Taemin Oh

Immunocompetent murine models for the study of glioblastoma immunotherapy

Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.

Time to pediatric epilepsy surgery is related to disease severity and nonclinical factors

Objective: To identify clinical and nonclinical factors associated with time from epilepsy onset to surgical evaluation and treatment among a cohort of children having epilepsy surgery. Methods: Data were abstracted from records of 430 children (younger than 18 years) who had epilepsy neurosurgery at the University of California, Los Angeles from 1986 to 2010. Multivariable Cox proportional hazards models were used to analyze unique associations of clinical severity, pre-referral brain MRI, and sociodemographic characteristics with time to surgery. Results: Shorter time to surgery was associated with active (hazard ratio [HR] 5.67, 95% confidence interval [CI] 3.74–8.70) and successfully treated infantile spasms (HR 2.20, 95% CI 1.63–2.96); daily or more seizures (HR 2.09, 95% CI 1.58–2.76); MRI before referral regardless of imaging findings (HR 1.95, 95% CI 1.47–2.58); private insurance (HR 1.54, 95% CI 1.14–2.09); and Hispanic ethnicity (HR 1.38, 95% CI 1.01–1.87). There were race/ethnicity by insurance interactions (log-rank p = 0.049) with shortest time to surgery for Hispanic children with private insurance. Conclusions: Shorter intervals to surgical treatment were associated with greater epilepsy severity and insurance type, consistent with existing literature. However, associations of shorter times to treatment with having a brain MRI before referral and Hispanic ethnicity were unexpected and warrant further investigation. More knowledgeable referring providers and parents with greater help-seeking capability may explain obtaining an MRI before referral. Shorter intervals to surgery among Hispanic children may relate to the same factors yielding an increased volume of Hispanic children receiving surgery at the University of California, Los Angeles since 2000.

A Prospective Study of Loss of Consciousness in Epilepsy Using Virtual Reality Driving Simulation and Other Video Games

Patients with epilepsy are at risk of traffic accidents when they have seizures while driving. However, driving is an essential part of normal daily life in many communities, and depriving patients of driving privileges can have profound consequences for their economic and social well-being. In the current study, we collected ictal performance data from a driving simulator and two other video games in patients undergoing continuous video/EEG monitoring. We captured 22 seizures in 13 patients and found that driving impairment during seizures differed in terms of both magnitude and character, depending on the seizure type. Our study documents the feasibility of a prospective study of driving and other behaviors during seizures through the use of computer-based tasks. This methodology may be applied to further describe differential driving impairment in specific types of seizures and to gain data on anatomical networks disrupted in seizures that impair consciousness and driving safety.

Anticonvulsant prophylaxis for brain tumor surgery: determining the current best available evidence

Patients who undergo craniotomy for brain tumor resection are prone to experiencing seizures, which can have debilitating medical, neurological, and psychosocial effects. A controversial issue in neurosurgery is the common practice of administering perioperative anticonvulsant prophylaxis to these patients despite a paucity of supporting data in the literature. The foreseeable benefits of this strategy must be balanced against potential adverse effects and interactions with critical medications such as chemotherapeutic agents and corticosteroids. Multiple disparate metaanalyses have been published on this topic but have not been applied into clinical practice, and, instead, personal preference frequently determines practice patterns in this area of management. Therefore, to select the current best available evidence to guide clinical decision making, the literature was evaluated to identify meta-analyses that investigated the efficacy and/or safety of anticonvulsant prophylaxis in this patient population. Six meta-analyses published between 1996 and 2011 were included in the present study. The Quality of Reporting of Meta-analyses and Oxman-Guyatt methodological quality assessment tools were used to score these meta-analyses, and the Jadad decision algorithm was applied to determine the highest-quality meta-analysis. According to this analysis, 2 metaanalyses were deemed to be the current best available evidence, both of which conclude that prophylactic treatment does not improve seizure control in these patients. Therefore, this management strategy should not be routinely used.

Overexpression of CD97 Confers an Invasive Phenotype in Glioblastoma Cells and Is Associated with Decreased Survival of Glioblastoma Patients

Mechanisms of invasion in glioblastoma (GBM) relate to differential expression of proteins conferring increased motility and penetration of the extracellular matrix. CD97 is a member of the epidermal growth factor seven-span transmembrane family of adhesion G-protein coupled receptors. These proteins facilitate mobility of leukocytes into tissue. In this study we show that CD97 is expressed in glioma, has functional effects on invasion, and is associated with poor overall survival. Glioma cell lines and low passage primary cultures were analyzed. Functional significance was assessed by transient knockdown using siRNA targeting CD97 or a non-target control sequence. Invasion was assessed 48 hours after siRNA-mediated knockdown using a Matrigel-coated invasion chamber. Migration was quantified using a scratch assay over 12 hours. Proliferation was measured 24 and 48 hours after confirmed protein knockdown. GBM cell lines and primary cultures were found to express CD97. Knockdown of CD97 decreased invasion and migration in GBM cell lines, with no difference in proliferation. Gene-expression based Kaplan-Meier analysis was performed using The Cancer Genome Atlas, demonstrating an inverse relationship between CD97 expression and survival. GBMs expressing high levels of CD97 were associated with decreased survival compared to those with low CD97 (p = 0.007). CD97 promotes invasion and migration in GBM, but has no effect on tumor proliferation. This phenotype may explain the discrepancy in survival between high and low CD97-expressing tumors. This data provides impetus for further studies to determine its viability as a therapeutic target in the treatment of GBM.

Evidence-Based Medicine of Traumatic Thoracolumbar Burst Fractures: A Systematic Review of Operative Management across 20 Years.

Study Design Systematic literature review. Objective The management of traumatic thoracolumbar burst fractures (TLBF) remains challenging, and analyzing the levels of evidence (LOEs) for treatment practices can reform the decision-making process. However, no review has yet evaluated the operative management of traumatic thoracolumbar burst fractures with particular attention placed on LOE from an established methodology. The objective of the present study was to characterize the literature evidence for TLBF, specifically for operative management. Methods A comprehensive search of the English literature over the past 20 years was conducted using PubMed (MEDLINE). The inclusion criteria consisted of (1) traumatic burst fractures (2) in the thoracic or lumbar spine. Exclusion criteria included (1) osteoporotic burst fractures, (2) pathologic burst fractures, (3) cervical fractures, (4) biomechanical studies or those involving cadavers, and (5) computer-based studies. Studies were assigned an LOE and those meeting level 1 or 2 were included. Results From 1,138 abstracts, 272 studies met the criteria. Twenty-three studies (8.5%) met level 1 (n = 4, 1.5%) or 2 (n = 19, 7.0%) criteria. All 23 studies were reported. Conclusions The literature contains a high LOE to support the operative management of traumatic thoracolumbar burst fractures. For patients who are neurologically intact, a high LOE demonstrated similar functional outcomes, lower complication rates, and less costs with conservative management when compared with surgical management. There is a high LOE for short- or long-segment pedicle instrumentation without fusion and less invasive (percutaneous and paraspinal) approaches. Furthermore, the posterior approaches are associated with lower complications as opposed to the anterior or combined approaches.

Cervical compensatory alignment changes following correction of adult thoracic deformity: a multicenter experience in 57 patients with a 2-year follow-up

OBJECT Alignment changes in the cervical spine that occur following surgical correction for thoracic deformity remain poorly understood. The purpose of this study was to evaluate such changes in a cohort of adults with thoracic deformity treated surgically. METHODS The authors conducted a multicenter retrospective analysis of consecutive patients with thoracic deformity. Inclusion criteria for this study were as follows: corrective osteotomy for thoracic deformity, upper-most instrumented vertebra (UIV) between T-1 and T-4, lower-most instrumented vertebra (LIV) at or above L-5 (LIV ≥ L-5) or at the ilium (LIV-ilium), and a minimum radiographic follow-up of 2 years. Sagittal radiographic parameters were assessed preoperatively as well as at 3 months and 2 years postoperatively, including the C-7 sagittal vertical axis (SVA), C2-7 cervical lordosis (CL), C2-7 SVA, T-1 slope (T1S), T1S minus CL (T1S-CL), T2-12 thoracic kyphosis (TK), apical TK, lumbar lordosis (LL), pelvic incidence (PI), PI-LL, pelvic tilt (PT), and sacral slope (SS). RESULTS Fifty-seven patients with a mean age of 49.1 ± 14.6 years met the study inclusion criteria. The preoperative prevalence of increased CL (CL > 15°) was 48.9%. Both 3-month and 2-year apical TK improved from baseline (p < 0.05, statistically significant). At the 2-year follow-up, only the C2-7 SVA increased significantly from baseline (p = 0.01), whereas LL decreased from baseline (p < 0.01). The prevalence of increased CL was 35.3% at 3 months and 47.8% at 2 years, which did not represent a significant change. Postoperative cervical alignment changes were not significantly different from preoperative values regardless of the LIV (LIV ≥ L-5 or LIV-ilium, p > 0.05 for both). In a subset of patients with a maximum TK ≥ 60° (35 patients) and 3-column osteotomy (38 patients), no significant postoperative cervical changes were seen. CONCLUSION Increased CL is common in adult spinal deformity patients with thoracic deformities and, unlike after lumbar corrective surgery, does not appear to normalize after thoracic corrective surgery. Cervical sagittal malalignment (C2-7 SVA) also increases postoperatively. Surgeons should be aware that spontaneous cervical alignment normalization might not occur following thoracic deformity correction.

Survival impact of time to initiation of chemoradiotherapy after resection of newly diagnosed glioblastoma.

OBJECT There are few and conflicting reports on the effects of delayed initiation of chemoradiotherapy on the survival of patients with glioblastoma. The standard of care for newly diagnosed glioblastoma is concurrent radiotherapy and temozolomide chemotherapy after maximal safe resection; however, the optimal timing of such therapy is poorly defined. Given the lack of consensus in the literature, the authors performed a retrospective analysis of The Cancer Genome Atlas (TCGA) database to investigate the effect of time from surgery to initiation of therapy on survival in newly diagnosed glioblastoma. METHODS Patients with primary glioblastoma diagnosed since 2005 and treated according to the standard of care were identified from TCGA database. Kaplan-Meier and multivariate Cox regression analyses were used to compare overall survival (OS) and progression-free survival (PFS) between groups stratified by postoperative delay to initiation of radiation treatment. RESULTS There were 218 patients with newly diagnosed glioblastoma with known time to initiation of radiotherapy identified in the database. The median duration until therapy was 27 days. Delay to radiotherapy longer than the median was not associated with worse PFS (HR = 0.918, p = 0.680) or OS (HR = 1.135, p = 0.595) in multivariate analysis when controlling for age, sex, KPS score, and adjuvant chemotherapy. Patients in the highest and lowest quartiles for delay to therapy (≤ 20 days vs ≥ 36 days) did not statistically differ in PFS (p = 0.667) or OS (p = 0.124). The small subset of patients with particularly long delays (> 42 days) demonstrated worse OS (HR = 1.835, p = 0.019), but not PFS (p = 0.74). CONCLUSIONS Modest delay in initiation of postoperative chemotherapy and radiation does not appear to be associated with worse PFS or OS in patients with newly diagnosed glioblastoma, while significant delay longer than 6 weeks may be associated with worse OS.

Intraoperative neuromonitoring techniques in the surgical management of acoustic neuromas

Unfavorable outcomes such as facial paralysis and deafness were once unfortunate probable complications following resection of acoustic neuromas. However, the implementation of intraoperative neuromonitoring during acoustic neuroma surgery has demonstrated placing more emphasis on quality of life and preserving neurological function. A modern review demonstrates a great degree of recent success in this regard. In facial nerve monitoring, the use of modern electromyography along with improvements in microneurosurgery has significantly improved preservation. Recent studies have evaluated the use of video monitoring as an adjunctive tool to further improve outcomes for patients undergoing surgery. Vestibulocochlear nerve monitoring has also been extensively studied, with the most popular techniques including brainstem auditory evoked potential monitoring, electrocochleography, and direct compound nerve action potential monitoring. Among them, direct recording remains the most promising and preferred monitoring method for functional acoustic preservation. However, when compared with postoperative facial nerve function, the hearing preservation is only maintained at a lower rate. Here, the authors analyze the major intraoperative neuromonitoring techniques available for acoustic neuroma resection.

Pigmented villonodular synovitis of the temporomandibular joint with intracranial extension: A case series and systematic review.

Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder of the synovial membrane. PVNS generally affects large joints but occasionally involves the temporomandibular joint (TMJ), with occasional extension into the middle cranial fossa. The purpose of this study was to report our experience with PVNS along with a focused literature review.