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Robert Lynagh, Mark Ishak, Joseph Georges, Danielle Lopez, Hany Osman, Michael Kakareka, Brandon Boyer, H. Warren Goldman, Jennifer Eschbacher, Mark C. Preul, Peter Nakaji, Alan Turtz, Steven Yocom and Denah Appelt


Accurate histopathological diagnoses are often necessary for treating neuro-oncology patients. However, stereotactic biopsy (STB), a common method for obtaining suspicious tissue from deep or eloquent brain regions, fails to yield diagnostic tissue in some cases. Failure to obtain diagnostic tissue can delay initiation of treatment and may result in further invasive procedures for patients. In this study, the authors sought to determine if the coupling of in vivo optical imaging with an STB system is an effective method for identification of diagnostic tissue at the time of biopsy.


A minimally invasive fiber optic imaging system was developed by coupling a 0.65-mm-diameter coherent fiber optic fluorescence microendoscope to an STB system. Human U251 glioma cells were transduced for stable expression of blue fluorescent protein (BFP) to produce U251-BFP cells that were utilized for in vitro and in vivo experiments. In vitro, blue fluorescence was confirmed, and tumor cell delineation by fluorescein sodium (FNa) was quantified with fluorescence microscopy. In vivo, transgenic athymic rats implanted with U251-BFP cells (n = 4) were utilized for experiments. Five weeks postimplantation, the rats received 5–10 mg/kg intravenous FNa and underwent craniotomies overlying the tumor implantation site and contralateral normal brain. A clinical STB needle containing our 0.65-mm imaging fiber was passed through each craniotomy and images were collected. Fluorescence images from regions of interest ipsilateral and contralateral to tumor implantation were obtained and quantified.


Live-cell fluorescence imaging confirmed blue fluorescence from transduced tumor cells and revealed a strong correlation between tumor cells quantified by blue fluorescence and FNa contrast (R2 = 0.91, p < 0.001). Normalized to background, in vivo FNa-mediated fluorescence intensity was significantly greater from tumor regions, verified by blue fluorescence, compared to contralateral brain in all animals (301.7 ± 34.18 relative fluorescence units, p < 0.001). Fluorescence intensity measured from the tumor margin was not significantly greater than that from normal brain (p = 0.89). Biopsies obtained from regions of strong fluorescein contrast were histologically consistent with tumor.


The authors found that in vivo fluorescence imaging with an STB needle containing a submillimeter-diameter fiber optic fluorescence microendoscope provided direct visualization of neoplastic tissue in an animal brain tumor model prior to biopsy. These results were confirmed in vivo with positive control cells and by post hoc histological assessment. In vivo fluorescence guidance may improve the diagnostic yield of stereotactic biopsies.

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Joseph Georges, Aqib Zehri, Elizabeth Carlson, Joshua Nichols, Michael A. Mooney, Nikolay L. Martirosyan, Layla Ghaffari, M. Yashar S. Kalani, Jennifer Eschbacher, Burt Feuerstein, Trent Anderson, Mark C. Preul, Kendall Van Keuren-Jensen and Peter Nakaji

Glioblastoma is the most common primary brain tumor with a median 12- to 15-month patient survival. Improving patient survival involves better understanding the biological mechanisms of glioblastoma tumorigenesis and seeking targeted molecular therapies. Central to furthering these advances is the collection and storage of surgical biopsies (biobanking) for research. This paper addresses an imaging modality, confocal reflectance microscopy (CRM), for safely screening glioblastoma biopsy samples prior to biobanking to increase the quality of tissue provided for research and clinical trials. These data indicate that CRM can immediately identify cellularity of tissue biopsies from animal models of glioblastoma. When screening fresh human biopsy samples, CRM can differentiate a cellular glioblastoma biopsy from a necrotic biopsy without altering DNA, RNA, or protein expression of sampled tissue. These data illustrate CRM's potential for rapidly and safely screening clinical biopsy samples prior to biobanking, which demonstrates its potential as an effective screening technique that can improve the quality of tissue biobanked for patients with glioblastoma.

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Jennifer Eschbacher, Nikolay L. Martirosyan, Peter Nakaji, Nader Sanai, Mark C. Preul, Kris A. Smith, Stephen W. Coons and Robert F. Spetzler


Frozen-section analysis is the current standard for the intraoperative diagnosis of brain tumors. Intraoperative confocal microscopy is an emerging technology with the potential to visualize tumor histopathological features and cell morphology in real time. The authors report their findings using this new intraoperative technology in vivo with sodium fluorescein contrast during the course of 50 microsurgical tumor resections.


Eighty-eight regions were visualized with confocal microscopy, and corresponding biopsy samples were examined with routine neuropathological analysis. The tumors studied included meningiomas, schwannomas, gliomas of various grades, and a hemangioblastoma. The confocal microscopic features of each tumor and of various artifacts inherent to the technology were documented. A pathologist working in a blinded fashion reviewed a subset of the images in a further evaluation of the usefulness of the device as a diagnostic tool.


Overall, intraoperative confocal imaging correlated surprisingly well with corresponding traditional histological findings, including the identification of many pathognomonic cytoarchitectural features of various brain tumors. In the blinded study, 26 (92.9%) of 28 lesions were diagnosed correctly.


Further study will be necessary for better definition of the role of intraoperative confocal microscopy as a routine adjunct for intraoperative brain tumor diagnosis.