The mFI-5 and Postoperative Outcomes in Brain Tumor Patients: A Bayesian Approach to Quantifying Uncertainty.

OBJECTIVE: To the best of our knowledge, prior research has not investigated the uncertainty in the relationship between patient frailty and postoperative outcomes after brain tumor surgery. The present study used Bayesian methods to quantify the statistical uncertainty between the 5-factor modified frailty index (mFI-5) and postoperative outcomes for patients undergoing brain tumor resection. METHODS: The present study used retrospective data collected from patients undergoing brain tumor resection during a 2-year period (2017-2019). Posterior probability distributions were used to estimate the means of model parameters that are most likely given the priors and the data. Additionally, 95% credible intervals (CrIs) were constructed for each parameter estimate. RESULTS: Our patient cohort included 2519 patients with a mean age of 55.27 years. Our multivariate analysis demonstrated that each 1-point increase in the mFI-5 score was associated with an 18.76% (95% CrI, 14.35%-23.36%) increase in hospital length of stay and a 9.37% (CrI, 6.82%-12.07%) increase in hospital charges. We also noted an association between an increasing mFI-5 score and greater odds of a postoperative complication (odds ratio [OR], 1.58; CrI, 1.34-1.87) and a nonroutine discharge (OR, 1.54; CrI, 1.34-1.80). However, no meaningful statistical association was found between the mFI-5 score and 90-day hospital readmission (OR, 1.16; CrI, 0.98-1.36) or between the mFI-5 score and 90-day mortality (OR, 1.12; CrI, 0.83-1.50). CONCLUSIONS: Although mFI-5 scores might be able to effectively predict short-term outcomes such as length of stay, our results demonstrate no meaningful association between mFI-5 scores and 90-day readmission or 90-day mortality. Our study highlights the need for rigorously quantifying statistical uncertainty to safely risk-stratify neurosurgical patients.

CAR T Cell Therapy in Glioblastoma: Overcoming Challenges Related to Antigen Expression.

Glioblastoma (GBM) is the most common primary brain tumor, yet prognosis remains dismal with current treatment. Immunotherapeutic strategies have had limited effectiveness to date in GBM, but recent advances hold promise. One such immunotherapeutic advance is chimeric antigen receptor (CAR) T cell therapy, where autologous T cells are extracted and engineered to express a specific receptor against a GBM antigen and are then infused back into the patient. There have been numerous preclinical studies showing promising results, and several of these CAR T cell therapies are being tested in clinical trials for GBM and other brain cancers. While results in tumors such as lymphomas and diffuse intrinsic pontine gliomas have been encouraging, early results in GBM have not shown clinical benefit. Potential reasons for this are the limited number of specific antigens in GBM, their heterogenous expression, and their loss after initiating antigen-specific therapy due to immunoediting. Here, we review the current preclinical and clinical experiences with CAR T cell therapy in GBM and potential strategies to develop more effective CAR T cells for this indication.

Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment.

BACKGROUND: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model. METHODS: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry. RESULTS: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines. CONCLUSIONS: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

Venous Stenosis and Hemorrhage After Radiosurgery for Cerebral Arteriovenous Malformations.

BACKGROUND: The risk of hemorrhage remains after radiosurgery for patients with arteriovenous malformations (AVMs), especially during the latency period. The effect of venous outflow stenosis on postradiosurgery AVM hemorrhage has been understudied. The present study sought to clarify the effect of venous stenosis on postradiation hemorrhage. METHODS: We retrospectively reviewed the records of patients with AVM seen at our institution from 1990 to 2015. Patients who had undergone radiosurgery were included, and those without sufficient data were excluded. We performed multivariable Cox regression to evaluate the predictors of postradiosurgery hemorrhage, with specific emphasis on venous stenosis. Patients were censored from the first radiosurgery to hemorrhage or the last follow-up visit. The baseline and angiographic characteristics were compared between those with venous stenosis and those without to address potential confounders. RESULTS: The present study included 240 patients, of whom 29 (12.1%) had venous stenosis. The venous stenosis cohort included more patients with venous varices (P = 0.009) and fewer with deep venous drainage (P = 0.048) compared with those without venous stenosis. Most patients had grade III or higher AVMs (63.2%), with an obliteration rate of 32.9%. In an all-inclusive multivariable Cox regression, hemorrhage risk was associated with venous stenosis (hazard ratio [HR], 3.70; P = 0.034), age (HR, 1.05; P = 0.002), AVM volume (HR, 1.04; P = 0.004), and hemorrhage before treatment (HR, 4.11; P = 0.014). Male gender was protective (HR, 0.31; P = 0.036) against hemorrhage. CONCLUSIONS: We identified statistically significant risk factors for postradiosurgery AVM hemorrhage, which included advanced age, female gender, the presence of venous stenosis, a larger AVM volume, and previous hemorrhage. We recommend cautious selection of patients for radiosurgery with close follow-up after treatment, especially for patients with these risk factors.

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system.

Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM.

The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

Population-based Study Determining Predictors of Cancer-Specific Mortality and Survival in Pediatric High-grade Brainstem Glioma.

BACKGROUND: Pediatric high-grade brainstem gliomas are aggressive tumors with dismal prognoses. Large-scale studies are needed to further characterize these tumors and determine factors influencing cancer-specific mortality and survival at varying time points. METHODS: We used the SEER (Surveillance Epidemiology and End Results) database to conduct a population-based study of pediatric patients with histologically confirmed anaplastic astrocytoma or glioblastoma tumors located within the brainstem. Multivariate analyses incorporating patient demographics, tumor characteristics, and treatments were used to determine predictors of cancer-specific mortality and survival at 6 months, 9 months, 1 year, and 2 years. RESULTS: We included 154 patients from the SEER database: 72 patients with anaplastic astrocytoma (47%) and 82 (53%) with glioblastoma. Median survival for the entire cohort was 10.0 months. Glioblastoma histology, developmental stage, and large tumor size were significantly associated with cancer-specific mortality. Six-month, 9-month, 1-year, and 2-year survival was 75%, 57%, 42%, and 20%, respectively. Glioblastoma histology was associated with worsened survival at 6 months (odds ratio [OR], 0.19; P = 0.0081), 9 months (OR, 0.18; P < 0.001), 1 year (OR, 0.19; P < 0.001), and 2 years (OR, 0.14; P = 0.0055). Radiation therapy was associated with improved survival at 6 (OR, 8.53; P = 0.0012) and 9 months (OR, 3.58; P = 0.035) but not at 1 or 2 years. Radiation therapy was associated with improved survival in glioblastoma (9.0 vs. 3.0 months; P < 0.001). CONCLUSIONS: This population-based study showed that glioblastoma histology is associated with a poor prognosis in pediatric patients with high-grade brainstem gliomas. Regardless of histology, radiation therapy improved survival at 6 and 9 months but not long-term.

Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma.

INTRODUCTION: The glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. Checkpoint blockade (CB) is being evaluated for GBM patients. However, biomarker analyses suggest that CB monotherapy may be effective only in a small fraction of GBM patients. We hypothesized that activation of antigen presentation would increase the therapeutic response to PD-1 blockade. RESULTS: We show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM. Mice treated with TLR3 agonist poly(I:C) and anti-PD-1 demonstrated increased DC activation and increased T cell proliferation in tumor draining lymph nodes. We show that DCs are necessary for the improved anti-tumor immune response. CONCLUSIONS: This study suggests that augmenting antigen presentation is an effective multimodal immunotherapy strategy that intensifies anti-tumor responses in GBM. Specifically, these data represent an expanded role for TLR3 agonists as adjuvants to CB. METHODS: Using a preclinical model of GBM, we tested the efficacy of combinatorial immunotherapy with anti-PD-1 and TLR3 agonist, poly(I:C). Characterization of the immune response in tumor infiltrating immune cells and in secondary lymphoid organs was performed. Additionally, dendritic cell (DC) depletion experiments were performed.

The Potential of Cellular- and Viral-Based Immunotherapies for Malignant Glioma-Dendritic Cell Vaccines, Adoptive Cell Transfer, and Oncolytic Viruses.

PURPOSE OF REVIEW: Malignant gliomas, including glioblastoma and anaplastic astrocytoma, are the most frequent primary brain tumors and present with many treatment challenges. In this review, we discuss the potential of cellular- and viral-based immunotherapies in the treatment of malignant glioma, specifically focusing on dendritic cell vaccines, adoptive cell therapy, and oncolytic viruses. RECENT FINDINGS: Diverse cellular- and viral-based strategies have been engineered and optimized to generate either a specific or broad antitumor immune response in malignant glioma. Due to their successes in the preclinical arena, many of these therapies have undergone phase I and II clinical testing. These early clinical trials have demonstrated the feasibility, safety, and efficacy of these immunotherapies. Dendritic cell vaccines, adoptive cell transfer, and oncolytic viruses may have a potential role in the treatment of malignant glioma. However, these modalities must be investigated in well-designed phase III trials to prove their efficacy.

Assessing the Role of Preoperative Embolization in the Surgical Management of Cerebral Arteriovenous Malformations.

BACKGROUND: Preoperative embolization is established as an advantageous adjunct in multimodality treatment of cerebral arteriovenous malformations (AVMs). However, the benefit of preoperative embolization in AVMs with favorable surgical risk profile is debatable, because it has yet to be supported by evidence in comparative studies. In this study, we assessed outcome of surgically treated patients in a comparative setting. METHODS: Our institutional AVM database of retrospectively and prospectively collected data between 1990 and 2015 was reviewed. Patients with complete clinical data who underwent surgical resection for AVMs were included. We performed a 1:1 ratio propensity score match for baseline variables that differed between patients with or without preoperative embolization. Differences in surgical risk and outcomes were evaluated between these 2 groups. RESULTS: AVM size, eloquence, deep drainage, middle cerebral artery feeder, and ruptured presentation differed significantly between the 2 groups. Forty-eight patients without preoperative embolization were matched to 48 with embolization, with no significant differences in baseline variables or AVM characteristics between the 2 groups. We found no significant differences in AVM obliteration and postoperative modified Rankin Scale (mRS) score between embolized and nonembolized patients, respectively. Change in mRS score from preoperative score was also not significant, although more embolized patients had a decline in mRS score. Secondary outcome measures including duration of surgery (P = 0.172), intraoperative bleeding (P = 0.280), duration of hospitalization (P = 0.368), and postoperative symptoms were also similar between both groups. CONCLUSIONS: Our data do not support substantial benefit of preoperative embolization for patients with a favorable surgical risk profile. Because of risks and costs with this intervention, the prudent use of preoperative embolization should be individually considered.

Pediatric spinal cord astrocytomas: a retrospective study of 348 patients from the SEER database.

OBJECTIVE Intramedullary spinal cord tumors comprise 1%-10% of all childhood central nervous system neoplasms, with astrocytomas representing the most common subtype. Due to their rarity and poor prognosis, large population-based studies are needed to assess the epidemiology and survival risk factors associated with these tumors in the hope of improving outcome. The authors undertook this retrospective study to explore factors that may influence survival in pediatric patients with spinal cord astrocytomas. METHODS Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, a prospective cancer registry, the authors retrospectively assessed survival in histologically confirmed, primary spinal cord astrocytomas in patients 21 years of age and younger. Survival was described with Kaplan-Meyer curves, and a multivariate regression analysis was used to assess the association of several variables with survival while controlling for confounding variables. RESULTS This analysis of 348 cases showed that age (hazard ratio [HR] 1.05, 95% CI 1.01-1.09, p = 0.017), nonwhite race (HR 1.74, 95% CI 1.11-2.74, p = 0.014), high-grade tumor status (HR 14.67, 95% CI 6.69-32.14, p < 0.001), distant or invasive extension of the tumor (HR 2.37, 95% CI 1.02-5.49, p = 0.046), and radiation therapy (HR 3.74, 95% CI 2.18-6.41, p < 0.001) were associated with decreased survival. Partial resection (HR 0.37, 95% CI 0.16-0.83, p = 0.017) and gross-total resection (HR 0.39, 95% CI 0.16-0.95, p = 0.039) were associated with improved survival. CONCLUSIONS Younger age appears to be protective, while high-grade tumors have a much worse prognosis. Early diagnosis and access to surgery appears necessary for improving outcomes, while radiation therapy has an unclear role. There is still much to learn about this disease in the hope of curing children with the misfortune of having one of these rare tumors.

The Role of Immune Checkpoint Inhibition in the Treatment of Brain Tumors.

The standard of care for malignant gliomas of the brain has changed very little over the last few decades, and does not offer a cure for these rare, but fatal, tumors. The field of immunotherapy has brought potent new drugs into the oncological armamentarium, and is becoming recognized as a potentially important arm in the treatment of glioblastoma for adults. Immune checkpoints are inhibitory receptors found on immune cells that, when stimulated, cause those immune cells to become quiescent. While this is a natural mechanism to prevent excessive inflammatory damage and autoimmunity in otherwise healthy tissues, cancer cells may utilize this process to grow in the absence of targeted immune destruction. Antibodies derived to block the stimulation of these negative checkpoints, allowing immune cells to remain activated and undergo effector function, are a growing area of immunotherapy. These therapies have seen much success in both the preclinical and clinical arenas for various tumors, particularly melanoma and nonsmall-cell lung cancer. Multiple clinical trials are underway to determine if these drugs have efficacy in glioblastoma. Here, we review the current evidence, from early preclinical data to lessons learned from clinical trials outside of glioblastoma, to assess the potential of immune checkpoint inhibition in the treatment of brain tumors and discuss how this therapy may be implemented with the present standard of care.

Postoperative Delayed Paradoxical Depression After Uncomplicated Unruptured Intracranial Aneurysm Surgery.

BACKGROUND: Postoperative delayed paradoxical depression (PDPD) is a psychiatric condition described in patients without a history of mood disorders who undergo major surgery without complications and become clinically depressed. PDPD has been recognized in major surgical interventions, including coronary artery bypass surgery. We sought to determine the incidence and potential factors associated with PDPD after surgical treatment of unruptured intracranial aneurysms. METHODS: The cohort of 105 patients was derived from a prospective observational data set of 3788 consecutive cases of intracranial aneurysms accrued from 1991 to 2015. Starting in 2010, patients with PDPD were identified, and psychiatric treatment and outcomes were documented. Incidence of PDPD and baseline characteristics were analyzed. Multivariate logistic regression was performed to analyze associations of variables with PDPD. Patients with preoperative depression or bipolar disorder were excluded. RESULTS: Of 105 patients, 10.5% (n = 11) were found to have newly diagnosed major depressive disorder after surgical treatment of intracranial aneurysms. By univariate and multivariate analysis, the only significant difference between the 2 groups was full return to daily activities (P = 0.017 and P = 0.029, odds ratio = 0.06, 95% confidence interval [0.00, 0.70]), which was a result and not a cause of PDPD. All 11 patients with PDPD recovered fully, 9 after psychotherapy and/or pharmacotherapy and 2 without intervention. CONCLUSIONS: PDPD after uncomplicated unruptured aneurysm surgery can be surprising to the neurosurgeon and the patient and should be promptly identified and addressed to achieve a full recovery. PDPD can be interpreted as a mild variant of post-traumatic stress disorder.

Temporal context and the organisational impairment of memory search in schizophrenia.

INTRODUCTION: An influential theory of schizophrenic deficits in executive function suggests that patients have difficulty maintaining and utilising an internal contextual representation, whose function is to ensure that stimuli are processed in a task-appropriate manner. In basic research on episodic memory, retrieved-context theories propose that an internal contextual representation is critically involved in memory search, facilitating the retrieval of task-appropriate memories. This contextual machinery is thought to give rise to temporal organisation during free recall: the tendency for successive recall responses to correspond to items from nearby positions on the study list. If patients with schizophrenia have a generalised contextual deficit, then this leads to the prediction that these patients will exhibit reduced temporal organisation in free recall. METHODS: Using a combination of classic and recently developed organisational measures, we characterised recall organisation in 75 patients with schizophrenia and 72 nondisordered control participants performing a multi-trial free-recall task. RESULTS: Patients with schizophrenia showed diminished temporal organisation, as well as diminished subjective organisation of their recall sequences relative to control participants. The two groups showed similar amounts of semantic organisation during recall. CONCLUSIONS: The observation of reduced temporal organisation in the patient group is consistent with the proposal that the memory deficit in schizophrenia can be characterised as a deficit in contextual processing.

Systematic Error in Hippocampal Volume Asymmetry Measurement is Minimal with a Manual Segmentation Protocol.

Hemispheric asymmetry of hippocampal volume is a common finding that has biological relevance, including associations with dementia and cognitive performance. However, a recent study has reported the possibility of systematic error in measurements of hippocampal asymmetry by magnetic resonance volumetry. We manually traced the volumes of the anterior and posterior hippocampus in 40 healthy people to measure systematic error related to image orientation. We found a bias due to the side of the screen on which the hippocampus was viewed, such that hippocampal volume was larger when traced on the left side of the screen than when traced on the right (p = 0.05). However, this bias was smaller than the anatomical right > left asymmetry of the anterior hippocampus. We found right > left asymmetry of hippocampal volume regardless of image presentation (radiological versus neurological). We conclude that manual segmentation protocols can minimize the effect of image orientation in the study of hippocampal volume asymmetry, but our confirmation that such bias exists suggests strategies to avoid it in future studies.

Vascular endothelial growth factor is upregulated by L-dopa in the parkinsonian brain: implications for the development of dyskinesia.

Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.

Mitochondrial abnormalities in the putamen in Parkinson's disease dyskinesia.

Prolonged treatment of Parkinson's disease (PD) with levodopa leads to disabling side effects collectively referred to as 'dyskinesias'. We hypothesized that bioenergetic function in the putamen might play a crucial role in the development of dyskinesias. To test this hypothesis, we used post mortem samples of the human putamen and applied real time-PCR approaches and gene expression microarrays. We found that mitochondrial DNA (mtDNA) levels are decreased in patients who have developed dyskinesias, and mtDNA damage is concomitantly increased. These pathologies were not observed in PD subjects without signs of dyskinesias. The group of nuclear mRNA transcripts coding for the proteins of the mitochondrial electron transfer chain was decreased in patients with dyskinesias to a larger extent than in patients who had not developed dyskinesias. To examine whether dopamine fluctuations affect mtDNA levels in dopaminoceptive neurons, rat striatal neurons in culture were repeatedly exposed to levodopa, dopamine or their metabolites. MtDNA levels were reduced after treatment with dopamine, but not after treatment with dopamine metabolites. Levodopa led to an increase in mtDNA levels. We conclude that mitochondrial susceptibility in the putamen plays a role in the development of dyskinesias.