computed-tomography-guided-time-domain-diffuse-fluorescence

Computed Tomography-guided Time-domain Diffuse Fluorescence Tomography in Small Animals for Localization of Cancer Biomarkers

Small animal fluorescence molecular imaging (FMI) can be a powerful tool for preclinical drug discovery and development studies1. However, light ...

Dartmouth College

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.

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.

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.

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

Complete resection of skull base meningiomas provides patients with the best chance for a cure; however, surgery is frequently difficult given the proximity of lesions to vital structures, such as cranial nerves, major vessels, and venous sinuses. Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative assessment of protoporphyrin IX (PpIX) fluorescence following the exogenous administration of 5-aminolevulinic acid (ALA) has demonstrated utility in malignant glioma resection but limited use in meningiomas. Here the authors demonstrate the use of ALA-induced PpIX fluorescence guidance in resecting a skull base meningioma and elaborate on the advantages and disadvantages provided by both quantitative and qualitative fluorescence methodologies in skull base meningioma resection.

Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas.

Biomarkers are indicators of biological processes and hold promise for the diagnosis and treatment of disease. Gliomas represent a heterogeneous group of brain tumors with marked intra- and inter-tumor variability. The extent of surgical resection is a significant factor influencing post-surgical recurrence and prognosis. Here, we used fluorescence and reflectance spectral signatures for in vivo quantification of multiple biomarkers during glioma surgery, with fluorescence contrast provided by exogenously-induced protoporphyrin IX (PpIX) following administration of 5-aminolevulinic acid. We performed light-transport modeling to quantify multiple biomarkers indicative of tumor biological processes, including the local concentration of PpIX and associated photoproducts, total hemoglobin concentration, oxygen saturation, and optical scattering parameters. We developed a diagnostic algorithm for intra-operative tissue delineation that accounts for the combined tumor-specific predictive capabilities of these quantitative biomarkers. Tumor tissue delineation achieved accuracies of up to 94% (specificity = 94%, sensitivity = 94%) across a range of glioma histologies beyond current state-of-the-art optical approaches, including state-of-the-art fluorescence image guidance. This multiple biomarker strategy opens the door to optical methods for surgical guidance that use quantification of well-established neoplastic processes. Future work would seek to validate the predictive power of this proof-of-concept study in a separate larger cohort of patients.

Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery.

Multifrequency (0 to 0.3  mm(-1)), multiwavelength (633, 680, 720, 800, and 820 nm) spatial frequency domain imaging (SFDI) of 5-aminolevulinic acid-induced protoporphyrin IX (PpIX) was used to recover absorption, scattering, and fluorescence properties of glioblastoma multiforme spheroids in tissue-simulating phantoms and in vivo in a mouse model. Three-dimensional tomographic reconstructions of the frequency-dependent remitted light localized the depths of the spheroids within 500 μm, and the total amount of PpIX in the reconstructed images was constant to within 30% when spheroid depth was varied. In vivo tumor-to-normal contrast was greater than ∼1.5 in reduced scattering coefficient for all wavelengths and was ∼1.3 for the tissue concentration of deoxyhemoglobin (ctHb). The study demonstrates the feasibility of SFDI for providing enhanced image guidance during surgical resection of brain tumors.

Spatial frequency domain tomography of protoporphyrin IX fluorescence in preclinical glioma models.

5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence can be used to identify tissue for resection using an adapted operating microscope. A multi-institutional clinical trial comparing fluorescence-guided versus white light tumor resection reported significant improvement in completeness of resection and 6-month progression-free survival. The degree of 5-ALA-induced fluorescence correlates with histopathologic grade of tumor, degree of tumor cell infiltration, and proliferation indices. Quantitative methodologies for assessment of tissue fluorescence have significantly improved the ability to detect tumor tissue and intraoperative diagnostic performance. These developments extend the applicability of this technology to additional tumor histologies and provide the rationale for further instrumentation development.

Article	Year
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference\| PubMed ID: 17959452	2006
The Review of scientific instruments\| PubMed ID: 19405660	2009
Journal of the Optical Society of America. A, Optics, image science, and vision\| PubMed ID: 19488184	2009
Optics express\| PubMed ID: 19516706	2006
Journal of biomedical optics\| PubMed ID: 19566285	2009
Journal of photochemistry and photobiology. B, Biology\| PubMed ID: 20031443	2010
Optics express\| PubMed ID: 20052253	2009
Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δ-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhance... Journal of neurosurgery\| PubMed ID: 20380535	2011
Physics in medicine and biology\| PubMed ID: 20505221	2010
AJR. American journal of roentgenology\| PubMed ID: 20651186	2010
Biomedical optics express\| PubMed ID: 21258566	2010
Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. Journal of neurosurgery\| PubMed ID: 21438658	2011
Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas. Neurosurgical focus\| PubMed ID: 21529179	2011
Applied optics\| PubMed ID: 21772380	2011
Optics letters\| PubMed ID: 21964076	2011
Philosophical transactions. Series A, Mathematical, physical, and engineering sciences\| PubMed ID: 22006905	2011
Biomedical optics express\| PubMed ID: 22076264	2011
Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery. Journal of biomedical optics\| PubMed ID: 22112112	2011
Journal of the Optical Society of America. A, Optics, image science, and vision\| PubMed ID: 22472763	2012
Spatial frequency domain tomography of protoporphyrin IX fluorescence in preclinical glioma models. Journal of biomedical optics\| PubMed ID: 22612131	2012
Optics letters\| PubMed ID: 22743454	2012
Glioblastoma multiforme treatment with clinical trials for surgical resection (aminolevulinic acid). Neurosurgery clinics of North America\| PubMed ID: 22748650	2012

Frederic Leblond

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