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OBJECTIVE Excision of intracranial meningiomas often requires resection or coagulation of the dura mater. The choice of dural closure technique is individualized and based on surgeon preference. The objective of this study was to determine outcomes following various dural closure techniques for supratentorial meningiomas. METHODS A retrospective, single-center cohort study was performed for patients who underwent excision of supratentorial meningiomas from 2000 to 2019. Outcomes including operative time, postoperative in-hospital complications, readmission, causes of readmission including surgical site infection, pseudomeningocele, need for shunt surgery, and imaging appearance of pseudomeningocele on long-term follow-up imaging were compared. Univariate and multivariable analyses were conducted. RESULTS A total of 353 patients who had complete clinical and operative data available for review were included. Of these patients, 227 (64.3%) had nonsutured dural graft reconstruction and 126 (35.7%) had sutured dural repair, including primary closure, artificial dura, or pericranial graft. There was significant variability in using nonsutured dural reconstruction compared with sutured dural repair technique among surgeons (p < 0.001). Tumors with sagittal sinus involvement were more likely to undergo nonsutured closure (n = 79, 34.8%) than dural repair (n = 26, 20.6%) (p = 0.003). There were no other differences in preoperative imaging findings or WHO grade. Frequency of surgical site infection and pseudomeningocele, need for shunt surgery, and recurrence were similar between those undergoing nonsutured and those undergoing sutured dural repair. The mean operative time for the study cohort was 234.9 (SD 106.6) minutes. The nonsutured dural reconstruction group had a significantly shorter mean operative time (223.9 [SD 99.7] minutes) than the sutured dural repair group (254.5 [SD 115.8] minutes) (p = 0.015). In a multivariable linear regression analysis, after controlling for tumor size and sinus involvement, nonsutured dural graft reconstruction was associated with a 36.8-minute reduction (95% CI −60.3 to −13.2 minutes; p = 0.002) in operative time. CONCLUSIONS Dural reconstruction using a nonsutured graft and sutured dural repair exhibit similar postoperative outcomes for patients undergoing resection for supratentorial meningiomas. Although sutured grafts may sometimes be necessary, nonsutured graft reconstruction for most supratentorial meningioma resections may suffice. The decreased operative time associated with nonsutured grafts may ultimately result in cost savings. These findings should be taken into consideration when selecting a dural reconstruction technique for supratentorial meningioma.

Patients with mild traumatic brain injury (TBI) and intracranial hemorrhage often receive neurosurgical consultation. However, only a small proportion of patients require intervention. Our hypothesis is that low-risk minimal TBI patients managed without immediate neurosurgical consultation will have a reasonable safety and effectiveness outcome profile.A non-neurosurgical management protocol for adult minimal TBI was implemented at a level I trauma center as an interdisciplinary quality-improvement initiative in November 2018. Minimal TBI was defined as Glasgow Coma Scale (GCS) of 15 secondary to blunt mechanism, without anticoagulant or antiplatelet therapy, and isolated pneumocephalus and/or traumatic subarachnoid hemorrhage on head CT imaging. Safety was assessed by in-hospital mortality, neurosurgical interventions, and ED revisits within two weeks of discharge. Effectiveness was assessed by neurosurgical consult rate and length of stay. Outcomes were compared 8-months pre- and post-protocol implementation.A total of 97 patients were included, of which 49 were pre-protocol and 48 were post-protocol There was no difference in rates of in-hospital mortality [0 (0%) vs 0 (0%)], neurosurgical procedure [1 (2.1%) vs 0 (0%)], operations [0 (0%) vs 0 (0%)], and ED revisits [1 (2.0%) vs 2 (4.2%), p = 0.985] between the periods. There was a significant reduction in neurosurgical consults post-protocol implementation (92% vs 29%, p0.001).A protocol for minimal TBI patients effectively reduced neurosurgical consultation without changes in safety profile. Such an interdisciplinary management protocol for low-risk neurotrauma can effectively utilize the neurosurgery consult services by stratifying neurologically stable TBI patient.

Acute subdural hematoma is a neurosurgical emergency. Thrombocytopenia poses a management challenge for these patients. We aimed to determine the impact of thrombocytopenia on preoperative hemorrhage expansion and postoperative outcomes.This retrospective study evaluated patients presenting at our institution with acute subdural hematoma between 2009 and 2019. Patients who underwent surgery, had thrombocytopenia (platelets150,000/μL), and had multiple preoperative computed tomography scans were included. Case control 1:1 matching was performed to generate a matched cohort with no thrombocytopenia. Univariate analyses were conducted to determine changes in subdural thickness and midline shift, postoperative Glasgow Coma Scale score, mortality, length of stay, and readmission rates.We identified 19 patients with both thrombocytopenia and multiple preoperative computed tomography scans. Median platelet count was 112,000/μL (Q1 69,000, Q3 127,000). Comparing the thrombocytopenia cohort with the control group, there was a statistically significant difference in change in subdural thickness (median 5 mm [Q1 2, Q3 7.4] vs. 0 mm [Q1 0, Q3 1.5]; P = 0.001) and change in midline shift (median 3 mm [Q1 0, Q3 9.5] vs. median 0.5 mm [Q1 0, Q3 1.5]; P = 0.018). The thrombocytopenia cohort had higher in-hospital mortality (10 [52.6%] vs. 2 [10.5%]; P = 0.003). No significant differences were found in postoperative Glasgow Coma Scale score, length of stay, number of readmissions, and number of reoperations.Thrombocytopenia is significantly associated with expansion of hematoma preoperatively in patients with acute subdural hematoma. While the benefit of early platelet correction cannot be determined from this study, patients who present with thrombocytopenia will benefit from close monitoring, a low threshold to obtain repeat imaging, and anticipating early surgical evacuation after platelet optimization.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

PDF file - 1 MB, Immunoblotting of c-Myc in (A) T4302 CD133+ cells or (B) T4302 CD133-cells treated with JQ1 for 24 hours at indicated concentrations.

Purpose: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma.Experimental Design: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped.Results: From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10−6). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10−4). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10−7).Conclusion: The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies. Clin Cancer Res; 18(11); 3154–62. ©2012 AACR.

Purpose: Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples.Experimental Design: The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.Results: We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21CIP1/WAF1, hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21CIP1/WAF1 attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors.Conclusion: Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors. Clin Cancer Res; 19(7); 1748–59. ©2013 AACR.

PDF file - 1 MB, (A) T4302 CD133+ cells were infected with lentivirus directing expression of non-targeting (NT) shRNA or p53-specific shRNA. Downregulation of p53 was determined by immunoblotting 24 hours after JQ1 treatment. (B) Rb expression was determined by qRT-PCR in T4302 CD133+ cells expressing NT shRNA or Rb-specific shRNA. (C) Immunoblotting of Bcl-xL in T4302 CD133+ cells infected with control lentivirus or virus directing expression of Bcl-xL. (D) Immunoblotting of p21 in T4302 CD133+ cells expressing NT shRNA or p21-specific shRNA.

PDF file - 3 MB, (A) The relative growth rates of T4597 tumors were determined as the weekly fold increases in bioluminescence intensity of individual tumors. Data shown were the mean � SEM (n=10). (B) The median bioluminescence intensities were generated from all 10 tumors in each arm. *: p< 0.05 by student's t-test.

PDF file - 4 MB, (A) Reduced expression of BRD2, BRD3, BRD4 following expression of corresponding shRNA sequences was determined by qRT-PCR in T4302 CD133+ cells. Cell growth was measured for 5 days following knockdown of (B) BRD2, (C) BRD3, or (D) BRD4 in T4302 CD133+ cells as described in Figure 2A.

PDF file, 406KB, Supplementary Table 1.115 TCGA SOC sample IDs used in the validation phase.; Supplementary Table 2. Proportionality tests based on the scaled Schoenfeld residules for the SNP effect in the log-additive Cox Proportional Hazards model adjusted for age and sex.; Supplementary Table 3. Validation of survival association with three SNPs in glioblastoma multiforme patients from three independent studies (Mayo Clinic10, GliomaSE11 and The Cancer Genome Atlas (TCGA17); Supplementary Table 4. Imputation analyiss of SSBP2 region:chr5: 80,680,000 -- 80,980,000, University of California, San Francisco Adult Glioma Study (AGS), Mayo Clinic, and The MACH, Hapmap 2, human genome build 18, 3 sites (University of California, San Francisco, Mayo Clinic and The Cancer Genome Atlas).

Supplementary Table 1. EGFR and PTEN mutational status in glioblastoma samples; Supplementary Figure 1. Expression of EGFR in glioblastoma cells cultured in serum-free medium; Supplemental Figure 2. Insulin, IGF1, and PDGF-AB confers resistance to gefitinib; Supplemental Figure 3. Inhibition of InsR/IGF1R improves response to EGFR inhibitors in Glioblastoma; Supplemental Figure 4. (A) GBM46 cells were starved overnight and stimulated with100 ng/ml insulin, IGF1 or EGF for 30 minutes in the presence of absence of 1 �M gefitinib. (B) GBM12 and (C) GBM46 were treated with gefitinib {plus minus} OSI-906 for 24 hours and collected for immunoblotting; Supplemental Figure 5. (A) GBM12 GBM39 were infected with control lentivirus or lentivirus directing expression of Myr-AKT1 and selected with puromycin for 2 days; Supplemental Figure 6. Inhibition of the PI3K/AKT pathway sensitizes glioblastoma cells to EGFR Inhibitors; Supplemental Figure 7. (A) PC9 cells were treated with gefitinib {plus minus} OSI-906 and cellular response was determined as described in Fig. 2A; Supplemental Figure 8. (A) Animals bearing GBM76 and (B) GBM39 subcutaneous tumors were treated as described in Fig. 4 and methods. Median animal weights throughout the course of treatment were presented.

PDF file - 4 MB, (A) Normal human neural progenitor (NHNP) cells were treated with JQ1 at various concentrations as indicated. Five days after treatment, cell viability was determined by the CellTiter-Glo assay kit and normalized to the values of vehicle-treated cells. (B) Three days after JQ1 treatment, caspase activity was determined as described in Figure 2B

PDF file - 21 KB, Real-time PCR primers used in this study.

Purpose: Aberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma.Experimental Design: We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy cotargeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R).Results: Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not express InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors.Conclusions: Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma. Clin Cancer Res; 22(7); 1767–76. ©2015 AACR.

PDF file - 5 MB, (A) Dose-response curves of JQ1 in match CD133+ and CD133- cells enriched from the T4105 or T4597 primary glioblastoma xenograft lines. (B) Growth rates of T4302 CD133+ cells for 5 days were measured in the presence of JQ1 at indicated concentrations. (C) Dose-response curve of (-)-JQ1 in T4302 CD133+ cells. (D) Dose-response curve of PFI-1 in T4302 CD133+ cells. (E) T4302 CD133+ cells were treated by JQ1 for 72 hours at indicated concentrations.

Introduction The middle fossa craniotomy (MFCs) is commonly utilized for spontaneous cerebrospinal fluid (CSF) leaks, encephaloceles, and superior semicircular canal dehiscence (SSCD). This study compares postoperative outcomes of MFCs with and without LD use. Methods A retrospective cohort study of adults over the age of 18 years presenting for the repair of nonneoplastic CSF leak, encephalocele, or SSCD via MFC from 2009 to 2021 was conducted. The main exposure of interest was the placement of an LD. The primary outcome was the presence of postoperative complications (acute/delayed neurologic deficit, meningitis, intracranial hemorrhage, and stroke). Secondary outcomes included operating room (OR) time, length of stay, recurrence, and need for reoperation. Results In total, 172 patients were included, 96 of whom received an LD and 76 who did not. Patients not receiving an LD were more likely to receive intraoperative mannitol (n = 24, 31.6% vs. n = 16, 16.7%, p = 0.02). On univariate logistic regression, LD placement did not influence overall postoperative complications (OR: 0.38, 95% confidence interval [CI]: 0.05–2.02, p = 0.28), CSF leak recurrence (OR: 0.75, 95% CI: 0.25–2.29, p = 0.61), or need for reoperation (OR: 1.47, 95% CI: 0.48–4.96, p = 0.51). While OR time was shorter for patients not receiving LD (349 ± 71 vs. 372 ± 85 minutes), this difference was not statistically significant (p = 0.07). Conclusion No difference in postoperative outcomes was observed in patients who had an intraoperative LD placed compared to those without LD. Operative times were increased in the LD cohort, but this difference was not statistically significant. Given the similar outcomes, we conclude that LD is not necessary to facilitate safe MCF for nonneoplastic skull base pathologies.

Barth Syndrome is an X-linked disorder of mitochondrial cardiolipin metabolism caused by pathogenic variants in TAFAZZIN with pleiotropic effects including cardiomyopathy, neutropenia, growth delay, and skeletal myopathy. Management requires a multidisciplinary approach to the organ-specific manifestations including specialists from cardiology, hematology, nutrition, physical therapy, genetics, and metabolism. Currently, treatment is centered on management of specific clinical features, and is not targeted towards remediating the underlying biochemical defect. However, two clinical trials have been recently undertaken which target the mitochondrial pathology of this disease: a study to examine the effects of elamipretide, a cardiolipin targeted agent, and a study to examine the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist. Treatments to directly target the defective TAFAZZIN pathway are under development, including enzyme and gene therapies. This article is protected by copyright. All rights reserved.

ImportanceGlioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.ObjectiveTo investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.Design, Setting, and ParticipantsThis phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.InterventionsThe active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.Main Outcomes and MeasuresThe primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.ResultsA total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P P = .03).Conclusions and RelevanceIn this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.Trial RegistrationClinicalTrials.gov Identifier: NCT00045968

OBJECTIVE To determine the influence extent of resection and tumor characteristics on facial nerve (FN) outcomes following microsurgical resection of vestibular schwannoma (VS). STUDY DESIGN Retrospective chart review. SETTING Tertiary referral center. PATIENTS Three hundred eighty-five patients who underwent VS microsurgical resection. INTERVENTIONS Microsurgical VS resection. MAIN OUTCOME MEASURES House-Brackmann (HB) scores postoperatively. Good FN function was defined as HB grade I and II and poor FN function was defined as HB grade III and VI. Gross total resection (GTR) versus subtotal resection (STR). Propensity-score matching was used in subset analysis to balance tumor volume between the surgical cohorts, followed by multivariable analysis. RESULTS Seventy-one patients (18%) underwent STR and 314 patients (82%) underwent GTR. Two hundred fourteen patients (63%) had good FN function at 2 to 3 weeks postoperatively, and 80% had good FN function at 1 year. In single predictor analysis, STR did not influence FN function at 2 to 3 weeks (p = 0.65). In propensity-score matched subset analysis (N = 178), patients with STR were less likely to have poor FN function at 2 to 3 weeks (p = 0.02) independent of tumor volume (p = 0.004), but there was no correlation between STR and FN function at 1 year (p = 0.09). Ventral extension of tumor relative to the internal auditory canal plane was associated with poor FN outcomes at 2 to 3 weeks (p = 0.0001) and 1-year postop (p = 0.002). CONCLUSIONS When accounting for tumor volume, STR is protective in immediate postoperative FN function compared to GTR. Ventral extension of the tumor is a clinical predictor of long-term FN outcomes.

To compare postoperative outcomes after cranioplasties performed by neurosurgery only (N) versus neurosurgery and plastic surgery combined (N+P).A single-center, multi-surgeon, retrospective cohort study was undertaken on all cranioplasties performed from 11/2006-12/2021. The primary exposure variable was operating team (N vs. N+P). The primary outcome was the need for reoperation. Secondary outcomes included surgical site infections, complications, length of stay (LOS), and length of drain placement.Of 188 patients undergoing cranioplasty during the study period, 106(56%) patients were in the N group, and 82(44%) in the N+P group. Patient demographics were similar between the two groups. For the primary outcome, a total of 20(18.9%) reoperations were seen in the N group, and 13(15.9%) in the N+P group (p=0.708). However, the median time to reoperation was slightly longer in the N+P group in the survival analysis. Wound dehiscence (1.9% vs. 3.7%,p=0.454), surgical site infection (5.7% vs. 9.8%,p=0.289) and complication rate (30.2% vs. 32.9%,p=0.688) did not differ between the two groups. Furthermore, N group had less JP drain use (58.5% vs. 85.4%,p0.001), earlier drain removal (1.9±1.6 vs. 3.4±3.9days, p0.001), and shorter LOS (3.8±5.9 vs 4.7±3.9days, p0.001). On multivariate regression analysis controlling for age, BMI, smoking, craniectomy type, reason for craniectomy, and graft type, N+P was associated with increased drain use (OR=4.90, 95%CI=2.28-11.30, p0.001) and longer drain duration (β=1.50, 95%CI=0.43-2.60, p=0.007).Despite similar complication and reoperation rates between groups, reoperations in the N group occurred sooner, whereas N+P group more commonly used drains and kept drains in for longer.

OBJECTIVE The number of unsolicited patient complaints (UPCs) about surgeons correlates with surgical complications and malpractice claims. Using a large, national patient complaint database, the authors sought to do the following: 1) compare the rates of UPCs for neurosurgeons to those for other physicians, 2) analyze the risk of UPCs with individual neurosurgeon characteristics, and 3) describe the types of UPCs made about neurosurgeons. METHODS Patient and family complaint reports among 36,265 physicians, including 423 neurosurgeons, 8292 other surgeons, and 27,550 nonsurgeons who practiced at 33 medical centers (22 academic and 11 regional) from January 1, 2014, to December 31, 2017, were coded with a previously validated Patient Advocacy Reporting System (PARS) algorithm. RESULTS Among 423 neurosurgeons, 93% were male, and most (71%) practiced in academic medical centers. Neurosurgical subspecialties included general practice (25%), spine (25%), tumor (16%), vascular (13%), functional (10%), and pediatrics (10%). Neurosurgeons had more average total UPCs per physician (8.68; 95% CI 7.68–9.67) than nonsurgeons (3.40; 95% CI 3.33–3.47) and other surgeons (5.01; 95% CI 4.85–5.17; p < 0.001). In addition, a significantly higher percentage of neurosurgeons received at least one UPC (71.6%; 95% CI 67.3%–75.9%) than did nonsurgeons (50.2%; 95% CI 49.6%–50.8%) and other surgeons (58.2%; 95% CI 57.1%–59.3%; p < 0.001). Factors most associated with increased average UPCs were younger age, measured as median medical school graduation year (1990.5 in the 0-UPC group vs 1993 in the 14+-UPC group, p = 0.009) and spine subspecialty (13.4 mean UPCs in spine vs 7.9 mean UPCs in other specialties, 95% CI 2.3–8.5, p < 0.001). No difference in complaints was seen in those who graduated from non-US versus US medical schools (p = 0.605). The most common complaint types were related to issues surrounding care and treatment, communication, and accessibility, each of which was significantly more common for neurosurgeons than other surgical specialties (p < 0.001). CONCLUSIONS Neurosurgeons were more likely to generate UPCs than other surgical specialties, and almost 3 out of 4 neurosurgeons (71.6%) had at least one UPC during the study period. Prior studies have shown that feedback to physicians about behavior can result in fewer UPCs. These results suggest that neurosurgeons have opportunities to reduce complaints and potentially improve the overall quality of care delivered.

Introduction Cystic meningiomas are rare, accounting for 2–7% of all intracranial meningiomas. Little is known regarding whether these meningiomas behave differently compared to solid meningiomas. We sought to study this relatively uncommon imaging appearance of meningioma and to evaluate its clinical significance. Methods A single-institution retrospective cohort study of surgically-treated meningioma patients between 2000–2019 was conducted. Cystic meningioma was defined as a tumor with an intratumoral or peritumoral cyst present on preoperative imaging. Demographics, preoperative imaging, histopathology characteristics, operative data, and surgical outcomes were reviewed. Imaging variables, histopathology and outcomes were reported for cystic meningiomas and compared with non-cystic meningiomas. Univariate/multivariable analyses were conducted. Results Of 737 total meningiomas treated surgically, 38 (5.2%) were cystic. Gross total resection (GTR) was achieved in 84.2% of cystic meningioma patients. Eighty-two percent of cystic meningiomas were WHO grade I (n = 31), 15.7% were grade II and 2.6% were grade III. Most cystic meningiomas had low Ki-67/MIB-1 proliferation index (n = 24, 63.2%). A total of 18.4% (n = 7) patients with cystic meningioma had recurrence compared to 12.2% (n = 80) of patients with non-cystic meningioma (p = 0.228). No significant difference in median time to recurrence was observed between cystic and non-cystic meningiomas (25.4, Q1:13.9, Q3:46.9 months vs. 13.4, Q1:8.6, Q3:35.5 months, p = 0.080). Conclusions A small portion of intracranial meningiomas have cystic characteristics on imaging. Cystic meningiomas are frequently WHO grade I, have low proliferation index, and had similar postoperative outcomes compared to non-cystic meningiomas, suggesting that cysts in meningioma may not be as aggressive a feature as previously thought.

Cystic meningiomas are rare, accounting for 2-7% of all intracranial meningiomas. Little is known regarding whether these meningiomas behave differently compared to solid meningiomas. We sought to study this relatively uncommon imaging appearance of meningioma and to evaluate its clinical significance.A single-institution retrospective cohort study of surgically-treated meningioma patients between 2000 and 2019 was conducted. Cystic meningioma was defined as a tumor with an intratumoral or peritumoral cyst present on preoperative imaging. Demographics, preoperative imaging, histopathology characteristics, operative data, and surgical outcomes were reviewed. Imaging variables, histopathology and outcomes were reported for cystic meningiomas and compared with non-cystic meningiomas. Univariate/multivariable analyses were conducted.Of 737 total meningiomas treated surgically, 38 (5.2%) were cystic. Gross total resection (GTR) was achieved in 84.2% of cystic meningioma patients. Eighty-two percent of cystic meningiomas were WHO grade I (n = 31), 15.7% were grade II and 2.6% were grade III. Most cystic meningiomas had low Ki-67/MIB-1 proliferation index (n = 24, 63.2%). A total of 18.4% (n = 7) patients with cystic meningioma had recurrence compared to 12.2% (n = 80) of patients with non-cystic meningioma (p = 0.228). No significant difference in median time to recurrence was observed between cystic and non-cystic meningiomas (25.4, Q1:13.9, Q3:46.9 months vs. 13.4, Q1:8.6, Q3:35.5 months, p = 0.080).A small portion of intracranial meningiomas have cystic characteristics on imaging. Cystic meningiomas are frequently WHO grade I, have low proliferation index, and had similar outcomes compared to non-cystic meningioma. Cysts in meningioma may not be a surrogate to determine aggressive meningioma behavior.

BACKGROUND: Cerebral vasospasm is a major contributor to disability and mortality after aneurysmal subarachnoid hemorrhage. Oxidation of cell-free hemoglobin plays an integral role in neuroinflammation and is a suggested source of tissue injury after aneurysm rupture. This study sought to determine if patients with subarachnoid hemorrhage and cerebral vasospasm were more likely to have been exposed to early hyperoxemia than those without vasospasm. METHODS: This single-center retrospective cohort study included adult patients presenting with aneurysmal subarachnoid hemorrhage to Vanderbilt University Medical Center between January 2007 and December 2017. Patients with an ICD-9/10 diagnosis of aneurysmal subarachnoid hemorrhage were initially identified (N=441) and subsequently excluded if they did not have intracranial imaging, arterial PaO(2) values, or died within 96 hours post-rupture (N=96). The final cohort was 345 subjects. The degree of hyperoxemia was defined by the highest PaO(2) measured within 72 hours after aneurysmal rupture. The primary outcome was development of cerebral vasospasm, which included asymptomatic vasospasm and delayed cerebral ischemia (DCI). Secondary outcomes were mortality and modified Rankin Scale. RESULTS: 345 patients met inclusion criteria; 218 patients (63%) developed vasospasm. Of those that developed vasospasm, 85 were diagnosed with delayed cerebral ischemia (DCI, 39%). The average patient age of the cohort was 55±13 years, and 68% were female. Ninety percent presented with Fisher Grade 3 or 4 hemorrhage (N=310) while 42% presented as Hunt-Hess Grade 4 or 5 (N=146). In univariable analysis, patients exposed to higher levels of PaO(2) by quintile of exposure had a higher mortality rate and were more likely to develop vasospasm in a dose-dependent fashion (P=0.015 and P=0.019, respectively). There were no statistically significant predictors that differentiated asymptomatic vasospasm from DCI and no significant difference in maximum PaO(2) between these two groups. In multivariable analysis, early hyperoxemia was independently associated with vasospasm (OR=1.15 per 50 mmHg increase in PaO2 [1.03, 1.28]; P=0.013), but not mortality (OR=1.10 [0.97, 1.25]; P=0.147) following subarachnoid hemorrhage. CONCLUSIONS: Hyperoxemia within 72 hours post-aneurysmal rupture is an independent predictor of cerebral vasospasm, but not mortality in subarachnoid hemorrhage. Hyperoxemia is a variable that can be readily controlled by adjusting the delivered FiO(2) and may represent a modifiable risk factor for vasospasm.

Tumor-induced osteomalacia (TIO) is a rare disease in which patients suffer from fractures and progressive disabling bone pain and muscle weakness. TIO is caused by the hypersecretion of Fibroblast Growth Factor 23 (FGF23) from rare neoplasms of mesenchymal origin. This case report describes a 29-year-old male with 2 years of low back/hip pain, gait changes, proximal muscle weakness, and multiple stress fractures. Bone densitometry was remarkable for severe osteoporosis, hypophosphatemia was seen on routine labs, and advanced labs demonstrated an “inappropriately normal” FGF23 level. A 68Ga-DOTATATE scan and MRI showed a 1.3 × 1.1 × 1.0 cm intracranial mass. The patient underwent tumor resection by Neurosurgery. Shortly after, laboratory levels normalized, and the patient's symptoms improved drastically. This case exemplifies the notion that TIO can be caused by FGF23 levels within normal limits, the role of 68-Ga DOTATATE imaging for establishing a diagnosis, and that these tumors can arise anywhere—even intracranially. We also review current surgical and nonsurgical treatment options, as well as emerging novel therapeutics. Keywords: TIO, Paraneoplastic syndrome, Tumor-induced osteomalacia, Fibroblast growth factor 23, 68Ga-DOTATATE, MRI, DXA, Burosumab

Glioblastomas (GBM) are tumors for which immune-targeted therapies have failed to show clinical benefit and for which few biomarkers provide context for meaningful therapeutic stratification. Radiographic contact of GBM tumors with the lateral ventricle stem cell niche correlates with worse patient prognosis; however, the extent to which proximity to the ventricle impacts antitumor immunity remains unknown. We demonstrate that T cell checkpoint receptor expression is elevated in ventricle-contacting GBM as is the abundance of a specific, suppressive CD32+CD44+HLADhigh myeloid population suggesting a distinct immunoregulatory influence on antitumor immunity in proximity to the lateral ventricle. Phospho-specific mass cytometric profiling revealed extensively impaired immune signaling in ventricle-contacting GBM in response to inflammatory cytokine stimulation, further supporting a suppressive milieu influencing immunity at the lateral ventricle. Collectively, we identify a regulatory impact of ventricle contact on antitumor immunity in the brain, and reveal novel clinically targetable mechanisms of immunomodulation in patients with glioblastoma.Significance StatementWe demonstrate that the immune microenvironment of glioblastoma tumors contacting the lateral ventricle differs from non-contacting tumors. This work connects immune-biology to a radiographically detectable feature, the lateral ventricle, and highlights non-invasive imaging as a means to identify targetable immune features in glioblastoma tumors.