Abstract
Maximal safe resection is a key strategy for improving patient prognosis in the management of brain tumors. Intraoperative fluorescence guidance has emerged as a standard in the surgery of high-grade gliomas. The administration of 5-aminolevulinic acid prior to surgery induces tumor-specific accumulation of protoporphyrin IX, which emits red fluorescence under blue-light illumination. The technology, however, is substantially limited for low-grade gliomas and weakly tumor-infiltrated brain, where low protoporphyrin IX concentrations are outweighed by tissue autofluorescence. In this context, fluorescence lifetime imaging has shown promise to distinguish spectrally overlapping fluorophores. We integrated frequency-domain fluorescence lifetime imaging in a surgical microscope and combined it with spatially registered fluorescence spectroscopy, which can be considered a research benchmark for sensitive protoporphyrin IX detection. Fluorescence lifetime maps and spectra were acquired for a representative set of fresh ex-vivo brain tumor specimens (low-grade gliomas n = 15, high-grade gliomas n = 80, meningiomas n = 41, and metastases n = 35). Combining the fluorescence lifetime with fluorescence spectra unveiled how weak protoporphyrin IX accumulations increased the lifetime respective to tissue autofluorescence. Infiltration zones (4.1ns ± 1.8ns, p = 0.017) and core tumor areas (4.8ns ± 1.3ns, p = 0.040) of low-grade gliomas were significantly distinguishable from non-pathologic tissue (1.6ns ± 0.5ns). Similarly, fluorescence lifetimes for infiltrated and reactive tissue as well as necrotic and core tumor areas were increased for high-grade gliomas and metastasis. Meningioma tumor specimens showed strongly increased lifetimes (12.2ns ± 2.5ns, p = 0.005). Our results emphasize the potential of fluorescence lifetime imaging to optimize maximal safe resection in brain tumors in future and highlight its potential toward clinical translation.
Highlights
A large variety of different tumors might occur with the human brain
FD-Fluorescence lifetime imaging (FLIM) Delineates Weak Protoporphyrin IX (PpIX) Fluorescence From Tissue Autofluorescence on Macroscale In FD-FLIM, the measured lifetime is a composed average of the lifetimes of all excited and detected fluorophore emissions, weighted by their respective signal contributions
Our results emphasize the capacity of FD-FLIM to detect weak PpIX fluorescence and distinguish it from spectrally overlapping tissue autofluorescence on macroscale
Summary
A large variety of different tumors might occur with the human brain. With an incidence rate of 7.1 and 16.7 per 100,000, around 25,000 primary malignant and 59,000 non-malignant brain and central nervous system tumors were expected to be diagnosed in the United States in 2020 [1]. According to the current World Health Organization (WHO) classification of primary brain tumors, gliomas are classified as WHO grades II, III, and IV. Considering recent epidemiologic data, glioblastomas WHO grade IV account for 50 % of malignant brain tumors with a median survival of about 8 months [1]. LGG account for approximately 20% of all primary brain tumors in adults [2]. Meningiomas (MNG) represent the most common primary brain tumor accounting for approximately 38% of cases [1]. Such tumors are divided into WHO grades I, II, and III, whereas MNG WHO grade I represents by far the most common tumor with a very good prognosis. Secondary brain tumors (metastases; MET) metastasizing frequently from lung, melanoma, renal, breast, or other cancers are common and characterized by poor patient prognosis [3]
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