This application is a revised competing renewal for a second funding period to support the development and evaluation of fluorescence imaging (FI) in guiding the resection of intracranial tumor. Utilizing quantitative FI (qFI) concepts developed during the first funding period, and realized in the form of an intraoperative probe, concentrations of d-aminolevulinic acid (ALA) induced protoporphyrin IX (PpIX) have been measured quantitatively in vivo in human brain tumors. These results are clinically profound because they indicate for the first time that diagnostically significant PpIX concentrations exist brain tumors which are below the threshold of human visual detection - even in low grade glioma (LGG) - tumors previously found inaccessible with visual FI (vFI), despite the significant clinical impact to be gained from improving their completeness of surgical resection through FI technique. Our overall research plan for continuation outlines clinical and technical/ preclinical studies that will be pursued in parallel - a strategy that has proved to be successful during the current funding period and creates a framework for iterative exchange that informs the clinical and technical requirements for solving the resection challenges facing the surgeon. In the second funding phase of the project, we implement and evaluate preclinically technical advances (in Aim 1) designed to achieve wide-field quantitative FI (qFI) and wide-field depth-detected FI (dFI). We will also enroll patients into clinical studies of ALA-induced PpIX FI (in Ai 2) to generate the data required to determine the probability of tumor for a given quantitative value of PpIX concentration. These studies will set the stage for prospective clinical enrollments (in Aim 3) designed to evaluate the addition of qFI and dFI to visual fluorescence imaging (vFI) when surgical accuracy is evaluated intra- and post-operatively with conventional methods . We will realize the combination of qFI and dFI (in Aim 4) to quantitatively detect PpIX concentration at depth by incorporating spatial light modulation imaging in fluorescence as well as reflectance modes. These techniques will also be extended to emerging fluorophores with excitation/emission spectra covering near-infrared wavelengths, which may ultimately have more potential than PpIX, and to enable simultaneous quantitative imaging of concentrations of multiple fluorophores. By the end of the proposed funding period, we will have implemented and evaluated wide-field qFI and dFI techniques in human surgeries and expect to demonstrate that these innovations improve surgical outcomes when added to vFI in a prospective enrollment of patients with malignant glioma.

Public Health Relevance

This application is a revised competing renewal for a second funding period to support the development and evaluation of fluorescence imaging (FI) in guiding the resection of intracranial tumor. In the second phase of funding, patients will be enrolled into clinical studies of ALA-induced PpIX FI to generate the data required to determine the probability of tumor for a given quantitative value of PpIX concentration. Preclinical studies will provide the testing ground the technical developments of wide-field quantitative FI (qFI) and wide-field depth- resolved FI (dFI), and ultimately their combination. These developments will set the stage for prospective clinical enrollments designed to evaluate the addition of qFI and dFI to visual fluorescence imaging (vFI) when surgical accuracy is evaluated intra- and post-operatively with conventional methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS052274-06A1
Application #
8578918
Study Section
Special Emphasis Panel (ZRG1-SBIB-Z (03))
Program Officer
Fountain, Jane W
Project Start
2005-07-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
$539,495
Indirect Cost
$166,760
Name
Dartmouth College
Department
Surgery
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Valdes, Pablo A; Bekelis, Kimon; Harris, Brent T et al. (2013) 5-Aminolevulinic-Acid-Induced Protoporphyrin IX Fluorescence in Meningioma: Qualitative and Quantitative Measurements In Vivo. Neurosurgery :
Valdes, Pablo A; Jacobs, Valerie L; Wilson, Brian C et al. (2013) System and methods for wide-field quantitative fluorescence imaging during neurosurgery. Opt Lett 38:2786-8
Valdes, Pablo A; Kim, Anthony; Leblond, Frederic et al. (2011) Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery. J Biomed Opt 16:116007
Hadjipanayis, Costas G; Jiang, Huabei; Roberts, David W et al. (2011) Current and future clinical applications for optical imaging of cancer: from intraoperative surgical guidance to cancer screening. Semin Oncol 38:109-18
Leblond, F; Ovanesyan, Z; Davis, S C et al. (2011) Analytic expression of fluorescence ratio detection correlates with depth in multi-spectral sub-surface imaging. Phys Med Biol 56:6823-37
Valdes, Pablo A; Leblond, Frederic; Kim, Anthony et al. (2011) Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. J Neurosurg 115:11-7
Valdés, Pablo A; Kim, Anthony; Brantsch, Marco et al. (2011) ?-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 13:846-56
Roberts, David W; Valdés, Pablo A; Harris, Brent T et al. (2011) Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between ?-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article. J Neurosurg 114:595-603
Whitson, Wesley J; Valdes, Pablo A; Harris, Brent T et al. (2011) Confocal microscopy for the histological fluorescence pattern of a recurrent atypical meningioma: case report. Neurosurgery 68:E1768-72; discussion E1772-3
Bekelis, Kimon; Valdes, Pablo A; Erkmen, Kadir et al. (2011) Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas. Neurosurg Focus 30:E8

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