Faculty Bibliography

Introduction & Objectives: Delay between prostate biopsy (PB) and pathologic diagnosis leads to a concern of inadequate sampling and repeated biopsy. Stimulated Raman Histology (SRH) is a novel microscopic technique allowing real time, label-free, high-resolution microscopic images of unprocessed, un-sectioned tissue. We evaluated the accuracy of pathologist interpretation of PB SRH as compared to traditional hematoxylin and eosin (H&E) stained slides.
Material(s) and Method(s): Men undergoing prostatectomy were included in an IRB approved prospective study. 18-gauge PB cores, taken ex vivo from prostatectomy specimen, were scanned in a SRH microscope at 20 microns depth over 10-14 minutes using two Raman shifts: 2845cm-1 and 2930cm-1, to create SRH images. The cores were then processed as per normal pathologic protocols. 16 PB containing benign/prostate cancer histology were used as a SRH training cohort for 4 GU pathologists (1, 3, 2x >15 yrs experience), who were then tested on a set of 32 PB imaged by SRH and processed by traditional H&E. Sensitivity, specificity, and concordance for PCa detection on SRH relative to a consensus H&E were assessed. With a two-sided alpha level of 5%, it was calculated 32 SRH imaged biopsies would provide 90% power to detect concordance (k).
Result(s): PB cores were imaged in 2-3 separate strips (11-21 minutes) shown in Figure 1. In identifying any cancer, pathologists achieved moderate concordance (k=0.570; p<0.001) which improved when identifying GGG 2-5 PCa only (k=0.640, p<0001; sensitivity 96.4%; specificity 58.3%). In predicting Gleason score, the concordance for each pathologist varied from poor to moderate (k range -0.163 to 0.457). After individual assessment was completed a pathology consensus conference was held for the interpretation of the SRH PB. In identifying any prostate cancer, pathologists achieved near perfect concordance (k=0.925; p<0.001; sensitivity 95.6%; specificity 100%). When evaluating SRH in a consensus conference, the group prediction of Gleason score improved to moderate concordance (k=0.470; p<0.001). (Figure Presented) (Figure Presented)
Conclusion(s): SRH produces high quality microscopic images that allow for accurate identification of PCa in real-time without need for sectioning or tissue-processing. Individual pathologist performance varied highly suggesting potential for improvement with further training. Future SRH interpretation by convolutional neural network may further enhance GGG prediction
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Background/UNASSIGNED:Diagnostic delays impact the quality of life and survival of patients with brain tumors. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain tumors. A simple, rapid blood test that can be administered easily in a primary care setting to efficiently identify symptomatic patients who are most likely to have a brain tumor would enable quicker referral to brain imaging for those who need it most. Methods/UNASSIGNED:Blood serum samples from 603 patients were prospectively collected and analyzed. Patients either had non-specific symptoms that could be indicative of a brain tumor on presentation to the Emergency Department, or a new brain tumor diagnosis and referral to the neurosurgical unit, NHS Lothian, Scotland. Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease. Results/UNASSIGNED:Our liquid biopsy approach reported an area under the receiver operating characteristic curve of 0.8. The sensitivity-tuned model achieves a 96% sensitivity with 45% specificity (NPV 99.3%) and identified 100% of glioblastoma multiforme patients. When tuned for a higher specificity, the model yields a sensitivity of 47% with 90% specificity (PPV 28.4%). Conclusions/UNASSIGNED:This simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients while providing reassurance to healthy patients. Minimizing time to diagnosis would facilitate the identification of brain tumor patients at an earlier stage, enabling more effective, less morbid surgical and adjuvant care.

Stimulated Raman histology (SRH) images are created by the label-free, nondestructive imaging of tissue using stimulated Raman scattering (SRS) microscopy. In a matter of seconds, these images provide real-time histologic information on biopsied tissue in the operating room. SRS microscopy uses two lasers (pump beam and Stokes beam) to amplify the Raman signal of specific chemical bonds found in macromolecules (lipids, proteins, and nucleic acids) in these tissues. The concentrations of these macromolecules are used to produce image contrast. These images are acquired and displayed using an imaging system with five main components: (1) fiber coupled microscope, (2) dual-wavelength fiber-laser module, (3) laser control module, (4) microscope control module, and (5) a computer. This manuscript details how to assemble the dual-wavelength fiber-laser module and how to generate an SRH image.

BACKGROUND/UNASSIGNED:Hyperglycemia has been associated with worse survival in glioblastoma. Attempts to lower glucose yielded mixed responses which could be due to molecularly distinct GBM subclasses. METHODS/UNASSIGNED:Clinical, laboratory, and molecular data on 89 IDH-wt GBMs profiled by clinical next-generation sequencing and treated with Stupp protocol were reviewed. IDH-wt GBMs were sub-classified into RTK I (Proneural), RTK II (Classical) and Mesenchymal subtypes using whole-genome DNA methylation. Average glucose was calculated by time-weighting glucose measurements between diagnosis and last follow-up. RESULTS/UNASSIGNED:= .02). Methylation clustering did not identify unique signatures associated with high or low glucose levels. Metabolomic analysis of 23 tumors showed minimal variation across metabolites without differences between molecular subclasses. CONCLUSION/UNASSIGNED:Higher average glucose values were associated with poorer OS in RTKI and Mesenchymal IDH-wt GBM, but not RTKII. There were no discernible epigenetic or metabolomic differences between tumors in different glucose environments, suggesting a potential survival benefit to lowering systemic glucose in selected molecular subtypes.

Safely maximizing extent of resection has become the central goal in glioma surgery. Especially in eloquent cortex, the goal of maximal resection is balanced with neurological risk. As new technologies emerge in the field of neurosurgery, the standards for maximal safe resection have been elevated. Fluorescence-guided surgery, intraoperative magnetic resonance imaging, and microscopic imaging methods are among the most well-validated tools available to enhance the level of accuracy and safety in glioma surgery. Each technology uses a different characteristic of glioma tissue to identify and differentiate tumor tissue from normal brain and is most effective in the context of anatomic, connectomic, and neurophysiologic context. While each tool is able to enhance resection, multiple modalities are often used in conjunction to achieve maximal safe resection. This paper reviews the mechanism and utility of the major adjuncts available for use in glioma surgery, especially in tumors within eloquent areas, and puts forth the foundation for a unified approach to how leverage currently available technology to ensure maximal safe resection.

ABSTRACT:The intersection of biology and technology has led to many advancements for the field of neurosurgery. Molecular developments have led to the identification of specific mutations, allowing for more accurate discussions in regard to prognosis and treatment effect. Even amid the progress from basic science benchwork, malignant gliomas continue to have a bleak natural history in lieu of the resistance to chemotherapy and the diffuse nature of the disease, leaving room for further research to discover more effective treatment modalities. Novel imaging methods, including the emerging field of radiogenomics, involve the merging of molecular and radiographic data, enabling earlier, detailed molecular diagnoses and improved surveillance of this pathology. Furthermore, surgical advancements have led to safer and more extensive resections. This review aims to delineate the various advancements in the many facets that are used daily in the care of our glioma population, specifically pertaining to its biology, imaging modalities, and perioperative adjuncts used in the operating room.