Preclinical evaluation of spatial frequency domain-enabled wide-field quantitative imaging for enhanced glioma resection (original) (raw)
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Biomedical optics express, 2015
Intraoperative 5- aminolevulinic acid induced-Protoporphyrin IX (PpIX) fluorescence guidance enables maximum safe resection of glioblastomas by providing surgeons with real-time tumor optical contrast. However, visual assessment of PpIX fluorescence is subjective and limited by the distorting effects of light attenuation and tissue autofluorescence. We have previously shown that non-invasive point measurements of absolute PpIX concentration identifies residual tumor that is otherwise non-detectable. Here, we extend this approach to wide-field quantitative fluorescence imaging by implementing spatial frequency domain imaging to recover tissue optical properties across the field-of-view in phantoms and ex vivo tissue.
2018
The extent of resection is now considered a significant prognostic factor; yet, safe complete resection is achieved in only 30% glioma patients. The challenge of surgery arises from the diffusive nature of gliomas known to infiltrate normal parenchyma beyond the resection cavity, which are left undetected. To better visualize glioma, intra-operative fluorescence-guided resection (FGR) has been a practical solution, providing real-time tumor contrast. In its most widely used form, FGR is mediated by the preferential overproduction of the fluorophore protoporphyrin IX (PpIX) in malignant tissue after an oral dose of its precursor 5-Aminolevulinic Acid (ALA). ALA-PpIX-FGR has been shown to significantly increase extent of resection. However, the visual assessment and the variable intrinsic optical attenuation of tissue limit this technique to delineating only high-grade tumors that display strong fluorescence. To this end, the work described in this thesis outlines the development of i...
Spatial frequency domain tomography of protoporphyrin IX fluorescence in preclinical glioma models
2012
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.
Neuro-Oncology, 2011
Extent of resection is a major goal and prognostic factor in the treatment of gliomas. In this study we evaluate whether quantitative ex vivo tissue measurements of d-aminolevulinic acid-induced protoporphyrin IX (PpIX) identify regions of increasing malignancy in low-and high-grade gliomas beyond the capabilities of current fluorescence imaging in patients undergoing fluorescence-guided resection (FGR). Surgical specimens were collected from 133 biopsies in 23 patients and processed for ex vivo neuropathological analysis: PpIX fluorimetry to measure PpIX concentrations (C PpIX ) and Ki-67 immunohistochemistry to assess tissue proliferation. Samples displaying visible levels of fluorescence showed significantly higher levels of C PpIX and tissue proliferation. C PpIX was strongly correlated with histopathological score (nonparametric) and tissue proliferation (parametric), such that increasing levels of C PpIX were identified with regions of increasing malignancy. Furthermore, a large percentage of tumor-positive biopsy sites (∼40%) that were not visibly fluorescent under the operating microscope had levels of C PpIX greater than 0.1 mg/mL, which indicates that significant PpIX accumulation exists below the detection threshold of current fluorescence imaging. Although PpIX fluorescence is recognized as a visual biomarker for neurosurgical resection guidance, these data show that it is quantitatively related at the microscopic level to increasing malignancy in both low-and high-grade gliomas. This work suggests a need for improved PpIX fluorescence detection technologies to achieve better sensitivity and quantification of PpIX in tissue during surgery. G liomas account for over 70% of all primary brain tumors. 1 -3 Currently brain tumor research seeks to find diagnostic and prognostic biomarkers for gliomas that would inform both surgical and/or medical treatment. Extent of resection is increasingly accepted as critical to optimal surgical treatment and patient prognosis. 4,5 Image guidance facilitates neurosurgical resection but is subject to intraoperative brain shift, which degrades the accuracy of relating navigational information with the surgical field presented to the surgeon. 6 -12 The use of d-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence-guided resection (FGR) of brain tumors has gained increased clinical interest. 13 FGR provides the operating surgeon with an intuitive, real-time surgical guidance tool for delineating tumor tissue that mitigates some of the challenges of image-guided neuro-navigation caused by intraoperative brain shift and deformation. ALA-induced PpIX FGR studies support its utility as a surgical tool for intraoperative delineation of a tumor. For example, the largest study to date, a multicenter, randomized phase III clinical study of ALA-induced PpIX for FGR of malignant gliomas, showed a significant improvement in gross total resection of the contrast-enhancing tumor (65% vs 36%), as well as a higher 6-month progression-free survival (41.0% vs 21.1%), in the FGR group compared with the conventional white-light treatment group. 14 -16 In a recent study of malignant gliomas, we found that visible levels of ALA-induced PpIX fluorescence correlate with tumor burden and World Health Organization (WHO) histopathological score of resected specimens. 17 To date, intraoperative detection of PpIX fluorescence for tumor delineation has largely been subjective (i.e., a modified surgical microscope is used to visualize "pink" fluorescence). 15 -21 This approach is limited in its sensitivity for identifying low (but significant) levels of accumulated PpIX in a tumor, potentially leaving some amount of resectable tumor unidentified. 22 Indeed, we recently reported preliminary in vivo results in human brain tumors 23 that indicate PpIX fluorescence may be a tumor-targeting biomarker with a diagnostic performance that exceeds subjective visible assessments when measured quantitatively with a new fiber optic approach. 24 Thus, even though ALA-induced PpIX fluorescence has been shown to be a successful biomarker for surgical resection of malignant glioma, the subjective assessments used to date do not appear to be sufficiently sensitive or quantitative to exhaust its full potential. As a result, establishing the underlying relationships between ALA-induced PpIX concentration in brain tumor tissues and their histologically determined malignancy profile is critical to further development and optimization of FGR.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2016
While extent of tumor resection is an important predictor of outcome in glioma, margin delineation remains challenging due to lack of inherent contrast between tumor and normal parenchyma. Fluorescence-guided surgery is promising for its ability to enhance contrast through exogenous fluorophores, however, the specificity and sensitivity of the underlying contrast mechanism and tumor delivery and uptake vary widely across approved and emerging agents. Rats with orthotopic F98 wild-type and F98 EGFR-positive gliomas received in vivo administration of IRDye680RD, 5-aminioleuvulinic acid, and ABY-029-markers of perfusion, protoporphyrin metabolism, and EGFR expression, respectively. Ex vivo imaging demonstrates the contrast mechanism-dependent spatial heterogeneity and enables within-animal comparisons of tumor-to-background ratio (TBR). Generally, ABY-029 outperformed PpIX in F98EGFR orthotopic tumor margins and core (50% and 60% higher TBR, respectively). PpIX outperformed ABY-029 in ...
World neurosurgery, 2018
Fluorescence-guided surgery with protoporphyrin IX (PpIX) as a photodiagnostic marker is gaining acceptance for resection of malignant gliomas. Current wide-field imaging technologies do not have sufficient sensitivity to detect low PpIX concentrations. We evaluated a scanning fiber endoscope (SFE) for detection of PpIX fluorescence in gliomas and compared it with an operating microscope (OPMI) equipped with fluorescence module and a benchtop confocal laser scanning microscope (CLSM). 5-aminolevulinic acid (5-ALA)-induced PpIX fluorescence was assessed in GL261-Luc2 cells in vitro and in vivo after implantation in mouse brains, at an invading glioma growth stage, simulating residual tumor. Intraoperative fluorescence of high and low PpIX concentrations in normal brain and tumor regions with SFE, OPMI, CLSM, and histopathology were compared. SFE imaging of PpIX correlated to CLSM at the cellular level. PpIX accumulated in normal brain cells but significantly less than in glioma cells...
2011
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 highgrade 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%