Long-term outcomes after surgery for subaxial cervical spine injuries in octogenarians, a matched population-based cohort study.

PURPOSE: We aimed to investigate surgical outcomes in octogenarians with subaxial cervical spine injuries and determine the predictors of complications and mortality. METHODS: Eligible for inclusion were all patients surgically treated between 2006 and 2018, with either anterior or posterior fixation for subaxial spine injuries. A cohort of octogenarians was identified and matched 1:1 to a corresponding cohort of younger adults. Primary outcomes were perioperative complications and mortality. RESULTS: Fifty-four patients were included in each of the octogenarian and younger groups (median age: 84.0 vs. 38.5). While the risks for surgical complications, including dural tears and wound infections, were similar between groups, the risks of postoperative medical complications, including respiratory or urinary tract infections, were significantly higher among the elderly (p < 0.05). Additionally, there were no differences in operative time (p = 0.625) or estimated blood loss (p = 0.403) between groups. The 30 and 90-day mortality rates were significantly higher among the elderly (p = 0.004 and p < 0.001). These differences were due to comorbidities in the octogenarian cohort as they were revoked when propensity score matching was performed to account for the differences in American Society of Anesthesiology (ASA) grade. Multivariable logistic regression revealed age and ASA score to be independent predictors of complications and the 90-day mortality, respectively. CONCLUSIONS: Octogenarians with comorbidities were more susceptible to postoperative complications, explaining the increased short-term mortality in this group. However, octogenarians without comorbidities had similar outcomes compared to the younger patients, indicating that overall health, including comorbidities, rather than chronological age should be considered in surgical decision-making.

Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.

We recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment. To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680). The validation of novel biomarkers of susceptibility to therapy is critical to elucidate the efficacy signal of therapeutic agents. This is especially important in the context of glioblastoma, where therapeutic benefit is variable and unpredictable, leading to negative trials, yet the outcome of subset of patients has outperformed expectations.

General Versus Nongeneral Anesthesia for Carotid Endarterectomy: A Prospective Multicenter Registry-Based Study on 25 000 Patients.

BACKGROUND AND OBJECTIVES: Carotid endarterectomy (CEA) is a well-established treatment option for carotid stenosis. The choice between general anesthesia (GA) and nongeneral anesthesia (non-GA) during CEA remains a subject of debate, with concerns regarding perioperative complications, particularly myocardial infarctions. This study aimed to evaluate the outcomes associated with GA vs non-GA CEA using a large, nationwide database. METHODS: The National Surgical Quality Improvement Project database was queried for patients undergoing CEA between 2013 and 2020. Primary outcome measures including surgical outcomes and 30-day postoperative complications were compared between the 2 anesthesia methods, after 2:1 propensity score matching. RESULTS: After propensity score matching, a total of 25 356 patients (16 904 in the GA and 8452 in the non-GA group) were included. Non-GA compared with GA CEA was associated with significantly shorter operative times (101.9, 95% CI: 100.5-103.3 vs 115.8 95% CI: 114.4-117.2 minutes, P < .001), reduced length of hospital stays (2.3, 95% CI: 2.15-2.4 vs 2.5, 95% CI: 2.4-2.6 days, P < .001), and lower rates of 30-day postoperative complications, including myocardial infarctions (0.8% vs 1.2%, P = .003), unplanned intubations (0.8% vs 1.1%, P = .016), pneumonia (0.5% vs 1%, P < .001), and urinary tract infections (0.4% vs 0.7%, P = .003). These outcomes were notably more pronounced in the younger (≤70 years) and high morbidity (American Society of Anesthesiologists 3-5) cohorts. CONCLUSION: In this nationwide registry-based study, non-GA CEA was associated with better short-term outcomes in terms of perioperative complications, compared with GA CEA. The findings suggest that non-GA CEA may be a safer alternative, especially in younger patients and those with more comorbidities.

Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma.

PURPOSE: We recently reported on clinical trials for patients with recurrent glioblastoma where low-intensity pulsed ultrasound and microbubbles (LIPU/MB) improved paclitaxel or carboplatin delivery into the brain. Here, we report variable local tumor control with paclitaxel at the maximal/target dose in our phase I trial (NCT04528680). To address this, we investigated the combination of paclitaxel with carboplatin in preclinical glioma models. EXPERIMENTAL DESIGN: We performed MRI-based analysis to evaluate disease control in patients from our trial. We studied the cytotoxicity of paclitaxel and carboplatin against 11 human glioma lines as monotherapy and in combination at concentrations derived from human intraoperative studies. Synergy was assessed with the Loewe model and the survival benefit evaluated in two xenografts. We examined the effects on cell cycle progression, DNA damage, and apoptosis. RESULTS: Patients treated with paclitaxel and LIPU/MB exhibited variable local tumor control, which correlated with overall survival. We observed limited cross-resistance to paclitaxel and carboplatin in glioma lines, with almost a third of them being exclusively susceptible to one drug. This combination led to susceptibility of 81% of lines and synergy in 55% of them. The combination proved more efficacious in two intracranial xenografts when administered with LIPU/MB, leading to complementary effects on cell cycle arrest. CONCLUSIONS: Combining paclitaxel and carboplatin in gliomas may be more efficacious than monotherapy, as in other cancers, due to synergy and independent susceptibility to each drug. These results form the basis for an ongoing phase II trial (NCT04528680) where we investigate this combination with LIPU/MB.

ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-guided Analysis.

PURPOSE: Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in patients with recurrent glioblastoma receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts. EXPERIMENTAL DESIGN: In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and OS. Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Biweekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REporting recommendations for tumor MARKER prognostic studies (REMARK) criteria, we conducted independent analyses for p-ERK quantification and statistical evaluations. Additional comparative analysis included prior cohorts, totaling 65 patients. Cox proportional hazards models and meta-analysis were employed to assess p-ERK as a predictive biomarker after immunotherapy. RESULTS: Lower median p-ERK+ cell density was observed compared with prior studies, likely due to variable tissue processing across cohorts. Nonetheless, high p-ERK was associated with prolonged OS, particularly in isocitrate dehydrogenase wild-type glioblastomas (P = 0.036). Median OS for high and low p-ERK patients were 55.6 and 30 weeks, respectively. Multivariable analysis reinforced p-ERK's significance in survival prediction (P = 0.011). Upon p-ERK normalization across cohorts (n = 65), meta-analysis supported the survival benefit of elevated tumor p-ERK levels (P = 0.0424). CONCLUSIONS: This study strengthens the role of p-ERK as a predictive biomarker for OS in patients with glioblastoma on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.

Vγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. The innate and adaptive immune responses play an important role in the pathogenesis of TBI. Gamma-delta (γδ) T cells have been shown to affect brain immunopathology in multiple different conditions, however, their role in acute and chronic TBI is largely unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year following injury in a mouse model. TCRδ-/- mice are characterized by reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We find that the Vγ1 and Vγ4 γδ T cell subsets play opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation. Vγ1 γδ T cells, however, secrete TGF-ß that maintains microglial homeostasis and dampens TBI upon infiltrating the brain. These findings provide new insights on the role of different γδ T cell subsets after brain injury and lay down the principles for the development of targeted γδ T-cell-based therapy for TBI.

Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade.

Whereas the contribution of tumor microenvironment to the profound immune suppression of glioblastoma (GBM) is clear, tumor-cell intrinsic mechanisms that regulate resistance to CD8 T cell mediated killing are less understood. Kinases are potentially druggable targets that drive tumor progression and might influence immune response. Here, we perform an in vivo CRISPR screen to identify glioma intrinsic kinases that contribute to evasion of tumor cells from CD8 T cell recognition. The screen reveals checkpoint kinase 2 (Chek2) to be the most important kinase contributing to escape from CD8 T-cell recognition. Genetic depletion or pharmacological inhibition of Chek2 with blood-brain-barrier permeable drugs that are currently being evaluated in clinical trials, in combination with PD-1 or PD-L1 blockade, lead to survival benefit in multiple preclinical glioma models. Mechanistically, loss of Chek2 enhances antigen presentation, STING pathway activation and PD-L1 expression in mouse gliomas. Analysis of human GBMs demonstrates that Chek2 expression is inversely associated with antigen presentation and T-cell activation. Collectively, these results support Chek2 as a promising target for enhancement of response to immune checkpoint blockade therapy in GBM.

Appraising the Quality of Development and Reporting in Surgical Prediction Models.

This cross-sectional study uses the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis reporting guideline to assess 120 published studies about surgical prediction models.

Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them.

Glioblastoma is the most common and aggressive primary malignant brain tumour. The prognosis of patients with glioblastoma is poor, and their overall survival averages at 1 year, despite advances made in cancer therapy. The emergence of immunotherapy, a strategy that targets the natural mechanisms of immune evasion by cancerous cells, has revolutionised the treatment of melanoma, lung cancer and other solid tumours; however, immunotherapy failed to improve the prognosis of patients with glioblastoma. This is attributed to the fact that glioblastoma is endowed with numerous mechanisms of resistance that include the intrinsic resistance, which refers to the location of the tumour within the brain and the nature of the blood-brain barrier, as well as the adaptive and acquired resistance that result from the tumour heterogeneity and its immunosuppressive microenvironment. Glioblastoma is notorious for its inter and intratumoral heterogeneity, which, coupled with its spatial and temporal evolution, limits its immunogenicity. In addition, the tumour microenvironment is enriched with immunosuppressive cells and molecules that hinder the reactivity of cytotoxic immune cells and the success of immunotherapies. In this article, we review the mechanisms of resistance of glioblastoma to immunotherapy and discuss treatment strategies to overcome them worthy of further exploration.

Western and ketogenic diets in neurological disorders: can you tell the difference?

The prevalence of obesity tripled worldwide between 1975 and 2016, and it is projected that half of the US population will be overweight by 2030. The obesity pandemic is attributed, in part, to the increasing consumption of the high-fat, high-carbohydrate Western diet, which predisposes to the development of the metabolic syndrome and correlates with decreased cognitive performance. In contrast, the high-fat, low-carbohydrate ketogenic diet has potential therapeutic roles and has been used to manage intractable seizures since the early 1920s. The brain accounts for 25% of total body glucose metabolism and, as a result, is especially susceptible to changes in the types of nutrients consumed. Here, we discuss the principles of brain metabolism with a focus on the distinct effects of the Western and ketogenic diets on the progression of neurological diseases such as epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury, highlighting the need to further explore the potential therapeutic effects of the ketogenic diet and the importance of standardizing dietary formulations to assure the reproducibility of clinical trials.

Mechanical Thrombectomy in Patients Presenting with NIHSS Score <6: A Safety and Efficacy Analysis.

BACKGROUND AND OBJECTIVES: Groundbreaking trials have shown the tremendous efficacy of mechanical thrombectomy for large vessel occlusions. Currently, mechanical thrombectomy is limited to patients with NIHSS scores ≥6. We investigated the feasibility and safety of MT in patients presenting with NIHSS scores <6. MATERIALS AND METHODS: A retrospective review of patient who presented with acute ischemic stroke due to large vessel occlusion with an NIHSS score <6 between 2015 - 2021. The patients were then divided into two groups: those who received mechanical thrombectomy and those who did not. RESULTS: Among 83 patients, 41 received a mechanical thrombectomy while 42 received medical treatment only. The mean age in the mechanical thrombectomy group was 66 years versus 60 years in the medical group (p = 0.06). Risk factors for stroke did not differ significantly between both groups. 14 patients (34.1%) in the mechanical thrombectomy group and 20 (47.6%) in the medical group received tissue plasminogen activator. No significant difference in clinical improvement (NIHSS) at discharge (p=0.85) or the mRS score at 90 days (p = 0.15) was noted. Mechanical thrombectomy was associated with smaller infarct size (p=0.04) and decreased mortality (p=0.03). CONCLUSIONS: Mechanical thrombectomy is safe and effective for patients who present with large vessel occlusions and low initial NIHSS scores. Therefore, the decision to offer the patient mechanical thrombectomy or not should not be decided by NIHSS score alone. Rather, the decision should be multifactorial with the aim of maximizing the patients' outcomes.

SARS-CoV-2 involvement in central nervous system tissue damage.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, it became evident that the SARS-CoV-2 virus infects multiple organs including the brain. Several clinical studies revealed that patients with COVID-19 infection experience an array of neurological signs ranging in severity from headaches to life-threatening strokes. Although the exact mechanism by which the SARS-CoV-2 virus directly impacts the brain is not fully understood, several theories have been suggested including direct and indirect pathways induced by the virus. One possible theory is the invasion of SARS-CoV-2 to the brain occurs either through the bloodstream or via the nerve endings which is considered to be the direct route. Such findings are based on studies reporting the presence of viral material in the cerebrospinal fluid and brain cells. Nevertheless, the indirect mechanisms, including blood-clotting abnormalities and prolonged activation of the immune system, can result in further tissue and organ damages seen during the course of the disease. This overview attempts to give a thorough insight into SARS-CoV-2 coronavirus neurological infection and highlights the possible mechanisms leading to the neurological manifestations observed in infected patients.

Drug Repurposing in Neurological Disorders: Implications for Neurotherapy in Traumatic Brain Injury.

Traumatic brain injury (TBI) remains a significant leading cause of death and disability among adults and children globally. To date, there are no Food and Drug Administration-approved drugs that can substantially attenuate the sequelae of TBI. The innumerable challenges faced by the conventional de novo discovery of new pharmacological agents led to the emergence of alternative paradigm, which is drug repurposing. Repurposing of existing drugs with well-characterized mechanisms of action and human safety profiles is believed to be a promising strategy for novel drug use. Compared to the conventional discovery pathways, drug repurposing is less costly, relatively rapid, and poses minimal risk of the adverse outcomes to study on participants. In recent years, drug repurposing has covered a wide range of neurodegenerative diseases and neurological disorders including brain injury. This review highlights the advances in drug repurposing and presents some of the promising candidate drugs for potential TBI treatment along with their possible mechanisms of neuroprotection. Edaravone, glyburide, ceftriaxone, levetiracetam, and progesterone have been selected due to their potential role as putative TBI neurotherapeutic agents. These drugs are Food and Drug Administration-approved for purposes other than brain injuries; however, preclinical and clinical studies have shown their efficacy in ameliorating the various detrimental outcomes of TBI.

Drug Repurposing: Promises of Edaravone Target Drug in Traumatic Brain Injury.

Edaravone is a potent free-radical scavenger that has been in the market for more than 30 years. It was originally developed in Japan to treat strokes and has been used there since 2001. Aside from its anti-oxidative effects, edaravone demonstrated beneficial effects on proinflammatory responses, nitric oxide production, and apoptotic cell death. Interestingly, edaravone has shown neuroprotective effects in several animal models of diseases other than stroke. In particular, edaravone administration was found to be effective in halting amyotrophic lateral sclerosis (ALS) progression during the early stages. Accordingly, after its success in Phase III clinical studies, edaravone has been approved by the FDA as a treatment for ALS patients. Considering its promises in neurological disorders and its safety in patients, edaravone is a drug of interest that can be repurposed for traumatic brain injury (TBI) treatment. Drug repurposing is a novel approach in drug development that identifies drugs for purposes other than their original indication. This review presents the biochemical properties of edaravone along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.

Frontal Sinus Morphometry in Relation to Surgically Relevant Landmarks in the Middle East Population: Can We Globalize?

BACKGROUND: The frontal bone is frequently approached during neurosurgical procedures. Feared complications of such surgeries include cerebrospinal fluid leak, among others, and frequently result from a breach of the frontal sinus. For this reason, the sinus should be avoided when possible. The supraorbital notch (SON) is a reliable and easily identifiable surgical landmark and its relation to the frontal sinus has been previously studied. However, the frontal sinus shows significant variability in size and shape between populations. METHODS: In the present study, we investigate the frontal sinus dimension and its relation to the SON in the Middle Eastern population. RESULTS: The analysis of a set of computed tomography scans reveals a significant variation in size between genders, and we subsequently provide neurosurgeons in the region with population-targeted, gender-specific risk maps. CONCLUSIONS: We finally conclude that a 2-cm margin rostral and lateral to the SON is safest.

Western diet aggravates neuronal insult in post-traumatic brain injury: Proposed pathways for interplay.

Traumatic brain injury (TBI) is a global health burden and a major cause of disability and mortality. An early cascade of physical and structural damaging events starts immediately post-TBI. This primary injury event initiates a series of neuropathological molecular and biochemical secondary injury sequelae, that last much longer and involve disruption of cerebral metabolism, mitochondrial dysfunction, oxidative stress, neuroinflammation, and can lead to neuronal damage and death. Coupled to these events, recent studies have shown that lifestyle factors, including diet, constitute additional risk affecting TBI consequences and neuropathophysiological outcomes. There exists molecular cross-talk among the pathways involved in neuronal survival, neuroinflammation, and behavioral outcomes, that are shared among western diet (WD) intake and TBI pathophysiology. As such, poor dietary intake would be expected to exacerbate the secondary damage in TBI. Hence, the aim of this review is to discuss the pathophysiological consequences of WD that can lead to the exacerbation of TBI outcomes. We dissect the role of mitochondrial dysfunction, oxidative stress, neuroinflammation, and neuronal injury in this context. We show that currently available data conclude that intake of a diet saturated in fats, pre- or post-TBI, aggravates TBI, precludes recovery from brain trauma, and reduces the response to treatment.

Histological Assessment of Cre-loxP Genetic Recombination in the Aging Subventricular Zone of Nestin-CreERT2/Rosa26YFP Mice.

The use of inducible transgenic Nestin-CreERT2 mice has proved to be an essential research tool for gene targeting and studying the molecular pathways implicated in adult neurogenesis, namely, inside the adult subgranular zone (SGZ) of the dentate gyrus and the adult subventricular zone (SVZ) lining the lateral ventricles. Several lines of Nestin-CreER-expressing mice were generated and used in adult neurogenesis research in the past two decades; however, their suitability for studying neurogenesis in aged mice remains elusive. Here, we assessed the efficiency of Cre-loxP genetic recombination in the aging SVZ using the Nestin-CreERT2/Rosa26YFP line designed by Lagace et al. (J Neurosci 27(46):12623-12629, 2007). This analysis was performed in 12-month-old (middle-aged) mice and 20-month-old (old) mice compared to 2-month-old (young adult) mice. To evaluate successful recombination, our approach relies on the histological assessment of Cre mRNA level of expression and the YFP reporter gene's expression inside the aging SVZ by combining in situ hybridization and immunohistochemistry. Using co-immunolabeling, this approach also provides the advantage of estimating the percentage of recombined progeny [(GFP+Nestin+)/Nestin+] and the rate of cell proliferation [(GFP+Ki67+)/GFP+] inside the aging SVZ niche.