P2X7 receptor antagonism by AZ10606120 significantly depletes glioblastoma cancer stem cells in vitro.

Glioblastoma is the most aggressive and lethal primary brain malignancy with limited treatment options and poor prognosis. Self-renewing glioblastoma cancer stem cells (GSCs) facilitate tumour progression, resistance to conventional treatment and tumour recurrence. GSCs are resistant to standard treatments. There is a need for novel treatment alternatives that effectively target GSCs. The purinergic P2X receptor 7 (P2X7R) is expressed in glioblastomas and has been implicated in disease pathogenesis. However, the roles of P2X7R have not been comprehensively elucidated in conventional treatment-resistant GSCs. This study characterised P2X7R channel and pore function and investigated the effect of pharmacological P2X7R inhibition in GSCs. Immunofluorescence and live cell fluorescent dye uptake experiments revealed P2X7R expression, and channel and pore function in GSCs. Treatment of GSCs with the P2X7R antagonist, AZ10606120 (AZ), for 72hours significantly reduced GSC numbers, compared to untreated cells. When compared with the effect of the first-line conventional chemotherapy, temozolomide (TMZ), GSCs treated with AZ had significantly lower cell numbers than TMZ-treated cultures, while TMZ treatment alone did not significantly deplete GSC numbers compared to the control. AZ treatment also induced significant lactate dehydrogenase release by GSCs, indicative of treatment-induced cytotoxic cell death. There were no significant differences in the expression of apoptotic markers, Annexin V and cleaved caspase-3, between AZ-treated cells and the control. Collectively, this study reveals for the first time functional P2X7R channel and pore in GSCs and significant GSC depletion following P2X7R inhibition by AZ. These results indicate that P2X7R inhibition may be a novel therapeutic alternative for glioblastoma, with effectiveness against GSCs resistant to conventional chemotherapy.

P2X7 receptor antagonism by AZ10606120 significantly reduced in vitro tumour growth in human glioblastoma.

Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14-18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas.

Risk Stratification of Elderly Patients Undergoing Spinal Surgery Using the Modified Frailty Index.

STUDY DESIGN: Retrospective cohort. OBJECTIVES: To validate the 11-item modified Frailty Index (mFI) as a perioperative risk stratification tool in elderly patients undergoing spine surgery. METHODS: All consecutive cases of spine surgery in patients aged 65 years or older between July 2016 and June 2018 at a state-wide trauma center were retrospectively reviewed. The primary outcome was post-operative major complication rate (Clavien-Dindo Classification ≥ III). Secondary outcome measures included the rate of all complications, 6-month mortality and surgical site infection. RESULTS: A total of 348 cases were identified. The major complication rate was significantly lower in patients with an mFI of 0 compared to ≥ 0.45 (18.3% versus 42.5%, P = .049). As the mFI increased from 0 to ≥ 0.45 there was a stepwise increase in risk of major complications (P < .001). Additionally, 6-month mortality rate was considerably lower when the mFI was 0 rather than ≥ 0.27 (4.2% versus 20.4%, P = .007). Multivariate analysis demonstrated an mFI ≥ 0.27 was significantly associated with an increased incidence of major complication (OR 2.80, 95% CI 1.46-5.35, P = .002), all complication (OR 2.93, 95% CI 1.70-15.11, P < .001), 6-month mortality (OR 7.39, 95% CI 2.55-21.43, P < .001) and surgical site infection (OR 4.43, 95% CI 1.71-11.51, P = .002). The American Society of Anesthesiologists' (ASA) index did not share a stepwise relationship with any outcome. CONCLUSION: The mFI is significantly associated in a gradated fashion with increased morbidity and mortality. Patients with an mFI ≥ 0.27 are at greater risk of major complications, all-complications, 6-monthy mortality, and surgical site infection.

Immune-related adverse events are associated with therapeutic efficacy of immunotherapy in patients with melanoma brain metastases.

Immunotherapy with T-cell checkpoint inhibitors have changed the treatment landscape for patients with melanoma brain metastases (MBMs), offering increased survival compared with historical outcomes. We sought to identify clinical features associated with intracranial tumour responses or progression-free survival (PFS) in patients with MBMs treated with immunotherapy. Patients with MBMs treated with immunotherapy from August 2013 to March 2020 were identified through local databases. Melanoma disease burdens and immune-related adverse events (irAEs) were assessed retrospectively by review of patient medical records. Efficacy was evaluated by determining objective response rates (ORRs) in brain metastases using immune-Response Evaluation Criteria in Solid Tumours criteria, MBM-specific survival and overall PFS. Twenty-six patients were identified as eligible for this study. The presence and volume of extracranial metastases (ECM) were associated with a non-significant trend of reduced intracranial ORRs and PFS. Patients with irAEs, on the other hand, had significantly increased intracranial ORRs and PFS compared to those without irAEs. Severe, grade ≥3 irAEs and co-occurrence of ≥2 irAEs were also significantly associated with longer PFS. The presence and volume of ECM correlated inversely with development and severity of irAEs. We report a strong association between the development of irAEs and favourable melanoma-specific outcomes in patients with MBMs receiving immunotherapy. Contrary to previous studies, we found that co-occurrence of ECM in these patients was associated with fewer irAEs and reduced treatment efficacy.

Somatic Mosaic Mutation Gradient Detected in Trace Brain Tissue From Stereo-EEG Depth Electrodes.

BACKGROUND AND OBJECTIVES: Mosaic pathogenic variants restricted to brain are increasingly recognized as a cause of focal epilepsies. We aimed to identify a mosaic pathogenic variant and its anatomical gradient in brain DNA derived from trace tissue on explanted stereo-electroencephalography (SEEG) electrodes. MATERIAL AND METHODS: We studied a patient with non-lesional multifocal epilepsy undergoing pre-surgical evaluation with SEEG. Following explantation, electrodes were divided into 3 pools based on their brain location (right posterior quadrant, left posterior quadrant, hippocampus/temporal neocortex). Tissue from each pool was processed and DNA whole genome amplified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. Brain-specific GFAP protein assay enabled cell-of-origin analysis. RESULTS: We demonstrated a mosaic gradient for a novel pathogenic KCNT1 loss-of-function variant, c.530G>A, p.W177X, predicted to lead to nonsense-mediated decay. Strikingly, the mosaic gradient correlated strongly with the SEEG findings as the highest mutant allele fraction was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. Elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. CONCLUSIONS: This study demonstrates proof-of-concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.

Posterior Instrumented Spinal Surgery Outcomes in the Elderly: A Comparison of the 5-Item and 11-Item Modified Frailty Indices.

STUDY DESIGN: Retrospective Cohort. OBJECTIVES: To validate the most concise risk stratification system to date, the 5-item modified frailty index (mFI-5), and compare its effectiveness with the established 11-item modified frailty index (mFI-11) in the elderly population undergoing posterior instrumented spine surgery. METHODS: A single centre retrospective review of posterior instrumented spine surgeries in patients aged 65 years and older was conducted. The primary outcome was rate of post-operative major complications (Clavien-Dindo Classification ≥ 4). Secondary outcome measures included rate of all complications, 6-month mortality and surgical site infection. Multi-variate analysis was performed and adjusted receiver operating characteristic curves were generated and compared by DeLong's test. The indices were correlated with Spearman's rho. RESULTS: 272 cases were identified. The risk of major complications was independently associated with both the mFI-5 (OR 1.89, 95% CI 1.01-3.55, P = .047) and mFI-11 (OR 3.73, 95% CI 1.90-7.30, P = .000). Both the mFI-5 and mFI-11 were statistically significant predictors of risk of all complications (P = .007 and P = .003), surgical site infection (P = .011 and P = .003) and 6-month mortality (P = .031 and P = .000). Adjusted ROC curves determined statistically similar c-statistics for major complications (.68 vs .68, P = .64), all complications (.66 vs .64, P = .10), surgical site infection (.75 vs .75, P = .76) and 6-month mortality (.83 vs .81, P = .21). The 2 indices correlated very well with a Spearman's rho of .944. CONCLUSIONS: The mFI-5 and mFI-11 are equally effective predictors of postoperative morbidity and mortality in this population. The brevity of the mFI-5 is advantageous in facilitating its daily clinical use.

The Impact of Preinjury Antiplatelet and Anticoagulant Use on Elderly Patients with Moderate or Severe Traumatic Brain Injury Following Traumatic Acute Subdural Hematoma.

BACKGROUND: Although it is often assumed that preinjury anticoagulant (AC) or antiplatelet (AP) use is associated with poorer outcomes among those with acute subdural hematoma (aSDH), previous studies have had varied results. This study examines the impact of preinjury AC and AP therapy on aSDH thickness, 30-day mortality, and extended Glasgow Outcome Scale at 6 months in elderly patients (aged ≥65). METHODS: A level 1 trauma center registry was interrogated to identify consecutive elderly patients who presented with moderate or severe traumatic brain injury (TBI) and associated traumatic aSDH between the first of January 2013 and the first of January 2018. Relevant demographic, clinical, and radiological data were retrieved from institutional medical records. The 3 primary outcome measures were aSDH thickness on initial computed tomography scan, 30-day mortality, and unfavorable outcome at 6 months (extended Glasgow Outcome Scale). RESULTS: One hundred thirty-two elderly patients were admitted with moderate or severe TBI and traumatic aSDH. The mean (±SD) age was 78.39 (±7.87) years, and a majority of patients (59.8%, n = 79) were male. There was a statistically significant difference in mean aSDH thickness, but there were no significant differences in 30-day mortality (P = 0.732) and unfavorable outcome between the AP, AC, combined AP and AC, and no antithrombotic exposure groups (P = 0.342). CONCLUSIONS: Further studies with larger sample sizes are necessary to confirm these observations, but our findings do not support the preconceived notion in clinical practice that antithrombotic use is associated with poor outcomes in elderly patients with moderate or severe TBI.

Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.

Monitoring and optimisation of brain tissue oxygen tension (PbtO2) has been associated with improved neurological outcome and survival in observational studies of severe traumatic brain injury (TBI). We carried out a systematic review of randomized controlled trials to determine if PbtO2-guided management is associated with differential neurological outcomes, survival, and adverse events. Searches were carried out to 10 February 2022 in Medline (OvidSP), 11 February in EMBASE (OvidSP) and 8 February in Cochrane library. Randomized controlled trials comparing PbtO2 and ICP-guided management to ICP-guided management alone were included. The primary outcome was survival with favourable neurological outcome at 6-months post injury. Data were extracted by two independent authors and GRADE certainty of evidence assessed. There was no difference in the proportion of patients with favourable neurological outcomes with PbtO2-guided management (relative risk [RR] 1.42, 95% CI 0.97 to 2.08; p = 0.07; I2 = 0%, very low certainty evidence) but PbtO2-guided management was associated with reduced mortality (RR 0.54, 95% CI 0.31 to 0.93; p = 0.03; I2 = 42%; very low certainty evidence) and ICP (mean difference (MD) - 4.62, 95% CI - 8.27 to - 0.98; p = 0.01; I2 = 63%; very low certainty evidence). There was no significant difference in the risk of adverse respiratory or cardiovascular events. PbtO2-guided management in addition to ICP-based care was not significantly associated with increased favourable neurological outcomes, but was associated with increased survival and reduced ICP, with no difference in respiratory or cardiovascular adverse events. However, based on GRADE criteria, the certainty of evidence provided by this meta-analysis was consistently very low. MESH: Brain Ischemia; Intensive Care; Glasgow Outcome Scale; Randomized Controlled Trial; Craniocerebral Trauma.

Implant Removal Versus Implant Retention Following Posterior Surgical Stabilization of Thoracolumbar Burst Fractures: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVES: To compare biomechanical and functional outcomes between implant removal and implant retention following posterior surgical fixation of thoracolumbar burst fractures. METHODS: A search of the MEDLINE, EMBASE, Google Scholar and Cochrane Databases was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Of the 751 articles initially retrieved, 13 published articles pooling 673 patients were included. Meta-analysis revealed there was a statistically significant improvement in sagittal Cobb Angle by 16.48 degrees (9.13-23.83, p < 0.01) after surgical stabilization of thoracolumbar burst fractures. This correction decremented to 9.68 degrees (2.02-17.35, p < 0.01) but remained significant at the time of implant removal approximately 12 months later. At final follow-up, the implant removal group demonstrated a 10.13 degree loss (3.00-23.26, p = 0.13) of reduction, while the implant retention group experienced a 10.17 degree loss (1.79-22.12, p = 0.10). There was no statistically significant difference in correction loss between implant retention and removal cohorts (p = 0.97). Pooled VAS scores improved by a mean of 3.32 points (0.18 to 6.45, p = 0.04) in the combined removal group, but by only 2.50 points (-1.81 to 6.81, p = 0.26) in the retention group. Oswestry Disability Index scores also improved after implant removal by 7.80 points (2.95-12.64, p < 0.01) at 1 year and 11.10 points (5.24-16.96, p < 0.01) at final follow-up. CONCLUSIONS: In younger patients with thoracolumbar burst fractures who undergo posterior surgical stabilization, planned implant removal results in superior functional outcomes without significant difference in kyphotic angle correction loss compared to implant retention.

Tumor characteristics and surgical outcomes of intracranial subependymomas: a systematic review and meta-analysis.

OBJECTIVE: The tumor characteristics and surgical outcomes of intracranial subependymomas are poorly defined. In this study the authors aimed to provide a comprehensive review of all clinical, pathological, radiological, and surgical aspects of this important neoplasm to inform future management strategies. METHODS: A systematic review and meta-analysis of MEDLINE, EMBASE, Cochrane, and Google Scholar databases adherent to PRISMA guidelines was conducted. RESULTS: Of the 1145 articles initially retrieved, 24 studies encompassing 890 cases were included. The authors identified 3 retrospective cohort studies and 21 case series, but no controlled trials. Mean age at presentation was 46.7 ± 18.1 years with a male predominance (70.2%). Common sites of tumor origin were the lateral ventricle (44.5%) and fourth ventricle (43.1%). Cumulative postoperative mortality and morbidity rates were 3.4% and 24.3% respectively. Meta-analysis revealed that male sex (HR 3.15, 95% CI 1.39-7.14, p = 0.006) was associated with poorer 5-year overall mortality rates. All-cause mortality rates were similar when performing subgroup meta-analyses for age (HR 0.50, 95% CI 0.03-7.36, p = 0.61), smaller subependymoma size (HR 1.51, 95% CI 0.78-2.92, p = 0.22), gross-total resection (HR 0.65, 95% CI 0.35-1.23, p = 0.18), and receipt of postoperative radiation therapy (HR 0.88, 95% CI 0.27-2.88, p = 0.84). Postoperative Karnofsky Performance Index scores improved by a mean difference of 1.62 ± 12.14 points (p = 0.42). The pooled overall 5-year survival rate was 89.2%, while the cumulative recurrence rate was 1.3% over a median follow-up ranging from 15.3 to 120.0 months. The pure subependymoma histopathological subtype was most prevalent (85.6%), followed by the mixed subependymoma-ependymoma tumor variant (13.7%). CONCLUSIONS: Surgical extirpation without postoperative radiotherapy results in excellent postoperative survival and functional outcomes in the treatment of intracranial subependymomas. Aggressive tumor behavior should prompt histological reevaluation for a mixed subependymoma-ependymoma subtype. Further high-quality controlled trials are still required to investigate this rare tumor.

Rate and Predictors of Failure in the Conservative Management of Stable Thoracolumbar Burst Fractures: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review. OBJECTIVES: Management of stable traumatic thoracolumbar burst fractures in neurologically-intact patients remains controversial. Conservative management fails in a subset of patients who require subsequent surgical fixation. The aim of this review is to (1) determine the rate of conservative management failure, and (2) analyze predictive factors at admission influencing conservative management failure. METHODS: A systematic review adhering to PRISMA guidelines was performed. Studies with data pertaining to traumatic thoracolumbar burst fractures without posterior osteoligamentous injury (e.g. AO Type A3/A4) and/or the rate and predictive factors of conservative management failure were included. Risk of bias appraisal was performed. Pooled analysis of rates of failure was performed with qualitative analysis of predictors of conservative management failure. RESULTS: 16 articles were included in this review (11 pertaining to rate of conservative management failure, 5 pertaining to predictive risk factors). Rate of failure of conservative management from a pooled analysis of 601 patients is 9.2% (95% CI: 4.5%-13.9%). Admission factors predictive of conservative management failure include age, greater initial kyphotic angle, greater initial interpedicular distance, smaller initial residual canal size, greater Load Sharing Classification (LSC) score and greater admission Visual Analog Scale (VAS) pain scores. CONCLUSION: A proportion (9.2%) of conservatively managed, neurologically-intact thoracolumbar burst fractures fail conservative management. Among other factors, age, kyphotic angle, residual canal area and interpedicular distance should be investigated in prospective studies to identify the subset of patients prone to failure of conservative management. Surgical management should be carefully considered in patients with the above risk factors.

Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer.

The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on immune cells and is highly upregulated in a number of human cancers where it can play a trophic role in tumorigenesis. Activation of this receptor leads to the formation of a non-selective cation channel, which has been associated with several cellular functions mediated by the PI3K/Akt pathway and protein kinases. Due to its broad range of functions, the receptor represents a potential therapeutic target for a number of cancers. This review describes the range of mechanisms associated with P2X7R activation in cancer settings and highlights the potential of targeted inhibition of P2X7R as a therapy. It also describes in detail a number of key P2X7R antagonists currently in pre-clinical and clinical development, including oxidised ATP, Brilliant Blue G (BBG), KN-62, KN-04, A740003, A438079, GSK1482160, CE-224535, JNJ-54175446, JNJ-55308942, and AZ10606120. Lastly, it summarises the in vivo studies and clinical trials associated with the use and development of these P2X7R antagonists in different disease contexts.

The Effects of Surgery and Adjuvant Therapy on Survival Outcomes in Clear Cell Ependymomas: A Systematic Review and Meta-Analysis of Individual Patient Data.

BACKGROUND: The survival outcomes of clear cell ependymomas are poorly understood. This study clarifies the role of surgery and adjuvant therapy when this morphologically distinct tumor is encountered. METHODS: A systematic search for studies relating to clear cell ependymomas was conducted. Primary outcomes were progression-free survival and overall survival. Prognostic variables were age, sex, tumor consistency, extent of resection, and postoperative adjuvant therapy. Kaplan-Meier survival curves were generated and compared by the log-rank test. Multivariate Cox regression models were constructed, interrogated with Schoenfeld residuals, and used to identify independent prognostic factors. RESULTS: Of the 384 articles retrieved, 8 articles comprising 77 cases of clear cell ependymoma were included. Five-year overall survival and progression-free survival were 58.1% (95% confidence interval [CI], 46.3%-72.9%) and 46.3% (95% CI, 34.2%-62.8%), respectively. Kaplan-Meier analysis with the log-rank test showed that gross total resection was superior to subtotal resection in prolonging survival (P = 0.047) and delayed time to recurrence (P < 0.01). Multivariate analysis confirmed gross total resection as an independent protective factor against relapse (odds ratio, 0.39; 95% CI, 0.17-0.89; P = 0.03). Age <50 years predicted longer overall survival (odds ratio, 0.16; 95% CI, 0.05-0.49; P < 0.01). Postoperative adjuvant therapy after gross total resection did not affect overall survival (P = 0.98) or progression-free survival (P = 0.93). Adjuvant therapy after subtotal resection favored improved overall survival (P = 0.052). CONCLUSIONS: Clear cell ependymomas are particularly aggressive in those aged >50 years. Gross total resection remains the cornerstone of management. Postoperative adjuvant therapy is likely to be of survival benefit only after subtotal resection.

Spinal Surgery in Patients Aged 80 Years and Older: Risk Stratification Using the Modified Frailty Index.

STUDY DESIGN: This was an ambispective clinical quality registry study. OBJECTIVE: To evaluate utility of 11-variable modified Frailty Index (mFI) in predicting postoperative outcomes among patients ≥80 years undergoing spinal surgery. METHODS: Consecutive patients ≥80 years who underwent spinal surgery between January 1, 2013, and June 30, 2018, were included. Primary outcome measure was rate of major complication. Secondary outcome measures were (1) overall complication rate, (2) surgical site infection, and (3) 6-month mortality. RESULTS: A total of 121 operations were performed. Demographic metrics were (1) age (mean ± SD) = 83.1 ± 2.8 years and (2) mFI (mean ± SD) = 2.1 ± 1.4 variables. As mFI increased from 0 to ≥4 variables, risk of major complication increased from 18.2% to 40.0% (P = .014); overall complication increased from 45.5% to 70.0% (P = .032); surgical site infection increased from 0.0% to 25.0% (P = .007). There were no significant changes in risk of 6-month mortality across mFIs (P = .115). Multivariate analysis showed that a higher mFI score of ≥3 variables was associated with a significantly higher risk of (1) major complication (P = .025); (2) overall complication (P = .015); (3) surgical site infection (P = .007); and (4) mortality (P = .044). CONCLUSIONS: mFI scores of ≥3/11 variables were associated with a higher risk of postoperative morbidity in patients aged ≥80 years undergoing spinal surgery. The mFI-associated risk stratification provides a valuable adjunct in surgical decision making for this rapidly growing subpopulation of patients.

Escalating Mean Arterial Pressure in Severe Traumatic Brain Injury: A Prospective, Observational Study.

To investigate cerebral autoregulatory status in patients with severe traumatic brain injury (TBI), guidelines now suggest active manipulation of mean arterial pressure (MAP). There is a paucity of data, however, describing the effect on intracranial pressure (ICP) when MAP is raised. Consecutive patients with TBI requiring ICP monitoring were enrolled from November 2019 to April 2020. The MAP and ICP were recorded continuously, and clinical annotations were made whenever intravenous vasopressors were commenced or adjusted to defend cerebral perfusion pressure (CPP) targets. A significant change in MAP burden was defined as MAP >100min.mm Hg over 15 min. The primary outcome was the change in ICP burden over the same 15-min period. Bedside and clinical parameters were then compared between these groups. Twenty-eight patients were enrolled, providing 212 clinical events, of which 60 were deemed significant. Over the first 15 min, 65% were associated with a net negative ICP burden. A greater reduction in ICP burden was observed with events occurring in patients without a history of hypotension at scene (p = 0.016), after three days post-injury (p = 0.0018), and where the pressure-reactivity index (PRx) was <0.25 (p = 0.0005) or the ICP amplitude to CPP correlation coefficient (RAC) was <-0.10 (p = 0.0036) at the initiation of vasopressor changes. The ICP burden in the first 15 min was highly correlated with the next 15-min period. In patients with severe TBI requiring ICP monitoring, increasing MAP to pursue a CPP target was followed by a net negative ICP burden in approximately two-thirds of events. These data suggest a MAP challenge may be a useful adjunct in managing intracranial hypertension.

Blood Biomarkers of Glioma in Response Assessment Including Pseudoprogression and Other Treatment Effects: A Systematic Review.

Imaging-based monitoring of disease burden in glioma patients is frequently confounded by treatment effects. Circulating biomarkers could theoretically augment imaging-based response monitoring. This systematic review aimed to present and evaluate evidence for differential expression and diagnostic accuracy of circulating biomarkers with respect to outcomes of tumor response, progression, stable disease, and treatment effects (pseudoprogression, radionecrosis, pseudoresponse, and pseudolesions) in patients undergoing treatment for World Health Organization grades II-IV diffuse astrocytic and oligodendroglial tumors. MEDLINE, EMBASE, Web Of Science, and SCOPUS databases were searched until August 18, 2019, for observational or diagnostic studies on multiple circulating biomarker types: extracellular vesicles, circulating nucleic acids, circulating tumor cells, circulating proteins, and metabolites, angiogenesis related cells, immune cells, and other cell lines. Methodological quality of included studies was assessed using an adapted Quality Assessment of Diagnostic Accuracy Studies-2 tool, and level of evidence (IA-IVD) for individual biomarkers was evaluated using an adapted framework from the National Comprehensive Cancer Network guidelines on evaluating tumor marker utility. Of 13,202 unique records, 58 studies met the inclusion criteria. One hundred thirty-three distinct biomarkers were identified in a total of 1,853 patients across various treatment modalities. Fifteen markers for response, progression, or stable disease and five markers for pseudoprogression or radionecrosis reached level IB. No biomarkers reached level IA. Only five studies contained data for diagnostic accuracy measures. Overall methodological quality of included studies was low. While extensive data on biomarker dysregulation in varying response categories were reported, no biomarkers ready for clinical application were identified. Further assay refinement and evaluation in larger cohorts with diagnostic accuracy study designs are required. PROSPERO Registration: CRD42018110658.

The Utility of the Modified Frailty Index in Outcome Prediction for Elderly Patients with Acute Traumatic Subdural Hematoma.

This study aimed to evaluate the utility of the 11-variable modified Frailty Index (mFI) in prognosticating elderly patients with traumatic acute subdural hematomas (aSDHs). A state-service level 1 trauma center registry was interrogated to investigate consecutive patients ≥65 years of age presenting with traumatic aSDH, with or without major extracranial injury, between January 2013 and December 2017. mFI on admission, demographics, and admission details, including Glasgow Coma Scale (GCS) and pupillary status and radiological findings, were retrospectively retrieved from institutional records. Clinical outcome data were retrieved from medical records and the Victorian State Trauma Registry (VSTR). Outcome measures were 1) 30-day mortality and 2) 6-month unfavorable outcome, defined by the Extended Glasgow Outcome Scale (GOS-E). Five hundred twenty-nine consecutive cases were identified from the registry. Demographic data included: 1) age (median; interquartile range) = 80.46; 74.17-85.89; 2) mFI (mean ± standard deviation) = 1.96 ± 1.42 of 11 variables. Four hundred sixteen cases (79%) had complete outcome data. As mFI increased from 0/11 variables to ≥5/11 variables (≥0.45), 30-day mortality risk increased from 17.72% to 39.29% (p = 0.023) and 6-month unfavorable outcome risk increased from 40.51% to 96.43% (p < 0.001). Multi-variate analysis showed that greater mFI score of ≥3/11 variables (≥0.27) suggested a significantly higher risk of 30-day mortality (p = 0.009) and unfavorable outcome (p < 0.001). We conclude that increasing frailty, as measured by the mFI, was associated with significantly higher risk of 30-day mortality and 6-month unfavorable outcome in elderly patients presenting with aSDH to a level 1 neurotrauma center. Assessment of mFI in elderly patients with aSDH may be a useful determinant of outcome for this rapidly growing population.

Cyanoacrylate Dermal Closure in Spine Surgery: Systematic Review and Pooled Analysis.

STUDY DESIGN: Systematic review. OBJECTIVES: Cyanoacrylate glue closure has been utilized for dermal closure in surgical incisions. Its safety and efficacy in spine surgery are not established. The authors perform a systematic review to determine the rate of surgical site infection (SSI), wound dehiscence, and wound erythema with cyanoacrylate dermal closure in spine surgery. METHODS: A systematic review adhering to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was performed utilizing the PubMed/MEDLINE, EMBASE, and Cochrane databases on patients undergoing spine surgery with cyanoacrylate dermal closure. Pooled analysis was performed with stratification of patients according to spinal level and the presence/absence of instrumentation. Risk-of-bias and methodological quality was appraised using 17 prespecified criteria. RESULTS: Five articles (1 retrospective cohort study, 4 cases series) with a total of 1282 patients were included. A total of 967 patients, all diagnosed with degenerative spine disease, were suitable for pooled analysis. In 290 patients who underwent anterior cervical discectomy and fusion, and in 23 patients with posterior cervical decompression (without instrumentation), there was 0% rate of SSI, wound dehiscence, and erythema. In 489 patients who underwent lumbar microdiscectomy, there was 0.41% rate of SSI, 0.20% rate of wound dehiscence, and 0.20% rate of wound erythema. In 165 lumbar laminectomy patients, there was a 1.82% rate of SSI, 0.61% rate of wound dehiscence, and 0% rate of wound erythema. CONCLUSION: Cyanoacrylate dermal closure for the aforementioned procedures is associated with low rates of wound complications (SSI, dehiscence, and erythema). Further studies should be performed, especially in nondegenerative surgery, instrumented thoracic and lumbar spine surgery.