Terence Verla

Immunotherapy for malignant glioma

Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12–15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

Preoperative serum albumin level as a predictor of postoperative complication after spine fusion.

Study Design. Retrospective cohort study. Objective. To investigate the association between preoperative baseline serum albumin and postoperative surgical complication. Summary of Background Data. The prevalence of malnutrition in the hospitalized patient population has only been recently recognized. Preoperative hypoalbuminemia (serum albumin <3.5 g/dL) has been shown to be associated with increased morbidity and mortality rates. The prognostic implications and significance of hypoalbuminemia after spine fusion surgery remain unknown. In this study, we assess the predictive value of preoperative nutritional status (serum albumin level) on postoperative complication rates. Methods. The medical records of 136 consecutive patients undergoing spine fusion at Duke University Medical Center were reviewed. Preoperative serum albumin level was assessed on all patients and used to quantify nutritional status. Albumin less than 3.5 g/dL was recognized as hypoalbuminemia (malnourished). Patient demographics, comorbidities, and postoperative complication rates were collected. Patients were also stratified into 2 groups based on their cause, namely elective degenerative/deformity versus nonelective cases. The association between preoperative serum albumin level and postoperative complication was assessed via logistic regression analysis. Results. Overall, 40 (29.4%) patients experience at least 1 postoperative complication. Patients undergoing elective surgery had more complications based on preoperative albumin levels (malnourished patients: 35.7% vs. nourished patients: 11.7%, P = 0.03), whereas those undergoing nonelective surgery had similar complication rates (malnourished patients: 46.5% vs. nourished patients: 42.1%, P = 0.75). For patients undergoing elective spinal surgery, logistic regression with and without propensity score adjustment for risk factors, demonstrated that preoperative serum albumin level was a significant predictor of postoperative complications (OR: 4.21; 95% CI: 1.09–16.19; P = 0.04) and (OR: 4.54; 95% CI: 1.17–19.32; P = 0.04), respectively. Conclusion. Preoperative hypoalbuminemia is an independent risk factor for postoperative complications after elective spine surgery for degenerative and deformity causes, and should be used more frequently as a prognostic tool to detect malnutrition and risk of adverse surgical outcomes. Level of Evidence: 2

Evaluation of pediatric skull fracture imaging techniques

Radiologic imaging is crucial in the diagnosis of skull fracture, but there is some doubt as to whether different imaging modalities can accurately identify fractures present on a human skull. While studies have been performed to evaluate the efficacy of radiologic imaging at other anatomical locations, there have been no systematic studies comparing various CT techniques, including high resolution imaging with and without 3D reconstructions to conventional radiologic imaging in children, we investigated which imaging modalities: high-resolution CT scan with 3D projections, clinical-resolution CT scans or X-rays, best showed fracture occurrence in a pediatric human cadaver skull by having an expert pediatric radiologist examine radiologic images from fractured skulls. The skulls used were taken from pediatric cadavers ranging in age from 5 months to 16 years. We evaluated the sensitivity and specificity for the imaging modalities using dissection findings as the gold standard. We found that high-resolution CT scans with 3D projections and conventional CT provided the most accurate fracture diagnosis (single-fracture sensitivity of 71%) followed by X-rays (single-fracture sensitivity of 63%). Linear fractures outsider the region of the sutures were more identifiable than diastatic fractures, though the incidence of false positives was greater for linear fractures. In the two cases where multiple fractures were present on the same anatomical skull location, the radiologist was less likely to identify the presence of additional fractures than a single fracture. Overall, the high-resolution and clinical-resolution CT scans had the similar accuracy for detecting skull fractures while the use of the X-ray was both less accurate and had a lower specificity.

Affective disorders influence clinical outcomes after revision lumbar surgery in elderly patients with symptomatic adjacent-segment disease, recurrent stenosis, or pseudarthrosis: clinical article.

OBJECT Depression and persistent low-back pain (LBP) are common and disabling problems in elderly patients (> 65 years old). Affective disorders, such as depression and anxiety, are also common in elderly patients, with a prevalence ranging from 4% to 16%. Depressive symptoms are consistently associated with functional disability. To date, few studies have assessed the predictive value of baseline depression on outcomes in the setting of revision spine surgery in elderly patients. Therefore, in this study, the authors assessed the predictive value of preoperative depression on 2-year postoperative outcomes. METHODS A total of 69 patients undergoing revision neural decompression and instrumented fusion for adjacent-segment disease (ASD, n = 28), pseudarthrosis (n = 17), or same-level recurrent stenosis (n = 24) were included in this study. Preoperative Zung Self-Rating Depression Scale (ZDS) scores were assessed for all patients. Preoperative and 2-year postoperative visual analog scale (VAS) scores for back pain (VAS-BP) and leg pain (VAS-LP) and the Oswestry Disability Index (ODI) were also assessed. The association between preoperative ZDS score and 2-year improvement in disability was assessed via multivariate regression analysis. RESULTS Compared with preoperative status, 2-year postoperative VAS-BP was significantly improved after surgery for ASD (9 ± 2 vs. 4.01 ± 2.56, respectively; p = 0.001), as were pseudarthrosis (7.41 ± 1 vs. 5.0 ± 3.08, respectively; p = 0.02) and same-level recurrent stenosis (7 ± 2.00 vs. 5.00 ± 2.34, respectively; p = 0.003). Two-year ODI was also significantly improved after surgery for ASD (29 ± 9 vs. 23.10 ± 10.18, respectively; p = 0.001), as were pseudarthrosis (28.47 ± 5.85 vs. 24.41 ± 7.75, respectively; p = 0.001) and same-level recurrent stenosis (30.83 ± 5.28 vs. 26.29 ± 4.10, respectively; p = 0.003). Independent of other factors-age, body mass index, symptom duration, smoking, comorbidities, severity of preoperative pain, and disability-increasing preoperative ZDS score was significantly associated with lower 2-year improvement in disability (ODI) after revision surgery in elderly patients with symptomatic ASD, pseudarthrosis, or recurrent stenosis. CONCLUSIONS The extent of preoperative depression is an independent predictor of less functional improvement following revision lumbar surgery in elderly patients with symptomatic ASD, pseudarthrosis, or recurrent stenosis. Timely diagnosis and treatment of depression and somatic anxiety in this cohort of patients may contribute to improvement in postoperative functional status.

Are BiTEs the “missing link” in cancer therapy?

Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administrations (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review, we dissect the role of T-cell therapeutics in the new era of cancer immunotherapy, appraise the value of CAR T-cells in the context of solid tumors, and discuss why the BiTE platform may rescue several of the apparent deficits and shortcomings of competing immunotherapies to support its widespread clinical application.

Perioperative cardiac complications and 30-day mortality in patients undergoing intracranial aneurysmal surgery with adenosine-induced flow arrest: A retrospective comparative study

BACKGROUND Adenosine-induced flow arrest is a technique used to assist in the surgical clipping of complex aneurysms. OBJECTIVE To assess the safety associated with adenosine-assisted intracranial aneurysm surgery. METHODS Medical records of all patients presenting between January 1, 2009, and December 31, 2012, for intracranial aneurysm surgery were analyzed. Patients were divided into 2 groups based on the intraoperative administration of adenosine: the nonadenosine group (n = 262) and the adenosine group (n = 64). The primary outcome compared between groups included a composite of 30-day mortality and incidences of perioperative cardiac complications (perioperative myocardial infarction or perioperative cardiac arrhythmias). RESULTS The study groups were statistically similar except for a difference in the size and location of cerebral aneurysms and the incidence of coronary artery disease. The primary composite outcome occurred in 4.6% and 9.4% of patients in the nonadenosine and adenosine groups, respectively (P = .13). After adjustment for differences in the incidence of coronary artery disease between the 2 groups, the odds of the primary outcome were not significantly different between the groups (adjusted odds ratio = 2.12; 95% confidence interval, 0.76-5.93; P = .15). There were also no significant differences in the durations of hospital and intensive care unit stay between the study groups. CONCLUSION Our results suggest that adenosine-assisted intracranial aneurysm surgery is not associated with an increase in perioperative cardiac complications or mortality in patients with low risk of coronary artery disease and may be considered a safe technique to assist clipping of complex aneurysms.

Anatomical location dictating major surgical complications for intradural extramedullary spinal tumors: a 10-year single-institutional experience

OBJECT Intradural extramedullary (IDEM) neoplasms are uncommon lesions that can pose a challenge for resection. Numerous factors affect the resectability and ultimately the outcome of these lesions. The authors report their 10-year institutional experience with the resection of IDEM neoplasms, focusing on the effect of location on surgical outcomes. METHODS The authors performed a retrospective review of 96 consecutive patients who presented with a cervical and/or thoracic IDEM tumor that was resected between February 2000 and July 2009. All patients underwent MRI, and the axial location of the tumor was categorized as anterior, posterior, or lateral. Postoperative complications were assessed, as was neurological status at the patients last follow-up clinic visit. Major complications assessed included CSF leakage requiring lumbar drainage, reexploration for epidural hematoma, and major postoperative neurological deficits. RESULTS The mean ± SD age at presentation was 51.16 ± 17.87 years. Major surgical approach-related complications occurred in 15% of patients. Major non-approach related surgical complications occurred in 7.1% of patients, while minor complications occurred in 14.2% of patients. Postoperative neurological deficits occurred most commonly in the thoracic spine between T-1 and T-8. Based on axial spinal cord location, the surgery-related complications rates for all anterior tumors (n = 12) was 41.6%, whereas that for all lateral tumors (n = 69) was 4.4% and that for all posteriorly located tumors (n = 17) was 0%. CONCLUSIONS Spinal IDEM tumors that are anteriorly located in the upper thoracic spine were found to have the highest rate of surgery-related complications and postoperative neurological deficits. This finding may be associated with the unforgiving anatomy of the upper thoracic spine in which there is a higher cord-to-canal ratio and a tenuous vascular supply.

The Incidence of Spinal Cord Injury in Implantation of Percutaneous and Paddle Electrodes for Spinal Cord Stimulation

Spinal cord stimulation (SCS) has been proven effective for multiple chronic pain syndromes. Over the past 40 years of use, the complication rates of SCS have been well defined in the literature; however, the incidence of one of the most devastating complications, spinal cord injury (SCI), remains largely unknown. The goal of the study was to quantify the incidence of SCI in both percutaneous and paddle electrode implantation.

Impact of advancing age on post-operative complications of deep brain stimulation surgery for essential tremor

Essential tremor (ET) was the original indication for deep brain stimulation (DBS), with USA Food and Drug Administration approval since 1997. Despite the efficacy of DBS, it is associated with surgical complications that cause sub-optimal clinical outcomes. Given that ET is a progressive disease with increase in symptom severity with increasing age, this study evaluated the impact of increasing age on short-term complications following DBS surgery for ET. The Thomson-Reuters MarketScan database was utilized (New York, NY, USA). Patients selected were over age 18 and underwent DBS for ET between the years 2000 and 2009. Multivariable logistic regression analysis was used to calculate complication odds ratios (OR) for a 5 year increase in age, after controlling for other covariates. Six hundred sixty-one patients were included in the analysis. The mean (standard deviation) age was 61.9 (14.3) years, with 17% of individuals aged ⩾75 years. Overall 56.9% of patients were male, and 44.6% had a Charlson Comorbidity Score of ⩾1. Additionally, 7.1% of patients experienced at least one complication within 90 days, including wound infections (3.0%), pneumonia (2.4%), hemorrhage or hematoma (1.5%), or pulmonary embolism (0.6%). Increasing age was not significantly associated with the overall 90 day complication rates (OR 0.89; 95% confidence interval [CI] 0.77-1.02; p=0.102). The risk of the two most common procedure-related complications, hemorrhage and infection, did not significantly increase with age (hemorrhage: OR 1.02; 95%CI 0.77-1.37; p=0.873; and infection: OR 0.88; 95%CI 0.72-1.07; p=0.203). Our findings suggest that age should not be a primary exclusion factor for determining candidacy for DBS and also suggest a possible expansion of the traditional therapeutic window since post-operative complications remained relatively stable.

Impact of Increasing Age on Outcomes of Spinal Fusion in Adult Idiopathic Scoliosis.

OBJECTIVE To investigate the role of advancing age on postoperative complications and revision surgery after fusion for scoliosis. METHODS A retrospective, cohort study was performed using the Thomson Reuters MarketScan database, examining patients with adult scoliosis who underwent spinal fusion from 2000 to 2009. Primary outcomes included infection, hemorrhage and pulmonary embolism (PE) within 90 days of surgery, and refusion. The effect of increasing age was estimated using the odds ratio (OR) of complications in a multivariate logistic regression analysis, and a Cox proportional hazard model estimated the hazard ratio of refusion. RESULTS A total of 8432 patients were included in this study. Overall, the average age was 53.3 years, with 26.90% males and 39% with a Charlson Comorbidity Score of ≥ 1. Most patients had commercial insurance (66.81%), with 26.03% and 7.16% covered by Medicare and Medicaid, respectively. Increasing age (per 5-year increment) was a significant predictor of hemorrhagic complication (OR, 1.06; confidence interval [CI], 1.01-1.11; P = 0.0196), PE (OR, 1.09; CI, 1.03-1.16; P = 0.0031), infection (OR, 1.04; CI, 1.01-1.07; P = 0.0053), and refusion (hazard ratio, 1.07; CI, 1.02-1.13; P = 0.0103). CONCLUSIONS In this study, age was associated with increased risk of hemorrhage, PE, infection, and refusion. With the aging population, the role of patient age on postoperative healing and outcomes deserves deeper investigation after repair of adult idiopathic scoliosis.