D006801:Humans; D008297:Male; D008875:Middle Aged; D038361:Neuronavigation / Q000379:methods*; D017319:Photosensitizing Agents; D011524:Protoporphyrins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX
keywords: 5-aminolevulinic acid; ALA = 5-aminolevulinic acid; AUC = area under the curve; CPpIX = concentration of PpIX; HGG = high-grade glioma; LGG = low-grade glioma; NPV = negative predictive value; PPV = positive predictive value; PpIX = protoporphyrin IX; ROC = receiver operating characteristic; biomedical optics; brain tumor; fluorescence-guided surgery; low-grade glioma; oncology; optical spectroscopy; protoporphyrin IX; quantitative fluorescence