J. Bradley Elder

Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma

Toca 511 and Toca FC show promising results in treating recurrent high-grade glioma, and a specific molecular signature correlates with treatment-related survival. Tag-team attack on glioma Toca FC (extended-release 5-fluorocytosine) and Toca 511 (vocimagene amiretrorepvec) are an investigational therapeutic combination for glioma, consisting of two parts: a prodrug that is inactive on its own and a modified virus that infects the tumor and delivers an enzyme, which then activates the drug and allows it to kill the glioma cells. Cloughesy et al. tested this therapy in 45 human patients with recurrent or progressive high-grade glioma and discovered that the treatment was well tolerated and improved survival compared to an external control group. In addition, the authors identified a gene signature that correlated with response to the treatment, which may help identify the patients most likely to benefit from this approach. Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).

Trends in central nervous system tumor incidence relative to other common cancers in adults, adolescents, and children in the United States, 2000 to 2010.

Time trends in cancer incidence rates (IR) are important to measure the changing burden of cancer on a population over time. The overall IR of cancer in the United States is declining. Although central nervous system tumors (CNST) are rare, they contribute disproportionately to mortality and morbidity. In this analysis, the authors examined trends in the incidence of the most common cancers and CNST between 2000 and 2010.

Virtual Reality-Based Simulation Training for Ventriculostomy: An Evidence-Based Approach

BACKGROUND:Virtual reality (VR) simulation-based technologies play an important role in neurosurgical resident training. The Congress of Neurological Surgeons (CNS) Simulation Committee developed a simulation-based curriculum incorporating VR simulators to train residents in the management of commonBACKGROUND Virtual reality (VR) simulation-based technologies play an important role in neurosurgical resident training. The Congress of Neurological Surgeons (CNS) Simulation Committee developed a simulation-based curriculum incorporating VR simulators to train residents in the management of common neurosurgical disorders. OBJECTIVE To enhance neurosurgical resident training for ventriculostomy placement using simulation-based training. METHODS A course-based neurosurgical simulation curriculum was introduced at the Neurosurgical Simulation Symposium at the 2011 and 2012 CNS annual meetings. A trauma module was developed to teach ventriculostomy placement as one of the neurosurgical procedures commonly performed in the management of traumatic brain injury. The course offered both didactic and simulator-based instruction, incorporating written and practical pretests and posttests and questionnaires to assess improvement in skill level and to validate the simulators as teaching tools. RESULTS Fourteen trainees participated in the didactic component of the trauma module. Written scores improved significantly from pretest (75%) to posttest (87.5%; P < .05). Seven participants completed the ventriculostomy simulation. Significant improvements were observed in anatomy (P < .04), burr hole placement (P < .03), final location of the catheter (P = .05), and procedure completion time (P < .004). Senior residents planned a significantly better trajectory (P < .01); junior participants improved most in terms of identifying the relevant anatomy (P < .03) and the time required to complete the procedure (P < .04). CONCLUSION VR ventriculostomy placement as part of the CNS simulation trauma module complements standard training techniques for residents in the management of neurosurgical trauma. Improvement in didactic and hands-on knowledge by course participants demonstrates the usefulness of the VR simulator as a training tool.

A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases

Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs.

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that plays a significant role in mitotic progression and cellular responses to DNA damage. While traditionally viewed as a tumor suppressor, inhibition of PP2A has recently come to attention as a novel therapeutic means of driving senescent cancer cells into mitosis and promoting cell death via mitotic catastrophe. These findings have been corroborated in numerous studies utilizing naturally produced compounds that selectively inhibit PP2A. To overcome the known human toxicities associated with these compounds, a water-soluble small molecule inhibitor, LB100, was recently developed to competitively inhibit the PP2A protein. This review summarizes the pre-clinical studies to date that have demonstrated the anti-cancer activity of LB100 via its chemo- and radio-sensitizing properties. These studies demonstrate the tremendous therapeutic potential of LB100 in a variety of cancer types. The results of an ongoing phase 1 trial are eagerly anticipated.

Translating the Simulation of Procedural Drilling Techniques for Interactive Neurosurgical Training

BACKGROUND: Through previous efforts we have developed a fully virtual environment to provide procedural training of otologic surgical technique. The virtual environment is based on high-resolution volumetric data of the regional anatomy. These volumetric data help drive an interactive multisensory, ie, visual (stereo), aural (stereo), and tactile, simulation environment. Subsequently, we have extended our efforts to support the training of neurosurgical procedural technique as part of the Congress of Neurological Surgeons simulation initiative. OBJECTIVE: To deliberately study the integration of simulation technologies into the neurosurgical curriculum and to determine their efficacy in teaching minimally invasive cranial and skull base approaches. METHODS: We discuss issues of biofidelity and our methods to provide objective, quantitative and automated assessment for the residents. RESULTS: We conclude with a discussion of our experiences by reporting preliminary formative pilot studies and proposed approaches to take the simulation to the next level through additional validation studies. CONCLUSION: We have presented our efforts to translate an otologic simulation environment for use in the neurosurgical curriculum. We have demonstrated the initial proof of principles and define the steps to integrate and validate the system as an adjuvant to the neurosurgical curriculum.

Intraoperative neurophysiologic monitoring and neurologic outcomes in patients with epidural spine tumors

PURPOSE Multimodal intraoperative neurophysiologic monitoring (IOM) provides assessment of spinal cord pathways during neurosurgery. Despite widespread use, few data exist regarding sensitivity and specificity of IOM in predicting neurologic outcome during decompression and instrumentation for epidural spine tumors. METHODS Retrospective analysis evaluated consecutive spine procedures involving IOM modalities (somatosensory evoked potentials [SSEP], motor evoked potentials [MEP], and electromyography [(EMG]) from 2007 to 2009. Demographic and surgical information, intraoperative neurophysiologic data, and pre- and postoperative neurologic status were collected. All cases involved neoplastic epidural spinal cord compression by a primary or metastatic tumor and included posterolateral decompression and instrumented fusion. RESULTS Two-hundred and eight consecutive patients had spine surgery during this time period and one hundred and fifty-two met inclusion criteria. All patients had SSEP monitoring, with 4 having transient changes and 7 persistent changes. One hundred and twenty-two patients had combined SSEP and MEP monitoring, with 3 having transient changes and 4 persistent changes in MEP signals. Two patients had neurophysiologic changes associated with hypotension and correction led to normalization. One developed new neurologic deficits after surgery. Two from the total cohort had new postoperative neurologic deficits. One had a transient decrease in MEP amplitude while the other had no intraoperative changes. DISCUSSION These cases are often long with significant blood loss, and stability of multiple IOM modalities provides reassurance that spinal cord function remains intact. Signal changes should result in scrutiny of blood pressure, surgical technique and anesthesia. Preserved IOM signals are suggestive of preserved neurologic outcome.

Biological and clinical impact of hemangioblastoma-associated peritumoral cysts in von Hippel-Lindau disease

OBJECTIVE Peritumoral cysts are frequently associated with CNS hemangioblastomas and often underlie neurological morbidity and mortality. To determine their natural history and clinical impact, the authors prospectively analyzed hemangioblastoma-associated peritumoral cysts in patients with von Hippel-Lindau (VHL) disease. METHODS Patients with VHL disease who had 2 or more years of follow-up and who were enrolled in a prospective study at the National Institutes of Health were included. Serial prospectively acquired laboratory, genetic, imaging, and clinical data were analyzed. RESULTS One hundred thirty-two patients (of 225 in the VHL study with at least 2 years of follow-up) had peritumoral cysts that were followed for more than 2 years (total of 292 CNS peritumoral cysts). The mean age at study entrance was 37.4 ± 13.1 years ([mean ± SD], median 37.9, range 12.3-65.1 years). The mean follow-up was 7.0 ± 1.7 years (median 7.3, range 2.1-9.0 years). Over the study period, 121 of the 292 peritumoral cysts (41.4%) became symptomatic. Development of new cysts was associated with a larger number cysts at study enrollment (p = 0.002) and younger age (p < 0.0001). Cyst growth rate was associated with anatomical location (cerebellum cysts grew faster than spine and brainstem cysts; p = 0.0002 and p = 0.0008), younger age (< 35 years of age; p = 0.0006), and development of new neurological symptoms (p < 0.0001). Cyst size at symptom production depended on anatomical location (p < 0.0001; largest to smallest were found, successively, in the cerebellum, spinal cord, and brainstem). The most common location for peritumoral cysts was the cerebellum (184 cysts [63%]; p < 0.0001). CONCLUSIONS Peritumoral cysts frequently underlie symptom formation that requires surgical intervention in patients with VHL disease. Development of new cysts was associated with a larger number of cysts at study enrollment and younger age. Total peritumoral cyst burden was associated with germline partial deletion of the VHL gene.

Methylation markers of malignant potential in meningiomas

OBJECT Although most meningiomas are benign, about 20% are atypical (Grade II or III) and have increased mortality and morbidity. Identifying tumors with greater malignant potential can have significant clinical value. This validated genome-wide methylation study comparing Grade I with Grade II and III meningiomas aims to discover genes that are aberrantly methylated in atypical meningiomas. METHODS Patients with newly diagnosed meningioma were identified as part of the Ohio Brain Tumor Study. The Infinium HumanMethylation27 BeadChip (Illumina, Inc.) was used to interrogate 27,578 CpG sites in 14,000 genes per sample for a discovery set of 33 samples (3 atypical). To verify the results, the Infinium HumanMethylation450 BeadChip (Illumina, Inc.) was used to interrogate 450,000 cytosines at CpG loci throughout the genome for a verification set containing 7 replicates (3 atypical), as well as 12 independent samples (6 atypical). A nonparametric Wilcoxon exact test was used to test for difference in methylation between benign and atypical meningiomas in both sets. Heat maps were generated for each set. Methylation results were validated for the 2 probes with the largest difference in methylation intensity by performing Western blot analysis on a set of 20 (10 atypical) samples, including 11 replicates. RESULTS The discovery array identified 95 probes with differential methylation between benign and atypical meningiomas, creating 2 distinguishable groups corresponding to tumor grade when visually examined on a heat map. The validation array evaluated 87 different probes and showed that 9 probes were differentially methylated. On heat map examination the results of this array also suggested the existence of 2 major groups that corresponded to histological grade. IGF2BP1 and PDCD1, 2 proteins that can increase the malignant potential of tumors, were the 2 probes with the largest difference in intensity, and for both of these the atypical meningiomas had a decreased median production of protein, though this was not statistically significant (p = 0.970 for IGF2BP1 and p = 1 for PDCD1). CONCLUSIONS A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas.

Real-time magnetic resonance imaging-guided frameless stereotactic brain biopsy: technical note

OBJECTIVE The object of this study was to assess the feasibility, accuracy, and safety of real-time MRI-compatible frameless stereotactic brain biopsy. METHODS Clinical, imaging, and histological data in consecutive patients who underwent stereotactic brain biopsy using a frameless real-time MRI system were analyzed. RESULTS Five consecutive patients (4 males, 1 female) were included in this study. The mean age at biopsy was 45.8 years (range 29-60 years). Real-time MRI permitted concurrent display of the biopsy cannula trajectory and tip during placement at the target. The mean target depth of biopsied lesions was 71.3 mm (range 60.4-80.4 mm). Targeting accuracy analysis revealed a mean radial error of 1.3 ± 1.1 mm (mean ± standard deviation), mean depth error of 0.7 ± 0.3 mm, and a mean absolute tip error of 1.5 ± 1.1 mm. There was no correlation between target depth and absolute tip error (Pearson product-moment correlation coefficient, r = 0.22). All biopsy cannulae were placed at the target with a single penetration and resulted in a diagnostic specimen in all cases. Histopathological evaluation of biopsy samples revealed dysembryoplastic neuroepithelial tumor (1 case), breast carcinoma (1 case), and glioblastoma multiforme (3 cases). CONCLUSIONS The ability to place a biopsy cannula under real-time imaging guidance permits on-the-fly alterations in the cannula trajectory and/or tip placement. Real-time imaging during MRI-guided brain biopsy provides precise safe targeting of brain lesions.