In recent years, fluorescence image-guided surgery (FIGS) with contrast provided by 5-aminolevulinic acid (5- ALA)-induced protoporphyrin IX (PpIX) has been demonstrated to improve surgical outcomes for glioma patients. However, there are limitations to this wide-field (low-resolution) imaging method. Specifically, it is diffiult to accurately identify a surgical margin based on subtle variations of fluorescence intensity in gliomas, which are diffuse and lack a distinct transition from tumor to normal tissue. Furthermore, wide-field (low- resolution) approaches, such as FIGS and MRI, provide pixel intensities that represent an average value from many cells, resulting in a diminished ability to detect the sparse tumor cell populations at the glioma periphery. This problem is exacerbated in low-grade gliomas, where 5-ALA-induced PpIX fluorescence is only generated by rare proliferating cell populations and is typically undetectable via wide-field FIGS. Recently, Dr. Nader Sanai, a collaborator on this project, has shown that intraoperative cellular-resolution confocal microscopy can be used to visualize these sparse fluorescent cells in low-grade glioma patients treated with 5-ALA. The implications of this finding are highly significant since reported rates of gross-total resection (GTR) have been suboptimal for low-grade gliomas (14% to 46%), suggesting a need for improved image-guidance techniques. Here, we propose to develop a hand-held intraoperative confocal microscope to visualize 5-ALA-induced PpIX expression in low-grade glioma tissues. Ex vivo imaging studies with clinical specimens will demonstrate that this real-time in vivo imaging technique 1) quantifies PpIX expression accurately compared to gold-standard histopathology, 2) has the sensitivity to identify tumor infiltration beyond conventional radiographic margins based on T2-weighted MRI, and 3) provides superior image quality compared to the only existing optical- sectioning microscope in neurosurgical use, the Zeiss Optiscan(R) confocal microscope. Finally, a first-in-human study is proposed to demonstrate the feasibility of incorporating our device into the operative workflow, providing a real-time quantitative """"""""optical biopsy"""""""" that complements existing wide-field imaging techniques in neurosurgery and helps to calibrate surgical decision-making at the final stages of tumor resection. Preclinical and clinical studies will leverage the existing expertise of Dr. Nader Sanai at the Barrow Neurological Institute (BNI), which is the highest-volume operative center for glioma resection in the United States and the only institution with extensive experience using both wide-field FIGS and intraoperative confocal microscopy. The results of these technological developments and translational studies will justify future clinical trials investigating quantitatie intraoperative confocal microscopy as a surgical strategy to maximize extent of resection, minimize operative morbidity, and improve overall survival for low-grade glioma patients.

Public Health Relevance

We propose to develop a miniature intraoperative confocal microscope to assist with the resection of low-grade gliomas. The aims of this project are translational and seek to develop clinical imaging technologies for improving human health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA175391-01A1
Application #
8696044
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Zhang, Huiming
Project Start
2014-05-01
Project End
2014-08-15
Budget Start
2014-05-01
Budget End
2014-08-15
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Liu, Qiang; Sanai, Nader; Jin, Wei-Na et al. (2016) Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. Nat Neurosci 19:243-52
Yin, C; Glaser, A K; Leigh, S Y et al. (2016) Miniature in vivo MEMS-based line-scanned dual-axis confocal microscope for point-of-care pathology. Biomed Opt Express 7:251-63
Singh, Shiv K; Fiorelli, Roberto; Kupp, Robert et al. (2016) Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-β Pathway. Cell Rep 16:950-66
Chen, Ye; Glaser, Adam; Liu, Jonathan T C (2016) Bessel-beam illumination in dual-axis confocal microscopy mitigates resolution degradation caused by refractive heterogeneities. J Biophotonics :
Wang, Yu; Kang, Soyoung; Doerksen, Josh D et al. (2016) Surgical Guidance via Multiplexed Molecular Imaging of Fresh Tissues Labeled with SERS-Coded Nanoparticles. IEEE J Sel Top Quantum Electron 22:
Glaser, A K; Wang, Y; Liu, J T C (2016) Assessing the imaging performance of light sheet microscopies in highly scattering tissues. Biomed Opt Express 7:454-66
Kupp, Robert; Shtayer, Lior; Tien, An-Chi et al. (2016) Lineage-Restricted OLIG2-RTK Signaling Governs the Molecular Subtype of Glioma Stem-like Cells. Cell Rep 16:2838-45
Chen, Ye; Liu, Jonathan T C (2015) Characterizing the beam steering and distortion of Gaussian and Bessel beams focused in tissues with microscopic heterogeneities. Biomed Opt Express 6:1318-30
Ji, Minbiao; Lewis, Spencer; Camelo-Piragua, Sandra et al. (2015) Detection of human brain tumor infiltration with quantitative stimulated Raman scattering microscopy. Sci Transl Med 7:309ra163
Leigh, Steven; Chen, Ye; Liu, Jonathan (2015) Modulated-alignment dual-axis (MAD) confocal microscopy optimized for speed and contrast. IEEE Trans Biomed Eng :

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