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 epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol.

The Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy (EpiBioS4Rx) is a longitudinal prospective observational study funded by the National Institute of Health (NIH) to discover and validate observational biomarkers of epileptogenesis after traumatic brain injury (TBI). A multidisciplinary approach has been incorporated to investigate acute electrical, neuroanatomical, and blood biomarkers after TBI that may predict the development of post-traumatic epilepsy (PTE). We plan to enroll 300 moderate-severe TBI patients with a frontal and/or temporal lobe hemorrhagic contusion. Acute evaluation with blood, imaging and electroencephalographic monitoring will be performed and then patients will be tracked for 2 years to determine the incidence of PTE. Validation of selected biomarkers that are discovered in planned animal models will be a principal feature of this work. Specific hypotheses regarding the discovery of biomarkers have been set forth in this study. An international cohort of 13 centers spanning 2 continents will be developed to facilitate this study, and for future interventional studies.

Endoscopic neuroendoscopy using a novel ventricular access port.

BACKGROUND: Hydrocephalus remains an important aspect of neurosurgical care and in select circumstances, the endoscopic third ventriculostomy (ETV) continues to remain an important treatment. In our initial experience of ETV using the commercially available plastic ventricular ports we found them both restrictive and expensive. Following this experience, we developed a stainless steel ventricular access port (VAP). We present our novel method of access involving this non-disposable ventricular port. METHOD: We have developed a series of custom-made, 316-grade stainless steel VAPs designed specifically for our ventricular endoscopes. Following a standard Burr-hole, cannulation of the lateral ventricle is performed inserting this port and removing the trocar allowing free access using a standard ventriculoscope without the requirement for disposable plastic ports. Since 2008 our unit has used a standard method of ventricular access using this device. We present our long-term experience of cases of endoscopic ventriculoscopy and ventriculostomy using this method of ventricular access. RESULTS: From December 2008 to January 2016, 56 patients underwent an endoscopic third ventriculostomy using the stainless steel ventricular port. Two 2 patients (3.6%) had a recorded complication in the form of minor self-limiting intraventricular haemorrhage. No cases of infection or mortality were noted in this patient series. CONCLUSION: We demonstrate our long-term experience with a non-disposable VAP for ventricular access. This method remains safe with results that are comparable to published series. We suggest this method may be a less expensive and safe alternative to standard disposable methods of ventricular access.

Enhanced immunosuppression by therapy-exposed glioblastoma multiforme tumor cells.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an extremely short time to relapse following standard treatment. Since recurrent GBM is often resistant to subsequent radiotherapy and chemotherapy, immunotherapy has been proposed as an alternative treatment option. Although it is well established that GBM induces immune suppression, it is currently unclear what impact prior conventional therapy has on the ability of GBM cells to modulate the immune environment. In this study, we investigated the interaction between immune cells and glioma cells that had been exposed to chemotherapy or irradiation in vitro. We demonstrate that treated glioma cells are more immunosuppressive than untreated cells and form tumors at a faster rate in vivo in an animal model. Cultured supernatant from in vitro-treated primary human GBM cells were also shown to increase suppression, which was independent of accessory suppressor cells or T regulatory cell generation, and could act directly on CD4(+) and CD8(+) T cell proliferation. While a number of key immunosuppressive cytokines were overexpressed in the treated cells, including IL-10, IL-6 and GM-CSF, suppression could be alleviated in a number of treated GBM lines by inhibition of prostaglandin E2. These results reveal for the first time that conventional therapies can alter immunosuppressive pathways in GBM tumor cells, a finding with important implications for the combination of immunotherapy with standard treatment.

Dendritic cell vaccination combined with temozolomide retreatment: results of a phase I trial in patients with recurrent glioblastoma multiforme.

There is no standard treatment for recurrent glioblastoma multiforme (GBM). Retreatment with temozolomide (TMZ) is one treatment option. We reasoned this could be more effective if combined with a vaccine that preferentially targeted TMZ-resistant cells. To test the feasibility and safety of such an approach, a phase 1 trial was conducted in which patients with GBM tumors relapsing after standard chemoradiotherapy were retreated with TMZ in combination with a vaccine consisting of monocyte-derived dendritic cells (DC) pulsed with autologous tumor cells that had previously been exposed to TMZ in vivo in the course of primary treatment. Of 14 participants, nine patients completed the initial phase of priming vaccinations and two cycles of TMZ, one proved to have radionecrosis, one rapidly progressed, and in three the yield of DC vaccine was insufficient to proceed with treatment. Other than expected toxicities related to TMZ, there were no adverse events attributable to the combined treatment. Two patients had objective radiological responses. Six month progression-free survival was 22 %, similar to retreatment with TMZ alone. Anti-tumor immune responses were assessed in peripheral blood mononuclear cells using interferon-γ ELISpot, with two patients meeting criteria for a vaccine-induced immune response, one of whom remained disease-free for nearly three years. Another patient with an anti-tumor immune response at baseline that was sustained post-vaccination experienced a 12-month period of progression-free survival. In summary, the combined treatment was safe and well-tolerated but feasibility in the recurrent setting was marginal. Evidence of immune responses in a few patients broadly correlated with better clinical outcome.

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 72 hours 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.

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.

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.

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.

Side population is not necessary or sufficient for a cancer stem cell phenotype in glioblastoma multiforme.

There is strong evidence for the existence of cancer stem cells (CSCs) in the aggressive brain tumor glioblastoma multiforme (GBM). These cells have stem-like self-renewal activity and increased tumor initiation capacity and are believed to be responsible for recurrence due to their resistance to therapy. Several techniques have been used to enrich for CSC, including growth in serum-free defined media to induce sphere formation, and isolation of a stem-like cell using exclusion of the fluorescent dye Hoechst 33342, the side population (SP). We show that sphere formation in GBM cell lines and primary GBM cells enriches for a CSC-like phenotype of increased self-renewal gene expression in vitro and increased tumor initiation in vivo. However, the SP was absent from all sphere cultures. Direct isolation of the SP from the GBM lines did not enrich for stem-like activity in vitro, and tumor-initiating activity was lower in sorted SP compared with non-SP and parental cells. Transient exposure to doxorubicin enhanced both CSC and SP frequency. However, doxorubicin treatment altered the cytometric profile and obscured the SP demonstrating the difficulty of identifying SP in cells under stress. Doxorubicin-exposed cells showed a transient increase in SP, but the doxorubicin-SP cells were still not enriched for a stem-like self-renewal phenotype. These data demonstrate that the GBM SP does not necessarily contribute to self-renewal or tumor initiation, key properties of a CSC, and we advise against using SP to enumerate or isolate CSC.

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.

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.

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.

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.

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.

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.

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.