Longitudinal multi-omics reveals pathogenic TSC2 variants disrupt developmental trajectories of human cortical organoids derived from Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC), an autosomal dominant condition, is caused by heterozygous mutations in either the TSC1 or TSC2 genes, manifesting in systemic growth of benign tumors. In addition to brain lesions, neurologic sequelae represent the greatest morbidity in TSC patients. Investigations utilizing TSC1/2-knockout animal or human stem cell models suggest that TSC deficiency-causing hyper-activation of mTOR signaling might precipitate anomalous neurodevelopmental processes. However, how the pathogenic variants of TSC1/2 genes affect the longitudinal trajectory of human brain development remains largely unexplored. Here, we employed 3-dimensional cortical organoids derived from induced pluripotent stem cells (iPSCs) from TSC patients harboring TSC2 variants, alongside organoids from age- and sex-matched healthy individuals as controls. Through comprehensively longitudinal molecular and cellular analyses of TSC organoids, we found that TSC2 pathogenic variants dysregulate neurogenesis, synaptogenesis, and gliogenesis, particularly for reactive astrogliosis. The altered developmental trajectory of TSC organoids significantly resembles the molecular signatures of neuropsychiatric disorders, including autism spectrum disorders, epilepsy, and intellectual disability. Intriguingly, single cell transcriptomic analyses on TSC organoids revealed that TSC2 pathogenic variants disrupt the neuron/reactive astrocyte crosstalk within the NLGN-NRXN signaling network. Furthermore, cellular and electrophysiological assessments of TSC cortical organoids, along with proteomic analyses of synaptosomes, demonstrated that the TSC2 variants precipitate perturbations in synaptic transmission, neuronal network activity, mitochondrial translational integrity, and neurofilament formation. Notably, similar perturbations were observed in surgically resected cortical specimens from TSC patients. Collectively, our study illustrates that disease-associated TSC2 variants disrupt the neurodevelopmental trajectories through perturbations of gene regulatory networks during early cortical development, leading to mitochondrial dysfunction, aberrant neurofilament formation, impaired synaptic formation and neuronal network activity.

Beyond childhood: exploring the state of transitional care in pediatric pilocytic astrocytoma.

OBJECTIVE: Pediatric pilocytic astrocytoma (PPA) requires prolonged follow-up after initial resection. The landscape of transitional care for PPA patients is not well characterized. The authors sought to examine the clinical course and transition to adult care for these patients to better characterize opportunities for improvement in long-term care. METHODS: Pediatric patients (younger than 18 years at diagnosis) who underwent biopsy or resection for PPA between May 2000 and November 2022 at the authors' large academic center were retrospectively reviewed. Patient demographics, tumor characteristics, recurrence, adjuvant therapies, and follow-up data were extracted from the electronic medical record via chart review. Charts of patients who were 18 years or older as of January 1, 2024, were reviewed for adult follow-up notes. RESULTS: The authors identified 315 patients who underwent biopsy or resection for PPA between May 2000 and November 2022. The most common tumor location was posterior fossa (59.7%), and gross-total resection (GTR) was achieved in 187 patients (59.4%). In patients with GTR, progression/recurrence occurred less frequently (8.6% vs 41.4%, p < 0.01) compared to patients with non-GTR. Among 177 patients found to be age-eligible for transition to adult care, the authors found that 31 (17.5%) successfully transitioned. The average age at transition from pediatric to adult care was 21.7 years, and the average age at last known adult follow-up was 25.0 years. The authors found that patients who transitioned to adult care were followed longer (12.5 vs 7.0 years, p < 0.01) and were diagnosed at an older age (12.1 vs 9.6 years, p < 0.01) than their untransitioned counterparts. CONCLUSIONS: The authors found that there was a low rate of successful transition from pediatric to adult care for PPA; 17.5% of age-eligible patients are now cared for by adult providers, whereas an additional 18.6% completed appropriate follow-up during childhood and did not require transition to adult care. These findings underscore opportunities for improvement in the pediatric-to-adult transition process for patients with PPA, particularly for those with non-GTR who were not followed for at least 10 years, during which the risk of disease progression is thought to be highest.

The Impact of Social Determinants on Receipt of Adjuvant Radiation Nationally Following Atypical Meningioma Surgery.

OBJECTIVE: We aimed to identify socioeconomic gaps in the administration of adjuvant radiotherapy (RT) for patients with atypical meningioma (AM) and secondarily to determine differences in survival between patients receiving radiation and those not receiving radiation at 12 and 60 months. METHODS: The National Cancer Database was queried for patients receiving AM surgery between 2004 and 2019. Statistical analyses were performed to assess the association between receipt of adjuvant radiation and social determinants. Secondarily, Kaplan-Meir curves were used to compare overall patient survival between those that received radiation and those that did not. RESULTS: Adjuvant radiation was less likely to be administered to patients over 65 (95% confidence interval [CI] = 0.53-22 0.77) and more likely to be administered to males (95% CI = 1.07-1.38). Compared to the Southern USA, patients were more likely to receive RT in the Northeastern (95% CI 24 = 1.40-2.05), Midwestern (95% CI = 1.06-1.54), and Western parts of the USA (95% 25 CI = 1.31-2.00). Patients residing furthest from their facility were less likely to receive radiation (95% CI = 0.65-0.98). Insured patients were more likely to receive radiation (P = 0.048) than uninsured patients. On multivariate analysis, no differences were found between racial groups regarding adjuvant radiation. For patients unstratified, radiation was shown to improve survival at 12 and 60 months. CONCLUSIONS: Disparities exist in the administration of adjuvant RT for AM. Patients over 65, women, those residing in the Southern USA, those living further from their facilities and uninsured patients are less likely to receive radiation than their counterparts.

Frailty in patients with IDH-mutant gliomas: experience from a high-volume tumor center.

PURPOSE: Gliomas are increasingly diagnosed in an aging population, with treatment outcomes influenced by factors like tumor genetics and patient frailty. This study focused on IDH-mutant gliomas and assessed how frailty affects 30-day readmission and overall survival (OS). We aimed to address a gap in understanding the impact of frailty on this specific glioma subtype. METHODS: 136 patients with an IDH-mutant glioma between 2007 and 2021 were identified at our institution. High frailty was classified by scores ≥ 1 on the 5-factor modified frailty index (mFI-5) and ≥ 3 on the Charlson Comorbidity Index (CCI). Patient and tumor characteristics including age, sex, race, Karnofsky Performance Status (KPS), Body Mass Index (BMI), tumor type and location, type of operation, and therapy course were recorded. Outcomes measured included 30-day readmission and overall survival (OS). Analysis was conducted utilizing logistic regression and Kaplan-Meier curves. RESULTS: Of the 136 patients, 52 (38%) had high frailty: 18 with CCI ≥ 3, 34 with mFI-5 ≥ 1. High frailty correlated with increased BMI (CCI: 30.2, mFI-5: 30.1 kg/m2), more neurological deficits (CCI: 61%, mFI-5: 56%), and older age at surgery (CCI: 63, mFI-5: 48 years). Hospital readmission within 30 days occurred in 8 (5.9%) patients. Logistic regression indicated no significant difference in 30-day readmission rates (CCI: p = 0.30, mFI-5: p = 0.62) or median OS between high and low frailty groups. However, patients treated at our institution with newly diagnosed tumors with high mFI-5 had a 6.79 times higher adjusted death hazard than those with low mFI-5 (p = .049). CONCLUSION: Our analysis revealed that CCI and mFI-5 were not significantly associated with 30-day nor OS. However, in patients with non-recurrent tumors, there was a significant association of mFI-5 with OS. Further study of frailty with larger cohorts is warranted to enhance prognostication of outcome after neurosurgical treatment.

Superior orbital fissure narrowing and tumor-associated pain in spheno-orbital meningiomas.

INTRODUCTION: Spheno-orbital meningiomas (SOMs) represent a distinct subtype of meningioma characterized by their unique multi-compartmental invasion pattern. Previous studies have investigated correlations between SOMs and visual manifestations. However, our comprehension of pain associated with SOMs remains limited. This study aims to provide insight into the pathophysiology underlying SOM-related pain through measurements of tumor volume and superior orbital fissure (SOF) narrowing. METHODS: This retrospective study included patients who underwent surgical resection of a SOM between 2000 and 2022. Preoperative CT and/or MRI scans were analyzed, and the tumor volume of each segment was measured. Bony 3D reconstructions were used to measure the area of the SOF, and SOF narrowing was calculated. RESULTS: The study cohort included 66 patients diagnosed with SOMs, among which 25.8% (n = 17) presented with pain. Postoperatively, 14/17 (82.4%) of patients reported pain improvement. There was no significant correlation between the total volume or the volume of tumor within each compartment and the presence of pain on presentation (p > 0.05). The median SOF narrowing was significantly different between patients presenting with and without tumor-associated pain with median of 11 mm2 (IQR 2.8-22.3) and 2 mm2 (IQR 0-6), respectively (p = 0.005). Using logistic regression, a significant correlation between the degree of SOF narrowing and the presence of SOM-associated pain on presentation was identified, with an aOR of 1.2 (95% CI 1.12-1.3, p = 0.02). CONCLUSION: While the exact cause of tumor-associated pain remains unclear, SOF narrowing seems to play a role in pain among SOM patients. Based on the radiological characteristics, SOF neurovascular decompression is recommended in SOM patients.

Does tocilizumab have an effect on the clinical outcomes in COVID-19 patients? A meta-analysis of randomized control trials.

BACKGROUND: This meta-analysis was conducted to investigate the impact of tocilizumab on clinical outcomes associated with COVID-19. METHODS: A comprehensive search was conducted across Scopus, PubMed (Medline), Cochrane Library, EMBASE (Elsevier), ClinicalTrials.gov, and Web of Sciences to identify pertinent studies published until May 2022. The primary search terms included "tocilizumab" and "COVID-19". Following the formulation of the search strategy, all identified studies were screened, and the data extraction process was initiated. Subsequently, the Cochrane risk of bias checklist was employed to evaluate the risk of bias. The effects of tocilizumab were assessed utilizing the pooled risk ratio (RR) and the fixed effect model in STATA (version 17). RESULTS: In this meta-analysis, we analyzed 17 clinical trial studies to assess the impact of tocilizumab on mortality in patients with COVID-19. The pooled risk ratio (RR) for mortality was 0.93 (RR: 0.93; 95% CI: 0.86, 1.00; I2: 72.39%; P value: 0.001). The findings indicated that tocilizumab use was associated with a 4% increase in ICU hospitalization (RR: 1.04; 95% CI: 0.90, 1.20; I2: 0.00%; P value: 0.65). Additionally, tocilizumab administration was linked to a 2% reduction in the requirement for a ventilator (RR: 0.98; 95% CI: 0.90, 1.08; I2: 26.87%; P value: 0.16). CONCLUSION: The administration of tocilizumab during the COVID-19 pandemic, prescribed to patients with the virus, exerted a noteworthy impact on reducing outcomes associated with COVID-19.

Survival analysis of coagulation disorders: A retrospective study with a 5-year follow-up.

Objective: Rare bleeding disorders (RBDs) are the diseases in which patients experience a deficiency of coagulation factors. In the management of these disorders, surveillance is a significant challenge. This study aimed to assess the survival of patients with RBDs in a five-year follow-up. Materials and methods: This descriptive cross-sectional study was conducted on 146 patients with RBDs who had referred to Be'sat Hospital of Hamadan, Iran from July 2017 to August 2022. A computerized record search was performed to identify the patients. The surveillance time for a five-year follow-up was assessed with the Kaplan-Meier curve. A log-rank test also served to compare the survival rates according to the type of factor. Results: Out of 146 patients, 117 (80.2%) were males and 29 (19.8%) were females. They were in the range of 2-59 years of age with a mean of 23.11 ± 14.6. The most common disorder was FVIII deficiency (65.8%), and the rarest one was FXIII deficiency (4.8%). The rate of survival for any reason was 54.42 ± 1.3 months. The survival in combined FV and FVIII deficiencies was found to be longer than in the other deficiencies (55.9 ± 5.7), but there was no significant difference (P ≥ 0.05). In contrast, the survival in FXIII deficiency was observed to be lower than the other cases (44 ± 9.6); however, no significant difference was found in this regard (P ≥ 0.05). Conclusion: The results of this study show that patients with RBDs have different rates of survival, which suggests that identifying high-risk patients may be helpful for the improvement of their survival time through timely therapeutic interventions.

Symptomatic intracranial tumors in pregnancy: an updated management algorithm. Illustrative case.

BACKGROUND: Intracranial tumors are infrequently encountered during pregnancy, and their diagnosis and management require a multidisciplinary approach to ensure the best possible outcomes for the mother and fetus. The pathophysiology and manifestations of these tumors are influenced by hormonal changes, hemodynamic modifications, and alterations in immunological tolerance that occur during pregnancy. Despite the complexity of this condition, no standardized guidelines exist. This study aims to highlight the key points of this presentation, along with the discussion of a possible management algorithm. OBSERVATIONS: The authors report the case of a 35-year-old woman who presented during the third trimester of pregnancy with severe signs of increased intracranial pressure (ICP) due to a posterior cranial fossa mass. The decision was made to stabilize the patient by placing an external ventricular drain to temporize her increased ICPs until the baby could be safely delivered via cesarean section. The mass was resected via suboccipital craniectomy 1 week postpartum. LESSONS: In considering treatment modalities and their timing in patients presenting with intracranial tumors during pregnancy, each patient should be managed on the basis of an individual treatment algorithm. Symptoms, prognosis, and gestational age should be taken into account to optimize the surgical and perioperative outcomes of both the mother and fetus.

Role of c-Met/ß1 integrin complex in the metastatic cascade in breast cancer.

Metastases cause 90% of human cancer deaths. The metastatic cascade involves local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. Although individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a complex between receptor tyrosine kinase c-Met and ß1 integrin in metastases. Using cell culture and in vivo assays, we found that c-Met/ß1 complex induction promoted intravasation and vessel wall adhesion in triple-negative breast cancer cells, but did not increase extravasation. These effects may have been driven by the ability of the c-Met/ß1 complex to increase mesenchymal and stem cell characteristics. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/ß1 complex induction. A ß1 integrin point mutation that prevented binding to c-Met reduced intravasation. OS2966, a therapeutic antibody disrupting c-Met/ß1 binding, decreased breast cancer cell invasion and mesenchymal gene expression. Bone-seeking breast cancer cells exhibited higher levels of c-Met/ß1 complex than parental controls and preferentially adhered to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/ß1 complex than brain metastases. Thus, the c-Met/ß1 complex drove intravasation of triple-negative breast cancer cells and preferential affinity for bone-specific matrix. Pharmacological targeting of the complex may have prevented metastases, particularly osseous metastases.

Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma.

Importance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood. Objective: To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery. Design, Setting, and Participants: This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019. Main Outcomes and Measures: Overall survival. Results: Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH-wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH-wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH-wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH-wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. Conclusions and Relevance: This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH-wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.

Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.

From bench to bedside: trends in National Institutes of Health funding for neurosurgeons from 1991 to 2015.

OBJECTIVE: Neurosurgeons play an important role in advancing medicine through research, the funding of which is historically linked to the National Institutes of Health (NIH). The authors defined variables associated with neurosurgical NIH funding, prevalence of funded topics by neurosurgical subspecialty, and temporal trends in NIH neurosurgical funding. METHODS: The authors conducted a retrospective review of NIH-funded American Association of Neurological Surgeons members using NIH RePORTER (http://report.nih.gov/) for the years 1991-2015. RESULTS: The authors followed 6515 neurosurgeons from 1991 to 2015, including 6107 (94%) non-MD-PhD physicians and 408 (6%) MD-PhDs. NIH grants were awarded to 393 (6%) neurosurgeons, with 23.2% of all first-time grants awarded to the top 5 funded institutions. The average total funded grant-years per funded neurosurgeon was 12.5 (range 1-85 grant-years). A higher percentage of MD-PhDs were NIH funded than MDs (22% [n = 91] vs 5% [n = 297], p < 0.0001). The most common grants awarded were R01 (128, 33%), K08 (69, 18%), F32 (60, 15%), M01 (50, 13%), and R21 (39, 10%). F32 and K08 recipients were 9-fold (18% vs 2%, p < 0.001) and 19-fold (38% vs 2%, p < 0.001) more likely to procure an R01 and procured R01 funding earlier in their careers (F32: 7 vs 12 years after residency, p = 0.03; K08: 9 vs 12 years, p = 0.01). Each year, the number of neurosurgeons with active grants linearly increased by 2.2 (R2 = 0.81, p < 0.001), whereas the number of total active grants run by neurosurgeons increased at nearly twice the rate (4.0 grants/year) (R2 = 0.91, p < 0.001). Of NIH-funded neurosurgical grants, 33 (9%) transitioned to funded clinical trial(s). Funded neurosurgical subspecialties included neuro-oncology (33%), functional/epilepsy (32%), cerebrovascular (17%), trauma (10%), and spine (6%). Finally, the authors modeled trends in the number of active training grants and found a linear increase in active R01s (R2 = 0.95, p < 0.001); however, both F32 (R2 = 0.36, p = 0.01) and K08 (R2 = 0.67, p < 0.001) funding had a significant parabolic rise and fall centered around 2003. CONCLUSIONS: The authors observed an upward trend in R01s awarded to neurosurgeons during the last quarter century. However, their findings of decreased K08 and F32 training grant funding to neurosurgeons and the impact of these training grants on the ultimate success and time to success for neurosurgeons seeking R01 funding suggests that this upward trend in R01 funding for neurosurgeons will be difficult to maintain. The authors' work underscores the importance of continued selection and mentorship of neurosurgeons capable of impacting patient care through research, including the MD-PhDs, who are noted to be more represented among NIH-funded neurosurgeons.

Growth hormone and prolactin-staining tumors causing acromegaly: a retrospective review of clinical presentations and surgical outcomes.

OBJECTIVE: Acromegaly results in disfiguring growth and numerous medical complications. This disease is typically caused by growth hormone (GH)-secreting pituitary adenomas, which are treated first by resection, followed by radiation and/or medical therapy if needed. A subset of acromegalics have dual-staining pituitary adenomas (DSPAs), which stain for GH and prolactin. Presentations and treatment outcomes for acromegalics with DSPAs are not well understood. METHODS: The authors retrospectively reviewed the records of more than 5 years of pituitary adenomas resected at their institution. Data were collected on variables related to clinical presentation, tumor pathology, radiological size, and disease recurrence. The Fisher's exact test, ANOVA, Student t-test, chi-square test, and Cox proportional hazards and multiple logistic regression were used to measure statistical significance. RESULTS: Of 593 patients with pituitary adenoma, 91 presented with acromegaly. Of these 91 patients, 69 (76%) had tumors that stained for GH only (single-staining somatotrophic adenomas [SSAs]), while 22 (24%) had tumors that stained for GH and prolactin (DSPAs). Patients with DSPAs were more likely to present with decreased libido (p = 0.012), signs of acromegalic growth (p = 0.0001), hyperhidrosis (p = 0.0001), and headaches (p = 0.043) than patients with SSAs. DSPAs presented with significantly higher serum prolactin (60.7 vs 10.0 µg/L, p = 0.0002) and insulin-like growth factor-1 (IGF-1) (803.6 vs 480.0 ng/ml, p = 0.0001), and were more likely to have IGF-1 levels > 650 ng/ml (n = 13 [81.3%] vs n = 6 [21.4%], p = 0.0001) than patients with SSAs despite similar sizes (1.8 vs 1.7 cm, p = 0.5). Patients with DSPAs under 35 years of age were more likely to have a recurrence (n = 4 [50.0%] vs n = 3 [11.1%], p = 0.01) than patients with SSAs under the age of 35. DSPA patients were less likely to achieve remission with surgery than SSA patients (n = 2 [20%] vs n = 19 [68%], p = 0.01). Univariate analysis identified single-staining tumors (p = 0.02), gross-total resection (p = 0.02), and tumor diameter (p = 0.05) as predictors of surgical remission. Multiple logistic regression demonstrated that SSAs (p = 0.04) were independently associated with surgical remission of acromegaly. Kaplan-Meier analysis revealed that DSPAs had more time until disease remission (p = 0.033). CONCLUSIONS: Acromegalics with tumors that stain for prolactin and GH, which represented almost a quarter of acromegalics in this cohort, had more aggressive clinical presentations and postoperative outcomes than SSAs. Prolactin staining provides useful information for acromegalics undergoing pituitary surgery.

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.

Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions.

Postoperative Delirium in Glioblastoma Patients: Risk Factors and Prognostic Implications.

BACKGROUND: Delirium is a postoperative neurological morbidity in glioblastoma whose risk factors, incidence, and prognostic implications remain undefined. OBJECTIVE: To develop an algorithm using preoperative factors to predict postoperative delirium. METHODS: Retrospective analysis of 554 consecutive patients (mean age = 61.5 yr; 42% female) undergoing first glioblastoma procedure at our institution 2005 to 2011. RESULTS: Postoperative delirium occurred in 7% of patients (n = 38). Patients undergoing biopsy (10%; n = 54) did not experience delirium. In patients undergoing resection (n = 500), multivariate logistic regression identified 5 factors independently predicting postoperative delirium: age, chronic pulmonary disease, psychiatric history, bihemispheric tumors, and tumor size. We developed a score function entitled "GRAD" (Glioblastoma Risk Assessment for Delirium) to stratify patients into risk categories by assigning point(s) to each preoperative factor based on the relative magnitude of its regression coefficient. Point totals were summed for each patient: patients with 0 to 2 (n = 227) and 3 to 7 (n = 221) points were designated as low and high risk with postoperative delirium rates of 2% vs 15%, respectively (chi-square; P < .001), with the model validated using a separate patient cohort. Postoperative delirium lengthened hospital stays (P < .001), decreased likelihood of discharge home (P < .001), and was independently associated with decreased survival (4.5 vs 13.4 mo; hazard ratio = 1.9 [1.2-2.8]) in multivariate analysis. CONCLUSION: We developed a model to predict development of postoperative delirium using 2 tumor-specific (bihemispheric tumors and tumor size) and 3 patient-specific (age, psychiatric history, and chronic pulmonary disease) factors. High-risk patients and their families should be counseled preoperatively, and this risk could be considered in the choice of biopsy vs resection, and resection patients should be monitored closely postoperatively.

A cross-sectional study of neurosurgical department chairs in the United States.

OBJECTIVEThe position of neurosurgery department chair undergoes constant evolution as the health care landscape changes. The authors' aim in this paper was to characterize career attributes of neurosurgery department chairs in order to define temporal trends in qualities being sought in neurosurgical leaders. Specifically, they investigated the hypothesis that increased qualifications in the form of additional advanced degrees and research acumen are becoming more common in recently hired chairs, possibly related to the increased complexity of their role.METHODSThe authors performed a retrospective study in which they collected data on 105 neurosurgeons who were neurosurgery department chairs as of December 31, 2016, at accredited academic institutions with a neurosurgery residency program in the United States. Descriptive data on the career of neurosurgery chairs, such as the residency program attended, primary subspecialty focus, and age at which they accepted their position as chair, were collected.RESULTSThe median age and number of years in practice postresidency of neurosurgery chairs on acceptance of the position were 47 years (range 36-63 years) and 14 years (range 6-33 years), respectively, and 87% (n = 91) were first-time chairs. The median duration that chairs had been holding their positions as of December 31, 2016, was 10 years (range 1-34 years). The most common subspecialties were vascular (35%) and tumor/skull base (27%), although the tendency to hire from these specialties diminished over time (p = 0.02). More recently hired chairs were more likely to be older (p = 0.02), have more publications (p = 0.007), and have higher h-indices (p < 0.001) at the time of hire. Prior to being named chair, 13% (n = 14) had a PhD, 4% (n = 4) had an MBA, and 23% (n = 24) were awarded a National Institutes of Health R01 grant, tendencies that were stable over time (p = 0.09-0.23), although when additional degrees were analyzed as a binary variable, chairs hired in 2010 or after were more likely to have an MBA and/or PhD versus those hired before 2010 (26% vs 10%, p = 0.04). The 3 most common residency programs attended by the neurosurgery chairs were Massachusetts General Hospital (n = 8, 8%), University of California, San Francisco (n = 8, 8%), and University of Michigan (n = 6, 6%). Most chairs (n = 63, 61%) attended residency at the institution and/or were staff at the institution before they were named chair, a tendency that persisted over time (p = 0.86).CONCLUSIONSMost neurosurgery department chairs matriculated into the position before the age of 50 years and, despite selection processes usually involving a national search, most chairs had a previous affiliation with the department, a phenomenon that has been relatively stable over time. In recent years, a large increase has occurred in the proportion of chairs with additional advanced degrees and more extensive research experience, underscoring how neurosurgical leadership has come to require scientific skills and the ability to procure grants, as well as the financial skills needed to navigate the ever-changing financial health care landscape.

Developing an Algorithm for Optimizing Care of Elderly Patients With Glioblastoma.

BACKGROUND: Elderly patients with glioblastoma have an especially poor prognosis; optimizing their medical and surgical care remains of paramount importance. OBJECTIVE: To investigate patient and treatment characteristics of elderly vs nonelderly patients and develop an algorithm to predict elderly patients' survival. METHODS: Retrospective analysis of 554 patients (mean age = 60.8; 42.0% female) undergoing first glioblastoma resection or biopsy at our institution (2005-2011). RESULTS: Of the 554 patients, 218 (39%) were elderly (≥65 yr). Compared with nonelderly, elderly patients were more likely to receive biopsy only (26% vs 16%), have ≥1 medical comorbidity (40% vs 20%), and develop postresection morbidity (eg, seizure, delirium; 25% vs 14%), and were less likely to receive temozolomide (TMZ) (78% vs 90%) and gross total resection (31% vs 45%). To predict benefit of resection in elderly patients (n = 161), we identified 5 factors known in the preoperative period that predicted survival in a multivariate analysis. We then assigned points to each (1 point: Charlson comorbidity score >0, subtotal resection, tumor >3 cm; 2 points: preoperative weakness, Charlson comorbidity score >1, tumor >5 cm, age >75 yr; 4 points: age >85 yr). Having 3 to 5 points (n = 78, 56%) was associated with decreased survival compared to 0 to 2 points (n = 41, 29%, 8.5 vs 16.9 mo; P = .001) and increased survival compared to 6 to 9 points (n = 20, 14%, 8.5 vs 4.5 mo; P < .001). Patients with 6 to 9 points did not survive significantly longer than elderly patients receiving biopsy only (n = 57, 4.5 vs 2.7 mo; P = .58). CONCLUSION: Further optimization of the medical and surgical care of elderly glioblastoma patients may be achieved by providing more beneficial therapies while avoiding unnecessary resection in those not likely to receive benefit from this intervention.

Atypical pituitary adenoma: a clinicopathologic case series.

OBJECTIVE In 2004, the WHO classified atypical pituitary adenoma as a distinct adenoma subtype. However, the clinical significance of this distinction remains undetermined. The authors sought to define patient characteristics, tumor features, and treatment outcomes associated with atypical pituitary adenoma. METHODS The authors reviewed records of patients who underwent resection of pituitary adenoma at the University of California, San Francisco, between 2007 and 2014. Per institutional protocol, adenomas exhibiting mitotic activity underwent evaluation for all 3 markers of atypicality (mitotic index, extensive p53 staining, and MIB-1 index ≥ 3%). Statistical analyses were performed using χ2, Fisher's exact test, t-test, log-rank, and logistic regression. RESULTS Between 2007 and 2014, 701 patients underwent resection for pituitary adenoma. Among these patients, 122 adenomas exhibited mitotic activity and therefore were evaluated for all 3 markers of atypicality, with 36 tumors (5%) proving to be atypical. There were 21 female patients (58%) and 15 male patients (42%) in the atypical cohort, and 313 female patients (47%) and 352 male patients (53%) in the nonatypical cohort (p = 0.231). The mean age of patients in the atypical cohort was 37 years (range 10-65 years), which was significantly lower than the mean age of 49 years (range 10-93 years) for patients in the nonatypical cohort (p < 0.001). The most common presenting symptoms for patients with atypical adenomas were headaches (42%) and visual changes (33%). Atypical adenomas were more likely to be functional (78%) than nonatypical adenomas (42%; p < 0.001). Functional atypical adenomas were significantly larger than functional nonatypical adenomas (mean diameter 2.2 vs 1.4 cm; p = 0.009), as were nonfunctional atypical adenomas compared with nonfunctional nonatypical adenomas (mean diameter 3.3 vs 2.3 cm; p = 0.01). Among the entire adenoma cohort, larger presenting tumor size was associated with cavernous sinus invasion (p < 0.001), and subtotal resection was associated with cavernous sinus invasion (p < 0.001) and larger size (p < 0.001) on binomial multivariate regression. The median time until recurrence was 56 months for atypical adenomas, 129 months for functional nonatypical adenomas, and 204 months for nonfunctional nonatypical adenomas (p < 0.001). Functional atypical adenomas recurred more frequently and significantly earlier than functional nonatypical adenomas (p < 0.001). When accounting for extent of resection, cavernous sinus invasion, size, age, sex, and functional subtype, atypicality remained a significant predictor of earlier recurrence among functional adenomas (p = 0.002). CONCLUSIONS When compared with nonatypical pituitary adenomas, atypical adenomas are more likely to present in younger patients at a larger size, are more often hormonally hypersecretory, and are associated with earlier recurrence. These features lend credence to atypical pituitary adenomas being a distinct clinical entity in addition to a discrete pathological diagnosis.

Cross-activating c-Met/ß1 integrin complex drives metastasis and invasive resistance in cancer.

The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/ß1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/ß1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/ß1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and ß1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/ß1 complex to maintain the high-affinity ß1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/ß1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from ß1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5ß1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/ß1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.

Improved Survival with Decreased Wait Time to Surgery in Glioblastoma Patients Presenting with Seizure.

BACKGROUND: Preoperative seizure is reported to confer favorable prognosis in glioblastoma patients, but studies to date have not investigated how broadly applicable seizure is as a prognostic factor. OBJECTIVE: To investigate if prompter surgical intervention affects the relationship between preoperative seizure and prognosis in glioblastoma patients, focusing on the development of tumor growth and/or additional preoperative symptoms after seizure. METHODS: Retrospective analysis of 443 patients (mean age = 60.2; 60% male) undergoing first glioblastoma resection at our institution (2005-2011). RESULTS: Preoperative seizure(s) occurred in 28% of patients (n = 124), of which 63 (51%) had only seizure at presentation. Patients experiencing seizure as their only preoperative symptom ("seizure-only"; n = 45) survived over twice as long as patients who presented with seizure and then later developed additional preoperative symptoms (n = 18; "other symptoms postseizure"; 26.8 vs 10.2 months, P < .001) and patients without preoperative seizure ("no seizure"; 26.8 vs 13.1 months, P < .001). Multivariate stepwise analysis revealed preoperative seizures only (hazard ratio 0.54 [0.37-0.75]; P < .001) to be independently associated with increased survival. Longer wait time from presentation (ie, diagnostic magnetic resonance imaging) to surgery was a risk factor for developing additional symptoms. Eleven "other symptoms postseizure" patients (69%) vs 6 of the "seizure-only" patients (15%) had wait times >45 days (P < .001). CONCLUSION: Seizure as the only preoperative symptom independently improved survival, however, when patients developed additional preoperative symptoms, typically due to surgical delay, no prognostic benefit was observed. Prompt diagnosis and neurosurgical intervention is warranted in patients with seizures without other preoperative symptoms to preserve their favorable prognosis.