Scanning Fiber Endoscope Improves Detection of 5-Aminolevulinic Acid–Induced Protoporphyrin IX Fluorescence at the Boundary of Infiltrative Glioma

Belykh, Evgenii; Miller, Eric J; Hu, Danying; Martirosyan, Nikolay L.; Woolf, Eric C.; Scheck, Adrienne C.; Byvaltsev, Vadim A.; Nakaji, Peter; Nelson, Leonard Y.; Seibel, Eric J.; Preul, Mark C.

doi:10.1016/j.wneu.2018.01.151

Cited by 49 publications

(41 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…87 Vague, diffuse fluorescence or lack of fluorescence in brain tumours may be due to infiltrative tumour invading healthy tissue 88 and the inability of 5-ALA to cross an intact blood-brain barrier. 89 Strategies aimed at improving detection include combining 5-ALA PDT with sensitive quantitative fluorescent measurement, 90 sophisticated fluorescence imaging tools such as a scanning fibre endoscope 91 and improving light penetration. 92 A better understanding of the mechanistic basis for the 'vulnerability' of tumours to the accumulation of 5-ALA should aid in the development of new approaches that improve the selectivity and sensitivity of this photosensitiser in the diagnosis and therapy of cancer.…”

Section: Discussionmentioning

confidence: 99%

In order for the light to shine so brightly, the darkness must be present—why do cancers fluoresce with 5-aminolaevulinic acid?

2019

View full text Add to dashboard Cite

Photodynamic diagnosis and therapy have emerged as a promising tool in oncology. Using the visible fluorescence from photosensitisers excited by light, clinicians can both identify and treat tumour cells in situ. Protoporphyrin IX, produced in the penultimate step of the haem synthesis pathway, is a naturally occurring photosensitiser that visibly fluoresces when exposed to light. This fluorescence is enhanced considerably by the exogenous administration of the substrate 5-aminolaevulinic acid (5-ALA). Significantly, 5-ALA-induced protoporphyrin IX accumulates preferentially in cancer cells, and this enhanced fluorescence has been harnessed for the detection and photodynamic treatment of brain, skin and bladder tumours. However, surprisingly little is known about the mechanistic basis for this phenomenon. This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon. A better understanding of why cancer cells fluoresce with 5-ALA would improve its use in cancer diagnostics and therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

In order for the light to shine so brightly, the darkness must be present—why do cancers fluoresce with 5-aminolaevulinic acid?

2019

View full text Add to dashboard Cite

show abstract

“…The CLE probe used in this study was optimized to operate with FNa and with other fluorophores that have excitation in the blue light range (488 nm); however, this wavelength is not optimal for imaging with the protoporphyrin IX metabolite after administration of 5-aminolevulinic acid (5-ALA). Visualization of 5-ALA-induced protoporphyrin IX with CLE requires a laser in the 405 nm range and adjustments in probe and/or scanning optics, which are under development 30–32…”

Section: Discussionmentioning

confidence: 99%

“…However, previous studies of 2D CLE imaging of the brain tumors were promising with high specificity and sensitivity values 2,35. Future steps in development of CLE systems include advanced application with other fluorophores (especially infrared probes,36 red fluorescent porphyrins37), label-free tissue assessment methods such as reflectance microscopy,38 Raman spectroscopy,39,40 and other technologies for in vivo microscopy 30,41…”

Section: Discussionmentioning

confidence: 99%

Probe-based three-dimensional confocal laser endomicroscopy of brain tumors: technical note

Belykh¹,

Patel²,

Miller³

et al. 2018

CMAR

Self Cite

View full text Add to dashboard Cite

BackgroundConfocal laser endomicroscopy (CLE) is used during fluorescence-guided brain tumor surgery for intraoperative microscopy of tumor tissue with cellular resolution. CLE could augment and expedite intraoperative decision-making and potentially aid in diagnosis and removal of tumor tissue.ObjectiveTo describe an extension of CLE imaging modality that produces Z-stack images and three-dimensional (3D) pseudocolored volumetric images.Materials and methodsHand-held probe-based CLE was used to collect images from GL261-luc2 gliomas in C57BL/6 mice and from human brain tumor biopsies. The mice were injected with fluorescein sodium (FNa) before imaging. Patients received FNa intraoperatively, and biopsies were imaged immediately in the operating room. Some specimens were counterstained with acridine orange, acriflavine, or Hoechst and imaged on a benchtop confocal microscope. CLE images at various depths were acquired automatically, compiled, rendered into 3D volumes using Fiji software and reviewed by a neuropathologist and neurosurgeons.ResultsCLE imaging, Z-stack acquisition, and 3D image rendering were performed using 19 mouse gliomas and 31 human tumors, including meningiomas, gliomas, and pituitary adenomas. Volumetric images and Z-stacks provided additional information about fluorescence signal distribution, cytoarchitecture, and the course of abnormal vasculature.Conclusion3D and Z-stack CLE imaging is a unique new option for live intraoperative endomicroscopy of brain tumors. The 3D images afford an increased spatial understanding of tumor cellular architecture and visualization of related structures compared with two-dimensional images. Future application of specific fluorescent probes could benefit from this rapid in vivo imaging technology for interrogation of brain tumor tissue.

show abstract

“…Here, we discuss the vehicles irrespective of the optical agent, assuming that criteria and considerations for optical agent selection are a completely separate issue mostly related to the detection methodology and tools. These optical considerations were reviewed previously (270)(271)(272)(273). It is worth noting that any study of novel molecular vehicles, even for non-imaging purposes of brain tumor treatment, is relevant to the development of fluorescence-guided surgical technology and strategy because localization experiments are necessarily involved as part of the study.…”

Section: Optimizing Delivery Of Optical Agents To Brain Tumors Acrossmentioning

confidence: 99%

Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors

et al. 2020

Self Cite

View full text Add to dashboard Cite

Recent advances in maximum safe glioma resection have included the introduction of a host of visualization techniques to complement intraoperative white-light imaging of tumors. However, barriers to the effective use of these techniques within the central nervous system remain. In the healthy brain, the blood-brain barrier ensures the stability of the sensitive internal environment of the brain by protecting the active functions of the central nervous system and preventing the invasion of microorganisms and toxins. Brain tumors, however, often cause degradation and dysfunction of this barrier, resulting in a heterogeneous increase in vascular permeability throughout the tumor mass and outside it. Thus, the characteristics of both the blood-brain and blood-brain tumor barriers hinder the vascular delivery of a variety of therapeutic substances to brain tumors. Recent developments in fluorescent visualization of brain tumors offer improvements in the extent of maximal safe resection, but many of these fluorescent agents must reach the tumor via the vasculature. As a result, these fluorescence-guided resection techniques are often limited by the extent of vascular permeability in tumor regions and by the failure to stain the full volume of tumor tissue. In this review, we describe the structure and function of both the blood-brain and blood-brain tumor barriers in the context of the current state of fluorescence-guided imaging of brain tumors. We discuss features of currently used techniques for fluorescence-guided brain tumor resection, with an emphasis on their interactions with the blood-brain and blood-tumor barriers. Finally, we discuss a selection of novel preclinical techniques that have the potential to enhance the delivery of therapeutics to brain tumors in spite of the barrier properties of the brain.

show abstract

Scanning Fiber Endoscope Improves Detection of 5-Aminolevulinic Acid–Induced Protoporphyrin IX Fluorescence at the Boundary of Infiltrative Glioma

Cited by 49 publications

References 38 publications

In order for the light to shine so brightly, the darkness must be present—why do cancers fluoresce with 5-aminolaevulinic acid?

In order for the light to shine so brightly, the darkness must be present—why do cancers fluoresce with 5-aminolaevulinic acid?

Probe-based three-dimensional confocal laser endomicroscopy of brain tumors: technical note

Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors

Contact Info

Product

Resources

About