Abstract
.Significance5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is currently used for image-guided glioma resection. Typically, this widefield imaging method highlights the bulk of high-grade gliomas, but it underperforms at the infiltrating edge where PpIX fluorescence is not visible to the eyes. Fluorescence lifetime imaging (FLIm) has the potential to detect PpIX fluorescence below the visible detection threshold. Moreover, simultaneous acquisition of time-resolved nicotinamide adenine (phosphate) dinucleotide [NAD(P)H] fluorescence may provide metabolic information from the tumor environment to further improve overall tumor detection.AimWe investigate the ability of pulse sampling, fiber-based FLIm to simultaneously image PpIX and NAD(P)H fluorescence of glioma infiltrative margins in patients.ApproachA mesoscopic fiber-based point-scanning FLIm device (355 nm pulses) was used to simultaneously resolve the fluorescence decay of PpIX (629/53 nm) and NAD(P)H (470/28 nm). The FLIm device enabled data acquisition at room light and rapid () augmentation of FLIm parameters on the surgical field-of-view. FLIm measurements from superficial tumors and tissue areas around the resection margins were performed on three glioblastoma patients in vivo following inspection of PpIX visible fluorescence with a conventional neurosurgical microscope. Microbiopsies were collected from FLIm imaged areas for histopathological evaluation.ResultsThe average lifetime from PpIX and NAD(P)H fluorescence distinguished between tumor and surrounding tissue. FLIm measurements of resection margins presented a range of PpIX and NAD(P)H lifetime values ( to 14 ns, to 6 ns) associated with unaffected tissue and areas of low-density tumor infiltration.ConclusionsIntraoperative FLIm could simultaneously detect the emission of PpIX and NAD(P)H from patients in vivo during craniotomy procedures. This approach doubles as a clinical tool to identify tumor areas while performing tissue resection and as a research tool to study tumor microenvironmental changes in vivo. Intraoperative FLIm of 5-ALA-induced PpIX and tissue autofluorescence makes a promising surgical adjunct to guide tumor resection surgery.
Highlights
Fluorescence-guided surgery (FGS) for primary brain tumor resection using 5-aminolevulinic acid (5-ALA) improves the extent of tumor resection in high-grade glioma patients, directly impacting patient survival
Fluorescence lifetime imaging (FLIm) measurements of resection margins presented a range of protoporphyrin IX (PpIX) and NAD(P)H lifetime values associated with unaffected tissue and areas of low-density tumor infiltration
Intraoperative FLIm could simultaneously detect the emission of PpIX and NAD(P)H from patients in vivo during craniotomy procedures
Summary
Fluorescence-guided surgery (FGS) for primary brain tumor (glioma) resection using 5-aminolevulinic acid (5-ALA) improves the extent of tumor resection in high-grade glioma patients, directly impacting patient survival. For the low-cellularity infiltrating edge of high-grade gliomas and most low-grade gliomas, the PpIX fluorescence intensity decreases below the visible threshold.[4] Current implementations of PpIX fluorescence visualization systems require working in a dark surgical field, hindering simultaneous tumor identification and resection. Visible PpIX fluorescence suffers from non-specific intensity variations (e.g., non-uniform illumination) that complicate the quantitative assessment of tumor with high accuracy.[5] Recent studies conducted on excised brain tissue have suggested that fluorescence spectroscopy and lifetime imaging enable further quantification of PpIX fluorescence below the visible detection threshold.[6,7] Time-resolved fluorescence is expected to increase the detection sensitivity of areas with weak fluorescence intensity because fluorescence lifetime is largely independent of tissue absorption and scattering properties, and unlike intensity alone, it is robust to variations in tissue-detector distance
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