Influence of dexamethasone on visible 5-ALA fluorescence and quantitative protoporphyrin IX accumulation measured by fluorescence lifetime imaging in glioblastomas: is pretreatment obligatory before fluorescence-guided surgery?

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  • 1 Department of Neurosurgery;
  • | 2 Center for Medical Physics and Biomedical Engineering;
  • | 3 Christian Doppler Laboratory OPTRAMED;
  • | 4 Department of Neurology–Division for Neuropathology and Neurochemistry;
  • | 5 Department of Biomedical Imaging and Image-guided Therapy, Division of General and Pediatric Radiology; and
  • | 6 Comprehensive Cancer Center–Central Nervous System Tumors Unit, Medical University of Vienna, Austria
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OBJECTIVE

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is nowadays widely applied for improved resection of glioblastomas (GBMs). Initially, pretreatment with dexamethasone was considered to be essential for optimal fluorescence effect. However, recent studies reported comparably high rates of visible fluorescence in GBMs despite absence of dexamethasone pretreatment. Recently, the authors proposed fluorescence lifetime imaging (FLIM) for the quantitative analysis of 5-ALA–induced protoporphyrin IX (PpIX) accumulation. The aim of this study was thus to investigate the influence of dexamethasone on visible fluorescence and quantitative PpIX accumulation.

METHODS

The authors prospectively analyzed the presence of visible fluorescence during surgery in a cohort of patients with GBMs. In this study, patients received dexamethasone preoperatively only if clinically indicated. One representative tumor sample was collected from each GBM, and PpIX accumulation was analyzed ex vivo by FLIM. The visible fluorescence status and mean FLIM values were correlated with preoperative intake of dexamethasone.

RESULTS

In total, two subgroups with (n = 27) and without (n = 20) pretreatment with dexamethasone were analyzed. All patients showed visible fluorescence independent from preoperative dexamethasone intake. Furthermore, the authors did not find a statistically significant difference in the mean FLIM values between patients with and without dexamethasone pretreatment (p = 0.097).

CONCLUSIONS

In this first study to date, the authors found no significant influence of dexamethasone pretreatment on either visible 5-ALA fluorescence during GBM surgery or PpIX accumulation based on FLIM. According to these preliminary data, the authors recommend administering dexamethasone prior to fluorescence-guided surgery of GBMs only when clinically indicated.

ABBREVIATIONS

5-ALA = 5-aminolevulinic acid; CE = contrast enhancement; FLIM = fluorescence lifetime imaging; GBM = glioblastoma; PpIX = protoporphyrin IX.

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  • 1

    Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008;62(4):753764.264266.

  • 2

    Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392401.

    • Search Google Scholar
    • Export Citation
  • 3

    Almeida JP, Chaichana KL, Rincon-Torroella J, Quinones-Hinojosa A. The value of extent of resection of glioblastomas: clinical evidence and current approach. Curr Neurol Neurosci Rep. 2015;15(2):517.

    • Search Google Scholar
    • Export Citation
  • 4

    Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, et al. Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery. 2008;62(3):564576.

    • Search Google Scholar
    • Export Citation
  • 5

    Hervey-Jumper SL, Berger MS. Maximizing safe resection of low- and high-grade glioma. J Neurooncol. 2016;130(2):269282.

  • 6

    Stummer W, Stocker S, Wagner S, Stepp H, Fritsch C, Goetz C, et al. Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery. 1998;42(3):518526.

    • Search Google Scholar
    • Export Citation
  • 7

    Tonn JC, Stummer W. Fluorescence-guided resection of malignant gliomas using 5-aminolevulinic acid: practical use, risks, and pitfalls. Clin Neurosurg. 2008;55:2026.

    • Search Google Scholar
    • Export Citation
  • 8

    Hadjipanayis CG, Widhalm G, Stummer W. What is the surgical benefit of utilizing 5-aminolevulinic acid for fluorescence-guided surgery of malignant gliomas?. Neurosurgery. 2015;77(5):663673.

    • Search Google Scholar
    • Export Citation
  • 9

    Lakomkin N, Hadjipanayis CG. Fluorescence-guided surgery for high-grade gliomas. J Surg Oncol. 2018;118(2):356361.

  • 10

    Widhalm G, Minchev G, Woehrer A, Preusser M, Kiesel B, Furtner J, et al. Strong 5-aminolevulinic acid-induced fluorescence is a novel intraoperative marker for representative tissue samples in stereotactic brain tumor biopsies. Neurosurg Rev. 2012;35(3):381391.

    • Search Google Scholar
    • Export Citation
  • 11

    Wadiura LI, Mischkulnig M, Hosmann A, Borkovec M, Kiesel B, Rötzer T, et al. Influence of corticosteroids and antiepileptic drugs on visible 5-aminolevulinic acid fluorescence in a series of initially suspected low-grade gliomas including World Health Organization grade. II, III, and IV gliomas. World Neurosurg. 2020;137:e437-e446.

    • Search Google Scholar
    • Export Citation
  • 12

    Kiesel B, Mischkulnig M, Woehrer A, Martinez-Moreno M, Millesi M, Mallouhi A, et al. Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas. J Neurosurg. 2018;129(2):341353.

    • Search Google Scholar
    • Export Citation
  • 13

    Mischkulnig M, Kiesel B, Borkovec M, Wadiura LI, Benner D, Hosmann A, et al. High interobserver agreement in the subjective classification of 5-aminolevulinic acid fluorescence levels in newly diagnosed glioblastomas. Lasers Surg Med. 2020;52(9):814821.

    • Search Google Scholar
    • Export Citation
  • 14

    Erkkilä MT, Reichert D, Hecker-Denschlag N, Wilzbach M, Hauger C, Leitgeb RA, et al. Surgical microscope with integrated fluorescence lifetime imaging for 5-aminolevulinic acid fluorescence-guided neurosurgery. J Biomed Opt. 2020;25(7):17.

    • Search Google Scholar
    • Export Citation
  • 15

    Erkkilä MT, Bauer B, Hecker-Denschlag N, Madera Medina MJ, Leitgeb RA, Unterhuber A, et al. Widefield fluorescence lifetime imaging of protoporphyrin IX for fluorescence-guided neurosurgery: An ex vivo feasibility study. J Biophotonics. 2019;12(6):e201800378.

    • Search Google Scholar
    • Export Citation
  • 16

    Reichert D, Erkkilä MT, Holst G, Hecker-Denschlag N, Wilzbach M, Hauger C, et al. Towards real-time wide-field fluorescence lifetime imaging of 5-ALA labeled brain tumors with multi-tap CMOS cameras. Biomed Opt Express. 2020;11(3):15981616.

    • Search Google Scholar
    • Export Citation
  • 17

    Erkkilä MT, Reichert D, Gesperger J, Kiesel B, Roetzer T, Mercea PA, et al. Macroscopic fluorescence-lifetime imaging of NADH and protoporphyrin IX improves the detection and grading of 5-aminolevulinic acid-stained brain tumors. Sci Rep. 2020;10(1):20492.

    • Search Google Scholar
    • Export Citation
  • 18

    Widhalm G, Kiesel B, Woehrer A, Traub-Weidinger T, Preusser M, Marosi C, et al. 5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement. PLoS One. 2013;8(10):e76988.

    • Search Google Scholar
    • Export Citation
  • 19

    Widhalm G, Wolfsberger S, Minchev G, Woehrer A, Krssak M, Czech T, et al. 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement. Cancer. 2010;116(6):15451552.

    • Search Google Scholar
    • Export Citation
  • 20

    Stummer W, Stepp H, Möller G, Ehrhardt A, Leonhard M, Reulen HJ. Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir (Wien). 1998;140(10):9951000.

    • Search Google Scholar
    • Export Citation
  • 21

    Berezin MY, Achilefu S. Fluorescence lifetime measurements and biological imaging. Chem Rev. 2010;110(5):26412684.

  • 22

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97109.

    • Search Google Scholar
    • Export Citation
  • 23

    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803820.

    • Search Google Scholar
    • Export Citation
  • 24

    Panciani PP, Fontanella M, Schatlo B, Garbossa D, Agnoletti A, Ducati A, Lanotte M. Fluorescence and image guided resection in high grade glioma. Clin Neurol Neurosurg. 2012;114(1):3741.

    • Search Google Scholar
    • Export Citation
  • 25

    Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg. 2000;93(6):10031013.

    • Search Google Scholar
    • Export Citation
  • 26

    Waljee AK, Rogers MAM, Lin P, Singal AG, Stein JD, Marks RM, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357:j1415.

    • Search Google Scholar
    • Export Citation
  • 27

    Weissman DE, Dufer D, Vogel V, Abeloff MD. Corticosteroid toxicity in neuro-oncology patients. J Neurooncol. 1987;5(2):125128.

  • 28

    Dixit KS, Kumthekar PU. Optimal management of corticosteroids in patients with intracranial malignancies. Curr Treat Options Oncol. 2020;21(9):77.

    • Search Google Scholar
    • Export Citation
  • 29

    Brophy T, Chalk JB, Ridgeway K, Tyrer JH, Eadie MJ. Cortisol production during high dose dexamethasone therapy in neurological and neurosurgical patients. J Neurol Neurosurg Psychiatry. 1984;47(10):10811086.

    • Search Google Scholar
    • Export Citation
  • 30

    Lawrence JE, Steele CJ, Rovin RA, Belton RJ Jr, Winn RJ. Dexamethasone alone and in combination with desipramine, phenytoin, valproic acid or levetiracetam interferes with 5-ALA-mediated PpIX production and cellular retention in glioblastoma cells. J Neurooncol. 2016;127(1):1521.

    • Search Google Scholar
    • Export Citation
  • 31

    Valdés PA, Jacobs V, Harris BT, Wilson BC, Leblond F, Paulsen KD, Roberts DW. Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery. J Neurosurg. 2015;123(3):771780.

    • Search Google Scholar
    • Export Citation
  • 32

    Valdés PA, Jacobs VL, Leblond F, Wilson BC, Paulsen KD, Roberts DW. Quantitative spectrally resolved intraoperative fluorescence imaging for neurosurgical guidance in brain tumor surgery: pre-clinical and clinical results. Proc SPIE. 2014;8928:892809.

    • Search Google Scholar
    • Export Citation
  • 33

    Bekelis K, Valdés PA, Erkmen K, Leblond F, Kim A, Wilson BC, et al. Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas. Neurosurg Focus. 2011;30(5):E8.

    • Search Google Scholar
    • Export Citation
  • 34

    Widhalm G, Olson J, Weller J, Bravo J, Han SJ, Phillips J, et al. The value of visible 5-ALA fluorescence and quantitative protoporphyrin IX analysis for improved surgery of suspected low-grade gliomas. J Neurosurg. 2020;133(1):7988.

    • Search Google Scholar
    • Export Citation
  • 35

    Strugar JG, Criscuolo GR, Rothbart D, Harrington WN. Vascular endothelial growth/permeability factor expression in human glioma specimens: correlation with vasogenic brain edema and tumor-associated cysts. J Neurosurg. 1995;83(4):682689.

    • Search Google Scholar
    • Export Citation
  • 36

    Hui CY, Rudra S, Ma S, Campian JL, Huang J. Impact of overall corticosteroid exposure during chemoradiotherapy on lymphopenia and survival of glioblastoma patients. J Neurooncol. 2019;143(1):129136.

    • Search Google Scholar
    • Export Citation
  • 37

    Petrelli F, De Stefani A, Ghidini A, Bruschieri L, Riboldi V, Dottorini L, et al. Steroids use and survival in patients with glioblastoma multiforme: a pooled analysis. J Neurol. 2021;268(2):440447.

    • Search Google Scholar
    • Export Citation
  • 38

    van Breemen MSM, Rijsman RM, Taphoorn MJB, Walchenbach R, Zwinkels H, Vecht CJ. Efficacy of anti-epileptic drugs in patients with gliomas and seizures. J Neurol. 2009;256(9):15191526.

    • Search Google Scholar
    • Export Citation
  • 39

    Newton HB, Dalton J, Goldlust S, Pearl D. Retrospective analysis of the efficacy and tolerability of levetiracetam in patients with metastatic brain tumors. J Neurooncol. 2007;84(3):293296.

    • Search Google Scholar
    • Export Citation
  • 40

    Kurzwelly D, Herrlinger U, Simon M. Seizures in patients with low-grade gliomas—incidence, pathogenesis, surgical management, and pharmacotherapy. Adv Tech Stand Neurosurg. 2010;35:81111.

    • Search Google Scholar
    • Export Citation
  • 41

    Vecht C, Royer-Perron L, Houillier C, Huberfeld G. Seizures and anticonvulsants in brain tumours: frequency, mechanisms and anti-epileptic management. Curr Pharm Des. 2017;23(42):64646487.

    • Search Google Scholar
    • Export Citation
  • 42

    Kiesel B, Millesi M, Woehrer A, Furtner J, Bavand A, Roetzer T, et al. 5-ALA-induced fluorescence as a marker for diagnostic tissue in stereotactic biopsies of intracranial lymphomas: experience in 41 patients. Neurosurg Focus. 2018;44(6):E7.

    • Search Google Scholar
    • Export Citation
  • 43

    Wiegell SR, Petersen B, Wulf HC. Topical corticosteroid reduces inflammation without compromising the efficacy of photodynamic therapy for actinic keratoses: a randomized clinical trial. Br J Dermatol. 2014;171(6):14871492.

    • Search Google Scholar
    • Export Citation
  • 44

    Wiegell SR, Petersen B, Wulf HC. Pulse photodynamic therapy reduces inflammation without compromising efficacy in the treatment of multiple mild actinic keratoses of the face and scalp: a randomized clinical trial. Br J Dermatol. 2016;174(5):979984.

    • Search Google Scholar
    • Export Citation

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