The goal of brain tumor surgery is to maximize removal of tumor without causing permanent neurologic deficits. Studies have shown that outcomes for patients depend strongly on these two variables. However, this is difficult because tumor tissue is often indistinguishable from healthy tissue in the operating room. Preoperative and intraoperative MRI through neuronavigation can be used to guide brain tumor surgery, but it is not able to accurately delineate the tumor margin due to the brain deformation and brain shift during surgery. H&E staining as the current gold standard is often performed intraoperatively for preliminary diagnosis, but it is not used to guide extent of resection routinely due to the limitations including tissue artifacts, labor-intensiveness, and time delay. Fluorescence guided surgery is beginning to be used to guided brain tumor surgery, but is generally not useful for low grade gliomas, the tumors which pose the greatest challenge and opportunity to extend survival and improve quality of life. Stimulated Raman imaging (SRI) has been used for rapid label-free biomolecular mapping in live tissue. Recently we have developed a novel approach with SRI to image nucleic acids, together with protein and lipids. Visualization of nucleic acids allows definition of nuclear morphology and chromatin structures, thereby enabling pathologic evaluation of clinically relevant cellular morphology, providing almost equivalent information to H&E staining. The goal of this translational research is to establish the methodology and practice for label-free histopathology with SRI for brain tumor diagnosis, and eventually develop it into a clinical device for ambient SR imaging of fresh tissue in the operating room in real time If the aims are achieved, this project will greatly improve the current clinical practice of brain tumor surgery by providing real time tissue diagnosis for more precise control of the extent of resection and preservation of neurologic function. Furthermore, this approach may be of value for all oncologic surgeries and other clinical pathology such as fine needle biopsies and bone marrow biopsy. The candidate for this award Dr. Fake Lu is a postdoctoral research fellow at Brigham and Women's Hospital. Dr. Lu has extensive experience and expertise in biophotonics and biomedical optics, specialized in system innovations of stimulated Raman microscopy and multiphoton microscopy for biomedical applications. BWH is an international leader in basic, clinical and translational research on human diseases, and has established multiple research programs to promote the work and professional career development of young investigators. BWH is also home to the National Center for Image Guided Therapy (P41) and the Advanced Multi-modality Image Guided operating suite (AMIGO) infrastructure which will greatly support to proposed research. Dr. Lu's long term research goal is to develop and apply advanced biophysical and optical technologies and devices to improve understanding, diagnosis, treatment, and prevention of diseases, such as cancers, for better health care. His long-term career goal is to become an independent investigator working at the frontier of translational research. The immediate objectives for the five-year award period is to 1) establish and evaluate label-free histopathology SRI for brain tumor diagnosis, 2) to demonstrate ambient imaging of surgically removed fresh tissue for diagnosis of brain tumors for real time guidance of neurosurgical resection, 3) to develop a novel stimulated Raman microscopy to collect full spectral data in parallel for label-free histopathology, as well as lipid biomarker screening, 4) t develop a computer algorithm for SR image analysis to realize automatic brain tumor diagnosis, and 5) finally by integrating the instrument and software to build and demonstrate a prototype of a clinical device for guiding neurosurgical resection of brain tumors. This device could also be used for other oncologic surgeries and will have great potential for commercialization. To conduct the proposed research, in addition to further develop his current strengths in biophotonics, stimulated Raman microscopy, and nonlinear optical microscopy, Dr. Lu plans to receive more education and training to enrich and expand his knowledge and expertise in the following four areas: 1) to receive critical training in conducting translational research, 2) to enrich his knowledge and deepen his understanding in brain tumor biology and medicine, 3) to learn skills in developing computer algorithms for SR image analysis, and 4) to prepare for writing grant applications and seeking funding independently. Dr. Lu will participate in 12 formal courses selected from those offered by Harvard Catalyst and Cold Spring Harbor Laboratory. He will attend weekly seminars at BWH and Harvard University, seminar series on biomedical image analysis organized by MIT Computer Science and Artificial Intelligence Laboratory. He will also attend one or two annual conferences per year to present his work for peer discussion. A strong mentoring team was organized to provide solid support to the proposed research and Dr. Lu's career development, including Dr. Alexandra Golby in neurosurgery at BWH, Prof. X. Sunney Xie in coherent Raman microscopy at Harvard, Prof. Nathalie Agar in molecular cancer diagnosis at BWH, Prof. Polina Golland in computer-based image analysis at MIT, and Dr. Sandro Santagata in neuropathology at BWH. This career development award will provide Dr. Lu with the training and skills needed to transition into an independent investigator in translational research.

Public Health Relevance

Surgery is the standard treatment for brain tumors, and the goal of brain tumor surgery is to completely remove the tumor without causing neurologic deficits. However, it is often difficult to distinguish normal and cancerous tissue during surgery. This project aims to develop a novel tool based on stimulated Raman microscopy to image fresh brain tissue in a label-free manner, providing comparable histological information to conventional H&E staining, to guide brain tumor resection in real time in the operating room.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Career Transition Award (K99)
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Special Emphasis Panel (ZEB1-OSR-C (M2))
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Erim, Zeynep
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Brigham and Women's Hospital
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Randall, Elizabeth C; Emdal, Kristina B; Laramy, Janice K et al. (2018) Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma. Nat Commun 9:4904
Vald├ęs, Pablo A; Roberts, David W; Lu, Fa-Ke et al. (2016) Optical technologies for intraoperative neurosurgical guidance. Neurosurg Focus 40:E8
Lu, Fa-Ke; Calligaris, David; Olubiyi, Olutayo I et al. (2016) Label-Free Neurosurgical Pathology with Stimulated Raman Imaging. Cancer Res 76:3451-62