PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response.

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

Racial disparities in recommendations for surgical resection of primary brain tumours: a registry-based cohort analysis.

BACKGROUND: Disparities in treatment and outcomes disproportionately affect minority ethnic and racial populations in many surgical fields. Although substantial research in racial disparities has focused on outcomes, little is known about how surgeon recommendations can be influenced by patient race. The aim of this study was to investigate racial and socioeconomic disparities in the surgical management of primary brain tumors. METHODS: In this registry-based cohort study, we used data from the Surveillance, Epidemiology, and End Results (SEER) database (1975-2016) and the American College of Surgeons National Cancer Database (NCDB) in the USA for independent analysis. Adults (aged ≥20 years) with a new diagnosis of meningioma, glioblastoma, pituitary adenoma, vestibular schwannoma, astrocytoma, and oligodendroglioma, with information on tumour size and surgical recommendation were included in the analysis. The primary outcome of this study was the odds of a surgeon recommending against surgical resection at diagnosis of primary brain neoplasms. This outcome was determined using multivariable logistic regression with clinical, demographic, and socioeconomic factors. FINDINGS: This study included US national data from the SEER (1975-2016) and NCDB (2004-17) databases of adults with a new diagnosis of meningioma (SEER n=63 674; NCDB n=222 673), glioblastoma (n=35 258; n=104 047), pituitary adenoma (n=27 506; n=87 772), vestibular schwannoma (n=11 525; n=30 745), astrocytoma (n=5402; n=10 631), and oligodendroglioma (n=3977; n=9187). Independent of clinical and demographic factors, including insurance status and rural-urban continuum code, Black patients had significantly higher odds of recommendation against surgical resection of meningioma (adjusted odds ratio 1·13, 95% CI 1·06-1·21, p<0·0001), glioblastoma (1·14, 1·01-1·28, p=0·038), pituitary adenoma (1·13, 1·05-1·22, p<0·0001), and vestibular schwannoma (1·48, 1·19-1·84, p<0·0001) when compared with White patients in the SEER dataset. Additionally, patients of unknown race had significantly higher odds of recommendation against surgical resection for pituitary adenoma (1·80, 1·41-2·30, p<0·0001) and vestibular schwannoma (1·49, 1·10-2·04, p=0·011). Performing a validation analysis using the NCDB dataset confirmed these significant results for Black patients with meningioma (1·18, 1·14-1·22, p<0·0001), glioblastoma (1·19, 1·12-1·28, p<0·0001), pituitary adenoma (1·21, 1·16-1·25, p<0·0001), and vestibular schwannoma (1·19, 1·04-1·35, p=0·0085), and indicated and indicated that the findings are independent of patient comorbidities. When further restricted to the most recent decade in SEER, these inequities held true for Black patients, except those with glioblastoma (meningioma [1·18, 1·08-1·28, p<0·0001], pituitary adenoma [1·20, 1·09-1·31, p<0·0001], and vestibular schwannoma [1·54, 1·16-2·04, p=0·0031]). INTERPRETATION: Racial disparities in surgery recommendations in the USA exist for patients with primary brain tumours, independent of potential confounders including clinical, demographic, and select socioeconomic factors. Further studies are needed to understand drivers of this bias and enhance equality in surgical care. FUNDING: None.

Functional virus-specific memory T cells survey glioblastoma.

Glioblastoma multiforme (GBM) is among the most aggressive, treatment-resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host and are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8 + T cells expressing tissue-resident markers populate the mouse and human glioblastoma microenvironment. Reactivating virus-specific memory T cells through intratumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to antineoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific memory T cells are a significant part of the glioblastoma immune microenvironment and may be leveraged to promote anti-tumoral immunity.

Clinical outcomes as a function of the number of samples taken during stereotactic needle biopsies: a meta-analysis.

BACKGROUND: Stereotactic needle biopsy remains the cornerstone for tissue diagnosis for tumors located in regions of the brain that are difficult to access through open surgery. OBJECTIVE: We perform a meta-analysis of the literature to examine the relation between number of samples taken during biopsy and diagnostic yield, morbidity and mortality. METHODS: We identified 2416 patients from 28 cohorts in studies published in PubMed database that studied stereotactic needle biopsies for tumor indications. Meta-analysis by proportions and meta-regression analyses were performed. RESULTS: On meta-analysis, the morbidity profile of the published needle biopsy studies clustered into three groups: studies that performed < 3 samples (n = 8), 3-6 samples (n = 13), and > 6 samples during biopsy (n = 7). Pooled estimates for biopsy related morbidity were 4.3%, 16.3%, and 17% for studies reporting < 3, 3-6, and > 6 biopsy samples, respectively. While these morbidity estimates significantly differed (p < 0.001), the diagnostic yields reported for studies performing < 3 biopsies, 3-6 samples, and > 6 samples were comparable. Pooled estimates of diagnostic yield for these three groups were 90.4%, 93.8%, and 88.1%, respectively. Mortality did not significantly differ between studies reporting differing number of samples taken during biopsy. CONCLUSIONS: Our meta-analysis suggests that morbidity risk in needle biopsy is non-linearly associated with the number of samples taken. There was no association between the number of biopsies taken, and diagnostic yield or mortality.

Short-term outcome following surgery for rare brain tumor entities in adults: a Swedish nation-wide registry-based study and comparison with SEER database.

OBJECTIVE: To investigate outcomes after surgery for rare brain tumors using the Swedish Brain Tumor Registry (SBTR). METHODS: This is a nationwide study of patient in the SBTR, validated in the Surveillance, Epidemiology, and End Results (SEER) registries. We included all adults diagnosed 2009-2015 with a rare brain tumor entity (n = 216), defined as ependymoma (EP, n = 64), subependymoma (SUBEP, n = 21), ganglioglioma (GGL, n = 54), pilocytic astrocytoma (PA, n = 56) and primitive neuroectodermal tumor (PNET, n = 21). We analyzed symptomatology, tumor characteristics and outcomes. RESULTS: Mean age was 38.3 ± 17.2 years in GGL, 36.2 ± 16.9 in PA, 37.0 ± 19.1 in PNET, 51.7 ± 16.3 in EP and 49.8 ± 14.3 in SUBEP. The most common symptom was focal deficit (39.6-71.4%), and this symptom was most common in GGL patients with 64.2% of GGL presenting with seizures. Most patients had no or little restriction in activity before surgery (Performance Status 0-1), although up to 15.0% of PNET patients had a performance status of 4. Gross total resection was achieved in most (> 50%) tumor categories. Incidence of new deficits was 11.1-34.4%. In terms of postoperative complications, 0-4.8% had a hematoma of any kind, 1.9-15.6% an infection, 0-7.8% a venous thromboembolism and 3.7-10.9% experienced a complication requiring reoperation. There were 3 deaths within 30-days of surgery, and a 1-year mortality of 0-14.3%. CONCLUSION: We have provided benchmarks for the current symptomatology, tumor characteristics and outcomes after surgery for rare brain tumors as collected by the SBTR and validated our results in an independent registry. These results may aid in clinical decision making and advising patients.

Cost-effectiveness of stereotactic laser ablation (SLA) for brain tumors.

BACKGROUND: Stereotactic laser ablation(SLA) or laser interstitial thermal therapy (LITT) has been increasingly adopted as a treatment for primary and metastatic brain cancers. Here, we examined the published economic assessments of SLA, and review the current state of knowledge. METHODS: The PubMed database was queried for articles investigating the cost-effectiveness of LITT. 3068 articles were screened. Two studies that met the inclusion criteria were included in this review. RESULTS: Cost-effectiveness analysis(CEA) favored SLA(n = 8) relative to craniotomy (n = 92) for brain metastases (Mean difference [MD]=-US$6522; 95% confidence interval (CI) -$11,911 to -$1133; p = 0.02). SLA (n = 19) was found to be cost equivalent to craniotomy (n = 248) (MD=-US$1669; 95%(CI) -$8192 to $4854, p = 0.62) for primary brain tumors in general. CEA favored SLA for a subset of primary brain cancers. SLA was found to be cost-effective for difficult to access high-grade gliomas(HGG). When compared to 'other' existing treatments, the cost per life-years gained (LYG) through SLA was ∼$29,340, a threshold below that set for new technology adaptation in the U.S. Factors contributing to these cost-effectiveness were: (1) SLA of HGGs was associated with three-months prolongation in survival; (2) SLA of brain metastasis was associated with (i) shorter average length of stay (SLA: 2.3 days; craniotomy: 4.7 days), (ii) decreased discharge to inpatient rehabilitation facility (IRF), skilled nursing facility (SNF), or home healthcare (SLA: 14.8%; craniotomy: 52%), (iii) lowered 30-day readmission (SLA: 0%; craniotomy: 14.1%). CONCLUSION: There is limited data on the cost-effectiveness of SLA. In the available literature, SLA compared favorably to craniotomy in terms of cost-effectiveness as a treatment for primary and metastatic brain cancers.

Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas.

BACKGROUND: This is an update of the review originally published in 2011 and first updated in 2015. In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs. OBJECTIVES: To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low-grade intracranial gliomas in people who had initial biopsy or surgical resection. SEARCH METHODS: Original searches were run up to September 2014. An updated literature search from September 2014 through November 2019 was performed on the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 11), MEDLINE via Ovid (September 2014 to November week 2 2019), and Embase via Ovid (September 2014 to 2019 week 46) to identify trials for inclusion in this Cochrane review update. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt-60 sources, intensity-modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS). DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta-analyses using a random-effects model with inverse variance weighting. MAIN RESULTS: We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P < 0.0001; 311 participants; 1 trial; low-quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P = 0.872; 311 participants; 1 trial; low-quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P = 0.0329, respectively). AUTHORS' CONCLUSIONS: Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who underwent early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.

Receipt of brachytherapy is an independent predictor of survival in glioblastoma in the Surveillance, Epidemiology, and End Results database.

INTRODUCTION: There has been a resurgence of interest in brachytherapy as a treatment for glioblastoma, with several currently ongoing clinical trials. To provide a foundation for the analysis of these trials, we analyze the Surveillance, Epidemiology, and End Results (SEER) database to determine whether receipt of brachytherapy conveys a survival benefit independent of traditional prognostic factors. MATERIALS AND METHODS: We identified 60,456 glioblastoma patients, of whom 362 underwent brachytherapy. We grouped patients based on receipt of brachytherapy and compared clinical and demographic variables between groups using Student's t-test and Pearson's chi-squared test. We assessed survival using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Median overall survival was 16 months in patients who received brachytherapy compared to 9 months in those who did not (log-rank p < 0.001). Patients who underwent brachytherapy tended to be younger (p < 0.001), suffered from smaller tumors (< 4 cm, p < 0.001), and were more likely to have undergone gross total resection (GTR, p < 0.001). In univariable Cox models, these variables were independently associated with improved overall survival. Additionally, improved survival was associated with known receipt of chemotherapy (HR 0.459, p < 0.001), external beam radiation (HR 0.447, p < 0.001), and brachytherapy (HR 0.637, p < 0.001). The association between brachytherapy and improved survival remained robust (HR 0.859, p = 0.031) in a multivariable model that adjusted for patient age, tumor size, tumor location, GTR, receipt of chemotherapy, and receipt of external beam radiation. CONCLUSION: Our SEER analysis indicates that brachytherapy is associated with improved survival in glioblastoma after controlling for age, tumor size/location, extent of resection, chemotherapy, and external beam radiation.

Association between medical academic genealogy and publication outcome: impact of unconscious bias on scientific objectivity.

BACKGROUND: Our previous studies suggest that the training history of an investigator, termed "medical academic genealogy", influences the outcomes of that investigator's research. Here, we use meta-analysis and quantitative statistical modeling to determine whether such effects contribute to systematic bias in published conclusions. METHODS: A total of 108 articles were identified through a comprehensive search of the high-grade glioma (HGG) surgical resection literature. Analysis was performed on the 70 articles with sufficient data for meta-analysis. Pooled estimates were generated for key academic genealogies. Monte Carlo simulations were performed to determine whether the effects attributed to genealogy alone can arise due to chance alone. RESULTS: Meta-analysis of the HGG literature without consideration for academic medical genealogy revealed that gross total resection (GTR) was associated with a significant decrease in the odds ratio (OR) for the hazard of death after surgery for both anaplastic astrocytoma (AA) and glioblastoma (AA: log [OR] = - 0.04, 95% CI [- 0.07 to - 0.01]; glioblastoma log [OR] = - 0.36, 95% CI [- 0.44 to - 0.29]). For the glioblastoma literature, meta-analysis of articles contributed by members of a genealogy consisting of mostly radiation oncologists revealed no reduction in the hazard of death after GTR [log [OR] = - 0.16, 95% CI [- 0.41 to 0.09]. In contrast, meta-analysis of published articles contributed by members of a genealogy consisting of mostly neurosurgeons revealed that GTR was associated with a significant reduction in the hazard of death [log [OR] = - 0.29, 95% CI [- 0.40 to 0.18]. Monte Carlo simulation revealed that the observed discrepancy between the articles contributed by the members of these two genealogies was unlikely to arise by chance alone (p < 0.006). CONCLUSIONS: Meta-analysis of articles contributed by authors belonging to the different medical academic genealogies yielded distinct and contradictory pooled point-estimates, suggesting that genealogy contributes to systematic bias in the published literature.

Post-operative imaging assessment of non-functioning pituitary adenomas.

BACKGROUND: Non-functioning pituitary adenomas (NFAs) are the most common pituitary tumors. There is significant variability in clinical practice in terms of post-operative imaging evaluation. The objective of this manuscript is to provide an exhaustive review of published articles pertaining to the post-operative imaging evaluation of NFAs. METHODS: The MEDLINE database was queried for studies investigating imaging for the post-operative evaluation of pituitary adenomas. From an initial search of 5589 articles, 37 articles were evaluated in detail and included in this review. RESULTS: Magnetic resonance imaging (MRI) is the gold standard for post-operative monitoring of NFAs, although functional imaging modalities may improve identification of residual tumor in conjunction with MRI. The residual tumor can be distinguished from post-operative changes by experienced practitioners using high-resolution MRI in the immediate post-operative setting (within 1 week of surgery). However, continued imaging evolution in the appearance of residual tumor or resection cavity is expected up to 3 months post-operatively. CONCLUSIONS: Post-operative imaging appearance of the pituitary gland, optic apparatus, and pneumocephalus patterns, correlated with the clinical outcomes. Long-term, lifetime follow-up is warranted for NFA patients who underwent surgical resection.

Comparison meta-analysis of intraoperative MRI-guided needle biopsy versus conventional stereotactic needle biopsies.

Background: MRI-guided needle biopsy (INB) is an emerging alternative to conventional frame-based or frameless stereotactic needle biopsy (SNB). Studies of INB have been limited to select case series, and comparative studies between INB and SNB remain a missing gap in the literature. We performed a meta-analysis to compare INB and SNB literature in terms of diagnostic yield, surgical morbidity and mortality, tumor size, and procedural time. Methods: We identified 36 separate cohorts in 26 studies of SNB (including both frameless and frame-based biopsies, 3374 patients) and 27 studies of INB (977 patients). Meta-regression and meta-analysis by proportions were performed. Results: Relative to publications that studied SNB, publications studying INB more likely involved brain tumors located in the eloquent cerebrum (79.4% versus 62.6%, P = 0.004) or are smaller in maximal diameter (2.7 cm in INB group versus 3.6 cm in the SNB group, P = .032). Despite these differences, the pooled estimate of diagnostic yield for INB was higher than SNB (95.4% versus 92.3%, P = .026). The pooled estimate of surgical morbidity was higher in the SNB group (12.0%) relative to the INB group (6.1%) (P = .004). Mortality after the procedure was comparable between INB and SNB (1.7% versus 2.3%, P = .288). Procedural time was statistically comparable at 90.3 min (INB) and 103.7 min (SNB), respectively (P = .526). Conclusions: Our meta-analysis indicates that, relative to SNB, INB is more often performed for the challenging, smaller-sized brain tumors located in the eloquent cerebrum. INB is associated with lower surgical morbidity and improved diagnostic yield.

Role of immunotherapy in treatment refractory chordomas: review of current evidence.

Introduction: Chordomas are aggressive tumors that are thought to arise from remnants of the embryological notochord. They can arise along the ventromedial aspect of the sacrum, mobile spine, and clivus-with most cases occurring in the sacrum or skull base. Despite surgery and radiation, chordomas often progress and become refractory to further treatment. The high recurrence rate of chordomas has created an urgent need to develop new systemic treatment options. Recent case reports and clinical trials have highlighted the use of immunotherapy for refractory chordomas. In this review, we summarize the results of these studies and discuss the potential role of immunotherapy for chordomas. Methods: The PUBMED database was queried for studies mentioning both "Chordoma" and "Immunotherapy." All case series and case reports that involved administration of an immunotherapy for chordoma were included. Additional studies that were found during literature review were added. ClinicalTrials.Gov was queried for studies mentioning both "Chordoma" and "Immunotherapy." The final cohort consisted of all clinical trials that utilized immunotherapy for chordomas of any location. Results: Eight case reports and series detailing the use of immunotherapy for treatment refractory chordoma were identified. Most patients received immunotherapy targeting the PD-1/PD-L1 interaction, and two patients received therapy targeting this interaction along with the tyrosine kinase inhibitor pazopanib. One patient received a vaccine derived from autologous tumor cells, and one patient received a viral vector that downregulated the effect of TGF-beta. One clinical trial utilized a brachyury vaccine in conjunction with standard of care radiotherapy. Conclusions: Immunotherapy for chordoma is a promising area of investigation with increasing, but small, numbers of case series and clinical trials. Despite challenges in patient accrual, future directions in chordoma immunotherapy may lie in vaccine-based therapies and immune checkpoint inhibitors. Understanding chordoma heterogeneity and microenvironment will likely elucidate important chordoma features that will inform future clinical trial design.

Spontaneous Spinal Hematoma in Patients Using Antiplatelets and Anticoagulants: A Systematic Review.

BACKGROUND: Spontaneous spinal hematoma (SSH) is a debilitating complication in patients taking either antiplatelet (AP) or anticoagulation (AC) medications. SSH is rare and, therefore, a systematic review is warranted to re-examine and outline trends, clinical characteristics, and outcomes associated with SSH formation. METHODS: PubMed, EMBASE, Scopus, and Web-of-Science were searched. Studies reporting clinical data of patients with SSH using AC medications were included. In addition, clinical studies meeting our a priori inclusion criteria limited to SSH were further defined in quality through risk bias assessment. RESULTS: We included 10 studies with 259 patients' pooled data post-screening 3083 abstracts. Within the cohort (n = 259), the prevalence of idiopathic, nontraumatic SSH with concomitant treatment with AC medications was greater 191 (73.75%) compared with AP treatment (27%). The lumbar spine was the most common site of hematoma (41.70%), followed by the cervical (22.01%) and thoracic (8.49%) spine. Most patients had surgical intervention (70.27%), and 29.73% had conservative management. The pooled data suggest that immediate diagnosis and intervention are the best prognostic factors in clinical outcomes. American Spinal Injury Association grading at initial symptom onset and post-treatment showed the greatest efficacy in symptomatic relief (87.64%) and return of motor and sensory symptoms (39.19%). CONCLUSIONS: Our review suggested that AC medications were related to SSH in most patients (74%), followed by APs (27%) and combined ACs + APs (1.9%). We recommend prompt intervention, a high suspicion for patients with neurologic deficits and diagnostic imaging before intervention to determine a case-specific treatment plan.

Influence of Body Mass Index on Surgical and Patient Outcomes for Cervical Spine Surgery.

STUDY DESIGN: Secondary analysis of prospectively collected registry. OBJECTIVE: We aim to investigate the effects of body mass index (BMI) on postsurgical cervical spine surgery outcomes and identify a potential substratification of obesity with worse outcomes. SUMMARY OF BACKGROUND DATA: The impact of BMI on cervical spine surgery is unknown, with controversial outcomes for patients high and low BMI. METHODS: The cervical spine Quality Outcomes Database was queried for a total of 10,381 patients who underwent single-stage cervical spine surgery. Patients were substratified into 6 groups based on BMI. Surgical outcomes, complications, hospitalization outcomes, and patient-reported outcomes for each cohort, including modified Japanese Orthopedic Association Score, Numeric Rating Scale arm pain, Numeric Rating Scale neck pain, Neck Disability Index, and EuroQol Health Survey, were assessed. Univariate analysis was performed for 3- and 12-month follow-up after surgical intervention. RESULTS: Obese patients (class I, II, and III) requiring spine surgery were statistically younger than nonobese patients and had higher rates of diabetes compared with normal BMI patients. The surgical length was found to be longer for overweight and all classes of obese patients ( P < 0.01). Class III obese patients had higher odds of postoperative complications. Patients with class II and III obesity had lower odds of achieving optimal modified Japanese Orthopedic Association Score at 3 months [OR = 0.8 (0.67-0.94), P < 0.01, OR = 0.68 (0.56-0.82), P < 0.001, respectively] and 12 months [OR = 0.82 (0.68-0.98), P = 0.03, OR = 0.79 (0.64-0.98), P = 0.03, respectively]. CONCLUSIONS: This study investigates the relationship between substratified BMI and postoperative outcomes of cervical spine surgery. Class II and III obese patients have substantially greater risk factors and poor outcomes postoperatively. In addition, low BMI also presents unique challenges for patients. Further research is needed for comprehensive analysis on outcomes of cervical spine surgery after correcting BMI.

Comparison of Stereotactic Radiosurgery and Hypofractionated Radiosurgery for Vestibular Schwannomas: A Meta-Analysis of Available Literature.

BACKGROUND: Stereotactic radiosurgery (SRS) and recently, hypofractionated radiosurgery (hSRS) are increasingly utilized as treatment for vestibular schwannomas (VS). We performed a meta-analysis of literature comparing these modalities. METHODS: The PubMed database of articles was searched for studies that compared SRS and hSRS in patients with VS. Variables analyzed include tumor control, hearing preservation, facial nerve preservation, trigeminal nerve preservation, and total complications. Heterogeneity across the studies was gauged using Higgins's inconsistency index. Funnel plots and Egger's regression intercept test were used to address the publication bias. RESULTS: Thirteen studies that satisfied the search criteria were selected for meta-analysis. The studies identified in our study included 353 SRS and 511 hSRS-treated patients. Analysis of heterogeneity showed that hSRS is employed for relatively larger tumor sizes in comparison to SRS. Pooled meta-analysis estimates showed no significant differences between SRS and hSRS in terms of tumor control (odds ratio [OR], 0.620; 95% confidence interval [CI], 0.21-1.86, P = 0.39), hearing preservation (OR, 1.07; 95% CI, 0.59-1.93, P = 0.83), facial nerve preservation (OR, 0.53; 5% CI, 0.23-1.21, P = 0.13), or trigeminal nerve preservation (OR, 0.67; 95% CI, 0.24-1.89, P = 0.49) at a mean follow-up of 39 months. Statistically significant heterogeneity was found across the studies only for tumor diameter (Higgins's inconsistency index = 65.69%, P = 0.003) but not for other variables. CONCLUSIONS: Meta-analysis of thirteen studies comparing SRS and hSRS as treatment for VS showed comparable tumor control, hearing preservation, facial nerve preservation, and trigeminal nerve preservation.

Sagittal balance in sitting and standing positions: A systematic review of radiographic measures.

Background: Sagittal imbalance can be caused by various etiologies and is among the most important indicators of spinal deformity. Sagittal balance can be restored through surgical intervention based on several radiographic measures. The purpose of this study is to review the normal parameters in the sitting position, which are not well understood and could have significant implications for non-ambulatory patients. Methods: A systematic review was performed adhering to PRISMA Guidelines. Using R-software, the weighted means and 95% confidence intervals of the radiographic findings were calculated using a random effect model and significance testing using unpaired t-tests. Results: 10 articles with a total of 1066 subjects reported radiographic measures of subjects with no spinal deformity in the sitting and standing position. In the healthy individual, standing sagittal vertical axis -16.8°was significantly less than sitting 28.4° (p < 0.0001), while standing lumbar lordosis 43.3°is significantly greater than sitting 21.3° (p < 0.0001). Thoracic kyphosis was not significantly different between the two groups (p = 0.368). Standing sacral slope 34.3° was significantly greater than sitting 19.5° (p < 0.0001) and standing pelvic tilt 14.0° was significantly less than sitting 33.9° (p < 0.0001). Conclusions: There are key differences between standing and sitting postures, which could lead to undue stress on surgical implants and poor outcomes, especially for non-ambulatory populations. There is a need for more studies reporting sitting and standing radiographic measures in different postures and spinal conditions.

Neurosurgery residency match for international medical graduates in the United States.

OBJECTIVE: Training of international medical graduates (IMGs) offers opportunities for the US neurosurgery community to engage the global talent pool and impact national and international healthcare. Here, the authors analyzed the time trend of IMGs matching into US neurosurgery programs and identified potential opportunities for enhancing IMG engagement. METHODS: The authors analyzed the National Resident Matching Program (NRMP) match results, NRMP program director (PD) surveys, and applicant surveys from 2013 to 2022. Regression methods were used to analyze time trends. RESULTS: Between 2013 and 2022, the number of US neurosurgery residency positions increased by 17.6% (from 204 to 240). During this period, the percentage of IMGs matching into neurosurgery increased from 3.5% to 7%, translating into a 6.8% increase in the likelihood of a successful IMG match per year (95% CI 0.3%-13.8%, p = 0.042). The likelihoods of a successful match for US MDs and IMGs scoring > 260 on the USMLE Step 1 were > 90% and approximately 55%, respectively. In PD surveys, approximately 90% of PDs indicated that they seldom/never interview or rank IMGs. In terms of factors that influenced the PD decision for interviewing/ranking, IMGs are disadvantaged in several categories, including the ability to secure an audition elective/rotation, and proper letters of recommendation, as well as the influence of the culture on the preconceived perception of poor interpersonal skills. CONCLUSIONS: The number of IMGs matching successfully in neurosurgery has increased marginally during the past decade. The authors outline the challenges that IMGs encounter in this process and suggest strategies for considerations of IMG training in NRMP-associated institutions.

Directionally non-rotating electric field therapy delivered through implanted electrodes as a glioblastoma treatment platform: A proof-of-principle study.

Background: While directionally rotating tumor-treating fields (TTF) therapy has garnered considerable clinical interest in recent years, there has been comparatively less focus on directionally non-rotating electric field therapy (dnEFT). Methods: We explored dnEFT generated through customized electrodes as a glioblastoma therapy in in vitro and in vivo preclinical models. The effects of dnEFT on tumor apoptosis and microglia/macrophages in the tumor microenvironment were tested using flow-cytometric and qPCR assays. Results: In vitro, dnEFT generated using a clinical-grade spinal cord stimulator showed antineoplastic activity against independent glioblastoma cell lines. In support of the results obtained using the clinical-grade electrode, dnEFT delivered through a customized, 2-electrode array induced glioblastoma apoptosis. To characterize this effect in vivo, a custom-designed 4-electrode array was fabricated such that tumor cells can be implanted into murine cerebrum through a center channel equidistant from the electrodes. After implantation with this array and luciferase-expressing murine GL261 glioblastoma cells, mice were randomized to dnEFT or placebo. Relative to placebo-treated mice, dnEFT reduced tumor growth (measured by bioluminescence) and prolonged survival (median survival gain of 6.5 days). Analysis of brain sections following dnEFT showed a notable increase in the accumulation of peritumoral macrophage/microglia with increased expression of M1 genes (IFNγ, TNFα, and IL-6) and decreased expression of M2 genes (CD206, Arg, and IL-10) relative to placebo-treated tumors. Conclusions: Our results suggest therapeutic potential in glioblastoma for dnEFT delivered through implanted electrodes, supporting the development of a proof-of-principle clinical trial using commercially available deep brain stimulator electrodes.

Attention and information processing in end stage renal disease and effect of hemodialysis: a bedside study.

The neurobehavioral syndrome of uremia in chronic kidney disease affects the functioning of the central nervous system. Cognitive impairment is one of the most important manifestations of this dysfunction. The process of hemodialysis is known to bring about conflicting changes in the cognitive status of patients. In the present study an assessment of cognitive status of patients with end stage renal disease was done in comparison to controls before and after a session of hemodialysis using simple bedside paper-pencil tests. Thirty patients of end stage renal disease on maintenance dialysis for at least one month with MMSE score >24 were assessed one hour before and one hour after hemodialysis using Digit Symbol Substitution Test, One Letter and Three Letter Cancellations tasks. Their results were compared to age and sex matched healthy controls. The patients with end stage renal disease had significantly lower performance in cognitive tests in comparison to controls. The performance improved 1 hour after hemodialysis in comparison to pre-dialysis values. However, the values after dialysis were significantly lower than in controls, thereby indicating that though the cognitive functions improved after hemodialysis, they did not reach the control levels. There was also a significant change in the biochemical parameters after dialysis. We conclude that patients with end stage renal disease suffered from cognitive impairment which improved on hemodialysis due to removal of metabolic waste products.