Faculty Bibliography

Conventional methods for intraoperative histopathologic diagnosis are labour- and time-intensive, and may delay decision-making during brain-tumour surgery. Stimulated Raman scattering (SRS) microscopy, a label-free optical process, has been shown to rapidly detect brain-tumour infiltration in fresh, unprocessed human tissues. Here, we demonstrate the first application of SRS microscopy in the operating room by using a portable fibre-laser-based microscope and unprocessed specimens from 101 neurosurgical patients. We also introduce an image-processing method - stimulated Raman histology (SRH) - which leverages SRS images to create virtual haematoxylin-and-eosin-stained slides, revealing essential diagnostic features. In a simulation of intraoperative pathologic consultation in 30 patients, we found a remarkable concordance of SRH and conventional histology for predicting diagnosis (Cohen's kappa, κ > 0.89), with accuracy exceeding 92%. We also built and validated a multilayer perceptron based on quantified SRH image attributes that predicts brain-tumour subtype with 90% accuracy. Our findings provide insight into how SRH can now be used to improve the surgical care of brain tumour patients.

OBJECTIVE Survival rates and prognostic factors for supratentorial hemispheric ependymomas have not been determined. The authors therefore designed a retrospective study to determine progression-free survival (PFS), overall survival (OS), and prognostic factors for hemispheric ependymomas. METHODS The study population consisted of 8 patients from our institution and 101 patients from the literature with disaggregated survival information (n = 109). Patient age, sex, tumor side, tumor location, extent of resection (EOR), tumor grade, postoperative chemotherapy, radiation, time to recurrence, and survival were recorded. Kaplan-Meier survival analyses and Cox proportional hazard models were completed to determine survival rates and prognostic factors. RESULTS Anaplastic histology/WHO Grade III tumors were identified in 62% of cases and correlated with older age. Three-, 5-, and 10-year PFS rates were 57%, 51%, and 42%, respectively. Three-, 5-, and 10-year OS rates were 77%, 71%, and 58%, respectively. EOR and tumor grade were identified on both Kaplan-Meier log-rank testing and univariate Cox proportional hazard models as prognostic for PFS and OS. Both EOR and tumor grade remained prognostic on multivariate analysis. Subtotal resection (STR) predicted a worse PFS (hazard ratio [HR] 4.764, p = 0.001) and OS (HR 4.216, p = 0.008). Subgroup survival analysis of patients with STR demonstrated a 5- and 10-year OS of 28% and 0%, respectively. WHO Grade III tumors also had worse PFS (HR 10.2, p = 0.004) and OS (HR 9.1, p = 0.035). Patients with WHO Grade III tumors demonstrated 5- and 10-year OS of 61% and 46%, respectively. Postoperative radiation was not prognostic for PFS or OS. CONCLUSIONS A high incidence of anaplastic histology was found in hemispheric ependymomas and was associated with older age. EOR and tumor grade were prognostic factors for PFS and OS on multivariate analysis. STR or WHO Grade III pathology, or both, predicted worse overall prognosis in patients with hemispheric ependymoma.

The ability to detect neuronal currents with high spatiotemporal resolution using magnetic resonance imaging (MRI) is important for studying human brain function in both health and disease. While significant progress has been made, we still lack evidence showing that it is possible to measure an MR signal time-locked to neuronal currents with a temporal waveform matching concurrently recorded local field potentials (LFPs). Also lacking is evidence that such MR data can be used to image current distribution in active tissue. Since these two results are lacking even in vitro, we obtained these data in an intact isolated whole cerebellum of turtle during slow neuronal activity mediated by metabotropic glutamate receptors using a gradient-echo EPI sequence (TR=100ms) at 4.7T. Our results show that it is possible (1) to reliably detect an MR phase shift time course matching that of the concurrently measured LFP evoked by stimulation of a cerebellar peduncle, (2) to detect the signal in single voxels of 0.1mm(3), (3) to determine the spatial phase map matching the magnetic field distribution predicted by the LFP map, (4) to estimate the distribution of neuronal current in the active tissue from a group-average phase map, and (5) to provide a quantitatively accurate theoretical account of the measured phase shifts. The peak values of the detected MR phase shifts were 0.27-0.37°, corresponding to local magnetic field changes of 0.67-0.93nT (for TE=26ms). Our work provides an empirical basis for future extensions to in vivo imaging of neuronal currents.

Despite advances in the surgical management of brain tumors, achieving optimal surgical results and identification of tumor remains a challenge. Raman spectroscopy, a laser-based technique that can be used to nondestructively differentiate molecules based on the inelastic scattering of light, is being applied toward improving the accuracy of brain tumor surgery. Here, the authors systematically review the application of Raman spectroscopy for guidance during brain tumor surgery. Raman spectroscopy can differentiate normal brain from necrotic and vital glioma tissue in human specimens based on chemical differences, and has recently been shown to differentiate tumor-infiltrated tissues from noninfiltrated tissues during surgery. Raman spectroscopy also forms the basis for coherent Raman scattering (CRS) microscopy, a technique that amplifies spontaneous Raman signals by 10,000-fold, enabling real-time histological imaging without the need for tissue processing, sectioning, or staining. The authors review the relevant basic and translational studies on CRS microscopy as a means of providing real-time intraoperative guidance. Recent studies have demonstrated how CRS can be used to differentiate tumor-infiltrated tissues from noninfiltrated tissues and that it has excellent agreement with traditional histology. Under simulated operative conditions, CRS has been shown to identify tumor margins that would be undetectable using standard bright-field microscopy. In addition, CRS microscopy has been shown to detect tumor in human surgical specimens with near-perfect agreement to standard H & E microscopy. The authors suggest that as the intraoperative application and instrumentation for Raman spectroscopy and imaging matures, it will become an essential component in the neurosurgical armamentarium for identifying residual tumor and improving the surgical management of brain tumors.

Differentiating tumor from normal brain is a major barrier to achieving optimal outcome in brain tumor surgery. New imaging techniques for visualizing tumor margins during surgery are needed to improve surgical results. We recently demonstrated the ability of stimulated Raman scattering (SRS) microscopy, a nondestructive, label-free optical method, to reveal glioma infiltration in animal models. We show that SRS reveals human brain tumor infiltration in fresh, unprocessed surgical specimens from 22 neurosurgical patients. SRS detects tumor infiltration in near-perfect agreement with standard hematoxylin and eosin light microscopy (kappa = 0.86). The unique chemical contrast specific to SRS microscopy enables tumor detection by revealing quantifiable alterations in tissue cellularity, axonal density, and protein/lipid ratio in tumor-infiltrated tissues. To ensure that SRS microscopic data can be easily used in brain tumor surgery, without the need for expert interpretation, we created a classifier based on cellularity, axonal density, and protein/lipid ratio in SRS images capable of detecting tumor infiltration with 97.5% sensitivity and 98.5% specificity. Quantitative SRS microscopy detects the spread of tumor cells, even in brain tissue surrounding a tumor that appears grossly normal. By accurately revealing tumor infiltration, quantitative SRS microscopy holds potential for improving the accuracy of brain tumor surgery.

OBJECTIVE:Myeloid sarcoma is a rare extramedullary solid tumor comprised of immature myeloid precursor cells, most commonly associated with acute myelogenous leukemia (AML). We present the case of a patient with a history of Shwachman-Diamond syndrome and AML who presented with myeloid sarcoma causing acute spinal cord compression. CASE DESCRIPTION/METHODS:The patient was a 20-year-old man who presented with acute onset weakness and numbness in his lower extremities. Magnetic resonance imaging revealed a thoracic dorsal epidural mass. Despite the history of AML, we elected to forego image-guided biopsy and up-front radiation due to the rapidly progressive nature of his myelopathy. Immediate surgical decompression was performed, but the patient had recurrence of tumor leading to further compression 13 days postoperatively. Subsequently, emergent radiation was performed, leading to resolution of cord compression and local disease control. CONCLUSIONS:To our knowledge, there are no randomized controlled trials examining the appropriate timing for postoperative radiation. Because most typical neuro-oncologic cases have no need for immediate postoperative radiation, our practice has been to wait 14 days to initiate postoperative radiation to ensure wound healing. One unique feature of our case was the rapid recurrence of symptoms due to tumor progression. Given this observation, we believe that radiation therapy should be considered as soon as possible after confirmatory pathology diagnosis for patients presenting with neurological compromise due to myeloid sarcoma of the spine.

Over the past 2 decades, extent of resection has emerged as a significant prognostic factor in patients with low-grade gliomas (LGGs). Greater extent of resection has been shown to improve overall survival, progression-free survival, and time to malignant transformation. The operative goal in most LGG cases is to maximize extent of resection, while avoiding postoperative neurologic deficits. Several advanced surgical techniques have been developed in an attempt to better achieve maximal safe resection. Intraoperative magnetic resonance imaging, fluorescence-guided surgery, intraoperative functional pathway mapping, and neuronavigation are some of the most commonly used techniques with multiple studies to support their efficacy in glioma surgery. By using these techniques either alone or in combination, patients harboring LGGs have a better prognosis with less surgical morbidity following tumor resection.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare, affecting only a small portion of the general population. In many cases, MPNSTs occur in association with neurofibromatosis Type 1 and at times arise secondary to previous radiation therapy (RT). These tumors can be found essentially anywhere a peripheral nerve is present, but they rarely originate primarily from the spinal nerve or cauda equina and cause leptomeningeal spread. This report describes the treatment course of a 43-year-old man with a history of testicular seminoma treated with RT a decade before, who was found to have a large sacral MPNST. The patient underwent complete sacrectomy for gross-total resection. Despite this effort, he was eventually found to have metastatic lesions throughout the spine and brain, ultimately resulting in acute hydrocephalus and death. Biopsy results of these metastatic lesions proved to be characteristic of his original MPNST. The literature is also reviewed and the diagnostic modalities, management strategies, and prognosis of MPNST are discussed.

For many intraoperative decisions surgeons depend on frozen section pathology, a technique developed over 150 y ago. Technical innovations that permit rapid molecular characterization of tissue samples at the time of surgery are needed. Here, using desorption electrospray ionization (DESI) MS, we rapidly detect the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas, under ambient conditions and without complex or time-consuming preparation. With DESI MS, we identify isocitrate dehydrogenase 1-mutant tumors with both high sensitivity and specificity within minutes, immediately providing critical diagnostic, prognostic, and predictive information. Imaging tissue sections with DESI MS shows that the 2-HG signal overlaps with areas of tumor and that 2-HG levels correlate with tumor content, thereby indicating tumor margins. Mapping the 2-HG signal onto 3D MRI reconstructions of tumors allows the integration of molecular and radiologic information for enhanced clinical decision making. We also validate the methodology and its deployment in the operating room: We have installed a mass spectrometer in our Advanced Multimodality Image Guided Operating (AMIGO) suite and demonstrate the molecular analysis of surgical tissue during brain surgery. This work indicates that metabolite-imaging MS could transform many aspects of surgical care.