title: Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δ-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article.
abstract: OBJECTIVE
  The aim of this study was to investigate the relationships between intraoperative fluorescence, features on MR imaging, and neuropathological parameters in 11 cases of newly diagnosed glioblastoma multiforme (GBM) treated using protoporphyrin IX (PpIX) fluorescence-guided resection.
  
  
  METHODS
  In 11 patients with a newly diagnosed GBM, δ-aminolevulinic acid (ALA) was administered to enhance endogenous synthesis of the fluorophore PpIX. The patients then underwent fluorescence-guided resection, coregistered with conventional neuronavigational image guidance. Biopsy specimens were collected at different times during surgery and assigned a fluorescence level of 0-3 (0, no fluorescence; 1, low fluorescence; 2, moderate fluorescence; or 3, high fluorescence). Contrast enhancement on MR imaging was quantified using two image metrics: 1) Gd-enhanced signal intensity (GdE) on T1-weighted subtraction MR image volumes, and 2) normalized contrast ratios (nCRs) in T1-weighted, postGd-injection MR image volumes for each biopsy specimen, using the biopsy-specific image-space coordinate transformation provided by the navigation system. Subsequently, each GdE and nCR value was grouped into one of two fluorescence categories, defined by its corresponding biopsy specimen fluorescence assessment as negative fluorescence (fluorescence level 0) or positive fluorescence (fluorescence level 1, 2, or 3). A single neuropathologist analyzed the H & E-stained tissue slides of each biopsy specimen and measured three neuropathological parameters: 1) histopathological score (0-IV); 2) tumor burden score (0-III); and 3) necrotic burden score (0-III).
  
  
  RESULTS
  Mixed-model analyses with random effects for individuals show a highly statistically significant difference between fluorescing and nonfluorescing tissue in GdE (mean difference 8.33, p = 0.018) and nCRs (mean difference 5.15, p < 0.001). An analysis of association demonstrated a significant relationship between the levels of intraoperative fluorescence and histopathological score (χ(2) = 58.8, p < 0.001), between fluorescence levels and tumor burden (χ(2) = 42.7, p < 0.001), and between fluorescence levels and necrotic burden (χ(2) = 30.9, p < 0.001). The corresponding Spearman rank correlation coefficients were 0.51 (p < 0.001) for fluorescence and histopathological score, and 0.49 (p < 0.001) for fluorescence and tumor burden, suggesting a strongly positive relationship for each of these variables.
  
  
  CONCLUSIONS
  These results demonstrate a significant relationship between contrast enhancement on preoperative MR imaging and observable intraoperative PpIX fluorescence. The finding that preoperative MR image signatures are predictive of intraoperative PpIX fluorescence is of practical importance for identifying candidates for the procedure. Furthermore, this study provides evidence that a strong relationship exists between tumor aggressiveness and the degree of tissue fluorescence that is observable intraoperatively, and that observable fluorescence has an excellent positive predictive value but a low negative predictive value.
authors.affiliation: Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA. David.W.Roberts@dartmouth.edu
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Valdés
authors.forename: Brent T
authors.initials: BT
authors.lastname: Harris
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Fontaine
authors.forename: Alexander
authors.initials: A
authors.lastname: Hartov
authors.forename: Xiaoyao
authors.initials: X
authors.lastname: Fan
authors.forename: Songbai
authors.initials: S
authors.lastname: Ji
authors.forename: S Scott
authors.initials: SS
authors.lastname: Lollis
authors.forename: Brian W
authors.initials: BW
authors.lastname: Pogue
authors.forename: Frederic
authors.initials: F
authors.lastname: Leblond
authors.forename: Tor D
authors.initials: TD
authors.lastname: Tosteson
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
authors.forename: Keith D
authors.initials: KD
authors.lastname: Paulsen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000622:Aminolevulinic Acid; D001706:Biopsy; D001932:Brain Neoplasms / Q000473:pathology* / Q000601:surgery*; D003627:Data Interpretation, Statistical; D005260:Female; D005453:Fluorescence; D005910:Glioma / Q000473:pathology* / Q000601:surgery*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D019635:Neurosurgical Procedures / Q000379:methods*; D016612:Paraffin Embedding; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D025321:Surgery, Computer-Assisted / Q000379:methods*
chemical_list: D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX