Background: In the next decades, the incidence of patients with glioblastoma (GBM) will increase due to the growth of the elderly population. Fluorescence-guided resection using 5-aminolevulinic acid (5-ALA) is widely applied to achieve maximal safe resection of GBM and is identified as a novel intraoperative marker for diagnostic tissue during biopsies. However, detailed analyses of the use of 5-ALA in resections as well as biopsies in a large elderly cohort are still missing. The aim of this study was thus to investigate the efficacy, outcome, and safety of surgically- treated GBM in the 5-ALA era in a large elderly cohort. Methods: All GBM patients aged 65 years or older who underwent neurosurgical intervention between 2007 and 2019 were included. Data on 5-ALA application, intraoperative fluorescence status, and 5-ALA-related side effects were derived from our databank. In the case of resection, the tumor resectability and the extent of resection were determined. Potential prognostic parameters relevant for overall survival were analyzed. Results: 272 GBM patients with a median age of 71 years were included. Intraoperative 5-ALA fluorescence was applied in most neurosurgical procedures (n = 255/272, 88%) and visible fluorescence was detected in most cases (n = 252/255, 99%). In biopsies, 5-ALA was capable of visualizing tumor tissue by visible fluorescence in all but one case (n = 91/92, 99%). 5-ALA administration did not result in any severe side effects. Regarding patient outcome, smaller preoperative tumor volume (<22.75 cm³), gross total resection, single lesions, improved postoperative neurological status, and concomitant radio-chemotherapy showed a significantly longer overall survival. Conclusions: Our data of this large elderly cohort demonstrate the clinical utility and safety of 5-ALA fluorescence in GBM for improved tumor visualization in both resections as well as biopsies. Therefore, we recommend the use of 5-ALA not only in resections, but also in open/stereotactic biopsies to optimize the neurosurgical management of elderly GBM patients.

Precise intraoperative brain tumor visualization supports surgeons in achieving maximal safe resection. In this sense, improved prognosis in patients with high-grade gliomas undergoing protoporphyrin IX fluorescence-guided surgery has been demonstrated. Phase fluorescence lifetime imaging in the frequency-domain has shown promise to distinguish weak protoporphyrin IX fluorescence from competing endogenous tissue fluorophores, thus allowing for brain tumor detection with high sensitivity. In this work, we show that this technique can be further improved by minimizing the crosstalk of autofluorescence signal contributions when only detecting the fluorescence emission above 615 nm. Combining fluorescence lifetime and spectroscopic measurements on a set of 130 ex vivo brain tumor specimens (14 low- and 56 high-grade gliomas, 39 meningiomas and 21 metastases) coherently substantiated the resulting increase of the fluorescence lifetime with respect to the detection band employed in previous work. This is of major interest for obtaining a clear-cut distinction from the autofluorescence background of the physiological brain. In particular, the median fluorescence lifetime of low- and high-grade glioma specimens lacking visual fluorescence during surgical resection was increased from 4.7 ns to 5.4 ns and 2.9 ns to 3.3 ns, respectively. While more data are needed to create statistical evidence, the coherence of what was observed throughout all tumor groups emphasized that this optimization should be taken into account for future studies.

SignificanceThe 5-aminolevulinic acid (5-ALA) fluorescence technique is now widely applied for intraoperative visualization of specific central nervous system (CNS) tumors. Previous technical implementations of this technique have relied on specifically modified surgical microscopes to visualize intratumoral fluorescent protoporphyrin (PpIX). While this approach evidently allows for reliable intraoperative tumor visualization, it requires the availability of specifically modified surgical microscopes and their use even in cases where the operating neurosurgeon would prefer to use surgical loupes. Recently, a novel loupe device was introduced that is also capable of visualizing 5-ALA fluorescence.AimThe aim of this study was therefore to compare the detected PpIX concentrations between the conventional fluorescence microscope and the novel loupe device.ApproachWe used fluorescence phantoms of different PpIX concentrations for comparison between a conventional fluorescence microscope and the novel loupe device. For this purpose, we created fluorescence images using the excitation light sources of the conventional fluorescence microscope and the loupe device with both available background illumination modes (low and high). Subsequently, the minimal detectable PpIX concentrations according to each technique were determined by five independent neurosurgeons.ResultsUsing the conventional fluorescence microscope, the median minimal detectable PpIX concentration was 0.16 μg / ml (range: 0.15 to 0.17 μg / ml). By the loupe device, the median minimal detectable PpIX concentration was 0.12 μg / ml (range: 0.10 to 0.12 μg / ml) and 0.08 μg / ml (range: 0.07 to 0.08 μg / ml) for the high- and low-modes, respectively. Altogether, the minimal detectable PpIX concentrations were significantly lower using the loupe device compared to the conventional fluorescence microscope (p = 0.007).ConclusionsOur data indicate that the novel loupe device is able to visualize 5-ALA fluorescence with high sensitivity and thus might serve as a powerful tool for visualization of specific CNS tumors in the future.

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