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BIO alleviates inflammation through inhibition of GSK-3β in a rat model of intracerebral hemorrhage

Sha Zhao, Zhen Liu, Zihan Yu, Xinran Wu, Rui Li and Xiaobo Tang

OBJECTIVE

Inflammation plays a key role in secondary brain damage following intracerebral hemorrhage (ICH). Glycogen synthase kinase–3β (GSK-3β) plays a strong proinflammatory role in many CNS diseases, including stroke. The present study was undertaken to examine the effects of 6-bromoindirubin-3ʹ-oxime (BIO), a specific inhibitor of GSK-3β, on inflammation in ICH rats.

METHODS

An ICH rat model was induced by autologous whole-blood injection into the striatum. First, 10, 20, 40, 60, 80, or 100 μg/kg BIO was applied to ICH animals to determine an optimal dosage for producing sufficient GSK-3β inhibition in rat ipsilateral hippocampus by Western blotting. Second, 40 μg/kg BIO was applied to ICH rats for 1, 3, 7, or 14 days, respectively, to determine a suitable intervention time course of BIO by Western blotting analysis on GSK-3β. Third, Western blotting and enzyme-linked immunosorbent assay were used for quantification of inflammation-related factors upstream or downstream of GSK-3β in rat ipsilateral hippocampus. Then, immunohistochemical staining was applied to detect activated microglia and apoptotic cells in rat ipsilateral hippocampus. Last, neurobehavioral tests were performed to assess the sensorimotor impairments in the ICH rats.

RESULTS

The results show that BIO 1) blocked GSK-3βTyr216 phosphorylation/activation, thus stabilizing β-catenin, increasing upstream brain-derived neurotrophic factor and downstream heat shock protein 70 levels, and decreasing the levels of nuclear factor–κB p65 and cyclooxygenase 2; 2) decreased the levels of the proinflammatory cytokines tumor necrosis factor–α and interleukin (IL)–1β and IL-6 and elevated the level of antiinflammatory cytokine IL-10; 3) inhibited microglia activation and cell apoptosis; and 4) improved the sensorimotor deficits of ICH rats.

CONCLUSIONS

BIO posttreatment inhibited microglia activation, prevented inflammation and hippocampal cell death, and ameliorated functional and morphological outcomes in a rat ICH model through inactivation of GSK-3β.

In Journal of Neurosurgery Publish Before Print

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Centers for Medicare & Medicaid Services Hierarchical Condition Category score as a predictor of readmission and reoperation following elective inpatient spine surgery

Presented at the 2019 AANS/CNS Joint Section on Disorders of the Spine and Peripheral Nerves

Justin Turcotte, Zachary Sanford, Andrew Broda and Chad Patton

OBJECTIVE

A universal, objective predictor of postoperative resource utilization following inpatient spine surgery has not been clearly established. The Centers for Medicare & Medicaid Services (CMS) Hierarchical Condition Category (HCC) risk adjustment model, based on a formula using patient demographics and coded diagnoses, is currently used to prospectively estimate financial risk in Medicare Advantage patients; however, the value of this score as a clinical tool is currently unknown. The authors present an analysis evaluating the utility of the CMS HCC score as a universal predictive tool for patients undergoing inpatient spine surgery.

METHODS

A total of 1966 consecutive patients (551 with lumbar laminectomy [LL] alone, 592 with lumbar laminectomy and fusion [LF], and 823 with anterior cervical discectomy and fusion [ACDF]) undergoing inpatient spine surgery at a single institution from January 2014 to May 2018 were included in this retrospective outcomes study. Perioperative outcome measures included procedure time, 30-day readmission, reoperation, hospital length of stay (LOS), opioid utilization measured by morphine milligram equivalents (MMEs), and cost of inpatient hospitalization (in US dollars). Published CMS algorithms were incorporated into the electronic health records and used to calculate HCC scores for all patients. Patients were stratified into HCC score quartiles. Linear regression was performed on LOS, procedure time, inpatient opioid consumption, discharge opioid prescriptions, and cost to identify predictors of HCC quartiles when controlling for procedure type. One-way ANOVA and Pearson’s chi-square analysis were used to compare perioperative outcomes stratified by HCC score.

RESULTS

Across all procedures, the HCC score demonstrated significant association with 30-day readmission (OR 1.45, 95% CI 1.11–1.91, p = 0.007). The average BMI, median American Society of Anesthesiologists score, and 30-day readmission rate were similar across procedures (LL: 30.6 kg/m2, 2, 3.6%; LF: 30.6 kg/m2, 2, 4.6%; ACDF: 30.2 kg/m2, 2, 3.9%; p = 0.265, 0.061, and 0.713, respectively). LOS (p < 0.0001), duration of procedure (p < 0.0001), discharge MME (p = 0.031), total cost (p < 0.001), daily MME (p < 0.001), reoperation (p < 0.001), and 30-day readmission rate (p < 0.001) were significantly different between HCC quartiles.

CONCLUSIONS

The HCC score may hold value as an objective, automated predictor of postoperative resource utilization and outcomes, including readmission and reoperation. This may have value as a universal, reproducible tool to target clinical interventions for higher-risk patients.

In Journal of Neurosurgery: Spine Publish Before Print

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Does index level sagittal alignment determine adjacent level disc height loss?

Ryan Snowden, Justin Miller, Tome Saidon, Joseph D. Smucker, K. Daniel Riew and Rick Sasso

OBJECTIVE

The authors sought to compare the effect of index level sagittal alignment on cephalad radiographic adjacent segment pathology (RASP) in patients undergoing cervical total disc arthroplasty (TDA) or anterior cervical discectomy and fusion (ACDF).

METHODS

This was a retrospective study of prospectively collected radiographic data from 79 patients who underwent TDA or ACDF and were enrolled and followed prospectively at two centers in a multicenter FDA investigational device exemption trial of the Bryan cervical disc prosthesis used for arthroplasty. Neutral lateral radiographs were obtained pre- and postoperatively and at 1, 2, 4, and up to 7 years following surgery. The index level Cobb angle was measured both pre- and postoperatively. Cephalad disc degeneration was determined by a previously described measurement of the disc height/anteroposterior (AP) distance ratio.

RESULTS

Sixty-eight patients (n = 33 ACDF; n = 35 TDA) had complete radiographs and were included for analysis. Preoperatively, there was no difference in the index level Cobb angle between the ACDF and TDA patients. Postoperatively, the ACDF patients had a larger segment lordosis compared to the TDA patients (p = 0.002). Patients who had a postoperative kyphotic Cobb angle were more likely to have undergone TDA (p = 0.01). A significant decrease in the disc height/AP distance ratio occurred over time (p = 0.035), by an average of 0.01818 at 84 months. However, this decrease was not influenced by preoperative alignment, postoperative alignment, or type of surgery.

CONCLUSIONS

In this cohort of patients undergoing TDA and ACDF, the authors found that preoperative and postoperative sagittal alignment have no effect on RASP at follow-up of at least 7 years. They identified time as the only significant factor affecting RASP.

In Journal of Neurosurgery: Spine Publish Before Print

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Endoscopic transorbital and endonasal approach for trigeminal schwannomas: a retrospective multicenter analysis (KOSEN-005)

Hun Ho Park, Sang Duk Hong, Yong Hwy Kim, Chang-Ki Hong, Kyung In Woo, In-Sik Yun and Doo-Sik Kong

OBJECTIVE

Trigeminal schwannomas are rare neoplasms with an incidence of less than 1% that require a comprehensive surgical strategy. These tumors can occur anywhere along the path of the trigeminal nerve, capable of extending intradurally into the middle and posterior fossae, and extracranially into the orbital, pterygopalatine, and infratemporal fossa. Recent advancements in endoscopic surgery have suggested a more minimally invasive and direct route for tumors in and around Meckel’s cave, including the endoscopic endonasal approach (EEA) and endoscopic transorbital superior eyelid approach (ETOA). The authors assess the feasibility and outcomes of EEA and ETOA for trigeminal schwannomas.

METHODS

A retrospective multicenter analysis was performed on 25 patients who underwent endoscopic surgical treatment for trigeminal schwannomas between September 2011 and February 2019. Thirteen patients (52%) underwent EEA and 12 (48%) had ETOA, one of whom underwent a combined approach with retrosigmoid craniotomy. The extent of resection, clinical outcome, and surgical morbidity were analyzed to evaluate the feasibility and selection of surgical approach between EEA and ETOA based on predominant location of trigeminal schwannomas.

RESULTS

According to predominant tumor location, 9 patients (36%) had middle fossa tumors (Samii type A), 8 patients (32%) had dumbbell-shaped tumors located in the middle and posterior cranial fossae (Samii type C), and another 8 patients (32%) had extracranial tumors (Samii type D). Gross-total resection (GTR, n = 12) and near-total resection (NTR, n = 7) were achieved in 19 patients (76%). The GTR/NTR rates were 81.8% for ETOA and 69.2% for EEA. The GTR/NTR rates of ETOA and EEA according to the classifications were 100% and 50% for tumors confined to the middle cranial fossa, 75% and 33% for dumbbell-shaped tumors located in the middle and posterior cranial fossae, and 50% and 100% for extracranial tumors. There were no postoperative CSF leaks. The most common preoperative symptom was trigeminal sensory dysfunction, which improved in 15 of 21 patients (71.4%). Three patients experienced new postoperative complications such as vasospasm (n = 1), wound infection (n = 1), and medial gaze palsy (n = 1).

CONCLUSIONS

ETOA provides adequate access and resectability for trigeminal schwannomas limited in the middle fossa or dumbbell-shaped tumors located in the middle and posterior fossae, as does EEA for extracranial tumors. Tumors predominantly involving the posterior fossa still remain a challenge in endoscopic surgery.

In Journal of Neurosurgery Publish Before Print

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Epidermal growth factor receptor mutations: association with favorable local tumor control following Gamma Knife radiosurgery in patients with non–small cell lung cancer and brain metastases

Cheng-Chia Lee, Sanford P. C. Hsu, Chung-Jung Lin, Hsiu-Mei Wu, Yu-Wei Chen, Yung-Hung Luo, Chi-Lu Chiang, Yong-Sin Hu, Wen-Yuh Chung, Cheng-Ying Shiau, Wan-Yuo Guo, David Hung-Chi Pan and Huai-Che Yang

OBJECTIVE

The presence of epidermal growth factor receptor (EGFR) mutations in non–small cell lung cancer (NSCLC) has been associated with elevated radiosensitivity in vitro. However, results from clinical studies on radiosensitivity in cases of NSCLC with EGFR mutations are inconclusive. This paper presents a retrospective analysis of patients with NSCLC who underwent regular follow-up imaging after radiotherapy for brain metastases (BMs). The authors also investigated the influence of EGFR mutations on the efficacy of Gamma Knife radiosurgery (GKRS).

METHODS

This study included 264 patients (1069 BMs) who underwent GKRS treatment and for whom EGFR mutation status, demographics, performance status, and tumor characteristics were available. Radiological images were obtained at 3 months after GKRS and at 3-month intervals thereafter. Kaplan-Meier plots and Cox regression analysis were used to correlate EGFR mutation status and other clinical features with tumor control and overall survival.

RESULTS

The tumor control rates and overall 12-month survival rates were 87.8% and 65.5%, respectively. Tumor control rates in the EGFR mutant group versus the EGFR wild-type group were 90.5% versus 79.4% at 12 months and 75.0% versus 24.5% at 24 months. During the 2-year follow-up period after SRS, the intracranial response rate in the EGFR mutant group was approximately 3-fold higher than that in the wild-type group (p < 0.001). Cox regression multivariate analysis identified EGFR mutation status, extracranial metastasis, primary tumor control, and prescribed margin dose as predictors of tumor control (p = 0.004, p < 0.001, p = 0.004, and p = 0.026, respectively). Treatment with a combination of GKRS and tyrosine kinase inhibitors (TKIs) was the most important predictor of overall survival (p < 0.001).

CONCLUSIONS

The current study demonstrated that, among patients with NSCLC-BMs, EGFR mutations were independent prognostic factors of tumor control. It was also determined that a combination of GKRS and TKI had the most pronounced effect on prolonging survival after SRS. In select patient groups, treatment with SRS in conjunction with EGFR-TKIs provided effective tumor control for NSCLC-BMs.

In Journal of Neurosurgery Publish Before Print

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In-hospital mortality and length of hospital stay with craniotomy versus craniectomy for acute subdural hemorrhage: a multicenter, propensity score–matched analysis

Keita Shibahashi, Kazuhiro Sugiyama, Jun Tomio, Hidenori Hoda and Akio Morita

OBJECTIVE

The optimal surgical treatment for acute subdural hemorrhage (ASDH) remains controversial. The purpose of this study was to compare outcomes in patients who underwent craniotomy with those in patients who underwent decompressive craniectomy for the treatment of ASDH.

METHODS

Using the Japan Trauma Data Bank, a nationwide trauma registry, the authors identified patients aged ≥ 18 years with ASDH who underwent surgical evacuation after blunt head trauma between 2004 and 2015. Logistic regression analysis was used to estimate a propensity score to predict decompressive craniectomy use. They then used propensity score–matched analysis to compare patients who underwent craniotomy with those who underwent decompressive craniectomy. To identify the potential benefits and disadvantages of decompressive craniectomy among different subgroups, they estimated the interactions between treatment and the subgroups using logistic regression analysis.

RESULTS

Of 236,698 patients who were registered in the database, 1788 were eligible for propensity score–matched analysis. The final analysis included 514 patients who underwent craniotomy and 514 patients who underwent decompressive craniectomy. The in-hospital mortality did not differ significantly between the groups (41.6% for the craniotomy group vs 39.1% for the decompressive craniectomy group; absolute difference −2.5%; 95% CI −8.5% to 3.5%). The length of hospital stay was significantly longer in patients who underwent decompressive craniectomy (median 23 days [IQR 4–52 days] vs 30 days [IQR 7–60 days], p = 0.005). Subgroup analyses demonstrated qualitative interactions between decompressive craniectomy and the patient subgroups, suggesting that patients who were more severely injured (Glasgow Coma Scale score < 9 and probability of survival < 0.64) and those involved in high-energy injuries may be good candidates for decompressive craniectomy.

CONCLUSIONS

The results of this study showed that overall, decompressive craniectomy did not appear to be superior to craniotomy in ASDH treatment in terms of in-hospital mortality. In contrast, there were significant differences in the effectiveness of decompressive craniectomy between the subgroups. Thus, future studies should prioritize the identification of a subset of patients who will possibly benefit from the performance of each of the procedures.

In Journal of Neurosurgery Publish Before Print

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Insurance type impacts the economic burden and survival of patients with newly diagnosed glioblastoma

Ankush Chandra, Jacob S. Young, Cecilia Dalle Ore, Fara Dayani, Darryl Lau, Harsh Wadhwa, Jonathan W. Rick, Alan T. Nguyen, Michael W. McDermott, Mitchel S. Berger and Manish K. Aghi

OBJECTIVE

Glioblastoma (GBM) carries a high economic burden for patients and caregivers, much of which is associated with initial surgery. The authors investigated the impact of insurance status on the inpatient hospital costs of surgery for patients with GBM.

METHODS

The authors conducted a retrospective review of patients with GBM (2010–2015) undergoing their first resection at the University of California, San Francisco, and corresponding inpatient hospital costs.

RESULTS

Of 227 patients with GBM (median age 62 years, 37.9% females), 31 (13.7%) had Medicaid, 94 (41.4%) had Medicare, and 102 (44.9%) had private insurance. Medicaid patients had 30% higher overall hospital costs for surgery compared to non-Medicaid patients ($50,285 vs $38,779, p = 0.01). Medicaid patients had higher intensive care unit (ICU; p < 0.01), operating room (p < 0.03), imaging (p < 0.001), room and board (p < 0001), and pharmacy (p < 0.02) costs versus non-Medicaid patients. Medicaid patients had significantly longer overall and ICU lengths of stay (6.9 and 2.6 days) versus Medicare (4.0 and 1.5 days) and privately insured patients (3.9 and 1.8 days, p < 0.01). Medicaid patients had similar comorbidity rates to Medicare patients (67.8% vs 68.1%), and both groups had higher comorbidity rates than privately insured patients (37.3%, p < 0.0001). Only 67.7% of Medicaid patients had primary care providers (PCPs) versus 91.5% of Medicare and 86.3% of privately insured patients (p = 0.009) at the time of presentation. Tumor diameter at diagnosis was largest for Medicaid (4.7 cm) versus Medicare (4.1 cm) and privately insured patients (4.2 cm, p = 0.03). Preoperative (70 vs 90, p = 0.02) and postoperative (80 vs 90, p = 0.03) Karnofsky Performance Scale (KPS) scores were lowest for Medicaid versus non-Medicaid patients, while in subgroup analysis, postoperative KPS score was lowest for Medicaid patients (80, vs 90 for Medicare and 90 for private insurance; p = 0.03). Medicaid patients had significantly shorter median overall survival (10.7 months vs 12.8 months for Medicare and 15.8 months for private insurance; p = 0.02). Quality-adjusted life year (QALY) scores were 0.66 and 1.05 for Medicaid and non-Medicaid patients, respectively (p = 0.036). The incremental cost per QALY was $29,963 lower for the non-Medicaid cohort.

CONCLUSIONS

Patients with GBMs and Medicaid have higher surgical costs, longer lengths of stay, poorer survival, and lower QALY scores. This study indicates that these patients lack PCPs, have more comorbidities, and present later in the disease course with larger tumors; these factors may drive the poorer postoperative function and greater consumption of hospital resources that were identified. Given limited resources and rising healthcare costs, factors such as access to PCPs, equitable adjuvant therapy, and early screening/diagnosis of disease need to be improved in order to improve prognosis and reduce hospital costs for patients with GBM.

In Journal of Neurosurgery Publish Before Print

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Letter to the Editor. Infantile hydrocephalus treated by choroid plexus coagulation

Hardik Sardana and Shweta Kedia

In Journal of Neurosurgery: Pediatrics Publish Before Print

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Letter to the Editor. Predictors for radiation toxicity and tumor control

Ian Paddick and Alexis Dimitriadis

In Journal of Neurosurgery Publish Before Print

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Letter to the Editor. The role of annexin A7 in SAH

Yaxing Chen and Liangxue Zhou

In Journal of Neurosurgery Publish Before Print