Abstract

We report a dual-band normalization technique for in vivo quantification of the metabolic biomarker, protoporphyrin IX (PpIX), during brain tumor resection procedures. The accuracy of the approach was optimized in tissue simulating phantoms with varying absorption and scattering properties, validated with fluorimetric assessments on ex vivo brain tissue, and tested on human data acquired in vivo during fluorescence-guided surgery of brain tumors. The results demonstrate that the dual-band normalization technique allows PpIX concentrations to be accurately quantified by correction with reflectance data recorded and integrated within only two narrow wavelength intervals. The simplicity of the method lends itself to the enticing prospect that the method could be applicable to wide-field applications in quantitative fluorescence imaging and dosimetry in photodynamic therapy.

© 2012 Optical Society of America

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  1. P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
    [CrossRef]
  2. W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
    [CrossRef]
  3. R. Richards-Kortum and E. Sevick-Muraca, Annu. Rev. Phys. Chem. 47, 555 (1996).
    [CrossRef]
  4. R. S. Bradley and M. S. Thorniley, J. R. Soc. Interface 3, 1 (2006).
    [CrossRef]
  5. A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, J. Biomed. Opt. 15, 067006 (2010).
    [CrossRef]
  6. L. Lilge, C. O’Carroll, and B. C. Wilson, J. Photochem. Photobiol. B 39, 229 (1997).
    [CrossRef]

2011

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

2010

A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, J. Biomed. Opt. 15, 067006 (2010).
[CrossRef]

2006

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
[CrossRef]

R. S. Bradley and M. S. Thorniley, J. R. Soc. Interface 3, 1 (2006).
[CrossRef]

1997

L. Lilge, C. O’Carroll, and B. C. Wilson, J. Photochem. Photobiol. B 39, 229 (1997).
[CrossRef]

1996

R. Richards-Kortum and E. Sevick-Muraca, Annu. Rev. Phys. Chem. 47, 555 (1996).
[CrossRef]

Bradley, R. S.

R. S. Bradley and M. S. Thorniley, J. R. Soc. Interface 3, 1 (2006).
[CrossRef]

Erkmen, K.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Fan, X.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Harris, B. T.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Hartov, A.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Ji, S.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Khurana, M.

A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, J. Biomed. Opt. 15, 067006 (2010).
[CrossRef]

Kim, A.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, J. Biomed. Opt. 15, 067006 (2010).
[CrossRef]

Leblond, F.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Lilge, L.

L. Lilge, C. O’Carroll, and B. C. Wilson, J. Photochem. Photobiol. B 39, 229 (1997).
[CrossRef]

Meinel, T.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
[CrossRef]

Moriyama, Y.

A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, J. Biomed. Opt. 15, 067006 (2010).
[CrossRef]

O’Carroll, C.

L. Lilge, C. O’Carroll, and B. C. Wilson, J. Photochem. Photobiol. B 39, 229 (1997).
[CrossRef]

Paulsen, K. D.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Pichlmeier, U.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
[CrossRef]

Reulen, H. J.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
[CrossRef]

Richards-Kortum, R.

R. Richards-Kortum and E. Sevick-Muraca, Annu. Rev. Phys. Chem. 47, 555 (1996).
[CrossRef]

Roberts, D. W.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Sevick-Muraca, E.

R. Richards-Kortum and E. Sevick-Muraca, Annu. Rev. Phys. Chem. 47, 555 (1996).
[CrossRef]

Simmons, N. E.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Stummer, W.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
[CrossRef]

Thorniley, M. S.

R. S. Bradley and M. S. Thorniley, J. R. Soc. Interface 3, 1 (2006).
[CrossRef]

Tosteson, T. D.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Valdes, P. A.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

Wiestler, O. D.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
[CrossRef]

Wilson, B. C.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, J. Biomed. Opt. 15, 067006 (2010).
[CrossRef]

L. Lilge, C. O’Carroll, and B. C. Wilson, J. Photochem. Photobiol. B 39, 229 (1997).
[CrossRef]

Zanella, F.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
[CrossRef]

Annu. Rev. Phys. Chem.

R. Richards-Kortum and E. Sevick-Muraca, Annu. Rev. Phys. Chem. 47, 555 (1996).
[CrossRef]

J. Biomed. Opt.

A. Kim, M. Khurana, Y. Moriyama, and B. C. Wilson, J. Biomed. Opt. 15, 067006 (2010).
[CrossRef]

J. Neurosurg.

P. A. Valdes, F. Leblond, A. Kim, B. T. Harris, B. C. Wilson, X. Fan, T. D. Tosteson, A. Hartov, S. Ji, K. Erkmen, N. E. Simmons, K. D. Paulsen, and D. W. Roberts, J. Neurosurg. 115, 11 (2011).
[CrossRef]

J. Photochem. Photobiol. B

L. Lilge, C. O’Carroll, and B. C. Wilson, J. Photochem. Photobiol. B 39, 229 (1997).
[CrossRef]

J. R. Soc. Interface

R. S. Bradley and M. S. Thorniley, J. R. Soc. Interface 3, 1 (2006).
[CrossRef]

Lancet Oncol.

W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella, and H. J. Reulen, Lancet Oncol. 7, 392 (2006).
[CrossRef]

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Figures (3)

Fig. 1.
Fig. 1.

Raw and corrected emission spectra measured on the tissue-phantoms. Optical phantoms with three different PpIX concentrations and a range of absorption and scattering values were used: (a, b, c) varying absorption with constant scattering; (d, e, f) varying scattering with constant absorption. The value of α=0.7 is used in (c) and (f).

Fig. 2.
Fig. 2.

Relationship between the true PpIX concentration in phantoms based on (a) raw fluorescence intensity (λ=635nm), and (b) estimated CPpIX levels derived following correction of the raw fluorescence by division with ΦxRef (integrated reflectance in the range λ=465 to 485 nm) (ΦFluo/ΦxRef). (c) Empirical determination of the optimal α value for PpIX quantification. (d) Relationship between the estimated and actual PpIX concentration in phantoms following correction of the raw fluorescence by the product of ΦxRefΦmRefα for α=0.7. R2, coefficient of determination; RMSE, root mean square error.

Fig. 3.
Fig. 3.

ROC curves quantifying the performance of three different fluorescence correction methods for optical datasets acquired in vivo during 14 brain tumor resection procedures.

Equations (1)

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Φ(λ)=ΦFluo(λ)ΦxRef×(ΦmRef)α,

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