Richard A. Rovin

Leptin Promotes Glioblastoma

The hormone leptin has a variety of functions. Originally known for its role in satiety and weight loss, leptin more recently has been shown to augment tumor growth in a variety of cancers. Within gliomas, there is a correlation between tumor grade and tumor expression of leptin and its receptor. This suggests that autocrine signaling within the tumor microenvironment may promote the growth of high-grade gliomas. Leptin does this through stimulation of cellular pathways that are also advantageous for tumor growth and recurrence: antiapoptosis, proliferation, angiogenesis, and migration. Conversely, a loss of leptin expression attenuates tumor growth. In animal models of colon cancer and melanoma, a decline in the expression and secretion of leptin resulted in a reduction of tumor growth. In these models, positive mental stimulation through environmental enrichment decreased leptin secretion and improved tumor outcome. This review explores the link between leptin and glioblastoma.

Development of an iPhone application for sideline concussion testing

Professional athletes are taking concussion very seriously, and missed play due to concussion is no longer stigmatized. One fortuitous consequence is increased awareness of the detrimental effects of concussion among student athletes. Whereas professional athletes have access to formal in-competition evaluation and out-of-competition monitoring programs, the majority of student athletes, especially at the middle school and high school levels, do not. The authors therefore set out to create an easy-to-use iPhone application for sideline concussion testing and serial monitoring of these at-risk athletes.

Quantification of Protoporphyrin IX Accumulation in Glioblastoma Cells: A New Technique.

Introduction. 5-Aminolevulinic Acid (5-ALA) is a precursor of heme synthesis. A metabolite, protoporphyrin IX (PpIX), selectively accumulates in neoplastic tissue including glioblastoma. Presurgical administration of 5-ALA forms the basis of fluorescence-guided resection (FGR) of glioblastoma (GBM) tumors. However, not all gliomas accumulate sufficient quantities of PpIX to fluoresce, thus limiting the utility of FGR. We therefore developed an assay to determine cellular and pharmacological factors that impact PpIX fluorescence in GBM. This assay takes advantage of a GBM cell line engineered to express yellow fluorescent protein. Methods. The human GBM cell line U87MG was transfected with a YFP expression vector. After treatment with a series of 5-ALA doses, both PpIX and YFP fluorescence were measured. The ratio of PpIX to YFP fluorescence was calculated. Results. YFP fluorescence permitted the quantification of cell numbers and did not interfere with 5-ALA metabolism. The PpIX/YFP fluorescence ratio provided accurate relative PpIX levels, allowing for the assessment of PpIX accumulation in tissue. Conclusion. Constitutive YFP expression strongly correlates with cell number and permits PpIX quantification. Absolute PpIX fluorescence alone does not provide information regarding PpIX accumulation within the cells. Our research indicates that our PpIX/YFP ratio assay may be a promising model for in vitro 5-ALA testing and its interactions with other compounds during FGR surgery.

113 Initial Experience With an Image-Guided Robotically Positioned Optical Platform for Aneurysm Surgery.

INTRODUCTION The conventional stereoscopic microscope (CS-m) made safe surgery for intracranial vascular pathology. Recently, an integrated image-guided robotic optical positioning system (ROVOT-m) has been released for clinical use. We undertook a benchside, cadaveric and clinical study to determine its applicability to aneurysm surgery. METHODS Benchside measurements of field of view (FOV) and depth of field (DOF) were obtained for CS-m and ROVOT-m. Two cadavers were operated on to simulate aneurysm surgery using both CS-m and ROVOT-m. Clinical feasibility of ROVOT-m was demonstrated during for surgery for both ruptured and unruptured aneurysms. RESULTS At highest magnification, ROVOT-m has a 25-mm FOV, 40% greater than that of CS-m. At the same FOV of 25 mm and working distance of 250 mm, ROVOT-m has a DOF of 14 mm, more than 3 times greater than CS-m. Cadaveric dissection confirmed that the volume of view (VOV) for the ROVOT-m was substantially larger than for the CS-m. Six aneurysms were clipped using the ROVOT-m: 4 ruptured middle cerebral artery aneurysms, 1 unruptured anterior communicating artery aneurysm, and 1 unruptured superior hypophyseal artery aneurysm. CONCLUSION The ROVOT-m has a substantially larger VOV the volume of surgical anatomy in focus and adequately illuminated. The larger immersive volume of surgical anatomy in focus was especially valuable when temporary clipping in the cases of middle cerebral artery aneurysm as the VOV extended from proximal internal carotid artery to distal M2 branches. The use of preset positions permits multiple relevant optical trajectories to be viewed rapidly and in sequence, which is particularly beneficial for assessing clip placement. Hands-free positioning allows for uninterrupted work flow.

Glioblastoma Derived Exosomes Induce Apoptosis in Cytotoxic T Cells Through a Fas Ligand Mediated Mechanism

Introduction Glioblastoma multiforme deploys a number of weapons to thwart the immune system. Within the tumor microenvironment, tumor infiltrating T cells fall victim to cellular and soluble mediators of apoptosis. In prostate and colorectal cancer models, exosomes can induce T cell apoptosis. Exosomes are tiny, membrane bound vesicles that are released from a cell. They contain functional mRNA and protein and have cell surface molecules representative of their parent cell. It is not known if GBM derived exosomes can also mediate apoptosis. In this study, the role of GBM derived exosomes in T cell apoptosis is explored.

Comparison of operative outcomes of eloquent glioma resection performed under awake versus general anesthesia: A systematic review and meta-analysis

Surgical resection of eloquent glioma can be achieved under general anesthesia (GA) or awake anesthesia (AA). The appeal of AA is that it facilitates intraoperative identification and avoidance of eloquent areas, which has the potential to minimize functional compromise. The aim of this meta-analysis was to compare the operative outcomes of eloquent glioma resection performed under GA compared to AA to assist in optimizing the decision algorithm between the two approaches. Searches of seven electronic databases from inception to December 2017 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 1037 articles identified for screening. Data were extracted and analyzed using meta-analysis of proportions. A total of 9 comparative studies were included for analysis. Resection of glioma involving eloquent areas achieved under AA is mostly comparable in terms of operative and functional outcomes to that of GA. AA did demonstrate significantly lower incidence of postoperative nausea and vomiting (PONV, OR, 0.17; p < 0.001) and shorter length of stay (LOS, MD, -1.76 days; p = 0.02) when compared to GA. Future studies that are larger, prospective, randomized, and include long term quality of life metrics will assist in elucidating the true clinical benefit of AA in resecting glioma involving eloquent areas. This will assist in further developing management protocol of these glioma.

Microsurgical Anatomy of the Vertical Rami of the Superior Longitudinal Fasciculus: An Intraparietal Sulcus Dissection Study

BACKGROUND A number of vertical prolongations of the superior longitudinal fasciculus, which we refer to as the vertical rami (Vr), arise at the level of the supramarginal gyrus, directed vertically toward the parietal lobe. OBJECTIVE To provide the first published complete description of the white matter tracts (WMT) of the Vr, their relationship to the intraparietal and parieto-occipital sulci (IPS-POS complex), and their importance in neurosurgical approaches to the parietal lobe. METHODS Subcortical dissections of the Vr and WMT of the IPS were performed. Findings were correlated with a virtual dissection using high-resolution diffusion tensor imaging (DTI) tractography data derived from the Human Connectome Project. Example planning of a transparietal, transsulcal operative corridor is demonstrated using an integrated neuronavigation and optical platform. RESULTS The Vr were shown to contain component fibers of the superior longitudinal fasciculus (SLF)-II and SLF-III, with contributions from the middle longitudinal fasciculus merging into the medial bank of the IPS. The anatomic findings correlated well with DTI tractography. The line extending from the lateral extent of the POS to the IPS marks an ideal sulcal entry point that we have termed the IPS-POS Kassam-Monroy (KM) Point, which can be used to permit a safe parafascicular surgical trajectory to the trigone. CONCLUSION The Vr are a newly conceptualized group of tracts merging along the banks of the IPS, mediating connectivity between the parietal lobe and dorsal stream/SLF. We suggest a refined surgical trajectory to the ventricular atrium utilizing the posterior third of the IPS, at or posterior to the IPS-POS Point, in order to mitigate risk to the Vr and its considerable potential for postsurgical morbidity.

MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20, KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ERα and Survivin inhibition and enhances response to temozolomide

The DNA damage repair enzyme, O6-methylguanine DNA methyltransferase (MGMT) is overexpressed in breast cancer, correlating directly with estrogen receptor (ER) expression and function. In ER negative breast cancer the MGMT promoter is frequently methylated. In ER positive breast cancer MGMT is upregulated and modulates ER function. Here, we evaluate MGMT’s role in control of other clinically relevant targets involved in cell cycle regulation during breast cancer oncogenesis. We show that O6-benzylguanine (BG), an MGMT inhibitor decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, cyclin B2, A2, D1, ERα and survivin and induces c-PARP and p21 and sensitizes ER positive breast cancer to temozolomide (TMZ). Further, siRNA inhibition of MGMT inhibits CDC2, TOP2A, AURKB, KIF20A, Cyclin B2, A2 and survivin and induces p21. Combination of BG+TMZ decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, Cyclin A2, B2, D1, ERα and survivin. Temozolomide alone inhibits MGMT expression in a dose and time dependent manner and increases p21 and cytochrome c. Temozolomide inhibits transcription of TOP2A, AURKB, KIF20A and does not have any effect on CDC2 and CDC20 and induces p21. BG+/-TMZ inhibits breast cancer growth. In our orthotopic ER positive breast cancer xenografts, BG+/-TMZ decreases ki-67, CDC2, CDC20, TOP2A, AURKB and induces p21 expression. In the same model, BG+TMZ combination inhibits breast tumor growth in vivo compared to single agent (TMZ or BG) or control. Our results show that MGMT inhibition is relevant for inhibition of multiple downstream targets involved in tumorigenesis. We also show that MGMT inhibition increases ER positive breast cancer sensitivity to alkylator based chemotherapy.

Racial Disparity Among Women Diagnosed With Invasive Breast Cancer in a Large Integrated Health System

Purpose Reasons for the well-described disparity in outcomes between African American (AA) and non-Hispanic white (NHW) women with invasive breast cancer are unclear, making it difficult to identify solutions. This study examined the effects of demographics, biomarkers, tumor characteristics, cancer stage, morphology, and treatment variables on overall and cancer-free survival in these patient populations. Methods We retrospectively reviewed data for 6231 patients diagnosed with invasive breast cancer throughout an integrated health system from January 2006 through March 2015. Included for analysis were 5023 NHW and 413 AA women. All category and continuous variables in the study were described in the two groups using appropriate statistics. Kaplan-Meier method of survival with log-rank test was used to compare the two racial groups (NHW and AA). Cox proportional hazards regression was used to find hazard ratios for the predictors of survival and recurrence-free survival probability. Propensity probability match method (1:1) was used to match 319 NSW women to 319 similar AA women. Matching was done using all significant predictors, including demographic variables. Results Compared to NHW women, AA women presented with invasive breast cancer at a younger age (P<0.001) and had a higher proportion of stage IV cancers (P<0.001), which were more often infiltrating ductal carcinoma (P<0.003) and poorly differentiated (P<0.001). Within 10-year follow-up, AA women had shorter overall and recurrence-free survival (log-rank P<0.001), were 1.4 times more likely to die (P=0.009), and were twice as likely to have recurrence (P<0.001) than NHW women. In the matched groups, overall survival was similar for AA and NHW (log-rank P=0.0793); however, recurrence-free survival was higher in NHW than in AA women (P=0.047). Conclusions When presenting characteristics of AA and NHW women with invasive breast cancer are matched, disparity in overall mortality and rate of recurrence appears to be reduced or perhaps eliminated, suggesting invasive breast cancers in AA and NHW women respond similarly to treatment. Further study is needed to explore the true effect of biological factors; however, rectifying delivery of and access to care might be expected to mitigate, in large part, the racial disparity currently seen in breast cancer outcomes.

Pomona Large Vessel Occlusion Screening Tool for Prehospital and Emergency Room Settings

Background: Early identification of patients with acute ischemic strokes due to large vessel occlusions (LVO) is critical. We propose a simple risk score model to predict LVO. Method: The proposed scale (Pomona Scale) ranges from 0 to 3 and includes 3 items: gaze deviation, expressive aphasia, and neglect. We reviewed a cohort of all acute stroke activation patients between February 2014 and January 2016. The predictive performance of the Pomona Scale was determined and compared with several National Institutes of Health Stroke Scale (NIHSS) cutoffs (≥4, ≥6, ≥8, and ≥10), the Los Angeles Motor Scale (LAMS), the Cincinnati Prehospital Stroke Severity (CPSS) scale, the Vision Aphasia and Neglect Scale (VAN), and the Prehospital Acute Stroke Severity Scale (PASS). Results: LVO was detected in 94 of 776 acute stroke activations (12%). A Pomona Scale ≥2 had comparable accuracy to predict LVO as the VAN and CPSS scales and higher accuracy than Pomona Scale ≥1, LAMS, PASS, and NIHSS. A Pomona Scale ≥2 had an accuracy (area under the curve) of 0.79, a sensitivity of 0.86, a specificity of 0.70, a positive predictive value of 0.71, and a negative predictive value of 0.97 for the detection of LVO. We also found that the presence of either neglect or gaze deviation alone had comparable accuracy of 0.79 as Pomona Scale ≥2 to detect LVO. Conclusion: The Pomona Scale is a simple and accurate scale to predict LVO. In addition, the presence of either gaze deviation or neglect also suggests the possibility of LVO.