Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker

Clinical article

Pablo A. Valdés Thayer School of Engineering, and
Dartmouth Medical School, Dartmouth College, Hanover;

Search for other papers by Pablo A. Valdés in
Current site
Google Scholar
PubMed
Close
 B.S.
,
Frederic Leblond Thayer School of Engineering, and

Search for other papers by Frederic Leblond in
Current site
Google Scholar
PubMed
Close
 Ph.D.
,
Anthony Kim University of Toronto, Ontario Cancer Institute/University Health Network, Toronto, Ontario, Canada

Search for other papers by Anthony Kim in
Current site
Google Scholar
PubMed
Close
 Ph.D.
,
Brent T. Harris Dartmouth Medical School, Dartmouth College, Hanover;
Department of Pathology, and

Search for other papers by Brent T. Harris in
Current site
Google Scholar
PubMed
Close
 M.D., Ph.D.
,
Brian C. Wilson University of Toronto, Ontario Cancer Institute/University Health Network, Toronto, Ontario, Canada

Search for other papers by Brian C. Wilson in
Current site
Google Scholar
PubMed
Close
 Ph.D.
,
Xiaoyao Fan Thayer School of Engineering, and

Search for other papers by Xiaoyao Fan in
Current site
Google Scholar
PubMed
Close
 B.E.
,
Tor D. Tosteson Dartmouth Medical School, Dartmouth College, Hanover;
Norris Cotton Cancer Center,

Search for other papers by Tor D. Tosteson in
Current site
Google Scholar
PubMed
Close
 Sc.D.
,
Alex Hartov Thayer School of Engineering, and

Search for other papers by Alex Hartov in
Current site
Google Scholar
PubMed
Close
 Ph.D.
,
Songbai Ji Thayer School of Engineering, and

Search for other papers by Songbai Ji in
Current site
Google Scholar
PubMed
Close
 D.Sc.
,
Kadir Erkmen Dartmouth Medical School, Dartmouth College, Hanover;
Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; and

Search for other papers by Kadir Erkmen in
Current site
Google Scholar
PubMed
Close
 M.D.
,
Nathan E. Simmons Dartmouth Medical School, Dartmouth College, Hanover;
Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; and

Search for other papers by Nathan E. Simmons in
Current site
Google Scholar
PubMed
Close
 M.D.
,
Keith D. Paulsen Thayer School of Engineering, and
Norris Cotton Cancer Center,

Search for other papers by Keith D. Paulsen in
Current site
Google Scholar
PubMed
Close
 Ph.D.
, and
David W. Roberts Dartmouth Medical School, Dartmouth College, Hanover;
Norris Cotton Cancer Center,
Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; and

Search for other papers by David W. Roberts in
Current site
Google Scholar
PubMed
Close
 M.D.
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $536.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $636.00
USD  $45.00
USD  $536.00
USD  $636.00
Print or Print + Online Sign in

Object

Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies.

Methods

The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board–approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo.

Results

A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeon's visual perception were classified correctly in an analysis of all tumors.

Conclusions

These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of intracranial tumors.

Abbreviations used in this paper:

ALA = δ-aminolevulinic acid; AUC = area under the curve; A615 = total light intensity associated with the integration of the fluorescence emission spectrum from λ = 615 to 740 nm; A660 = total light intensity associated with the integration of the fluorescence emission spectrum from λ = 660 to 740 nm; CPpIX = absolute concentration of PpIX; HGG = high-grade glioma; LGG = low-grade glioma; NPV = negative predictive value; PpIX = protoporphyrin IX; PPV = positive predictive value; P635 = peak intensity of the fluorescence emission spectrum at λ = 635 nm; P710 = peak intensity of the fluorescence emission spectrum at λ = 710 nm; ROC = receiver operating characteristic.
  • Collapse
  • Expand
  • 1

    Brenner H, & Gefeller O: Variation of sensitivity, specificity, likelihood ratios and predictive values with disease prevalence. Stat Med 16:981991, 1997

  • 2

    Collaud S, , Juzeniene A, , Moan J, & Lange N: On the selectivity of 5-aminolevulinic acid-induced protoporphyrin IX formation. Curr Med Chem Anticancer Agents 4:301316, 2004

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Dysart JS, & Patterson MS: Photobleaching kinetics, photoproduct formation, and dose estimation during ALA induced PpIX PDT of MLL cells under well oxygenated and hypoxic conditions. Photochem Photobiol Sci 5:7381, 2006

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Floeth FW, & Stummer W: The value of metabolic imaging in diagnosis and resection of cerebral gliomas. Nat Clin Pract Neurol 1:6263, 2005

  • 5

    Galloway RL Jr: The process and development of image-guided procedures. Annu Rev Biomed Eng 3:83108, 2001

  • 6

    Haj-Hosseini N, , Richter J, , Andersson-Engels S, & Wårdell K: Optical touch pointer for fluorescence guided glioblastoma resection using 5-aminolevulinic acid. Lasers Surg Med 42:914, 2010

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Kim A, , Khurana M, , Moriyama Y, & Wilson BC: Quantification of in vivo fluorescence decoupled from the effects of tissue optical properties using fiber-optic spectroscopy measurements. J Biomed Opt 15:067006, 2010

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Nabavi A, , Thurm H, , Zountsas B, , Pietsch T, , Lanfermann H, & Pichlmeier U, et al.: Five-aminolevulinic acid for fluorescence-guided resection of recurrent malignant gliomas: a phase ii study. Neurosurgery 65:10701077, 2009

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Pichlmeier U, , Bink A, , Schackert G, & Stummer W: Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 10:10251034, 2008

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Pogue BW, , Gibbs-Strauss SL, , Valdes PA, , Samkoe KS, , Roberts DW, & Paulsen KD: Review of neurosurgical fluorescence imaging methodologies. IEEE J Sel Top Quantum Electron 16:493505, 2010

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Pouratian N, , Asthagiri A, , Jagannathan J, , Shaffrey ME, & Schiff D: Surgery insight: the role of surgery in the management of low-grade gliomas. Nat Clin Pract Neurol 3:628639, 2007

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Ramanujam N: Fluorescence spectroscopy of neoplastic and non-neoplastic tissues. Neoplasia 2:89117, 2000

  • 13

    Richards-Kortum R, & Sevick-Muraca E: Quantitative optical spectroscopy for tissue diagnosis. Annu Rev Phys Chem 47:555606, 1996

  • 14

    Roberts DW, , Valdes PA, , Harris BT, , Fontaine KM, , Hartov A, & Fan X, et al.: 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. J Neurosurg 114:595603, 2011

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Shapiro DE: The interpretation of diagnostic tests. Stat Methods Med Res 8:113134, 1999

  • 16

    Sokolov K, , Follen M, & Richards-Kortum R: Optical spectroscopy for detection of neoplasia. Curr Opin Chem Biol 6:651658, 2002

  • 17

    Stummer W, , Novotny A, , Stepp H, , Goetz C, , Bise K, & Reulen HJ: Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93:10031013, 2000

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Stummer W, , Pichlmeier U, , Meinel T, , Wiestler OD, , Zanella F, & Reulen HJ: Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392401, 2006

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Stummer W, , Reulen HJ, , Meinel T, , Pichlmeier U, , Schumacher W, & Tonn JC, et al.: Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564576, 2008

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Uematsu Y, , Owai Y, , Okita R, , Tanaka Y, & Itakura T: The usefulness and problem of intraoperative rapid diagnosis in surgical neuropathology. Brain Tumor Pathol 24:4752, 2007

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Valdés PA, , Fan X, , Ji S, , Harris BT, , Paulsen KD, & Roberts DW: Estimation of brain deformation for volumetric image updating in protoporphyrin IX fluorescence-guided resection. Stereotact Funct Neurosurg 88:110, 2010

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Weissleder R, & Pittet MJ: Imaging in the era of molecular oncology. Nature 452:580589, 2008

  • 23

    Widhalm G, , Wolfsberger S, , Minchev G, , Woehrer A, , Krssak M, & Czech T, et al.: 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement. Cancer 116:15451552, 2010

    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 4736 1343 237
Full Text Views 566 77 2
PDF Downloads 339 55 0
EPUB Downloads 0 0 0