The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

Functional alterations in cortical processing of speech in glioma-infiltrated cortex.

Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma-neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity in a manner similar to normal-appearing cortex but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. Here, we use subdural electrocorticography to sample both normal-appearing and glioma-infiltrated cortex during speech. We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex but recruits a diffuse spatial network. On a temporal scale, we show that signals from glioma-infiltrated cortex have decreased entropy, which may affect its ability to encode information during nuanced tasks such as production of monosyllabic versus polysyllabic words. Furthermore, we show that temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex but not from glioma-infiltrated cortex. These findings inform our understanding of cognitive processing in chronic disease states and have implications for neuromodulation and prosthetics in patients with malignant gliomas.

Resistance to immune checkpoint blockade: Mechanisms, counter-acting approaches, and future directions.

Immunotherapies seek to unleash the immune system against cancer cells. While a variety of immunotherapies exist, one of the most commonly used is immune checkpoint blockade, which refers to the use of antibodies to interfere with immunosuppressive signaling through immune checkpoint molecules. Therapies against various checkpoints have had success in the clinic across cancer types. However, the efficacy of checkpoint inhibitors has varied across different cancer types and non-responsive patient populations have emerged. Non-responders to these therapies have highlighted the importance of understanding underlying mechanisms of resistance in order to predict which patients will respond and to tailor individual treatment paradigms. In this review we discuss the literature surrounding tumor mediated mechanisms of immune checkpoint resistance. We also describe efforts to overcome resistance and combine checkpoint inhibitors with additional immunotherapies. Finally, we provide insight into the future of immune checkpoint blockade, including the need for improved preclinical modeling and predictive biomarkers to facilitate personalized cancer treatments for patients.

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

The immunology of low-grade gliomas.

Low-grade gliomas (LGGs), which harbor an isocitrate dehydrogenase (IDH) mutation, have a better prognosis than their high-grade counterparts; nonetheless, they remain incurable and impart significant negative impacts on patients' quality of life. Although immunotherapies represent a novel avenue of treatment for patients with LGGs, they have not yet been successful. Accurately selecting and evaluating immunotherapies requires a detailed understanding of LGG tumor immunology and the underlying tumor immune phenotype. A growing body of literature suggests that LGGs significantly differ in their immunology from high-grade gliomas, highlighting the importance of investigation into LGG immunology specifically. In this review, the authors aimed to discuss relevant research surrounding the LGG tumor immune microenvironment, including immune cell infiltration, tumor immunogenicity, checkpoint molecule expression, the impact of an IDH mutation, and implications for immunotherapies, while also briefly touching on current immunotherapy trials and future directions for LGG immunology research.

Reducing complication rates for repeat craniotomies in glioma patients: a single-surgeon experience and comparison with the literature.

BACKGROUND: There is a concern that glioma patients undergoing repeat craniotomies are more prone to complications. The study's goal was to assess if the complication profiles for initial and repeat craniotomies were similar, to determine predictors of complications, and to compare results with those in the literature. METHODS: A retrospective study was conducted of glioma patients (WHO grade II-IV) who underwent either an initial or repeat craniotomy performed by the senior author from 2012 until 2019. Complications were recorded by discharge, 30 days, and 90 days postoperatively. New neurologic deficits were recorded by 90 days postoperatively. Multivariate regression was performed to identify factors associated with complications. A meta-analysis was performed to identify rates of complications based on number of prior craniotomies. RESULTS: Within the cohort of 714 patients, 400 (56%) had no prior craniotomies, 218 (30.5%) had undergone 1 prior craniotomy, and 96 (13.5%) had undergone ≥ 2 prior craniotomies. There were 27 surgical and 10 medical complications in 30 patients (4.2%) and 19 reoperations for complications in 19 patients (2.7%) with no deaths by 90 days. Complications, reoperation rates, and new neurologic deficits did not differ based on number of prior craniotomies. On multivariate analysis, older age (OR1.5, 95%CI 1.0-2.2) and significant leukocytosis due to steroid use (OR12.6, 95%CI 2.5-62.9) were predictors of complications. Complication rates in the cohort were lower than rates reported in the literature. CONCLUSION: Contrary to prior reports in the literature, repeat craniotomies can be as safe as initial operations if surgeons implement best practices.

Immunologic aspects of viral therapy for glioblastoma and implications for interactions with immunotherapies.

INTRODUCTION: The treatment for glioblastoma (GBM) has remained unchanged for the past decade, with only minimal improvements in patient survival. As a result, novel treatments are needed to combat this devastating disease. Immunotherapies are treatments that stimulate the immune system to attack tumor cells and can be either local or systemically delivered. Viral treatments can lead to direct tumor cell death through their natural lifecycle or through the delivery of a suicide gene, with the potential to generate an anti-tumor immune response, making them interesting candidates for combinatorial treatment with immunotherapy. METHODS: We review the current literature surrounding the interactions between oncolytic viruses and the immune system as well as the use of oncolytic viruses combined with immunotherapies for the treatment of GBM. RESULTS: Viral therapies have exhibited preclinical efficacy as single-agents and are being investigated in that manner in clinical trials. Oncolytic viruses have significant interactions with the immune system, although this can also vary depending on the strain of virus. Combinatorial treatments using both oncolytic viruses and immunotherapies have demonstrated promising preclinical findings. CONCLUSIONS: Studies combining viral and immunotherapeutic treatment modalities have provided exciting results thus far and hold great promise for patients with GBM. Additional studies assessing the clinical efficacy of these treatments as well as improved preclinical modeling systems, safety mechanisms, and the balance between treatment efficacy and immune-mediated viral clearance should be considered.

A single institution retrospective analysis on survival based on treatment paradigms for patients with anaplastic oligodendroglioma.

INTRODUCTION: Anaplastic oligodendrogliomas are high-grade gliomas defined molecularly by 1p19q co-deletion. There is no curative therapy, and standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone has not been demonstrated in a randomized control trial. Given the potential long-term consequences of radiation therapy, such as cognitive impairment, arteriopathy, endocrinopathy, and hearing/visual impairment, there is an effort to balance longevity with radiation toxicity. METHODS: We performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years. RESULTS: 159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996 and 2016. Of those, 40 patients were found to have AO at original diagnosis and had documented 1p19q co-deletion with a median of 7.1 years of follow-up (range: 0.6-16.7 years). After surgery, 45 % of patients were treated with radiation and chemotherapy at diagnosis, and 50 % were treated with adjuvant chemotherapy alone. The group treated with chemotherapy alone had a trend of receiving more cycles of chemotherapy than patients treated with radiation and chemotherapy upfront (p = 0.051). Median overall survival has not yet been reached. The related risk of progression in the upfront, adjuvant chemotherapy only group was almost 5-fold higher than the patients who received radiation and chemotherapy (hazard ratio = 4.85 (1.74-13.49), p = 0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p = 0.8). Univariate analysis of age, KPS, extent of resection, or upfront versus delayed radiation was not associated with improved survival. CONCLUSIONS: Initial treatment with adjuvant chemotherapy alone, rather than radiation and chemotherapy, may be an option for some patients with anaplastic oligodendroglioma, as it is associated with similar overall survival despite shorter progression free survival.

Using viral vectors to deliver local immunotherapy to glioblastoma.

The treatment for glioblastoma (GBM) has not seen significant improvement in over a decade. Immunotherapies target the immune system against tumor cells and have seen success in various cancer types. However, the efficacy of immunotherapies in GBM thus far has been limited. Systemic immunotherapies also carry with them concerns surrounding systemic toxicities as well as penetration of the blood-brain barrier. These concerns may potentially limit their efficacy in GBM and preclude the use of combinatorial immunotherapy, which may be needed to overcome the severe multidimensional immune suppression seen in GBM patients. The use of viral vectors to deliver immunotherapies directly to tumor cells has the potential to improve immunotherapy delivery to the CNS, reduce systemic toxicities, and increase treatment efficacy. Indeed, preclinical studies investigating the delivery of immunomodulators to GBM using viral vectors have demonstrated significant promise. In this review, the authors discuss previous studies investigating the delivery of local immunotherapy using viral vectors. They also discuss the future of these treatments, including the reasoning behind immunomodulator and vector selection, patient safety, personalized therapies, and the need for combinatorial treatment.

Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults.

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N = 144 males and females across 3 samples) and one meta-analytic (Study 2: N = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting, but other clinical conditions, such as Parkinson's disease, obesity, and attention-deficit/hyperactivity disorder, were characterized by positive correlations between DA and discounting. Together, the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice versa.SIGNIFICANCE STATEMENT Decisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in DA D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of DA function and reward discounting behavior.

Awake glioma surgery: technical evolution and nuances.

INTRODUCTION: Multiple studies have demonstrated that improved extent of resection is associated with longer overall survival for patients with both high and low grade glioma. Awake craniotomy was developed as a technique for maximizing resection whilst preserving neurological function. METHODS: We performed a comprehensive review of the literature describing the history, indications, techniques and outcomes of awake craniotomy for patients with glioma. RESULTS: The technique of awake craniotomy evolved to become an essential tool for resection of glioma. Many perceived contraindications can now be managed. We describe in detail our preferred technique, the testing paradigms utilized, and critically review the literature regarding functional and oncological outcome. CONCLUSIONS: Awake craniotomy with mapping has become the gold standard for safely maximizing extent of resection for tumor in or near eloquent brain. Cortical and subcortical mapping methods have been refined and the technique is associated with an extremely low rate of complications.

The influence of race and socioeconomic status on therapeutic clinical trial screening and enrollment.

PURPOSE: Under-enrollment in clinical trials significantly limits valid analyses of clinical interventions and generalizability of findings. Often it results in premature study termination, with estimates of 22% to 50% of clinical trials terminated due to poor accrual. Currently, there are limited reports addressing the influence of race/ethnicity and socioeconomic status on clinical trial enrollment in adult glioma patients. The goal of this study was to test the hypothesis that race and socioeconomic status negatively impact therapeutic clinical trial enrollment. METHODS: 988 adult patients were identified from the UCSF Tumor Board Registry and analyzed to determine the rate of therapeutic clinical trial screening and study enrollment. RESULTS: At initial diagnosis, 43.6% and 17.5% of glioma patients were screened and enrolled in a therapeutic clinical trial, respectively. At recurrence, 49.8% and 26.3% of patients were screened and enrolled in a clinical trial, respectively. Thirty-three percent of the study population belonged to a NIH-designated underrepresented minority group; Asian/Pacific-Islander comprised 19.6% of the overall cohort. On univariate analysis, only in-state location, distance to the hospital, and WHO grade were associated with enrollment at initial diagnosis and recurrence. Minority status, insurance type, median household income, and percent below poverty were not associated with clinical trial enrollment. CONCLUSION: Minority and socioeconomic status did not impact adult glioma clinical trial enrollment. Proximity to the tertiary care cancer center may be an important consideration for minority patients. Patient screening should be carefully considered in order to avoid bias based on minority and socioeconomic status.

Intraoperative Stereotactic Frame Registration Using a Three-Dimensional Imaging System with and without Preoperative Computed Tomography for Image Fusion.

BACKGROUND: The O-arm O2 imaging system (OAO2) is an intraoperative cone beam 3D tomogram imaging tool with a wide enough field of view to perform intraoperative fiducial registration with standard stereotactic frames. However, the OAO2 3D images (cone beam CT) provide limited tissue contrast, which may reduce the accuracy of fusion to a preoperative targeting MRI for planning awake deep brain stimulation (DBS) surgeries. Therefore, most users obtain a preoperative CT scan to use as the reference exam for computational fusion with the preoperative targeting MRI and the intraoperative OAO2 cone beam CT. OBJECTIVE: In this study, we retrospectively analyzed the discrepancy between stereotactic coordinates of deep brain targets on MRI derived from intraoperative OAO2 fiducial registration with and without the use of preoperative CT as the reference for image fusion. METHODS: Preoperative stereotactic CT/MRI and intraoperative OAO2 cone beam CT were retrospectively evaluated for 27 consecutive DBS patients, using two commercial surgical planning software packages (BrainLab Elements and Medtronic Stealth 8). The anterior commissure, posterior commissure, and left subthalamic nucleus were identified on preoperative MRI. Each patient had intraoperative fiducial registration using the OAO2 with a Leksell headframe. For each subject, the reference scan for image fusion was set as either the preoperative CT or the preoperative MRI (volumetric T1 with contrast). Computed stereotactic coordinates for each target were then compared. RESULTS: For 8 of 27 subjects, a discrepancy greater than 1.0 mm for at least one designated target was observed utilizing the Medtronic Stealth S8 planning station when a preoperative CT scan was not used. An additional 5 (5/27) had a discrepancy greater than 2 mm. The most common discrepancy was in the z axis. No coordinate discrepancies greater than 1 mm were observed utilizing BrainLab Elements. CONCLUSIONS: Caution is advised in fusing intraoperative OAO2 images directly to preoperative MRI without a preoperative CT as the reference exam for image fusion, as the specific fusion algorithm employed may unpredictably affect targeting accuracy.

Clinical characteristics and outcomes of null-cell versus silent gonadotroph adenomas in a series of 1166 pituitary adenomas from a single institution.

OBJECTIVE: Nonfunctioning pituitary adenomas present without biochemical or clinical signs of hormone excess and are the second most common type of pituitary adenomas. The 2017 WHO classification scheme of pituitary adenomas differentiates null-cell adenomas (NCAs) and silent gonadotroph adenomas (SGAs). The present study sought to highlight the differences in patient characteristics and clinical outcomes between NCAs and SGAs. METHODS: The records of 1166 patients who underwent transsphenoidal surgery for pituitary adenoma between 2012 and 2019 at a single institution were retrospectively reviewed. Patient demographics and clinical outcomes were collected. RESULTS: Of the overall pituitary adenoma cohort, 12.8% (n = 149) were SGAs and 9.2% (n = 107) NCAs. NCAs were significantly more common in female patients than SGAs (61.7% vs 26.8%, p < 0.001). There were no differences in patient demographics, initial tumor size, or perioperative and short-term clinical outcomes. There was no significant difference in the amount of follow-up between patients with NCAs and those with SGAs (33.8 months vs 29.1 months, p = 0.237). Patients with NCAs had significantly higher recurrence (p = 0.021), adjuvant radiation therapy usage (p = 0.002), and postoperative diabetes insipidus (p = 0.028). NCA pathology was independently associated with tumor recurrence (HR 3.64, 95% CI 1.07-12.30; p = 0.038), as were cavernous sinus invasion (HR 3.97, 95% CI 1.04-15.14; p = 0.043) and anteroposterior dimension of the tumor (HR 2.23, 95% CI 1.09-4.59; p = 0.030). CONCLUSIONS: This study supports the definition of NCAs and SGAs as separate subgroups of nonfunctioning pituitary adenomas, and it highlights significant differences in long-term clinical outcomes, including tumor recurrence and the associated need for adjuvant radiation therapy, as well as postoperative diabetes insipidus. The authors also provide insight into independent risk factors for these outcomes in the adenoma population studied, providing clinicians with additional predictors of patient outcomes. Follow-up studies will hopefully uncover mechanisms of biological aggressiveness in NCAs and associated molecular targets.

Molecular characteristics of diffuse lower grade gliomas: what neurosurgeons need to know.

The importance of genomic information in intrinsic brain tumors is highlighted in the World Health Organization (WHO) 2016 classification of gliomas, which now incorporates both phenotype and genotype data to assign a diagnosis. By using genetic markers to both categorize tumors and advise patients on prognosis, this classification system has minimized the risk of tissue sampling error, improved diagnostic accuracy, and reduced inter-rater variability. In the neurosurgical community, it is critical to understand the role genetics plays in tumor biology, what certain mutations mean for the patient's prognosis and adjuvant treatment, and how to interpret the results of sequencing data that are generated following tumor resection. In this review, we examine the critical role of genetics for diagnosis and prognosis and highlight the importance of tumor genetics for neurosurgeons caring for patients with diffuse lower grade gliomas.

Relationship between tumor location, size, and WHO grade in meningioma.

OBJECTIVE Prior studies have investigated preoperative risk factors for meningioma; however, no association has been shown between meningioma tumor size and tumor grade. The objective of this study was to investigate the relationship between tumor size and grade in a large single-center study of patients undergoing meningioma resection. METHODS A retrospective chart review of patients undergoing meningioma resection at the University of California, San Francisco, between 1985 and 2015 was performed. Patients with incomplete information, spinal meningiomas, multiple meningiomas, or WHO grade III meningiomas were excluded. The largest tumor dimension was used as a surrogate for tumor size. Univariate and multivariate logistic regression models were used to investigate the relationship between tumor grade and tumor size. A recursive partitioning analysis was performed to identify groups at higher risk for atypical (WHO grade II) meningioma. RESULTS Of the 1113 patients identified, 905 (81%) had a WHO grade I tumor and in 208 (19%) the tumors were WHO grade II. The median largest tumor dimension was 3.6 cm (range 0.2-13 cm). Tumors were distributed as follows: skull base (n = 573, 51%), convexity/falx/parasagittal (n = 431, 39%), and other (n = 109, 10%). On univariate regression, larger tumor size (p < 0.001), convexity/falx/parasagittal location (p < 0.001), and male sex (p < 0.001) were significant predictors of WHO grade II pathology. After controlling for interactions, multivariate regression found male sex (OR 1.74, 95% CI 1.25-2.43), size 3-6 cm (OR 1.69, 95% CI 1.08-2.66), size > 6 cm (OR 3.01, 95% CI 1.53-5.94), and convexity/falx/parasagittal location (OR 1.83, 95% CI 1.19-2.82) to be significantly associated with WHO grade II. Recursive partitioning analysis identified male patients with tumors > 3 cm as a high-risk group (32%) for WHO grade II meningioma. CONCLUSIONS Larger tumor size is associated with a greater likelihood of a meningioma being WHO grade II, independent of tumor location and male sex, which are known risk factors.

Safety and outcomes of resection of butterfly glioblastoma.

OBJECTIVE Butterfly glioblastoma (bGBM) is a rare type of GBM, characterized by a butterfly pattern on MRI studies because of its bihemispheric involvement and invasion of the corpus callosum (CC). There is a profound gap in the knowledge regarding the optimal treatment approach as well as the safety and survival benefits of resection in treating this aggressive brain tumor. In this retrospective study, authors add to our understanding of these tumors by identifying the clinical characteristics and outcomes of patients with bGBM. METHODS An institutional database was reviewed for GBM cases treated in the period from 2004 to 2014. Records were reviewed to identify adult patients with bGBM. Cases of GBM with invasion of the CC without involvement of the contralateral hemisphere and bilateral GBMs without involvement of the CC were excluded from the study. Patient and tumor characteristics were gleaned from the medical records, and volumetric analysis was performed using T1-weighted MRI studies. RESULTS From among 1746 cases of GBM, 39 cases of bGBM were identified. Patients had a mean age of 57.8 years at diagnosis. Headache and confusion were the most common presenting symptoms (48.7% and 33.3%, respectively). The median overall survival was 3.2 months from diagnosis with an overall 6-month survival rate of 38.1%. Age, Karnofsky Performance Status at diagnosis, preoperative tumor volume, postoperative tumor volume, and extent of resection were found to significantly impact survival in the univariate analysis. On multivariate analysis, preoperative tumor volume and treatment approach of resection versus biopsy were identified as independent prognostic factors regardless of the patient-specific characteristics of age and KPS at diagnosis. Resection and biopsy were performed in 35.9% and 64.1% of patients, respectively. Resection was found to confer a better prognosis than biopsy (HR 0.37, p = 0.009) with a minimum extent of resection of 86% to observe survival benefits (HR 0.054, p = 0.03). The rate of persistent neurological deficits from resection was 7.14%. Patients younger than 70 years had a better prognosis (HR 0.32, p = 0.003). Patients undergoing resection and receiving adjuvant chemoradiation had a better prognosis than patients who lacked one of the three treatment modalities (HR = 0.34, p = 0.015). CONCLUSIONS Resection of bGBM is associated with low persistent neurological deficits, with improvement in survival compared to biopsy. A more aggressive treatment approach involving aggressive resection and adjuvant chemoradiation has significant survival benefits and improves outcome.

Single dose GLP toxicity and biodistribution study of a conditionally replicative adenovirus vector, CRAd-S-pk7, administered by intracerebral injection to Syrian hamsters.

BACKGROUND: CRAd-S-pk7 is a conditionally replicative oncolytic adenoviral vector that contains a survivin promoter and a pk7 fiber modification that confer tumor-specific transcriptional targeting and preferential replication in glioma while sparing the surrounding normal brain parenchyma. METHODS: This IND-enabling study performed under GLP conditions evaluated the toxicity and biodistribution of CRAd-S-pk7 administered as a single intracerebral dose to Syrian hamsters, a permissive model of adenoviral replication. Two hundred and forty animals were stereotactically administered either vehicle (n = 60) or CRAd-S-pk7 at 2.5 × 10(7), 2.5 × 10(8), or 2.5 × 10(9) viral particles (vp)/animal (each n = 60) on day 1. The animals were closely monitored for toxicology evaluation, assessment of viral distribution, and immunogenicity of CRAd-S-pk7. RESULTS: Changes in hematology, clinical chemistry, and coagulation parameters were minor and transient, and consistent with the inflammatory changes observed microscopically. These changes were considered to be of little toxicological significance. The vector remained localized primarily in the brain and to some degree in the tissues at the incision site. Low levels of vector DNA were detected in other tissues in a few animals suggesting systemic circulation of the virus. Viral DNA was detected in brains of hamsters for up to 62 days. However, microscopic changes and virus-related toxicity to the central nervous system were considered minor and decreased in incidence and severity over time. Such changes are not uncommon in studies using adenoviral vectors. CONCLUSION: This study provides safety and toxicology data justifying a clinical trial of CRAd-S-pk7 loaded in FDA-approved HB1.F3.CD neural stem cell carriers administered at the tumor resection bed in humans with recurrent malignant glioma.