Kinetics of protoporphyrin IX formation in rat oral mucosa and skin after application of 5-aminolevulinic acid and its methylester

OBJECTIVE 5-Aminolevulinic acid (5-ALA) induces fluorescence in high-grade glioma (HGG), which is used for resection. However, the value of 5-ALA–induced fluorescence in low-grade glioma (LGG) is unclear. Time dependency and time kinetics have not yet been investigated. The purpose of this study was to investigate real-time kinetics of protoporphyrin IX (PpIX) in LGG based on hyperspectral fluorescence-based measurements and identify factors that predict fluorescence. METHODS Patients with grade II gliomas and imaging from which HGGs could not be completely ruled out received 5-ALA at 20 mg/kg body weight 4 hours prior to surgery. Fluorescence intensity (FI) and PpIX concentration (CPpIX) were measured in tumor tissue utilizing a hyperspectral camera. Apparent diffusion coefficient (ADC)–based tumor cell density, Ki-67/MIB-1 index, chromosomal 1p/19q codeletion, and 18F-fluoroethyl-l-tyrosine (18F-FET) PET values and their role for predicting fluorescence were evaluated. RESULTS Eighty-one biopsies from 25 patients were included. Tissues with fluorescence demonstrated FI and CPpIX maxima between 7 and 8 hours after administration. When visible fluorescence was observed, peaks of FI and CPpIX were observed within this 7- to 8-hour time frame, regardless of any MRI gadolinium contrast enhancement. Gadolinium enhancement (p = 0.008), Ki-67/MIB-1 index (p < 0.001), 18F-FET PET uptake ratio (p = 0.004), and ADC-based tumor cellularity (p = 0.017) significantly differed between fluorescing and nonfluorescing tissue, but not 1p/19q codeletions. Logistic regression demonstrated that 18F-FET PET uptake and Ki-67/MIB-1 index were independently related to fluorescence. CONCLUSIONS This study reports a fluorescence-based assessment of CPpIX in human LGG tissues related to 18F-FET PET uptake and Ki-67/MIB-1. As in HGGs, fluorescence in LGGs peaked between 7 and 8 hours after 5-ALA application, which has consequences for the timing of administration.

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The Fluorescence Biodistribution And Kinetics Of Aminolevulinic Acid Induced Protoporphyrin IX In The Bladder Of A Rat Model With Orthotopic Urothelial Carcinoma

The Journal of Urology ◽

10.1097/00005392-200204000-00093 ◽

2002 ◽

pp. 1848-1853

Author(s):

SARI GR??NLUND-PAKKANEN ◽

JARMO WAHLFORS ◽

KIMMO M??KINEN ◽

TIMO M. PAKKANEN ◽

MARTTI TALJA ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Rat Model ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Kinetics Of

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Fluorescence-Based Measurement of Real-Time Kinetics of Protoporphyrin IX After 5-Aminolevulinic Acid Administration in Human In Situ Malignant Gliomas

Neurosurgery ◽

10.1093/neuros/nyz129 ◽

2019 ◽

Vol 85 (4) ◽

pp. E739-E746 ◽

Cited By ~ 9

Author(s):

Sadahiro Kaneko ◽

Eric Suero Molina ◽

Christian Ewelt ◽

Nils Warneke ◽

Walter Stummer

Keyword(s):

Tumor Tissue ◽

Aminolevulinic Acid ◽

Malignant Gliomas ◽

Protoporphyrin Ix ◽

Time Dependency ◽

Average Maximum ◽

Kinetics Of ◽

Acid Administration ◽

Time Point

Abstract BACKGROUND Five-aminolevulinic acid (5-ALA) is well established for fluorescence-guided resections of malignant gliomas by eliciting the accumulation of fluorescent protoporphyrin IX (PpIX) in tumors. Because of the assumed time point of peak fluorescence, 5-ALA is recommended to be administered 3 h before surgery. However, the actual time dependency of tumor fluorescence has not yet been evaluated in humans and may have important implications. OBJECTIVE To investigate the time dependency of PpIX by measuring fluorescence intensities in tumors at various time points during surgery. METHODS Patients received 5-ALA (20 mg/kg b.w.) 3 to 4 h before surgery. Fluorescence intensities (FI) and estimated tumor PpIX concentrations (CPPIX) were measured in the tumors over time with a hyperspectral camera. CPPIX was assessed using hyperspectral imaging and by evaluating fluorescence phantoms with known CPPIX. RESULTS A total of 201 samples from 68 patients were included in this study. On average, maximum values of calculated FI and CPPIX were observed between 7 and 8 h after 5-ALA administration. FI and CPPIX both reliably distinguished central strong and marginal weak fluorescence, and grade III compared to grade IV gliomas. Interestingly, marginal (weak) fluorescence was observed to peak later than strong fluorescence (8-9 vs 7-8 h). CONCLUSION In human in Situ brain tumor tissue, we determined fluorescence after 5-ALA administration to be maximal later than previously thought. In consequence, 5-ALA should be administered 4 to 5 h before surgery, with timing adjusted to internal logistical circumstances and factors related to approaching the tumor.

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