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Journal of Neuro-Oncology

Erschienen in:

15.12.2018 | Topic Review

Visualization technologies for 5-ALA-based fluorescence-guided surgeries

verfasst von: Linpeng Wei, David W. Roberts, Nader Sanai, Jonathan T. C. Liu

Erschienen in: Journal of Neuro-Oncology | Ausgabe 3/2019

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Abstract

Introduction

5-ALA-based fluorescence-guided surgery has been shown to be a safe and effective method to improve intraoperative visualization and resection of malignant gliomas. However, it remains ineffective in guiding the resection of lower-grade, non-enhancing, and deep-seated tumors, mainly because these tumors do not produce detectable fluorescence with conventional visualization technologies, namely, wide-field (WF) surgical microscopy.

Methods

We describe some of the main factors that limit the sensitivity and accuracy of conventional WF surgical microscopy, and then provide a survey of commercial and research prototypes being developed to address these challenges, along with their principles, advantages and disadvantages, as well as the current status of clinical translation for each technology. We also provide a neurosurgical perspective on how these visualization technologies might best be implemented for guiding glioma surgeries in the future.

Results

Detection of PpIX expression in low-grade gliomas and at the infiltrative margins of all gliomas has been achieved with high-sensitivity probe-based visualization techniques. Deep-tissue PpIX imaging of up to 5 mm has also been achieved using red-light illumination techniques. Spectroscopic approaches have enabled more accurate quantification of PpIX expression.

Conclusion

Advancements in visualization technologies have extended the sensitivity and accuracy of conventional WF surgical microscopy. These technologies will continue to be refined to further improve the extent of resection in glioma patients using 5-ALA-induced fluorescence.

Sanai N, Berger MS (2018) Surgical oncology for gliomas: the state of the art. Nat Rev Clin Oncol 15(2):112–125. https://doi.org/10.1038/nrclinonc.2017.171 CrossRefPubMed

Stummer W, van den Bent MJ, Westphal M (2011) Cytoreductive surgery of glioblastoma as the key to successful adjuvant therapies: new arguments in an old discussion. Acta Neurochir 153(6):1211–1218. https://doi.org/10.1007/s00701-011-1001-x CrossRefPubMed

Tonn JC, Stummer W (2008) Fluorescence-guided resection of malignant gliomas using 5-aminolevulinic acid: practical use, risks, and pitfalls. Clin Neurosurg 55:20–26PubMed

Price SJ, Gillard JH (2011) Imaging biomarkers of brain tumour margin and tumour invasion. Br J Radiol 84(Spec No 2):S159–S167. https://doi.org/10.1259/bjr/26838774 CrossRefPubMedPubMedCentral

Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX Development Corp.) as an optical imaging agent indicated in patients with gliomas (2017). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208630s000lbl.pdf

Gibbs SL, Chen B, O’Hara JA, Hoopes PJ, Hasan T, Pogue BW (2006) Protoporphyrin IX level correlates with number of mitochondria, but increase in production correlates with tumor cell size. Photochem Photobiol 82(5):1334–1341. https://doi.org/10.1562/2006-03-11-RA-843 CrossRefPubMed

Valdes PA, Kim A, Brantsch M, Niu C, Moses ZB, Tosteson TD, Wilson BC, Paulsen KD, Roberts DW, Harris BT (2011) delta-aminolevulinic acid-induced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy. Neuro Oncol 13(8):846–856. https://doi.org/10.1093/neuonc/nor086 CrossRefPubMedPubMedCentral

Valdes PA, Leblond F, Kim A, Harris BT, Wilson BC, Fan XY, Tosteson TD, Hartov A, Ji SB, Erkmen K, Simmons NE, Paulsen KD, Roberts DW (2011) Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. J Neurosurg 115(1):11–17. https://doi.org/10.3171/2011.2.Jns101451 CrossRefPubMedPubMedCentral

Belykh E, Miller EJ, Hu D, Martirosyan NL, Woolf EC, Scheck AC, Byvaltsev VA, Nakaji P, Nelson LY, Seibel EJ, Preul MC (2018) Scanning fiber endoscope improves detection of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence at the boundary of infiltrative glioma. World Neurosurg 113:e51–e69. https://doi.org/10.1016/j.wneu.2018.01.151 CrossRefPubMedPubMedCentral

10.

Stummer W, Tonn JC, Goetz C, Ullrich W, Stepp H, Bink A, Pietsch T, Pichlmeier U (2014) 5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging. Neurosurgery 74(3):310–319. https://doi.org/10.1227/NEU.0000000000000267 discussion 319–320.CrossRefPubMed

11.

Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ (2000) Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93(6):1003–1013. https://doi.org/10.3171/jns.2000.93.6.1003 CrossRefPubMed

12.

Panciani PP, Fontanella M, Schatlo B, Garbossa D, Agnoletti A, Ducati A, Lanotte M (2012) Fluorescence and image guided resection in high grade glioma. Clin Neurol Neurosurg 114(1):37–41. https://doi.org/10.1016/j.clineuro.2011.09.001 CrossRefPubMed

13.

Yamada S, Muragaki Y, Maruyama T, Komori T, Okada Y (2015) Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas. Clin Neurol Neurosurg 130:134–139. https://doi.org/10.1016/j.clineuro.2015.01.005 CrossRefPubMed

14.

Roberts DW, Valdes PA, Harris BT, Fontaine KM, Hartov A, Fan X, Ji S, Lollis SS, Pogue BW, Leblond F, Tosteson TD, Wilson BC, Paulsen KD (2011) Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between delta-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article. J Neurosurg 114(3):595–603. https://doi.org/10.3171/2010.2.JNS091322 CrossRefPubMed

15.

Diez Valle R, Tejada Solis S, Idoate Gastearena MA, Garcia de Eulate R, Dominguez Echavarri P, Aristu Mendiroz J (2011) Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience. J Neurooncol 102(1):105–113. https://doi.org/10.1007/s11060-010-0296-4 CrossRefPubMed

16.

Hefti M, von Campe G, Moschopulos M, Siegner A, Looser H, Landolt H (2008) 5-aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institutuion. Swiss Med Wkly 138(11–12):180–185. doi:2008/11/smw-12077PubMed

17.

Acerbi F, Broggi M, Eoli M, Anghileri E, Cuppini L, Pollo B, Schiariti M, Visintini S, Orsi C, Franzini A, Broggi G, Ferroli P (2013) Fluorescein-guided surgery for grade IV gliomas with a dedicated filter on the surgical microscope: preliminary results in 12 cases. Acta Neurochir (Wien) 155(7):1277–1286. https://doi.org/10.1007/s00701-013-1734-9 CrossRef

18.

Tsugu A, Ishizaka H, Mizokami Y, Osada T, Baba T, Yoshiyama M, Nishiyama J, Matsumae M (2011) Impact of the combination of 5-aminolevulinic acid-induced fluorescence with intraoperative magnetic resonance imaging-guided surgery for glioma. World Neurosurg 76(1–2):120–127. https://doi.org/10.1016/j.wneu.2011.02.005 CrossRefPubMed

19.

Hadjipanayis CG, Widhalm G, Stummer W (2015) What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas? Neurosurgery 77(5):663–673. https://doi.org/10.1227/NEU.0000000000000929 CrossRefPubMedPubMedCentral

20.

Rapp M, Kamp M, Steiger HJ, Sabel M (2014) Endoscopic-assisted visualization of 5-aminolevulinic acid-induced fluorescence in malignant glioma surgery: a technical note. World Neurosurg 82(1–2):E277–E279. https://doi.org/10.1016/j.wneu.2013.07.002 CrossRefPubMed

21.

Belloch JP, Rovira V, Llacer JL, Riesgo PA, Cremades A (2014) Fluorescence-guided surgery in high grade gliomas using an exoscope system. Acta Neurochir (Wien) 156(4):653–660. https://doi.org/10.1007/s00701-013-1976-6 CrossRef

22.

Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, Group AL-GS (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401. https://doi.org/10.1016/S1470-2045(06)70665-9 CrossRefPubMed

23.

Sanai N, Snyder LA, Honea NJ, Coons SW, Eschbacher JM, Smith KA, Spetzler RF (2011) Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas. J Neurosurg 115(4):740–748. https://doi.org/10.3171/2011.6.JNS11252 CrossRefPubMed

24.

Valdes PA, Jacobs V, Harris BT, Wilson BC, Leblond F, Paulsen KD, Roberts DW (2015) Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery. J Neurosurg 123(3):771–780. https://doi.org/10.3171/2014.12.JNS14391 CrossRefPubMedPubMedCentral

25.

Valdes PA, Leblond F, Jacobs VL, Wilson BC, Paulsen KD, Roberts DW (2012) Quantitative, spectrally-resolved intraoperative fluorescence imaging. Sci Rep 2:798. https://doi.org/10.1038/srep00798 CrossRefPubMedPubMedCentral

26.

Richter JCO, Haj-Hosseini N, Hallbeck M, Wardell K (2017) Combination of hand-held probe and microscopy for fluorescence guided surgery in the brain tumor marginal zone. Photodiagnosis Photodyn Ther 18:185–192. https://doi.org/10.1016/j.pdpdt.2017.01.188 CrossRefPubMed

27.

Konecky SD, Owen CM, Rice T, Valdes PA, Kolste K, Wilson BC, Leblond F, Roberts DW, Paulsen KD, Tromberg BJ (2012) Spatial frequency domain tomography of protoporphyrin IX fluorescence in preclinical glioma models. J Biomed Opt 17(5):056008. https://doi.org/10.1117/1.JBO.17.5.056008 CrossRefPubMedPubMedCentral

28.

Kepshire DS, Gibbs-Strauss SL, O’Hara JA, Hutchins M, Mincu N, Leblond F, Khayat M, Dehghani H, Srinivasan S, Pogue BW (2009) Imaging of glioma tumor with endogenous fluorescence tomography. J Biomed Opt 14(3):030501. https://doi.org/10.1117/1.3127202 CrossRefPubMedPubMedCentral

29.

Kim A, Roy M, Dadani FN, Wilson BC (2010) Topographic mapping of subsurface fluorescent structures in tissue using multiwavelength excitation. J Biomed Opt 15(6):066026. https://doi.org/10.1117/1.3523369 CrossRefPubMedPubMedCentral

30.

Leblond F, Ovanesyan Z, Davis SC, Valdes PA, Kim A, Hartov A, Wilson BC, Pogue BW, Paulsen KD, Roberts DW (2011) Analytic expression of fluorescence ratio detection correlates with depth in multi-spectral sub-surface imaging. Phys Med Biol 56(21):6823–6837. https://doi.org/10.1088/0031-9155/56/21/005 CrossRefPubMedPubMedCentral

31.

Kolste KK, Kanick SC, Valdes PA, Jermyn M, Wilson BC, Roberts DW, Paulsen KD, Leblond F (2015) Macroscopic optical imaging technique for wide-field estimation of fluorescence depth in optically turbid media for application in brain tumor surgical guidance. J Biomed Opt 20(2):26002. https://doi.org/10.1117/1.JBO.20.2.026002 CrossRefPubMed

32.

Jermyn M, Kolste K, Pichette J, Sheehy G, Angulo-Rodriguez L, Paulsen KD, Roberts DW, Wilson BC, Petrecca K, Leblond F (2015) Macroscopic-imaging technique for subsurface quantification of near-infrared markers during surgery. J Biomed Opt 20(3):036014. https://doi.org/10.1117/1.JBO.20.3.036014 CrossRefPubMedPubMedCentral

33.

Roberts DW, Olson JD, Evans LT, Kolste KK, Kanick SC, Fan X, Bravo JJ, Wilson BC, Leblond F, Marois M, Paulsen KD (2018) Red-light excitation of protoporphyrin IX fluorescence for subsurface tumor detection. J Neurosurg 128(6):1690–1697. https://doi.org/10.3171/2017.1.JNS162061 CrossRefPubMed

34.

Meza D, Wang D, Wang Y, Borwege S, Sanai N, Liu JT (2015) Comparing high-resolution microscopy techniques for potential intraoperative use in guiding low-grade glioma resections. Lasers Surg Med 47(4):289–295. https://doi.org/10.1002/lsm.22347 CrossRefPubMedPubMedCentral

35.

Stummer W, Stocker S, Wagner S, Stepp H, Fritsch C, Goetz C, Goetz AE, Kiefmann R, Reulen HJ (1998) Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery 42(3):518–525 (discussion 525–516)CrossRefPubMed

36.

Stummer W, Stepp H, Moller G, Ehrhardt A, Leonhard M, Reulen HJ (1998) Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir (Wien) 140(10):995–1000CrossRef

37.

Liu JT, Meza D, Sanai N (2014) Trends in fluorescence image-guided surgery for gliomas. Neurosurgery 75(1):61–71. https://doi.org/10.1227/NEU.0000000000000344 CrossRefPubMedPubMedCentral

38.

Valdes PA, Roberts DW, Lu FK, Golby A (2016) Optical technologies for intraoperative neurosurgical guidance. Neurosurg Focus 40(3):E8. https://doi.org/10.3171/2015.12.FOCUS15550 CrossRefPubMedPubMedCentral

39.

Pogue BW, Gibbs-Strauss S, Valdes PA, Samkoe K, Roberts DW, Paulsen KD (2010) Review of Neurosurgical Fluorescence Imaging Methodologies. IEEE J Sel Top Quantum Electron 16(3):493–505. https://doi.org/10.1109/JSTQE.2009.2034541 CrossRefPubMedPubMedCentral

40.

Belykh E, Martirosyan NL, Yagmurlu K, Miller EJ, Eschbacher JM, Izadyyazdanabadi M, Bardonova LA, Byvaltsev VA, Nakaji P, Preul MC (2016) Intraoperative fluorescence imaging for personalized brain tumor resection: current state and future directions. Front Surg 3:55. https://doi.org/10.3389/fsurg.2016.00055 CrossRefPubMedPubMedCentral

41.

Tamura Y, Kuroiwa T, Kajimoto Y, Miki Y, Miyatake S, Tsuji M (2007) Endoscopic identification and biopsy sampling of an intraventricular malignant glioma using a 5-aminolevulinic acid-induced protoporphyrin IX fluorescence imaging system. Technical note. J Neurosurg 106(3):507–510. https://doi.org/10.3171/jns.2007.106.3.507 CrossRefPubMed

42.

Haj-Hosseini N, Richter J, Andersson-Engels S, Wårdell K (2009) Photobleaching behavior of protoporphyrin IX during 5-aminolevulinic acid marked glioblastoma detection. Proc. SPIE 7161, Photonic Therapeutics and Diagnostics V, 716131. https://doi.org/10.1117/12.808156

43.

Potapov AA, Usachev DJ, Loshakov VA, Cherekaev VA, Kornienko VN, Pronin IN, Kobiakov GL, Kalinin PL, Gavrilov AG, Stummer W, Golbin DA, Zelenkov PV (2008) First experience in 5-ALA fluorescence-guided and endoscopically assisted microsurgery of brain tumors. Med Laser Appl 23(4):202–208. https://doi.org/10.1016/j.mla.2008.07.006 CrossRef

44.

Haj-Hosseini N, Richter J, Andersson-Engels S, Wardell K (2010) Optical touch pointer for fluorescence guided glioblastoma resection using 5-aminolevulinic acid. Lasers Surg Med 42(1):9–14. https://doi.org/10.1002/lsm.20868 CrossRefPubMed

45.

Kim A, Khurana M, Moriyama Y, Wilson BC (2010) Quantification of in vivo fluorescence decoupled from the effects of tissue optical properties using fiber-optic spectroscopy measurements. J Biomed Opt 15(6):067006CrossRefPubMedPubMedCentral

46.

Ishihara R, Katayama Y, Watanabe T, Yoshino A, Fukushima T, Sakatani K (2007) Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas. Neurol Med Chir (Tokyo) 47(2):53–57; discussion 57CrossRef

47.

Utsuki S, Oka H, Sato S, Suzuki S, Shimizu S, Tanaka S, Fujii K (2006) Possibility of using laser spectroscopy for the intraoperative detection of nonfluorescing brain tumors and the boundaries of brain tumor infiltrates—Technical note. J Neurosurg 104(4):618–620. doi:https://doi.org/10.3171/jns.2006.104.4.618 CrossRefPubMed

48.

Utzinger U, Richards-Kortum RR (2003) Fiber optic probes for biomedical optical spectroscopy. J Biomed Opt 8(1):121–147. https://doi.org/10.1117/1.1528207 CrossRefPubMed

49.

Valdes PA, Jacobs VL, Wilson BC, Leblond F, Roberts DW, Paulsen KD (2013) System and methods for wide-field quantitative fluorescence imaging during neurosurgery. Opt Lett 38(15):2786–2788. https://doi.org/10.1364/OL.38.002786 CrossRefPubMed

50.

Bravo JJ, Olson JD, Davis SC, Roberts DW, Paulsen KD, Kanick SC (2017) Hyperspectral data processing improves PpIX contrast during fluorescence guided surgery of human brain tumors. Sci Rep 7(1):9455. https://doi.org/10.1038/s41598-017-09727-8 CrossRefPubMedPubMedCentral

51.

Markwardt NA, Haj-Hosseini N, Hollnburger B, Stepp H, Zelenkov P, Ruhm A (2016) 405 nm versus 633 nm for protoporphyrin IX excitation in fluorescence-guided stereotactic biopsy of brain tumors. J Biophotonics 9(9):901–912. https://doi.org/10.1002/jbio.201500195 CrossRefPubMed

52.

Cuccia DJ, Bevilacqua F, Durkin AJ, Tromberg BJ (2005) Modulated imaging: quantitative analysis and tomography of turbid media in the spatial-frequency domain. Opt Lett 30(11):1354–1356CrossRefPubMed

53.

Wirth D, Kolste K, Kanick S, Roberts DW, Leblond F, Paulsen KD (2017) Fluorescence depth estimation from wide-field optical imaging data for guiding brain tumor resection: a multi-inclusion phantom study. Biomed Opt Express 8(8):3656–3670. https://doi.org/10.1364/BOE.8.003656 CrossRefPubMedPubMedCentral

54.

Wei L, Chen Y, Yin C, Borwege S, Sanai N, Liu JTC (2017) Optical-sectioning microscopy of protoporphyrin IX fluorescence in human gliomas: standardization and quantitative comparison with histology. J Biomed Opt 22(4):46005. https://doi.org/10.1117/1.JBO.22.4.046005 CrossRefPubMed

55.

Yin C, Glaser AK, Leigh SY, Chen Y, Wei L, Pillai PC, Rosenberg MC, Abeytunge S, Peterson G, Glazowski C, Sanai N, Mandella MJ, Rajadhyaksha M, Liu JT (2016) Miniature in vivo MEMS-based line-scanned dual-axis confocal microscope for point-of-care pathology. Biomed Opt Express 7(2):251–263. https://doi.org/10.1364/BOE.7.000251 CrossRefPubMedPubMedCentral

56.

Wei L, Yin C, Liu JTC (2019) Dual-axis confocal microscopy for point-of-care pathology. IEEE J Sel Top Quantum Electron 25(1):1–10. https://doi.org/10.1109/JSTQE.2018.2854572 CrossRef

57.

Liu JT, Loewke NO, Mandella MJ, Levenson RM, Crawford JM, Contag CH (2011) Point-of-care pathology with miniature microscopes. Anal Cell Pathol (Amst) 34(3):81–98. https://doi.org/10.3233/ACP-2011-011 CrossRef

58.

Gmitro AF, Aziz D (1993) Confocal microscopy through a fiber-optic imaging bundle. Opt Lett 18(8):565–567. https://doi.org/10.1364/OL.18.000565 CrossRefPubMed

59.

Descour RR-KLSSBR (2002) Fiber-optic confocal imaging apparatus and methods of use. US6370422B1. https://patents.google.com/patent/US6370422B1/en

60.

Udovich JA, Kirkpatrick ND, Kano A, Tanbakuchi A, Utzinger U, Gmitro AF (2008) Spectral background and transmission characteristics of fiber optic imaging bundles. Appl Opt 47(25):4560–4568. https://doi.org/10.1364/Ao.47.004560 CrossRefPubMed

Titel: Visualization technologies for 5-ALA-based fluorescence-guided surgeries
verfasst von: Linpeng Wei
David W. Roberts
Nader Sanai
Jonathan T. C. Liu
Publikationsdatum: 15.12.2018
Verlag: Springer US
Erschienen in: Journal of Neuro-Oncology / Ausgabe 3/2019
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-018-03077-9

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Visualization technologies for 5-ALA-based fluorescence-guided surgeries

Abstract

Introduction

Methods

Results

Conclusion

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Abstract

Introduction

Methods

Results

Conclusion

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