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BACKGROUND Migratory disc herniations can mimic neoplasms clinically and on imaging. Far lateral lumbar disc herniations usually compress the exiting nerve root and can be challenging to distinguish from a nerve sheath tumor due to the proximity of the nerve and characteristics on magnetic resonance imaging (MRI). These lesions can occasionally present in the upper lumbar spine region at the L1–2 and L2–3 levels. OBSERVATIONS The authors describe 2 extraforaminal lesions in the far lateral space at the L1–2 and L2–3 levels, respectively. On MRI, both lesions tracked along the corresponding exiting nerve roots with avid postcontrast rim enhancement and edema in the adjacent muscle tissue. Thus, they were initially concerning for peripheral nerve sheath tumors. One patient underwent fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET-CT) screening and demonstrated moderate FDG uptake on PET-CT scan. In both cases, intraoperative and postoperative pathology revealed fibrocartilage disc fragments. LESSONS Differential diagnosis for lumbar far lateral lesions that are peripherally enhancing on MRI should include migratory disc herniation, regardless of the level of the disc herniations. Accurate preoperative diagnosis can aid in decision making for management, surgical approach, and resection.

Background Superior semicircular canal dehiscence (SSCD) is an abnormality of the otic capsule, which normally overlies the superior semicircular canal. Surgical management is indicated in patients with persistent and debilitating symptoms. Given the complexity of the disease, there are patients who experience less favorable surgical outcomes and require revision surgery. The purpose of this study was to report to the rate of postoperative symptomatic improvement in patients who required revision surgery. Methods A retrospective analysis of patients undergoing SSCD surgical repair at a single institution was performed. Information on patient demographics, primary and secondary surgical approaches, surgical outcomes, and follow-up length was collected. Results Seventeen patients underwent 20 revision surgeries. There were eleven (65%) females and six (35%) males. Mean age of the cohorts was 50 years (range 30−68 years), and mean follow-up length was 6.8 months (range 0.1−31.1 months). Cerebrospinal fluid leak was noted in 67% of cases. The greatest postoperative symptomatic resolution was reported in oscillopsia (100%), headache (100%), and internal sound amplification (71%), while the least postoperative symptomatic resolution was reported in tinnitus (42%), aural fullness (40%), and dizziness (29%). Conclusions Revision surgery can provide symptomatic improvement in select SSCD patients; however, patients should be cautioned about the possibility of less favorable outcomes than in index surgery. Revision surgeries are associated with a considerably higher rate of perioperative cerebrospinal fluid leak.

There is no consensus on the management of post-craniotomy pain. Several randomized controlled trials have examined the use of a regional scalp block for post-craniotomy pain. We aim to investigate whether scalp block affected short or long-term pain levels and opioid use after craniotomy. This study prospectively administered selective scalp blocks (lesser occipital, preauricular nerve block + pin site block) in 20 consecutive patients undergoing craniotomy for semicircular canal dehiscence. Anesthesia, pain, and opioid outcomes in these patients were compared to 40 consecutive historic controls. There was no significant difference in patient demographics between the two groups and no complications related to selective scalp block. The time between the end of procedure and end of anesthesia decreased in the scalp block group (16 vs 21 min, P = 0.047). Pain scores were significantly less in the scalp block group for the first 4 h, after which there was no statistically significant difference. Time to opioid rescue was longer in the scalp block group (3.6 vs 1.8 h, HR 0.487, P = 0.0361) and opioid use in the first 7 h was significantly less in the scalp block group. Total opioid use, outpatient opioid use, and length of stay did not differ. Selective scalp block is a safe and effective tool for short-term management of postoperative pain after craniotomy and decreases the medication requirement during emergence and recovery. Selective scalp block can speed up OR turnover but is not efficacious in the treatment of postoperative pain beyond this point.

PURPOSE: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature. METHODS: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression. RESULTS: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression. CONCLUSION: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.

Background Superficial temporal artery (STA)-to−middle cerebral artery bypass is frequently performed for moyamoya disease. We discuss an unusual case in a moyamoya patient complicated by the development of dural and pial arteriovenous fistulae (AVF). Both AVF then spontaneously resolved 2 years after surgery. Case Description A patient in the fifth decade of life presented after multiple strokes resulting in right-sided weakness and numbness. Magnetic resonance imaging revealed remote strokes, and angiography revealed Suzuki grade 3 moyamoya angiopathy bilaterally. With a diminutive left STA, we initially performed left-sided dual-vessel pial synangioses. After radiographic evidence of robust revascularization and improved hemispheric perfusion, a combined right STA−middle cerebral artery bypass was done. However, routine 8-month postoperative angiography identified dural and pial AVF within the prior operative field. On the 2-year surveillance cerebral angiogram, both AVF were no longer present. Conclusions AVF as a complication of revascularization surgery is rare. Here, we discuss the possible pathophysiologic mechanisms that we theorize may have contributed and current treatment options and indications. We also review the literature surrounding this phenomenon.

Background Superior semicircular canal dehiscence (SSCD) is a rare inner ear disorder; currently, it is unknown whether the etiopathology underlying this structural irregularity affects neighboring structures. The goal is to investigate the prevalence of bone thinning in areas of the middle cranial fossa (MCF) floor in SSCD and non-SSCD patients. Methods This retrospective study analyzed 100 patients from March 2011 to June 2017 at a tertiary referral center. 100 patients undergoing 118 SSCD repair surgeries (18 bilateral) were identified. 12 SSCD ears were excluded due to lack of pre-operative computed tomography (CT) scans or history of prior SSCD repair at an outside facility. Non-SSCD ears were identified from routinely-obtained CT scans for temporal bone fracture (fractured sides excluded) for a total of 101 ears; 26 non-SSCD ears were excluded due to lack of high-resolution imaging. Results Univariate analyses reveal that SSCD diagnosis is associated with higher rates of geniculate ganglion (GG) dehiscence compared with non-SSCD controls (42.7 vs. 24%; χ 2 (1) = 9.69, P = 0.008). Individuals with SSCD depicted significantly thinner bone overlying the geniculate ganglion (GG) (0.23 ± 1.2 mm) compared to controls (0.28 ± 1.8 mm, (t(1 6 4)) = 2.1, P = 0.04). SSCD patients presented thinner bone overlying the internal auditory canal (IAC) (0.33 ± 1.3 mm) compared to patients without SSCD (0.46 ± 1.6 mm, (t(2 5 7) = 6.4, P Conclusions The increased prevalence of dehiscence of the MCF in this cohort of SSCD patients compared to non-SSCD patients suggests that the etiology underlying SSCD affects surrounding structures.

Background Superior semicircular canal dehiscence (SSCD) is an osseous defect of the arcuate eminence of the petrosal temporal bone. Patients typically present with auditory and vestibular symptoms, such as hearing loss and disequilibrium. Using advanced imaging segmentation techniques, we evaluated whether the volume of SSCD correlated with preoperative symptoms and postoperative outcomes. Methods Our laboratory previously described a novel method of quantifying the size of an SSCD via manual segmentation. High-resolution computed tomography images of the temporal bones were imported into a specialized segmentation software. The volume of the dehiscence was outlined on consecutive slices of the coronal and axial planes via a single-pixel-thick paintbrush tool and was then calculated according to the number of nonzero image voxels. Results This study included 111 patients (70 women and 41 men; mean age, 55.1 years; age range, 24–87 years) with a total of 164 SSCDs. Mean postoperative follow-up time was 5.2 months (range, 0.03–59.5 months). The most common preoperative and postoperative symptoms were tinnitus (n = 85) and dizziness (n = 45), respectively. Surgery resulted in improvement of symptoms in most patients. The average volume of 164 SSCDs was 1.3 mm3. SSCD volume was not significantly associated with either preoperative symptoms or postoperative outcomes. Conclusions Advances in imaging techniques have allowed increased visualization of SSCD. Further research will be necessary to evaluate the potential correlation of volume of the dehiscence with clinical variables.

Author(s): Sun, Matthew Z; Babayan, Diana; Chen, Jia-Shu; Wang, Maxwell M; Naik, Priyanka K; Reitz, Kara; Li, Jingyi Jessica; Pouratian, Nader; Kim, Won | Abstract: BackgroundThe neurointensive care unit (NICU) has traditionally been the default recovery unit after elective craniotomies.ObjectiveTo assess whether admitting adult patients without significant comorbidities to the neuroscience ward (NW) instead of NICU for recovery resulted in similar clinical outcome while reducing length of stay (LOS) and hospitalization cost.MethodsWe retrospectively analyzed the clinical and cost data of adult patients undergoing supratentorial craniotomy at a university hospital within a 5-yr period who had a LOS less than 7 d. We compared those admitted to the NICU for 1 night of recovery versus those directly admitted to the NW.ResultsThe NICU and NW groups included 340 and 209 patients, respectively, and were comparable in terms of age, ethnicity, overall health, and expected LOS. NW admissions had shorter LOS (3.046nvs 3.586 d, Pnln.001), and independently predicted shorter LOS in multivariate analysis. While the NICU group had longer surgeries (6.8nvs 6.4 h), there was no statistically significant difference in the cost of surgery. The NW group was associated with reduced hospitalization cost by $3193 per admission on average (Pnln.001). Clinically, there were no statistically significant differences in the rate of return to Operating Room, Emergency Department readmission, or hospital readmission within 30 d.ConclusionAdmitting adult craniotomy patients without significant comorbidities, who are expected to have short LOS, to NW was associated with reduced LOS and total cost of admission, without significant differences in postoperative clinical outcome.

Superior semicircular canal dehiscence (SSCD) is a rare inner ear disorder with variable amounts of auditory and vestibular dysfunction. In addition to the absence of bone overlying the superior semicircular canal, thinning of bone in this area can also initiate the vestibulocochlear symptoms of SSCD. We evaluated normal bone thickness overlying the course of the semicircular canal using computed tomography (CT) scans and assessed correlations between bone thickness and age, gender, and location of the thinnest bone. A single-institution retrospective chart review was conducted on 133 high-resolution CT scans from 76 healthy, asymptomatic patients between ages 9 and 96 years. These CT scans of the temporal bone were obtained between January 2012 and August 2017. The superior semicircular canal dome thickness at the apex was reported with a mean of 1.25 mm for all 76 patients; the 10th percentile was 0.60 mm, and the 90th percentile was 2.08 mm. The thinnest area of bone at any location yielded a mean of 0.86 mm. The normal bone thickness overlying the superior semicircular canal does not depend on gender or age. The thinnest location was evenly distributed across the superior semicircular canal. A bone thickness of 0.40 mm or greater was present in 90% of normal patients based on CT scan measurements at the thinnest location.

Introduction The association between Cushing syndrome and a hypercoagulable state has been demonstrated in the literature. A standard venous thromboembolism (VTE) prophylaxis regimen has yet to be established for patients undergoing surgery for Cushing disease. Here we present outcomes associated with VTE prophylaxis in patients with Cushing disease undergoing endoscopic transsphenoidal surgery for pituitary tumor resection. Methods A review of Cushing disease patients undergoing endoscopic transsphenoidal pituitary surgery between January 2010 and June 2020 was performed. Administration and type of VTE prophylaxis was recorded, and comparison was made between VTE and hemorrhagic complications before and after institution of a VTE prophylaxis protocol. Results A total of 65 patients were identified, 98.5% of which underwent VTE prophylaxis with either 5,000 units of subcutaneous heparin twice daily (n = 44) or 40 mg enoxaparin nightly (n = 20). VTE complications were not significantly different between the subcutaneous heparin and enoxaparin cohorts (4.5% v 0%; p = 0.61). The overall incidence of hemorrhagic complications requiring blood transfusion was 1.5%, and there was no significant difference in hemorrhagic complications between heparin and enoxaparin cohorts (0% v 5%; p = 0.32). Conclusion VTE prophylaxis in addition to sequential compression devices and early ambulation are critical in reducing VTE complications in patients with hypercortisolism from Cushing disease. Pharmacologic prophylaxis can be safely instituted in these patients with low risk of hemorrhagic complications.

Object The use of stereotactic radiosurgery (SRS) has increased. SRS training has not risen congruently. Neurosurgeons have conducted surveys and advocated implementation of widespread, standardized radiosurgery training. Here we analyze the SRS surveys conducted throughout the past decade. Methods This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic literature review. A broad search of the literature was conducted in October 2018 through the PubMed, Scopus, Embase, and Web of Science databases. This study included surveys evaluating SRS training in neurosurgery and excluded those regarding other specialties. Results An overview of surveys showed that neurosurgery residents possess gaps in SRS knowledge and procedural competency that have persisted through the past decade. There is an overwhelming sentiment that current radiosurgery training is not adequate to prepare residents for future practice. Our recommendation is for residency programs to integrate formal SRS training electives, with a movement towards creating more options for extended SRS fellowships post-residency. Conclusions We present data from SRS competency and current training surveys. Although resident SRS training still lags behind other subspecialties, we see indications for growth. To keep up with the role of SRS in neurosurgery, residencies need more formalized SRS rotations.

INTRODUCTION The lack of immunotherapeutic antigen targets selectively expressed on meningiomas have historically hindered its immunotherapy development. However, recent literature showed that in meningiomas, NY-ESO-1 is the most frequently expressed Cancer-Testis(CT)-antigen, which is a group of proteins silent in somatic cells but reactivated in cancers. NY-ESO-1 also has higher expression in higher-grade meningiomas. Decitabine is known to upregulate CT-antigens and augment immunotherapy. To evaluate systemic adoptive transfer for meningiomas, we tested the efficacy of NY-ESO-1 T-cell-receptor(TCR)-transduced T-cells in vitro and in vivo, and the role of decitabine in meningioma immunotherapy. METHODS NY-ESO-1 TCR-Transduced T-cells were generated by double-transfection with supernatants from PG-13 retroviral packaging cell line encoding HLA-A*0201–restricted NY-ESO-1(157 – 165)-specific TCR. In vitro cytolysis was measured using the xCelligence Real-Time Cell Analyzer System. We utilized human meningioma cells SF1335(Grade I, HLA-A2.1 positive) and CH157(Grade III, HLA-A2.1 negative) in vitro and in vivo. RESULTS CH157 and SF1335 have high and low NY-ESO-1 expression, respectively. Decitabine upregulated NY-ESO-1 mRNA expression in SF1335 by 6-fold after 2 days and by 100-fold after 9 days, with similar effect on protein expression. Co-culturing CH157, CH157-HLA-A2.1(CH157 transduced with HLA-A2.1 vector), SF1335, and decitabine-pretreated-SF1335 cells individually with NY-ESO-1 TCR transduced T-cells at a ratio of 1:1 resulted in 0%, 65%, 20% and 40% cytolysis at 10hours, respectively. Systemic(intravenous) adoptive transfer of TCR-transduced T-cells significantly increased overall survival in NSG mice with intracranial xenografts of CH157-HLA-A2.1 (p=0.04) and SF1335(not treated with decitabine) (p=0.06). CONCLUSIONS NY-ESO-1 TCR-transduced T-cells induce NY-ESO-1 and HLA-A2.1-specific cytolysis in meningioma in vitro, and systemic adoptive transfer confers a statistically significant survival benefit in vivo for meningiomas with high NY-ESO-1 expression. Decitabine upregulates NY-ESO-1 expression and increases tumor cytolysis by TCR-transduced T-cells in meningiomas. Targeting NY-ESO-1 may be a clinically feasible immunotherapeutic strategy to treat aggressive meningiomas.

Objective We performed a retrospective analysis in a cohort of 1185 patients at our institution who were identified as undergoing ≥1 head computed tomography (CT) examinations during their inpatient stay on the neurosurgery service, to quantify the number, type, and associated radiation burden of head CT procedures performed by the neurosurgery service. Methods CT procedure records and radiology reports were obtained via database search and directly validated against records retrieved from manual chart review. Next, dosimetry data from the head CT procedures were extracted via automated text mining of electronic radiology reports. Results Among 4510 identified adult head CT procedures, 88% were standard head CT examinations. A total of 3.65 ± 3.60 head CT scans were performed during an average adult admission. The most common primary diagnoses were neoplasms, trauma, and other hemorrhage. The median cumulative effective dose per admission was 5.66 mSv (range, 1.06–84.5 mSv; mean, 8.56 ± 8.95 mSv). The median cumulative effective dose per patient was 6.4 mSv (range, 1.1–127 mSv; mean, 9.26 ± 10.0 mSv). Conclusions The median cumulative radiation burden from head CT imaging in our cohort equates approximately to a single chest CT scan, well within accepted limits for safe CT imaging in adults. Refined methods are needed to characterize the safety profile of the few pediatric patients identified in our study.

On-time starts for the first case of the day are critical to maintaining efficiency in operating rooms (ORs). We studied whether a resident-led initiative to ensure on-time site marking and documentation of surgical consent could lead to improved first-case start time.In a resident-led initiative at a large 600-bed academic hospital with 25 ORs, we aimed to complete site marking and surgical consents half an hour before the scheduled start time for all first-case neurosurgical patients. We monitored the occurrence of delayed first starts and the length of delay during our initiative, and compared these cases to neurosurgical cases 3 months before the implementation of the initiative and to first-start nonneurosurgical cases.In the year of the initiative, both site marking and surgical consents were completed 30 minutes before the case start in 97% of neurosurgical cases. The average delay across all first-case starts was reduced to 7.17 minutes (N = 1271), compared with 9.67 minutes before the intervention (N = 345). During the study period, non-neurosurgical cases were delayed on average 10.3 minutes (N = 3592). There was a significant difference in latencies between the study period and the period before the initiative (p0.001), and also between neurosurgical cases and nonneurosurgical cases (p0.001). There was no reduction in delay times seen on the non-neurosurgical services in the study period when compared to the case 3 months before. Considering its effect across 1271 cases, this initiative over 1 year resulted in a total reduction of 52 hours and 57 minutes in delays.Through a resident-led quality improvement program, neurosurgical trainees successfully reduced delays in first-case starts on a surgical service. Engaging physician trainees in quality improvement and enhancing OR efficiency can be successfully achieved and can have a significant clinical and financial effect.

Malignant glioma, associated with a poor prognosis, is the most common primary malignant brain tumor in adults. We and others have documented immune responses following dendritic cell (DC) vaccination as an active immunotherapeutic treatment for these patients. In this phase II clinical trial, we randomized malignant glioma patients to receive autologous tumor lysate pulsed DC vaccination with and without adjuvant Toll-like receptor (TLR) agonists. TLRs are present on dendritic cells and serve to modulate immune responses. Twenty-three patients with WHO grade III or IV glioma were treated with three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 followed by an adjuvant placebo, TLR-7 agonist (resiquimod), or TLR-3 agonist (Poly ICLC). Mass cytometry (CyTOF) was used to analyze immune cell populations of patient peripheral blood mononuclear cells (PBMC) before and following treatment. DC-vaccinated patients who received adjuvant Poly ICLC treatment had a significantly improved median survival of 54 months over placebo (11 months) and adjuvant resiquimod (17 months) groups (P This abstract is also being presented as Poster B27. Citation Format: Joseph P. Antonios, Richard G. Everson, Aaron Mochizuki, Sara Khattab, Horacio Soto, Prashant Romiyo, Matthew Z. Sun, Diana Moughon, Emma Billingslea-Yoon, Sylvia Odesa, Gang Li, Eric Kawaguchi, Alex Salazar, William Yong, Jason Schlossman, Benjamin Ellingson, Anthony C. Wang, Timothy Cloughesy, Robert M. Prins, Linda M. Liau. Adjuvant TLR-3 administration enhances proinflammatory immune responses and is associated with extended survival in glioblastoma patients treated with dendritic cell vaccination [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR13.

Objective The use of SRS for treatment of cystic vestibular schwannoma is a topic of mild controversy. This review serves to introduce a renewed understanding of the efficacy of SRS as a viable treatment modality for cystic VS. Patients and methods This study was conducted in accordance with the PRISMA guidelines. A broad search of the literature was conducted in October 2018 through the PubMed, Scopus, Embase, Web of Science, and Cochrane databases. Meta-analysis was conducted on tumor control rates and heterogeneity between articles was assessed using τ2, Cochran’s Q, and I2 statistics. Results A total of 246 patients underwent SRS for cystic VS, with reported mean or median follow-up ranging from 49.7 to 150 months, and an overall range of 6–201 months. Following SRS treatment for cystic VS across all studies, 92% of patients had tumor control at follow up, (95%-CI: 88–95%). Tumor control rate specifically for patients who underwent GammaKnife was 93% (95-CI: 88%–95%). Conclusion Despite the paucity of pertinent data, the results of our meta-analysis suggest that SRS exhibits effective tumor control rates in patients with cystic VS. Therefore, SRS can be considered a viable treatment modality when choosing amongst interventions for cystic VS.

Despite advances in the understanding of glioblastoma multiforme (GBM) molecular biology, genomics, and tumor microenvironment, prognosis for patients diagnosed with this disease remains dismal with standard therapies. We and others have shown utility in dendritic cell (DC) vaccination as an active immunotherapeutic treatment for these patients. In this study, we evaluated the use of autologous tumor lysate puled DC vaccine with and without adjuvant toll-like receptor (TLR) agonists. TLRs are present on dendritic cells and serve to modulate immune responses. Twenty-three patients with WHO Grade III or IV glioma were treated with three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 followed by adjuvant placebo treatment, resiquimod (TLR-7 agonist), or poly ICLC (TLR-3 agonist). Gene expression profiling, immunohistochemistry, and mass cytometry (cyTOF) were performed on patient tumors and peripheral blood mononuclear cells. Patients that received adjuvant poly ICLC had a significantly improved median survival of 54 months over placebo (11 months) and adjuvant resiquimod (17 months) groups. Within each treatment cohort, patients with Grade III tumors had increased overall survival over Grade IV tumors. Overall, patients with MGMT methylated tumors on pathology had a median survival of 57 months, while patients with MGMT unmethylated tumors had a median survival of 19 months. Our findings suggest that adjuvant TLR-3 agonist improves outcomes with autologous lysate-pulsed DC vaccine treatment.

OBJECT There are few and conflicting reports on the effects of delayed initiation of chemoradiotherapy on the survival of patients with glioblastoma. The standard of care for newly diagnosed glioblastoma is concurrent radiotherapy and temozolomide chemotherapy after maximal safe resection; however, the optimal timing of such therapy is poorly defined. Given the lack of consensus in the literature, the authors performed a retrospective analysis of The Cancer Genome Atlas (TCGA) database to investigate the effect of time from surgery to initiation of therapy on survival in newly diagnosed glioblastoma. METHODS Patients with primary glioblastoma diagnosed since 2005 and treated according to the standard of care were identified from TCGA database. Kaplan-Meier and multivariate Cox regression analyses were used to compare overall survival (OS) and progression-free survival (PFS) between groups stratified by postoperative delay to initiation of radiation treatment. RESULTS There were 218 patients with newly diagnosed glioblastoma with known time to initiation of radiotherapy identified in the database. The median duration until therapy was 27 days. Delay to radiotherapy longer than the median was not associated with worse PFS (HR = 0.918, p = 0.680) or OS (HR = 1.135, p = 0.595) in multivariate analysis when controlling for age, sex, KPS score, and adjuvant chemotherapy. Patients in the highest and lowest quartiles for delay to therapy (≤ 20 days vs ≥ 36 days) did not statistically differ in PFS (p = 0.667) or OS (p = 0.124). The small subset of patients with particularly long delays (> 42 days) demonstrated worse OS (HR = 1.835, p = 0.019), but not PFS (p = 0.74). CONCLUSIONS Modest delay in initiation of postoperative chemotherapy and radiation does not appear to be associated with worse PFS or OS in patients with newly diagnosed glioblastoma, while significant delay longer than 6 weeks may be associated with worse OS.

Background Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder of the synovial membrane. PVNS generally affects large joints but occasionally involves the temporomandibular joint (TMJ), with occasional extension into the middle cranial fossa. The purpose of this study was to report our experience with PVNS along with a focused literature review. Methods Patients with PVNS of the TMJ treated at the University of California – San Francisco from 2007 to 2013 were reviewed. A PubMed search was performed to identify additional cases. Results Five patients underwent surgical resection, with 1 recurrence at 61 months. A literature review identified 58 patients, 19 of which had intracranial involvement. Interestingly, intracranial extension was more common in men. Intracranial extension was not associated with an increased rate of recurrence. Conclusion PVNS of the TMJ is a rare entity associated with excellent outcomes, even with intracranial extension. Management should consist of maximal resection, with radiotherapy reserved for extensive or recurrent lesions. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1213–1224, 2015

Objective Hemostatic agents are widely used in patients undergoing intracranial tumor resection to facilitate local hemostasis. We hypothesized that systemic activation of the clotting cascade after local application of hemostatic agents may result in unintended thromboembolic events, including deep venous thrombosis (DVT) and pulmonary embolism (PE). We performed a retrospective analysis to identify potential associations between hemostatic agent use and DVT/PE. Methods A single-institution review of patients undergoing surgical resection of cranial meningiomas was performed. Patient demographics including gender and BMI, procedure duration, estimated blood loss (EBL), tumor pathology, use of hemostatic matrix, and the presence of DVT/PE within 14 days of surgery were collected from the medical record. Results A total of 467 patients underwent a craniotomy for meningioma from 2009 to 2012. There were 331 women and 136 men with a mean age of 58±14 years (range 18–92) and mean BMI of 28±6. Tumor pathology included 359 grade I, 77 grade II, and 31 grade III tumors. There were 12 patients (2.6%) with thromboembolic events. Age ( p =0.66), gender ( p =0.33), EBL ( p =0.99), and procedure duration ( p =0.17) were not associated with an increased incidence of DVT/PE. Use of DVT prophylaxis initiated 72h after surgery did not significantly alter the incidence of DVT/PE ( p =0.20). Body mass index ( p =0.04) and tumor grade ( p =0.05) were associated with increased incidence of DVT/PE. Patients receiving greater than 10ml of a hemostatic agent intraoperatively had an increased incidence of DVT/PE ( p =0.02). In a multivariate model, both BMI (OR=1.07, 95% CI: 1.00–1.15, p =0.048) and use of more than 10ml of hemostatic agent (OR=8.03, CI: 1.02–63.40, p =0.048) were found to be significantly associated with the risk of DVT/PE. Conclusion Hemostatic agents are valuable tools in modern neurosurgery, however their use may be associated with an increased risk of DVT/PE in patients undergoing meningioma resection. This finding provides the impetus for more definitive clinical and laboratory studies to characterize the biology of this association and helps identify patients at increased risk for thromboembolism. This study also affirms the association between high BMI and the risk of thromboembolism. Interestingly the use of prophylactic anticoagulation after surgery did not decrease the incidence of DVT/PE.

BACKGROUND Intracranial meningiomas have been associated with a heterogenous set of genetic and molecular alterations. Despite these genetic associations, targeted therapies have been unable to increase survival in recurrent or residual meningiomas. There is a need for identification of therapeutic targets in meningioma. MATERIALS & METHODS Normal brain tissue from routine autopsy and tumor specimens from patients undergoing primary surgical resection of meningioma were analyzed. Pathologic diagnosis and grade were identified. Samples were stained with anti-EMP2 antisera and visualized with DAB (3,3’-Diaminobenzidine). Western blot analysis was carried out RESULTS In 17 patients with meningioma, there was statistically significant EMP2 staining in fresh brain tumor samples. EMP2 expression was confirmed and quantified with western blot which demonstrated significant positive expressivity. There were 12 grade I, 4 grade II, and 1 grade III meningiomas in our dataset and a significant trend towards increased EMP2 expression with higher grade. EMP2 expression was not identified in normal brain tissue samples from different locations including gray matter, white matter, and meninges in 3 control patients. CONCLUSIONS EMP2 is a protein associated with cell migration, invasion, and angiogenesis not identified in normal brain tissue but found in meningioma. EMP2 expression may be associated with increased tumor invasion and is a potential therapeutic target for residual or recurrent meningioma.

Objectives Reports of glioblastoma (GBM) progression following treatment with bevacizumab indicate that a subset of patients develop disseminated, often minimally enhancing tumors that differ from the typical pattern of focal recurrence. We have reviewed our institutional experience with bevacizumab for GBM to evaluate the prognostic factors and outcomes of patients with disseminated progression. Patients and methods Medical records of patients treated for GBM at the University of California San Francisco from 2005 to 2009 were reviewed. Patients receiving bevacizumab for focal disease were evaluated and imaging was reviewed to identify patients who progressed in a disseminated pattern. Tumor and treatment factors were compared between focal and disseminated progressors to identify predictive factors for dissemination. Clinical outcomes were compared between progression groups. Results Seventy-one patients received adjuvant bevacizumab at some point in their disease course in addition to surgical resection and standard chemoradiotherapy. Of these, 12 patients (17%) had disseminated progression after bevacizumab. There were no differences in patient demographics, surgical treatment, or bevacizumab administration between disseminated and focal progressors. Length of bevacizumab treatment for disseminated progressors trended toward increased time (7.4 vs. 5.4 months) but was not statistically significant ( p =0.1). Although progression-free survival and overall survival did not differ significantly between progression groups (median survival from progression was 3.8 vs. 4.6 months, p =0.5), over 30% of focal progressors had a subsequent resection and enrollment in a surgically based clinical trial, whereas none of the disseminated progressors had further surgical intervention. Compared to previously published reports of GBM dissemination with and without prior bevacizumab treatment, our patients had a rate of disease dissemination similar to the baseline rate observed in patients treated without bevacizumab. Conclusion The risk of dissemination does not appear to be considerably increased due to the use of bevacizumab, and the pattern of disease at progression does not affect subsequent survival. Therefore, the risk of dissemination should not influence the decision to treat with bevacizumab, especially for recurrent disease.

Diffusely infiltrative astrocytomas (World Health Organization [WHO] grades II–IV) are characterized by their potential to widely penetrate the normal brain parenchyma.1 Glioblastoma multiforme (GBM) is the highest-grade astrocytoma, and its patterns of dissemination have been directly linked to survival, where widespread dissemination is thought to give rise to more aggressive phenotypes.2 Increasing evidence suggests that all GBM tumors consist of heterogeneous populations of tumor cells in varied differentiation status,3 including well-differentiated tumor cells and less-differentiated stem cells. The less-differentiated stem cells from tumors are characterized by their expression of neural stem cell markers, such as CD133,4 nestin,5 and Sox2 (sex determining region Y-box 2).6 Functionally, these glioblastoma stem cells have been defined by their potent capacity for developing tumors when implanted in animals, as well as their ability to give rise to both stem cells and well-differentiated tumor cells.4,7–13 Thus, the less-differentiated tumor stem cells have also been called brain tumor-initiating cells (BTICs).4 In addition to their enhanced self-renewal and cell differentiation potential, BTICs have been shown to have increased resistance to chemo- and radiotherapy.4,7–13 Therefore, they have been identified as potentially important targets of GBM therapy. While increasing evidence suggests that they play a role in glioma pathogenesis, very little evidence exists to date characterizing the invasive potential of BTICs. Limited evidence, based primarily on in vitro experiments, initially suggested that BTICs might be more invasive than differentiated glioma cells.14–16 However, the mechanism of the elevated invasive potential of BTICs has not been clearly delineated. Conversely, there is also evidence that cancer stem cells are not always invasive, depending on their phenotype, which further complicates our understanding of cancer stem cell biology.17 Recent research suggests that gliomas utilize ion channels, including Na+/K+-ATPase, to support their unusual growth and invasion by adjusting their shape and volume rapidly as they invade the brain parenchyma.18 The various isoforms of the β-subunit of Na+/K+-ATPase have been shown to act in regulating cellular adhesion, particularly in the context of cancer progression.19–21 The β2 isoform, also known as the adhesion molecule on glia (AMOG), is a heavily glycosylated protein that plays a role in cellular adhesion in the CNS.22,23 It is diffusely expressed in the gray matter but is expressed in only perivascular astrocytes in the white matter.24 Although AMOG is highly expressed in the normal adult CNS, evidence suggests that it may be downregulated in GBM.25 However, given the heterogeneity that exists among GBM tumors, it is not known whether this is universally true of GBM. Initial functional data characterizing AMOG suggest that it plays an active role in cellular adhesion and migration in the normal CNS.22,26 While loss of AMOG has been implicated in glioma invasion and migration, currently there are no data characterizing its function in invasion and migration specifically in human glioma cells. To further our understanding of the role of AMOG in GBM and particularly in BTICs in the context of glioma migration and invasion, we specifically investigated (i) whether AMOG protein expression correlated with glioma grade, (ii) whether AMOG is globally downregulated in GBM, (iii) whether AMOG is differentially expressed in BTICs compared with differentiated GBM cells from patient-matched tumor tissues, (iv) whether overexpression of AMOG in low-expressing GBM cells decreases invasion and affects migration or proliferation, (v) whether AMOG knockdown increases invasion of normal glial cells, and (vi) whether downregulation of AMOG in GBM is associated with worse clinical outcome.

Object Ependymomas are primary central nervous system tumors that occur more frequently in the spines of adults than they do there in children. Previous studies consist mainly of retrospective single-institutional experiences or case studies. In this study, a comprehensive literature review was performed on reported cases of spinal ependymoma treated with resection to determine whether tumor location along the spinal axis conveys important prognostic information. Methods A PubMed search was performed to identify all papers that included data on patients with spinal ependymoma. Only cases involving adult patients who underwent ependymoma resection with a clearly reported tumor location were included for analysis. Tumor locations were separated into 6 groups: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus + cauda equina. Kaplan-Meier survival and Cox regression analyses were performed to determine the effect of tumor location on progression-free survival (PFS) and overall survival (OS). Results A total of 447 patients who underwent resection of spinal ependymomas with clearly indicated location of tumor were identified. The most common locations of spinal ependymomas were the cervical (32.0%) and conus + cauda equina (26.8%) regions. The thoracolumbar and cervicomedullary regions had the fewest tumors (accounting for, respectively, 5.1% and 3.4% of the total number of cases). The conus + cauda equina and thoracolumbar regions had the highest percentage of WHO Grade I tumors, while tumors located above these regions consisted of mostly WHO Grade II tumors. Despite the tendency for benign grades in the lower spinal regions, PFS for patients with spinal ependymomas in the lower 3 regions (thoracic, thoracolumbar, conus + cauda equina) was significantly shorter (p < 0.001) than for those with tumors in the upper regions (cervicomedullary, cervical, cervicothoracic), but the difference in OS did not achieve statistical significance (p = 0.131). Conclusions Spinal ependymomas along different regions of spinal axis have different characteristics and clinical behaviors. Tumor grade, extent of resection, and PFS varied by tumor location (upper vs lower spinal regions), while OS did not. Recurrence rates were higher for the lower spinal cord tumors, despite a greater prevalence of lower WHO grade lesions, compared with upper spinal cord tumors, suggesting that tumor location along the spinal axis is an important prognostic factor.

Object Ependymoma is a common CNS tumor in children, with spinal cord ependymomas making up 13.1% of all ependymomas in this age group. The clinical features that affect prognosis in pediatric spinal cord ependymomas are not well understood. A comprehensive literature review was performed to determine whether a tumor location along the spinal cord is prognostically significant in children undergoing surgery for spinal cord ependymomas. Methods A PubMed search was performed to identify all papers that contained data on patients with spinal cord ependymomas. Only pediatric patients (age < 18 years) who underwent resection with a clearly reported tumor location were included in the analysis. Myxopapillary tumors were excluded from study. Tumor location was subdivided into 6 regions: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus medullaris. Kaplan-Meier survival and Cox regression analyses were performed to determine the effects of tumor location on progression-free survival (PFS) and overall survival (OS). Results Fifty-eight patients who underwent resection of spinal cord ependymomas were identified. Ependymomas were located all along the spinal cord but occurred with the highest frequency in the cervical region (29.3%). Progression-free survival was significantly better in patients with tumors arising in the upper portion of the spinal cord (p = 0.031), which remained significant in the multivariate Cox regression analysis (p < 0.05). Moreover, OS was significantly better in patients with upper spinal cord ependymomas than in those harboring ependymomas in the lower spinal cord (p = 0.048). Conclusions Although more common in adults, spinal ependymomas can occur anywhere along the spinal cord in the pediatric population; however, tumors occurring in the lower half of the spinal cord carry a worse prognosis with shorter PFS and OS. By comparison, ependymomas in the upper spinal cord recur later and less frequently, with little or no mortality in this patient group.

Object Extent of resection (EOR) has been shown to be an important prognostic factor for survival in patients undergoing initial resection of glioblastoma (GBM), but the significance of EOR at repeat craniotomy for recurrence remains unclear. In this study the authors investigate the impact of EOR at initial and repeat resection of GBM on overall survival. Methods Medical records were reviewed for all patients undergoing craniotomy for GBM at the University of California San Francisco Medical Center from January 1, 2005, through August 15, 2009. Patients who had a second craniotomy for pathologically confirmed recurrence following radiation and chemotherapy were evaluated. Volumetric EOR was measured and classified as gross-total resection (GTR, > 95% by volume) or subtotal resection (STR, ≤ 95% by volume) after independent radiological review. Overall survival was compared between groups using univariate and multivariate analysis accounting for known prognostic factors, including age, eloquent location, Karnofsky Performance Status (KPS), and adjuvant therapies. Results Multiple resections were performed in 107 patients. Fifty-two patients had initial GTR, of whom 31 (60%) had GTR at recurrence, with a median survival of 20.4 months (standard error [SE] 1.0 months), and 21 (40%) had STR at recurrence, with a median survival of 18.4 months (SE 0.5 months) (difference not statistically significant). Initial STR was performed in 55 patients, of whom 26 (47%) had GTR at recurrence, with a median survival of 19.0 months (SE 1.2 months), and 29 (53%) had STR, with a median survival of 15.9 months (SE 1.2 months) (p = 0.004). A Cox proportional hazards model was constructed demonstrating that age (HR 1.03, p = 0.004), KPS score at recurrence (HR 2.4, p = 0.02), and EOR at repeat resection (HR 0.62, p = 0.02) were independent predictors of survival. Extent of initial resection was not a statistically significant factor (p = 0.13) when repeat EOR was included in the model, suggesting that GTR at second craniotomy could overcome the effect of an initial STR. Conclusions Extent of resection at recurrence is an important predictor of overall survival. If GTR is achieved at recurrence, overall survival is maximized regardless of initial EOR, suggesting that patients with initial STR may benefit from surgery with a GTR at recurrence.

Optic nerve sheath meningiomas (ONSM) are rare tumors of the meninges that surround the optic nerve as it enters the orbit. If left untreated, these benign tumors lead to progressive compression of the optic nerve and vascular compromise resulting in visual loss. Surgical resection of ONSM is associated with a high morbidity due to injury to the vascular supply of the optic nerve, with up to 94% of patients reporting worsened vision post-operatively. Fractionated radiotherapy is a non-invasive alternative to surgery for the treatment of ONSM that has demonstrated improved outcomes. The reported long-term tumor control rates approach 100%, with greater than 80% vision preservation or improvement after treatment. Recently, improved technology for delivery of radiotherapy, including stereotactic and three-dimensional conformal radiotherapy has emerged. The literature suggests that the modality of radiotherapy does not affect the outcomes as long as conformal targeting with a total dose of 50 Gy to 54 Gy and a fractional dose of less than 2.0 Gy is used. Radiosurgery is not generally used for ONSM due to the high toxicity to the optic nerve when high-dose single fraction radiation is given. Therefore, conformal fractionated radiotherapy appears to be the most effective treatment for ONSM, and should be used as a primary therapy unless there is a specific indication for surgical intervention.

Epidermal growth factor (EGF) module-containing mucin-like receptor 2 (EMR2) is a member of the seven span transmembrane adhesion G-protein coupled receptor subclass. This protein is expressed in a subset of glioblastoma (GBM) cells and associated with an invasive phenotype. The expression pattern and functional significance of EMR2 in low grade or anaplastic astrocytomas is unknown and our goal was to expand and further define EMR2's role in gliomas with an aggressive invasive phenotype. Using the TCGA survival data we describe EMR2 expression patterns across histologic grades of gliomas and demonstrate an association between increased EMR2 expression and poor survival (p < 0.05). This data supports prior functional data depicting that EMR2-positive neoplasms possess a greater capacity for infiltrative and metastatic spread. Genomic analysis suggests that EMR2 overexpression is associated with the mesenchymal GBM subtype (p < 0.0001). We also demonstrate that immunohistorchemistry is a feasible method for screening GBM patients for EMR2 expression. Protein and mRNA analysis demonstrated variable expression of all isoforms of EMR2 in all glioma grades, however GBM displayed the most diverse isoforms expression pattern as well as the highest expression of the EGF1-5 isoform of EMR2. Finally, a correlation of an increased EMR2 expression after bevacizumab treatment in glioma cells lines is identified. This observation should serve as the impetus for future studies to determine if this up-regulation of EMR2 plays a role in the observation of the diffuse and increasingly invasive recurrence patterns witnessed in a subset of GBM patients after bevacizumab treatment.

Epidermal growth factor (EGF) module-containing mucin-like receptor 2 (EMR2) is a member of the seven span transmembrane adhesion G-protein coupled receptor subclass. This protein is expressed in a subset of glioblastoma (GBM) cells and associated with an invasive phenotype. The expression pattern and functional significance of EMR2 in low grade or anaplastic astrocytomas is unknown and our goal was to expand and further define EMR2's role in gliomas with an aggressive invasive phenotype. Using the TCGA survival data we describe EMR2 expression patterns across histologic grades of gliomas and demonstrate an association between increased EMR2 expression and poor survival (p < 0.05). We support this data with qPCR of EMR2 expression in 3 separate tumor grades from our own brain tumor research center showing increase in EMR2 expression correlates with tumor grade (p < 0.05). This data supports our prior functional data depicting that EMR2-positive neoplasms possess a greater capacity for infiltrative and metastatic spread. Genomic analysis suggests that EMR2 overexpression is associated with the mesenchy mal GBM subtype(p < 0.0001). We also demonstrate that immunohistorchemistry (IHC) is a feasible method for screening GBM patients for EMR2 expression. Protein and mRNA analysis demonstrated variable expression of all isoforms of EMR2 in all glioma grades, however GBM displayed the most diverse isoforms expression pattern as well as the highest expression of the EGF1-5 isoform of EMR2. Finally, a correlation of an increase in EMR2 expression after bevacizumab treatment in glioma cells lines as well as in an animal model is identified (P < 0.05). This observation should serve as the impetus for future studies to determine if this up-regulation of EMR2 plays a role in the observation of the diffuse and increasingly invasive recurrence patterns witnessed in a subset of GBM patients after bevacizumab treatment.

Atypical meningiomas (AMs) and malignant meningiomas (MMs) are tumors with a lower incidence and poorer prognosis than benign meningiomas. The role of radiotherapy as an adjuvant to surgical resection, especially for AMs, is incompletely defined. In this study, the English-language literature was systematically reviewed for studies that reported tumor characteristics, treatment parameters, and clinical outcomes after adjuvant radiotherapy for AM and MM, including overall survival, progression-free survival, and/or time to recurrence or mortality. Clinical outcomes were further assessed in the context of resection status, timing of administration, and radiation dose. Outcomes after stereotactic radiosurgery were also examined. Treatment toxicity and other potential prognostic or confounding factors were appraised. Ten and 11 studies for AM and MM, respectively, met the inclusion criteria. The median 5-year progression-free survival and overall survival after adjuvant radiotherapy were 54.2% and 67.5%, respectively, for AM and 48% and 55.6% for MM. The complication rates were 11.1% for AM and 5.1% for MM. Incomplete resection and radiation dose

Giant cell glioblastoma (GCG) is a rare subtype of glioblastoma (GBM) that is believed to carry an improved prognosis. However, given the rarity of this tumor, best management practices for GCG have yet to be ascertained. Here, we present our experience in managing GCG tumors at the University of California, San Francisco. Patients were retrospectively identified through chart review, and data pertaining to patient demographics, treatment plans, and follow-up were extracted from existing medical records. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively. In sum, we identified 22 patients who were managed or followed for GCG. Most patients (78%) initially underwent subtotal resection as primary treatment for their tumor, and most also received post-operative adjuvant therapy (90%), with radiation being the most frequently administered modality (85%). Within this institutional cohort, median OS and PFS were 15.4 months and 5.7 months, respectively. On multivariate survival analysis, age (p=0.84), sex (p=0.05), and adjuvant radiation plus temozolomide (p=0.12) were not associated with prolonged OS. However, adjuvant radiation plus temozolomide was associated with longer PFS (p=0.01), and patients receiving this therapy demonstrated a median PFS of 32.9 months versus 13.1 months. These findings confirm the comparatively improved prognosis of GCG over GBM. Moreover, they suggest that extent of resection may not significantly delay recurrence or extend survival, and that combination radiation with temozolomide may represent the optimum adjuvant paradigm to delay tumor progression.