Quantitative fluorescence in intracranial tumor: Implications for ALA-induced PpIX as an intraoperative biomarker - Clinical article

Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire, USA.
Journal of Neurosurgery (Impact Factor: 3.74). 03/2011; 115(1):11-7. DOI: 10.3171/2011.2.JNS101451
Source: PubMed


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.
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.
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.
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.

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    • "During prolonged surgeries possible problems with detection of fluorescence may result from its time-dependent deterioration or bleaching due to excessive or prolonged use of the ultraviolet light or microscope illumination [29] [30]. Finally, tissue fluorescence may be below the threshold of the visual perception [34] [35]. On the other hand, false positive tissue fluorescence may be identified in the areas of high vascularization , reactive astrocytosis and fibrosis, macrophages infiltration, inflammation, brain edema, or BBB impairment in the absence of the neoplastic elements [31] [36] [37] [45] [48] [49]. "
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    ABSTRACT: Objective: To evaluate the role of the neurochemical navigation with 5-aminolevulinic acid (5-ALA) during intraoperative MRI (iMRI)-guided resection of the intracranial malignant gliomas. Methods: The analysis included 99 consecutive surgical cases. Resection of the bulk of the neoplasm was mainly guided by the updated neuronavigation based on the low-field-strength (0.3T) iMRI, whereas at the periphery of the lesion neurochemical navigation with 5-ALA was additionally used. Results: In total, 286 tissue specimens were obtained during surgeries for histopathological examination. According to iMRI 98 samples with strong (91 cases), weak (6 cases), or absent (1 case) fluorescence corresponded to the bulk of the lesion and all of those ones contained tumor. Out of 188 tissue specimens obtained from the "peritumoral brain," the neoplastic elements were identified in 89%, 81% and 29% of samples with, respectively, strong (107 cases), weak (47 cases) and absent (34 cases) fluorescence. Positive predictive values of the tissue fluorescence for presence of neoplasm within and outside of its boundaries on iMRI were 100% and 86%, respectively. Conclusion: Neurochemical navigation with 5-ALA is useful adjunct during iMRI-guided resection of intracranial malignant gliomas, which allows identification of the tumor extension beyond its radiological borders.
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    • "PpIX is lipophilic; in vivo it is in contact with the lipid membrane of mitochondria and its microenvironment is complex. The emission peak at 634 nm is known to be predominant in HGG [2,3,6,7]. However some results indicate that the emission spectrum can be more complicated [10–12] due to either a shift in the position of the emission maximum towards shorter wavelength or the presence of photoproducts. In the former case, PpIX fluorescence emission is the result of the two PpIX states which are simultaneously present. "
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    ABSTRACT: 5-ALA-induced protoporphyrin IX (PpIX) fluorescence enables to guiding in intra-operative surgical glioma resection. However at present, it has yet to be shown that this method is able to identify infiltrative component of glioma. In extracted tumor tissues we measured a two-peaked emission in low grade gliomas and in the infiltrative component of glioblastomas due to multiple photochemical states of PpIX. The second emission peak appearing at 620 nm (shifted by 14 nm from the main peak at 634 nm) limits the sensibility of current methods to measured PpIX concentration. We propose new measured parameters, by taking into consideration the two-peaked emission, to overcome these limitations in sensitivity. These parameters clearly distinguish the solid component of glioblastomas from low grade gliomas and infiltrative component of glioblastomas.
    Full-text · Article · Apr 2013 · Biomedical Optics Express
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    • "Perhaps more convincing in addressing the issue of auto-fluorescence is the fact that the levels of ALA-induced PpIX fluorescence from brain tumors (including high-and low-grade gliomas, meningiomas and metastases) are two to three orders of magnitude larger when compared to normal adjacent brain tissue. The high specificity of this contrast mechanism is such that fluorescence emanating from areas other than the tumor is in the vast majority of cases negligible (Valdes et al 2011). We expect that the point-like approximation will not be compromised by the presence of auto-fluorescence and non-specific fluorescence in clinical applications such as ALA-induced PpIX fluorescenceguided resection. "
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    ABSTRACT: Here we derived analytical solutions to diffuse light transport in biological tissue based on spectral deformation of diffused near-infrared measurements. These solutions provide a closed-form mathematical expression which predicts that the depth of a fluorescent molecule distribution is linearly related to the logarithm of the ratio of fluorescence at two different wavelengths. The slope and intercept values of the equation depend on the intrinsic values of absorption and reduced scattering of tissue. This linear behavior occurs if the following two conditions are satisfied: the depth is beyond a few millimeters and the tissue is relatively homogeneous. We present experimental measurements acquired with a broad-beam non-contact multi-spectral fluorescence imaging system using a hemoglobin-containing diffusive phantom. Preliminary results confirm that a significant correlation exists between the predicted depth of a distribution of protoporphyrin IX molecules and the measured ratio of fluorescence at two different wavelengths. These results suggest that depth assessment of fluorescence contrast can be achieved in fluorescence-guided surgery to allow improved intra-operative delineation of tumor margins.
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