Introduction: In recent years several techniques have been proposed with the aim of improving tumors visualization and extent of resection and, among them, the use of photosensitive dyes is gaining great interest. Regarding the application of the two most used dyes, 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SF), there is still a lack of shared and established protocols among different centers. The main objective of the present study was to evaluate the current practice of fluorescence-guided techniques in neuro-oncological surgery in Europe.

Methods: An online questionnaire consisting of 33 questions was completed by 136 European Association of Neurosurgical Societies (EANS) neurosurgeons. Responses were entered into a database and subsequently analyzed.

Results: Data were analyzed from 136 out of 1476 active European neurosurgeons which had been contacted. Based on the data from the questionnaire, Germany was the most responsive country (15% of the total respondents) and the main indications for 5-ALA and SF utilization were high-grade gliomas. 5-ALA was mainly used as defined in Gliolan® datasheet, while SF as off-label technique with a 5 mg/kg dose of injection at the end of patient intubation. Pentero Zeiss® microscope with appropriate filters loaded on it was the preferred brand for both 5-ALA and SF users. Both the dyes were mainly used in adult population, more frequently by neurosurgeons with less-than 20 cases per year expertise. Mean price per patient were 817,6 € and 7,7 € for 5-ALA and SF, respectively.

Conclusions: 5-ALA is still the preferred and more established fluorescent dye used during high-grade gliomas resection, with SF as a gaining-attention, really cheaper and more ductile alternative.

Patient Care: Regarding the use of fluorescent dyes in neuro-oncological surgery, there is still a lack of shared and established protocols among different centers in Europe, that eventually lead to confusion and misunderstandings when comparing results obtained in different hospitals with different clinical and surgical settings, ultimately leading to patients treatment not really science-based. Given also that SF has recently gained great interest and since its first application in neurosurgery it has been used more frequently year after year, we considered the present time a good moment to create and present a current practice-picture of florescent tracers use in neurosurgery. We strongly believe that studies such the present one may help in identifying differences among common practices in different hospital and countries, shedding light on the need to review our methods, aiming to the best possible protocol of treatment for patients.

Learning Objectives: By the conclusion of this session, participants should be able to: 1) describe the main indications and methods of use for the two most used fluorescent tracers in neuro-oncological surgery; 2) Discuss, in small groups, indications, contraindications, limits and benefits given by the use of sodium fluorescein or 5-aminolevulinic acid in neurosurgery; 3) To present a current-practice-picture of fluorescent tracers use in European neurosurgical community.

References: [1] M.L. Bondy, M.E. Scheurer, B. Malmer, J.S. Barnholtz-Sloan, F.G. Davis, D. Il’yasova, C. Kruchko, B.J. McCarthy, P. Rajaraman, J.A. Schwartzbaum, S. Sadetzki, B. Schlehofer, T. Tihan, J.L. Wiemels, M. Wrensch, P.A. Buffler, Brain tumor epidemiology: Consensus from the Brain Tumor Epidemiology Consortium, Cancer. 113 (2008) 1953–1968. doi:10.1002/cncr.23741. [2] P.Y. Wen, S. Kesari, Malignant gliomas in adults, N. Engl. J. Med. 359 (2008) 492–507. doi:10.1056/NEJMra0708126. [3] M. Preusser, S. de Ribaupierre, A. Wöhrer, S.C. Erridge, M. Hegi, M. Weller, R. Stupp, Current concepts and management of glioblastoma., Ann. Neurol. 70 (2011) 9–21. doi:10.1002/ana.22425. [4] R. Stupp, M.E. Hegi, W.P. Mason, M.J. van den Bent, M.J. Taphoorn, R.C. Janzer, S.K. Ludwin, A. Allgeier, B. Fisher, K. Belanger, P. Hau, A.A. Brandes, J. Gijtenbeek, C. Marosi, C.J. Vecht, K. Mokhtari, P. Wesseling, S. Villa, E. Eisenhauer, T. Gorlia, M. Weller, D. Lacombe, J.G. Cairncross, R.-O. Mirimanoff, Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial, Lancet Oncol. 10 (2009) 459–466. doi:10.1016/S1470-2045(09)70025-7. [5] C. Ewelt, A. Nemes, V. Senner, J. Wölfer, B. Brokinkel, W. Stummer, M. Holling, Fluorescence in neurosurgery: Its diagnostic and therapeutic use. Review of the literature, J. Photochem. Photobiol. B Biol. 148 (2015) 302–309. doi:10.1016/j.jphotobiol.2015.05.002. [6] W. Stummer, S. Stocker, A. Novotny, A. Heimann, O. Sauer, O. Kempski, N. Plesnila, J. Wietzorrek, H.J. Reulen, In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid, J. Photochem. Photobiol. B Biol. 45 (1998) 160–169. [7] J.C. Tonn, W. Stummer, Fluorescence-guided resection of malignant gliomas using 5-aminolevulinic acid: practical use, risks, and pitfalls., Clin. Neurosurg. 55 (2008) 20–26. doi:10.1117/12.652069. [8] W. Stummer, U. Pichlmeier, T. Meinel, O.D. Wiestler, F. Zanella, H.J. Reulen, Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial, Lancet Oncol. 7 (2006) 392–401. doi:10.1016/S1470-2045(06)70665-9. [9] S. Marbacher, E. Klinger, L. Schwyzer, I. Fischer, E. Nevzati, M. Diepers, U. Roelcke, A.-R. Fathi, D. Coluccia, J. Fandino, Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases., Neurosurg. Focus. 36 (2014) E10. doi:10.3171/2013.12.FOCUS13464. [10] N. Ferraro, E. Barbarite, T.R. Albert, E. Berchmans, A.H. Shah, A. Bregy, M.E. Ivan, T. Brown, R.J. Komotar, The role of 5-aminolevulinic acid in brain tumor surgery: a systematic review, Neurosurg. Rev. 39 (2016) 545–555. doi:10.1007/s10143-015-0695-2. [11] T. Inoue, T. Endo, K. Nagamatsu, M. Watanabe, T. Tominaga, 5-aminolevulinic acid fluorescence-guided resection of intramedullary ependymoma: Report of 9 cases, Neurosurgery. 72 (2013) ons159-168. doi:10.1227/NEU.0b013e31827bc7a3. [12] R.J. Diaz, R.R. Dios, E.M. Hattab, K. Burrell, P. Rakopoulos, N. Sabha, C. Hawkins, G. Zadeh, J.T. Rutka, A.A. Cohen-Gadol, Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance, J. Neurosurg. 122 (2015) 1360–1369. doi:10.3171/2015.2.JNS132507. [13] F. Acerbi, M. Broggi, M. Eoli, E. Anghileri, C. Cavallo, C. Boffano, R. Cordella, L. Cuppini, B. Pollo, M. Schiariti, S. Visintini, C. Orsi, E. La Corte, G. Broggi, P. Ferroli, Is fluorescein-guided technique able to help in resection of high-grade gliomas?, Neurosurg. Focus. 36 (2014) E5. doi:10.3171/2013.11.FOCUS13487. [14] F. Acerbi, M. Broggi, K.-M. Schebesch, J. Höhne, C. Cavallo, C. De Laurentis, M. Eoli, E. Anghileri, M. Servida, C. Boffano, B. Pollo, M. Schiariti, S. Visintini, C. Montomoli, L. Bosio, E. La Corte, G. Broggi, A. Brawanski, P. Ferroli, Fluorescein-guided surgery for resection of high-grade gliomas: A multicentric prospective phase II study (FLUOGLIO)., Clin. Cancer Res. (2017). doi:10.1158/1078-0432.CCR-17-1184. [15] F. Acerbi, M. Broggi, M. Eoli, E. Anghileri, L. Cuppini, B. Pollo, M. Schiariti, S. Visintini, C. Orsi, A. Franzini, G. Broggi, P. Ferroli, Fluorescein-guided surgery for grade IV gliomas with a dedicated filter on the surgical microscope: preliminary results in 12 cases., Acta Neurochir. (Wien). 155 (2013) 1277–1286. doi:10.1007/s00701-013-1734-9. [16] W. Stummer, Fluorescein in brain metastasis and glioma surgery, Acta Neurochir. (Wien). 157 (2015) 2199–2200. doi:10.1007/s00701-015-2576-4. [17] K. Schebesch, J. Hoehne, C. Hohenberger, M. Proescholdt, M.J. Riemenschneider, C. Wendl, A. Brawanski, Fluorescein sodium-guided resection of cerebral metastases — experience with the first 30 patients, Acta Neurochir. (Wien). 157 (2015) 899–904. doi:10.1007/s00701-015-2395-7. [18] K.M. Schebesch, J. Hoehne, C. Hohenberger, F. Acerbi, M. Broggi, M. Proescholdt, C. Wendl, M.J. Riemenschneider, A. Brawanski, Fluorescein sodium-guided surgery in cerebral lymphoma, Clin. Neurol. Neurosurg. 139 (2015) 125–128. doi:10.1016/j.clineuro.2015.09.015. [19] R. Rey-dios, A.A. Cohen-gadol, Intraoperative fluorescence for resection of hemangioblastomas, Acta Neurochir. (Wien). 155 (2013) 1287–1292. doi:10.1007/s00701-013-1723-z. [20] B.C. Lane, A.A. Cohen-Gadol, A prospective study of microscope-integrated intraoperative fluorescein videoangiography during arteriovenous malformation surgery: preliminary results., Neurosurg. Focus. 36 (2014) E15. doi:10.3171/2013.11.FOCUS13483. [21] B. Lane, B.N. Bohnstedt, A.A. Cohen-Gadol, A prospective comparative study of microscope-integrated intraoperative fluorescein and indocyanine videoangiography for clip ligation of complex cerebral aneurysms, J. Neurosurg. 122 (2015) 618–626. doi:10.3171/2014.10.jns132766. [22] F. Acerbi, C. Cavallo, M. Broggi, R. Cordella, E. Anghileri, M. Eoli, M. Schiariti, G. Broggi, P. Ferroli, Fluorescein-guided surgery for malignant gliomas: a review, Neurosurg. Rev. 37 (2014) 547–557. doi:10.1007/s10143-014-0546-6. [23] B.C. Lane, A.A. Cohen-Gadol, Fluorescein fluorescence use in the management of intracranial neoplastic and vascular lesions: a review and report of a new technique., Curr. Drug Discov. Technol. 10 (2013) 160–169. http://www.ncbi.nlm.nih.gov/pubmed/23363235. [24] W. Stummer, A. Novotny, H. Stepp, C. Goetz, K. Bise, H.J. Reulen, Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients., J. Neurosurg. 93 (2000) 1003–1013. doi:10.3171/jns.2000.93.6.1003. [25] L.A. Yannuzzi, K.T. Rohrer, L.J. Tindel, R.S. Sobel, M.A. Costanza, W. Shields, E. Zang, Fluorescein Angiography Complication Survey, Ophthalmology. 93 (1986) 611–617. doi:10.1016/S0161-6420(86)33697-2. [26] I.W.H. Chung, S. Eljamel, Risk factors for developing oral 5-aminolevulinic acid-induced side effects in patients undergoing fluorescence guided resection., Photodiagnosis Photodyn. Ther. 10 (2013) 362–367. doi:10.1016/j.pdpdt.2013.03.007. [27] E. Suero Molina, J. Wölfer, C. Ewelt, A. Ehrhardt, B. Brokinkel, W. Stummer, Dual-labeling with 5–aminolevulinic acid and fluorescein for fluorescence-guided resection of high-grade gliomas: technical note, J. Neurosurg. (2017) 1–7. doi:10.3171/2016.11.JNS161072. [28] J. Coburger, A. Nabavi, R. König, C. Rainer, A. Pala, Contemporary use of intraoperative imaging in glioma surgery?: A survey among EANS members, Clin. Neurol. Neurosurg. 163 (2017) 133–141. doi:10.1016/j.clineuro.2017.10.033. [29] F. Acerbi, F. Restelli, M. Broggi, M. Schiariti, P. Ferroli, Feasibility of simultaneous sodium fluorescein and indocyanine green injection in neurosurgical procedures, Clin. Neurol. Neurosurg. 146 (2016) 123–129. doi:10.1016/j.clineuro.2016.05.003. [30] B.D. Killory, P. Nakaji, L.F. Gonzales, F.A. Ponce, S.D. Wait, R.F. Spetzler, Prospective evaluation of surgical microscope-integrated intraoperative near-infrared indocyanine green angiography during cerebral arteriovenous malformation surgery., Neurosurgery. 65 (2009) 456–462. doi:10.1227/01.NEU.0000346649.48114.3A.