Validation and Comparison of Common Thoracolumbar Injury Classification Treatment Algorithms and a Novel Modification.

BACKGROUND AND OBJECTIVES: The most common thoracolumbar trauma classification systems are the Thoracolumbar Injury Classification and Severity Score (TLICS) and the Thoracolumbar AO Spine Injury Score (TL AOSIS). Predictive accuracy of treatment recommendations is a historical limitation. Our objective was to validate and compare TLICS, TL AOSIS, and a modified TLICS (mTLICS) that awards 2 points for the presence of fractured vertebral body height loss >50% and/or spinal canal stenosis >50% at the fracture site. METHODS: The medical records of adult patients with acute, traumatic thoracolumbar injuries at an urban, Level 1 trauma center were retrospectively reviewed. TLICS, mTLICS, and TL AOSIS scores were calculated for 476 patients using computed tomography, MRI, and the documented neurological examination. Treatment recommendations were compared with treatment received. Standard validity measures were calculated. RESULTS: Treatment recommendations matched actual treatments in 95.6% (455/476) of patients for mTLICS, 91.3% (435/476) for TLICS, and 92.6% (441/476) for TL AOSIS. The differences between the accuracy of mTLICS and TLICS (95.6% vs 91.3%, P < .001) and between mTLICS and TL AOSIS (95.6% vs 91.3%, P = .003) were significant. The sensitivity of mTLICS was higher than that of TLICS (96.3% vs 81.3%, P < .001), and the sensitivity of TL AOSIS was higher than that of TLICS (92.5% vs 81.3%, P < .001). The specificity of mTLICS was equal to that of TLICS (95.3%) and higher than that of TL AOSIS (95.3% vs 92.7%, P = .02). The modifier led to substantial outperformance of mTLICS over TLICS due to 38 patients (20 of whom received surgery) moving from a TLICS score of <4 to a mTLICS score equal to 4. CONCLUSION: All systems performed well. The mTLICS had improved sensitivity and accuracy compared with TLICS and higher accuracy and specificity than TL AOSIS. The sensitivity of TL AOSIS was higher than that of TLICS. Prospective, multi-institutional reliability and validity studies of this mTLICS are needed for adoption.

Characterization of the influence of spinopelvic parameters on thoracolumbar trauma.

OBJECTIVE: The current Roussouly classification identifies four groups of "normal" sagittal spine morphology, which has greatly expanded the understanding of normal heterogeneity of the spine. While there has been extensive characterization of the influence of spinopelvic parameters on outcomes after degenerative spine surgery, the influence of spinopelvic parameters on thoracolumbar trauma has yet to be described. The goal of this study was to determine if spinopelvic parameters and global spine morphology influence fracture location, fracture morphology, and rate of neurological deficit in the setting of thoracolumbar trauma. METHODS: Of 2896 patients reviewed in the authors' institutional spine database between January 2014 and April 2020 with an ICD-9/10 diagnosis of thoracolumbar trauma, 514 met the inclusion criteria of acute thoracolumbar fracture on CT and visible femoral heads on sagittal CT. Pelvic incidence (PI) was calculated on sagittal CT. Demographic and clinical data including age, sex, BMI, smoking status, concomitant cervical fracture, mechanism of injury, major fracture location, neurological deficit, AO Spine thoracolumbar injury classification, and management type (operative vs nonoperative) were collected. Patients were stratified into high-PI (≥ 50°) and low-PI (< 50°) groups. RESULTS: Patients with high PI had a lower incidence of fractures in the lower lumbar spine (below L2) compared with patients with low PI (16% vs 8%, p < 0.01). The last lordotic vertebrae were observed between T10 and L4, and of fractures that occurred at these levels, 75% were at the last lordotic vertebrae. Fall from height was the most common cause of neurological deficit, accounting for 47%. Of the patients presenting with a fall from height, AO Spine type B distraction injuries were more common in the high-PI group (41% vs 18%, p = 0.01). Similarly, within the same subgroup, AO Spine type A compression injuries were more common in the low-PI group (73% vs 53%, p = 0.01). CONCLUSIONS: Spinopelvic parameters and sagittal balance influence the location and morphology of thoracolumbar fractures. Fractures of the thoracolumbar junction are strongly associated with the inflection point, which is defined by sagittal alignment. While the importance of considering sagittal balance is known for decision-making in degenerative spinal pathology, further studies are required to determine if spinopelvic parameters and sagittal balance should play a role in the decision-making for management of thoracolumbar fractures.

Neurosurgical Performance in the First 2 Years of Merit-Based Incentive Payment System: A Descriptive Analysis and Predictors of Receiving Bonus Payments.

BACKGROUND: The merit-based incentive payment system (MIPS) program was implemented to tie Medicare reimbursements to value-based care measures. Neurosurgical performance in MIPS has not yet been described. OBJECTIVE: To characterize neurosurgical performance in the first 2 years of MIPS. METHODS: Publicly available data regarding MIPS performance for neurosurgeons in 2017 and 2018 were queried. Descriptive statistics about physician characteristics, MIPS performance, and ensuing payment adjustments were performed, and predictors of bonus payments were identified. RESULTS: There were 2811 physicians included in 2017 and 3147 in 2018. Median total MIPS scores (99.1 vs 90.4, P < .001) and quality scores (97.9 vs 88.5, P < .001) were higher in 2018 than in 2017. More neurosurgeons (2758, 87.6%) received bonus payments in 2018 than in 2017 (2013, 71.6%). Of the 2232 neurosurgeons with scores in both years, 1347 (60.4%) improved their score. Reporting through an alternative payment model (odds ratio [OR]: 32.3, 95% CI: 16.0-65.4; P < .001) and any practice size larger than 10 (ORs ranging from 2.37 to 10.2, all P < .001) were associated with receiving bonus payments. Increasing years in practice (OR: 0.99; 95% CI: 0.982-0.998, P = .011) and having 25% to 49% (OR: 0.72; 95% CI: 0.53-0.97; P = .029) or ≥50% (OR: 0.48; 95% CI: 0.28-0.82; P = .007) of a physician's patients eligible for Medicaid were associated with lower rates of bonus payments. CONCLUSION: Neurosurgeons performed well in MIPS in 2017 and 2018, although the program may be biased against surgeons who practice in small groups or take care of socially disadvantaged patients.

The Many Faces of Astrocytes in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common cause of dementia in an aging population. The majority of research effort has focused on the role of neurons in neurodegeneration and current therapies have limited ability to slow disease progression. Recently more attention has been given to the role of astrocytes in the process of neurodegeneration. Specifically, reactive astrocytes have both advantageous and adverse effects during neurodegeneration. The ability to isolate and depict astrocyte phenotype has been challenging. However, with the recent development of single-cell sequencing technologies researchers are provided with the resource to delineate specific biomarkers associated with reactive astrocytes in AD. In this review, we will focus on the role of astrocytes in normal conditions and the pathological development of AD. We will further review recent developments in the understanding of astrocyte heterogeneity and associated biomarkers. A better understanding of astrocyte contributions and phenotypic changes in AD can ultimately lead to more effective therapeutic targets.

Angiogenic gene networks are dysregulated in opioid use disorder: evidence from multi-omics and imaging of postmortem human brain.

Opioid use disorder (OUD) is a public health crisis in the U.S. that causes over 50 thousand deaths annually due to overdose. Using next-generation RNA sequencing and proteomics techniques, we identified 394 differentially expressed (DE) coding and long noncoding (lnc) RNAs as well as 213 DE proteins in Brodmann Area 9 of OUD subjects. The RNA and protein changes converged on pro-angiogenic gene networks and cytokine signaling pathways. Four genes (LGALS3, SLC2A1, PCLD1, and VAMP1) were dysregulated in both RNA and protein. Dissecting these DE genes and networks, we found cell type-specific effects with enrichment in astrocyte, endothelial, and microglia correlated genes. Weighted-genome correlation network analysis (WGCNA) revealed cell-type correlated networks including an astrocytic/endothelial/microglia network involved in angiogenic cytokine signaling as well as a neuronal network involved in synaptic vesicle formation. In addition, using ex vivo magnetic resonance imaging, we identified increased vascularization in postmortem brains from a subset of subjects with OUD. This is the first study integrating dysregulation of angiogenic gene networks in OUD with qualitative imaging evidence of hypervascularization in postmortem brain. Understanding the neurovascular effects of OUD is critical in this time of widespread opioid use.

Cerebral hemorrhage in the LVAD patient: A case series and literature review.

INTRODUCTION: A left ventricular assist device (LVAD) is used in certain heart failure cases, but LVADs can have significant neurological complications including intracranial hemorrhages (ICH). Prediction and management of ICHs is challenging due to medical comorbidities and blood thinners. METHODS: A retrospective review of LVAD patients with ICHs from 2015 to 2019 was performed. The data included demographics, premorbid conditions, hemorrhage type, treatments, and outcomes. RESULTS: Twenty-two patients were included with a median age of 53 and a median time of 16 months from LVAD insertion to ICH. All patients were on blood thinners prior to ICH. The hemorrhage type included subarachnoid hemorrhage (41 %), intracerebral hemorrhage (32 %), and subdural hematomas (23 %). The blood-thinning agent was reversed in 64 % of patients with a median of 3.5 days prior to resumption of these medications. Ten re-hemorrhages occurred with 4 of these hemorrhages within two weeks of anticoagulation resumption. Open cranial surgery was performed in 32 % of all patients, and the mortality was 41 %. CONCLUSIONS: Management of these patients is challenging with a relatively high rate of re-hemorrhage and need for surgical intervention. Despite maximal management, the mortality remains high.

Open Surgery for Extraction of an Embolized Pellet in the Middle Cerebral Artery From a Shotgun Injury.

BACKGROUND AND IMPORTANCE: Embolization of shotgun pellet from the peripheral vasculature to the cerebral vessels has been a known phenomenon that has been reported previously in the literature. However, there is no consensus on clinical indications for intervention, best modality of intervention or management upon leaving the hospital. We describe a case of a shotgun pellet in the neck that embolized to the middle cerebral artery that was treated with open surgery. Discussed is the initial management on presentation, timing of intervention from surgery and detailed surgical technique. CLINICAL PRESENTATION: A 20-yr-old man presented after being shot at close range with a shotgun. He was neurologically intact on exam. Initial screening computed tomography (CT) of the brain noted a shotgun pellet in the region of the sylvian fissure without intracranial hemorrhage. Computed tomography angiography again displayed pellet in the vicinity of the left middle cerebral artery. He was emergently taken for an awake cerebral angiogram and subsequent surgical extraction of the shotgun pellet. CONCLUSION: Missile embolization of a bullet fragment to the intracranial vasculature is rare and requires difficult decisions regarding management. Critical factors that are to be considered prior to treatment include neurological clinical presentation, timing of the trauma, and anatomic location of injury. Patients who are without neurological deficit that display compromised blood flow require immediate cerebral angiogram followed by surgical intervention depending on location.

pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma.

Highly malignant brain tumors harbor the aberrant propensity for aerobic glycolysis, the excessive conversion of glucose to lactic acid even in the presence of ample tissue oxygen. Lactic acid is rapidly effluxed to the tumor microenvironment via a group of plasma-membrane transporters denoted monocarboxylate transporters (MCTs) to prevent "self-poisoning." One isoform, MCT2, has the highest affinity for lactate and thus should have the ability to respond to microenvironment conditions such as hypoxia, lactate, and pH to help maintain high glycolytic flux in the tumor. Yet, MCT2 is considered to not respond to hypoxia, which is counterintuitive. Its response to tumor lactate has not been reported. In this report, we experimentally identify the transcription initiation site/s for MCT2 in astrocytes (normal) and glioma (tumor). We then use a BACmid library to isolate a 4.2-kbp MCT2 promoter-exon I region and examine promoter response to glycolysis-mediated stimuli in glioma cells. Reporter analysis of nested-promoter constructs indicated response of MCT2 to hypoxia, pH, lactate, and glucose, the major physiological "players" that facilitate a tumor's growth and proliferation. Immunoblot analysis of native MCT2 expression under altered pH and hypoxia reflected the reporter data. The pH-mediated gene-regulation studies we describe are the first to record H+-based reporter studies for any mammalian system and demonstrate the exquisite response of the MCT2 gene to minute changes in tumor pH. Identical promoter usage also provides the first evidence of astrocytes harnessing the same gene regulatory regions to facilitate astrocyte-neuron lactate shuttling, a metabolic feature of normal brain.

Increased metastasis with loss of E2F2 in Myc-driven tumors.

In human breast cancer, mortality is associated with metastasis to distant sites. Therefore, it is critical to elucidate the biological mechanisms that underlie tumor progression and metastasis. Using signaling pathway signatures we previously predicted a role for E2F transcription factors in Myc induced tumors. To test this role we interbred MMTV-Myc transgenic mice with E2F knockouts. Surprisingly, we observed that the loss of E2F2 sharply increased the percentage of lung metastasis in MMTV-Myc transgenic mice. Examining the gene expression profile from these tumors, we identified genetic components that were potentially involved in mediating metastasis. These genes were filtered to uncover the genes involved in metastasis that also impacted distant metastasis free survival in human breast cancer. In order to elucidate the mechanism by which E2F2 loss enhanced metastasis we generated knockdowns of E2F2 in MDA-MB-231 cells and observed increased migration in vitro and increased lung colonization in vivo. We then examined genes that were differentially regulated between tumors from MMTV-Myc, MMTV-Myc E2F2-/-, and lung metastases samples and identified PTPRD. To test the role of PTPRD in E2F2-mediated breast cancer metastasis, we generated a knockdown of PTPRD in MDA-MB-231 cells. We noted that decreased levels of PTPRD resulted in decreased migration in vitro and decreased lung colonization in vivo. Taken together, these data indicate that E2F2 loss results in increased metastasis in breast cancer, potentially functioning through a PTPRD dependent mechanism.

Low-cost media formulation for culture of brain tumor spheroids (neurospheres).

Recent studies have found that the biological features of primary tumors are faithfully recapitulated when a patient's tumor is processed and then maintained as a 3-D spheroid in specialized cell culture media. However, a major drawback for maintenance and routine passage of primary tumors as spheroids has been the high cost of custom-formulated media compared to regular serum-supplemented media. Here we report the formulation of a cost-effective, serum-free medium in which high-grade primary brain tumor (glioblastoma) explants can be established and maintained as spheroids. Based on DMEM, this formulation requires only supplementation with several amino acids, vitamins, synthetic EGF, and bFGF, with most of the cost being associated with the growth factors. A simple addition of BSA (fraction V) obviated the need for numerous other components (or human serum) commonly used in the specialized commercial media formulations.

Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study.

Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs). We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA), a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain) slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion). Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity.