Risk of developing glioblastoma following non-CNS primary cancer: a SEER analysis between 2000 and 2018.

BACKGROUND: Patients with a prior malignancy are at elevated risk of developing subsequent primary malignancies (SPMs). However, the risk of developing subsequent primary glioblastoma (SPGBM) in patients with a prior cancer history is poorly understood. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database and identified patients diagnosed with non-CNS malignancy between 2000 and 2018. We calculated a modified standardized incidence ratio (M-SIR), defined as the ratio of the incidence of SPGBM among patients with initial non-CNS malignancy to the incidence of GBM in the general population, stratified by sex latency, and initial tumor location. RESULTS: Of the 5,326,172 patients diagnosed with a primary non-CNS malignancy, 3559 patients developed SPGBM (0.07%). Among patients with SPGBM, 2312 (65.0%) were men, compared to 2,706,933 (50.8%) men in the total primary non-CNS malignancy cohort. The median age at diagnosis of SPGBM was 65 years. The mean latency between a prior non-CNS malignancy and developing a SPGBM was 67.3 months (interquartile range [IQR] 27-100). Overall, patients with a primary non-CNS malignancy had a significantly elevated M-SIR (1.13, 95% CI 1.09-1.16), with a 13% increased incidence of SPGBM when compared to the incidence of developing GBM in the age-matched general population. When stratified by non-CNS tumor location, patients diagnosed with primary melanoma, lymphoma, prostate, breast, renal, or endocrine malignancies had a higher M-SIR (M-SIR ranges: 1.09-2.15). Patients with lung cancers (M-SIR 0.82, 95% CI 0.68-0.99), or stomach cancers (M-SIR 0.47, 95% CI 0.24-0.82) demonstrated a lower M-SIR. CONCLUSION: Patients with a history of prior non-CNS malignancy are at an overall increased risk of developing SPGBM relative to the incidence of developing GBM in the general population. However, the incidence of SPGBM after prior non-CNS malignancy varies by primary tumor location, with some non-CNS malignancies demonstrating either increased or decreased predisposition for SPGBM depending on tumor origin. These findings merit future investigation into whether these relationships represent treatment effects or a previously unknown shared predisposition for glioblastoma and non-CNS malignancy.

Trends and outcomes of early and late palliative care consultation for adult patients with glioblastoma: A SEER-Medicare retrospective study.

Background: Glioblastoma (GBM) carries a poor prognosis despite standard of care. Early palliative care (PC) has been shown to enhance survival and quality of life while reducing healthcare costs for other cancers. This study investigates differences in PC timing on outcomes for patients with GBM. Methods: This study used Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 1997 to 2016. Based on ICD codes, three groups were defined: (1) early PC within 10 weeks of diagnosis, (2) late PC, and (3) no PC. Outcomes were compared between the three groups. Results: Out of 10 812 patients with GBM, 1648 (15.24%) patients had PC consultation with an overall positive trend over time. There were no significant differences in patient characteristics. The late PC group had significantly higher number of hospice claims (1.06 ± 0.69) compared to those without PC, in the last month of life. There were significant differences in survival among the three groups (P < .0001), with late PC patients with the longest mean time to death from diagnosis (11.72 ± 13.20 months). Conclusion: We present the first investigation of PC consultation prevalence and outcomes, stratified by early versus late timing, for adult GBM patients. Despite an overall increase in PC consultations, only a minority of GBM patients receive PC. Patients with late PC had the longest survival times and had greater hospice use in the last month of life compared to other subgroups. Prospective studies can provide additional valuable information about this unique population of patients with GBM.

An integrated risk model stratifying seizure risk following brain tumor resection among seizure-naive patients without antiepileptic prophylaxis.

OBJECTIVE: The natural history of seizure risk after brain tumor resection is not well understood. Identifying seizure-naive patients at highest risk for postoperative seizure events remains a clinical need. In this study, the authors sought to develop a predictive modeling strategy for anticipating postcraniotomy seizures after brain tumor resection. METHODS: The IBM Watson Health MarketScan Claims Database was canvassed for antiepileptic drug (AED)- and seizure-naive patients who underwent brain tumor resection (2007-2016). The primary event of interest was short-term seizure risk (within 90 days postdischarge). The secondary event of interest was long-term seizure risk during the follow-up period. To model early-onset and long-term postdischarge seizure risk, a penalized logistic regression classifier and multivariable Cox regression model, respectively, were built, which integrated patient-, tumor-, and hospitalization-specific features. To compare empirical seizure rates, equally sized cohort tertiles were created and labeled as low risk, medium risk, and high risk. RESULTS: Of 5470 patients, 983 (18.0%) had a postdischarge-coded seizure event. The integrated binary classification approach for predicting early-onset seizures outperformed models using feature subsets (area under the curve [AUC] = 0.751, hospitalization features only AUC = 0.667, patient features only AUC = 0.603, and tumor features only AUC = 0.694). Held-out validation patient cases that were predicted by the integrated model to have elevated short-term risk more frequently developed seizures within 90 days of discharge (24.1% high risk vs 3.8% low risk, p < 0.001). Compared with those in the low-risk tertile by the long-term seizure risk model, patients in the medium-risk and high-risk tertiles had 2.13 (95% CI 1.45-3.11) and 6.24 (95% CI 4.40-8.84) times higher long-term risk for postdischarge seizures. Only patients predicted as high risk developed status epilepticus within 90 days of discharge (1.7% high risk vs 0% low risk, p = 0.003). CONCLUSIONS: The authors have presented a risk-stratified model that accurately predicted short- and long-term seizure risk in patients who underwent brain tumor resection, which may be used to stratify future study of postoperative AED prophylaxis in highest-risk patient subpopulations.

Hemorrhage risk of direct oral anticoagulants in real-world venous thromboembolism patients.

INTRODUCTION: Venous thromboembolism (VTE) management increasingly involves anticoagulation with direct oral anticoagulants (DOACs). Few studies have used competing-risks analyses to ascertain the mortality-adjusted hemorrhage and recurrent VTE (rVTE) risk of individual DOACs. Furthermore, hemorrhage risk factors in patients treated with apixaban remain underexplored. MATERIALS AND METHODS: Patients diagnosed with VTE receiving anticoagulation were identified from the Optum Clinformatics Data Mart (2003-2019). Study endpoints included readmissions for intracranial hemorrhage (ICH), non-intracranial hemorrhage (non-ICH hemorrhage), and rVTE. Coarsened exact matching was used to balance baseline clinical characteristics. Complication incidence was evaluated using a competing-risks framework. We additionally modeled hemorrhage risk in apixaban-treated patients. RESULTS: Overall, 225,559 patients were included, of whom 34,201 received apixaban and 46,007 received rivaroxaban. Compared to rivaroxaban, apixaban was associated with decreased non-ICH hemorrhage (sHR = 0.560, 95%CI = 0.423-0.741), but not ICH, and rVTE (sHR = 0.802, 95%CI = 0.651-0.988) risk. This was primarily in emergent readmissions (sHR[emergent hemorrhage] = 0.515, 95%CI = 0.372-0.711; sHR[emergent rVTE] = 0.636, 95%CI = 0.488-0.830). Contributors to emergent hemorrhage in apixaban-treated patients include older age (sHR = 1.025, 95%CI = 1.011-1.039), female sex (sHR = 1.662, 95%CI = 1.252-2.207), prior prescription antiplatelet therapy (sHR = 1.591, 95%CI = 1.130-2.241), and complicated hypertension (sHR = 1.936, 95%CI = 1.134-3.307). Patients anticipated to be "high-risk" experienced elevated ICH (sHR = 3.396, 95%CI = 1.375-8.388) and non-ICH hemorrhage (sHR = 3.683, 95%CI = 2.957-4.588) incidence. CONCLUSIONS: In patients with VTE receiving anticoagulation, apixaban was associated with reduced non-ICH hemorrhage and rVTE risk, compared to rivaroxaban. Risk reduction was restricted to emergent readmissions. We present a risk-stratification approach to predict hemorrhage in patients receiving apixaban, potentially guiding future clinical decision-making.

Enhancing proteasomal processing improves survival for a peptide vaccine used to treat glioblastoma.

Despite its essential role in antigen presentation, enhancing proteasomal processing is an unexploited strategy for improving vaccines. pepVIII, an anticancer vaccine targeting EGFRvIII, has been tested in several trials for glioblastoma. We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model in mice. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti-PD-1 therapy cured 45% of the Y6-pepVIII-vaccinated mice but was ineffective for pepVIII-treated mice. Liquid chromatography-tandem mass spectrometry analysis of proteasome-digested pepVIII and Y6-pepVIII revealed that most fragments were similar but more abundant in Y6-pepVIII digests and 77% resulted from proteasome-catalyzed peptide splicing (PCPS). We identified 10 peptides that bound human and murine MHC class I. Nine were PCPS products and only one peptide was colinear with EGFRvIII, indicating that PCPS fragments may be a component of MHC class I recognition. Despite not being colinear with EGFRvIII, two of three PCPS products tested were capable of increasing survival when administered independently as vaccines. We hypothesize that the immune response to a vaccine represents the collective contribution from multiple PCPS and linear products. Our work suggests a strategy to increase proteasomal processing of a vaccine that results in an augmented immune response and enhanced survival in mice.

Status epilepticus after intracranial neurosurgery: incidence and risk stratification by perioperative clinical features.

OBJECTIVE: Status epilepticus (SE) is associated with significant mortality, cost, and risk of future seizures. In one of the first studies of SE after neurosurgery, the authors assess the incidence, risk factors, and outcome of postneurosurgical SE (PNSE). METHODS: Neurosurgical admissions from the MarketScan Claims and Encounters database (2007 through 2015) were assessed in a longitudinal cross-sectional sample of privately insured patients who underwent qualifying cranial procedures in the US and were older than 18 years of age. The incidence of early (in-hospital) and late (postdischarge readmission) SE and associated mortality was assessed. Procedural, pathological, demographic, and anatomical covariates parameterized multivariable logistic regression and Cox models. Multivariable logistic regression and Cox proportional hazards models were used to study the incidence of early and late PNSE. A risk-stratification simulation was performed, combining individual predictors into singular risk estimates. RESULTS: A total of 197,218 admissions (218,217 procedures) were identified. Early PNSE occurred during 637 (0.32%) of 197,218 admissions for cranial neurosurgical procedures. A total of 1045 (0.56%) cases of late PNSE were identified after 187,771 procedure admissions with nonhospice postdischarge follow-up. After correction for comorbidities, craniotomy for trauma, hematoma, or elevated intracranial pressure was associated with increased risk of early PNSE (adjusted OR [aOR] 1.538, 95% CI 1.183-1.999). Craniotomy for meningioma resection was associated with an increased risk of early PNSE compared with resection of metastases and parenchymal primary brain tumors (aOR 2.701, 95% CI 1.388-5.255). Craniotomies for infection or abscess (aHR 1.447, 95% CI 1.016-2.061) and CSF diversion (aHR 1.307, 95% CI 1.076-1.587) were associated with highest risk of late PNSE. Use of continuous electroencephalography in patients with early (p < 0.005) and late (p < 0.001) PNSE rose significantly over the study time period. The simulation regression model predicted that patients at high risk for early PNSE experienced a 1.10% event rate compared with those at low risk (0.07%). Similarly, patients predicted to be at highest risk for late PNSE were significantly more likely to eventually develop late PNSE than those at lowest risk (HR 54.16, 95% CI 24.99-104.80). CONCLUSIONS: Occurrence of early and late PNSE was associated with discrete neurosurgical pathologies and increased mortality. These data provide a framework for prospective validation of clinical and perioperative risk factors and indicate patients for heightened diagnostic suspicion of PNSE.

An Analysis of Public Interest in Elective Neurosurgical Procedures During the COVID-19 Pandemic Through Online Search Engine Trends.

OBJECTIVE: In the wake of the COVID-19 pandemic, the Centers for Medicare & Medicaid Services (CMS) has recommended the temporary cessation of all elective surgeries. The effects on patients' interest of elective neurosurgical procedures are currently unexplored. METHODS: Using Google Trends, search terms of 7 different neurosurgical procedure categories (trauma, spine, tumor, movement disorder, epilepsy, endovascular, and miscellaneous) were assessed in terms of relative search volume (RSV) between January 2015 and September 2020. Analyses of search terms were performed for over the short term (February 18, 2020, to April 18, 2020), intermediate term (January 1, 2020, to May 31, 2020), and long term (January 2015 to September 2020). State-level interest during phase I reopening (April 28, 2020, to May 31, 2020) was also evaluated. RESULTS: In the short term, RSVs of 4 categories (epilepsy, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. In the intermediate term, RSVs of 5 categories (miscellaneous, epilepsy, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. In the long term, RSVs of nearly all categories (endovascular, epilepsy, miscellaneous, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. Only the movement disorder procedure category had significantly higher RSV in states that reopened early. CONCLUSIONS: With the recommendation for cessation of elective surgeries, patient interests in overall elective neurosurgical procedures have dropped significantly. With gradual reopening, there has been a resurgence in some procedure types. Google Trends has proven to be a useful tracker of patient interest and may be used by neurosurgical departments to facilitate outreach strategies.

Tumors in the cauda equina: A SEER analysis of tumor types and predictors of outcome.

Caudaequinatumors are histologically diverse. International Classification of Diseases for Oncology (ICD-O3) confers dedicated site code (C72. 1) for cauda equina. This code is excluded during analyses of other primary spinal cord tumors. In this retrospective study, the Surveillance, Epidemiology and End Results (SEER) data for primary cauda equina tumors (PCET, C72. 1) excluding the tumors of spinal meninges (C70. 1) from 1992 to 2015 were reviewed. Demographic characteristics, tumor types, and clinical outcomes were analyzed using univariable analysis. Overall survival was estimated using Kaplan-Meier methods and compared for age, histology and treatment type. 293 patients with PCET met inclusion criteria. The most common tumors comprised schwannoma (32%), myxopapillary ependymoma (21%), malignant ependymoma (22%). The median age at diagnosis was 50 years (range < 1 year to 98 years), 57% of patients were males. 77% of the patients underwent surgery. Median follow up time for these patients was 70 months. Of the 293 patients, 250 (85%) were living at the end of 2015. The cause of death was tumor or CNS related in 15 patients. 136 patients were followed for <5 years, of which 102 were censored and 34 died (11.6%) before 5 years. Using univariable analysis, age at diagnosis (Hazard Ratio, HR 1.05; confidence interval, CI 1.03-1.07; p < 0.001), malignant tumor type (HR 2.88, CI 1.15-7.19, p = 0.0239) and absence of surgical intervention (HR 2.54, CI1.26-5.11, p = 0.0092) were predictors of increased mortality. Although most patients did well, older age and lack of surgical intervention were associated with worse survival.

Implementation of a patient-specific tapering protocol at discharge decreases total opioid dose prescribed for 6 weeks after elective primary spine surgery.

BACKGROUND AND OBJECTIVES: At our institution, we developed an individualized discharge opioid prescribing and tapering protocol for joint replacement patients and implemented the same protocol for neurosurgical spine patients. We then tested the hypothesis that this protocol will decrease the oral morphine milligram equivalent (MME) dose of opioid prescribed postdischarge after elective primary spine surgery. METHODS: In this retrospective cohort study, we identified all consecutive elective primary spine surgery cases 1 year before and after introduction of the protocol. This protocol used the patient's prior 24-hour inpatient opioid consumption to determine discharge opioid pill count and tapering schedule. The primary outcome was total opioid dose prescribed in oral MME from discharge through 6 weeks. Secondary outcomes included in-hospital opioid consumption in MME, hospital length of stay, MME prescribed at discharge, opioid refills, and rates of minor and major adverse events. RESULTS: Eighty-three cases comprised the final sample (45 preintervention and 38 postintervention). There were no differences in baseline characteristics. The total oral MME (median (IQR)) from discharge through 6 weeks postoperatively was 900 (420-1440) preintervention compared with 300 (112-806) postintervention (p<0.01, Mann-Whitney U test), and opioid refill rates were not different between groups. There were no differences in other outcomes. CONCLUSIONS: This patient-specific prescribing and tapering protocol effectively decreases the total opioid dose prescribed for 6 weeks postdischarge after elective primary spine surgery. Our experience also demonstrates the potential generalizability of this protocol, which was originally designed for joint replacement patients, to other surgical populations.

Simulating Episode-Based Bundled Payments for Cranial Neurosurgical Procedures.

BACKGROUND: Episode-based bundled payments were introduced by Medicare in 2013 as the Bundled Payments for Care Improvement (BPCI) in order to improve care coordination and cost efficiency. BPCI has not yet been applied to cranial neurosurgical procedures. OBJECTIVE: To determine projected values of episode-based bundled payments when applied to common cranial neurosurgical procedures using retrospective data from a large database. METHODS: We performed a large retrospective observational study using the MarketScan administrative database to project bundled payment payments for 4 groups of common cranial neurosurgical procedures. RESULTS: We identified 15 276 procedures that met our inclusion criteria. We observed significant variability between groups, with 90-d bundle projected payments ranging from $ 58,200 for craniotomy for meningioma to $ 102,073 for craniotomy for malignant glioma. We also found significant variability in projected bundled payments within each class of operation. On average, payment for the index hospitalization accounted for 85% of projected payments for a 30-d bundle and 70.5% of projected payments for a 90-d bundle. Multivariable analysis showed that hospital readmission, discharge to postacute care facilities, venous-thrombo-embolism, medical comorbidities, adjuvant therapies, and payer status significantly contributed to projected cranial bundle payments. CONCLUSION: For the first time, to our knowledge, we project the values of episode-based bundled payments for common vascular and tumor cranial operations. As previously identified in orthopedic procedures, there is significant variability in total bundle payments within each cranial procedure. Compared to spine and orthopedic procedures, postdischarge care significantly impacts total bundle payments in cranial neurosurgery.

A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer.

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

Intracranial Hemorrhage in Deep Vein Thrombosis/Pulmonary Embolus Patients Without Atrial Fibrillation.

Background and Purpose- Deep vein thrombosis (DVTs) is a common disease with high morbidity if it progresses to pulmonary embolus (PE). Anticoagulation is the treatment of choice; warfarin has long been the standard of care. Early experience with direct oral anticoagulants (DOACs) suggests that these agents may be may be a safer and equally effective alternative in the treatment of DVT/PE. Nontraumatic intracranial hemorrhage (ICH) is one of the most devastating potential complications of anticoagulation therapy. We sought to compare the rates of ICH in patients treated with DOACs versus those treated with warfarin for DVT/PE. Methods- The MarketScan Commercial Claims and Medicare Supplemental databases were used. Adult DVT/PE patients without known atrial fibrillation and with prescriptions for either a DOAC or warfarin were followed for the occurrence of inpatient admission for ICH. Coarsened exact matching was used to balance the treatment cohorts. Cox proportional-hazards regressions and Kaplan-Meier survival curves were used to estimate the association between DOACs and the risk of ICH compared with warfarin. Results- The combined cohort of 218 620 patients had a median follow-up of 3.0 months, mean age of 55.4 years, and was 52.1% women. The DOAC cohort had 26 980 patients and 8 ICH events (1.0 cases per 1000 person-years), and the warfarin cohort had 191 640 patients and 324 ICH events (3.3 cases per 1000 person-years; P<0.0001). The DOAC cohort had a lower hazard ratio for ICH compared with warfarin in both the unmatched (hazard ratio=0.26; P=0.0002) and matched (hazard ratio=0.20; P=0.0001) Cox proportional-hazards regressions. Conclusions- DOACs show superior safety to warfarin in terms of risk of ICH in patients with DVT/PE.

National Trends for Reoperation in Older Patients with Glioblastoma.

BACKGROUND: Despite multimodal therapies extending patient survival, glioblastoma (GBM) recurrence is all but a certainty. To date, there are few single-center studies of reoperations. Our study aimed to assess GBM reoperation trends nationally in older patients, with emphasis on outcomes. METHODS: The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was searched to identify patients 66 years and older with GBM from 1997 to 2010. The primary outcome was survival after diagnosis. Kaplan-Meier curves and multivariate analysis with proportional hazard ratios were used. RESULTS: Three thousand nine hundred sixty-three patients with recurrent GBM who initially received a surgical resection were identified (mean age = 74.7 years). Four hundred ninety-six (12%) of the patients with recurrent GBM underwent at least one reoperation at an average of 7.2 months after the initial diagnosis. Reoperation increased survival in patients compared with those who did not have surgical resection (12 vs. 5 months; P < 0.0001; hazard ratio [HR] = 0.666). Within the reoperated cohort, gross total resection improved median survival over subtotal resection (HR = 0.779). Two or more reoperations upon GBM recurrence improved survival to 17 months (P = 0.002). The overall complication rate was 21.7% in the initial resection-only group, versus 20.4% in the 1-reoperation group and 25.3% in the 2-reoperation group. CONCLUSIONS: Although definitive conclusions cannot be made given the lack of granularity, our national database study supports gross total resection as the initial treatment of choice, followed by reoperation at the time of recurrence, if tolerated, even in older patients.

Survival in elderly glioblastoma patients treated with bevacizumab-based regimens in the United States.

BACKGROUND: The efficacy of bevacizumab (BEV) in elderly patients with glioblastoma remains unclear. We evaluated the effect of BEV on survival in this patient population using the Survival, Epidemiology, and End Results (SEER)-Medicare database. METHODS: This retrospective, cohort study analyzed SEER-Medicare data for patients (aged ≥66 years) diagnosed with glioblastoma from 2006 to 2011. Two cohorts were constructed: one comprised patients who had received BEV (BEV cohort); the other comprised patients who had received any anticancer treatment other than BEV (NBEV cohort). The primary analysis used a multivariate Cox proportional hazards model to compare overall survival in the BEV and NBEV cohorts with initiation of BEV as a time-dependent variable, adjusting for potential confounders (age, gender, Charlson comorbidity index, region, race, radiotherapy after initial surgery, and diagnosis of coronary artery disease). Sensitivity analyses were conducted using landmark survival, propensity score modeling, and the impact of poor Karnofsky Performance Status. RESULTS: We identified 2603 patients (BEV, n = 597; NBEV, n = 2006). In the BEV cohort, most patients were Caucasian males and were younger with fewer comorbidities and more initial resections. In the primary analysis, the BEV cohort showed a lower risk of death compared with the NBEV cohort (hazard ratio, 0.80; 95% confidence interval, 0.72-0.89; P < .01). The survival benefit of BEV appeared independent of the number of temozolomide cycles or frontline treatment with radiotherapy and temozolomide. CONCLUSION: BEV exposure was associated with a lower risk of death, providing evidence that there might be a potential benefit of BEV in elderly patients with glioblastoma.

The effect of postoperative infection on survival in patients with glioblastoma.

OBJECTIVE Glioblastoma is a primary glial neoplasm with a median survival of approximately 1 year. There are anecdotal reports that postoperative infection may confer a survival advantage in patients with glioblastoma. However, only a few case reports in the literature, along with 2 retrospective cohort studies, show some potential link between infection and prolonged survival in patients with glioblastoma. The objective of this study was to evaluate the effect of postoperative infection in patients with glioblastoma using a large national database. METHODS The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was searched to identify patients 66 years of age and older with glioblastoma, with and without infection, from 1997 to 2010. The primary outcome was survival after diagnosis. The statistical analysis was performed with a graphical representation using Kaplan-Meier curves, univariate analysis with the log-rank test, and multivariate analysis with proportional hazards modeling. RESULTS A total of 3784 patients with glioblastoma were identified from the database, and from these, 369 (9.8%) had postoperative infection within 1 month of surgery. In patients with glioblastoma who had an infection within 1 month of surgery, there was no significant difference in survival (median 5 months) compared with patients with no infection (median 6 months; p = 0.17). The study also showed that older age, increased Gagne comorbidity score, and having diabetes may be negatively associated with survival. CONCLUSIONS Infection after craniotomy within 1 month was not associated with a survival benefit in patients with glioblastoma.

Patterns of Care and Outcomes of Adjuvant Radiotherapy for Meningiomas: A Surveillance, Epidemiology, and End Results and Medicare Linked Analysis.

BACKGROUND: The role of adjuvant stereotactic radiosurgery (SRS) and fractionated radiotherapy (XRT) are unknown in patients with resected meningiomas. OBJECTIVE: To identify patterns of care and outcomes of adjuvant radiotherapy for meningiomas in the Linked Surveillance, Epidemiology, and End Results (SEER) Medicare data. METHODS: A total of 1,964 patients older than 66 years included in the SEER-Medicare data, who were diagnosed with meningioma, and underwent craniotomy were included for analysis. RESULTS: Patients were less likely to receive adjuvant therapy if they were older than 75 (OR 0.730, 95% CI 0.548-0.973), female sex (OR 0.731, 95% CI 0.547-0.978), or unmarried (OR 0.692, 95% CI 0.515-0.929). Patients were more likely to receive adjuvant treatment for Grade II/III tumors (OR 5.586, 95% CI 2.135-13.589), tumors over 5 cm (OR 1.850, 95% CI 1.332-2.567), or partial resection (OR 3.230, 95% CI 2.327-4.484). Yearly between 2000 and 2009, 10.65 - 19.77% of patients received adjuvant therapy. Although no survival benefit was seen with the addition of adjuvant therapy (p = 0.1236), the subgroup of patients receiving SRS had a decreased risk of death compared to those receiving surgery alone (aHR 0.544, 95% CI 0.318 - 0.929). CONCLUSION: Utilization of adjuvant XRT and SRS remained stable between 2000 and 2010. Male sex, young age, marriage, partial resection, Grade II/III tumors, and large tumors predicted the use of adjuvant therapy. For all patients, SRS decreased the risk of death compared to craniotomy alone.

A Surveillance, Epidemiology and End Results-Medicare data analysis of elderly patients with glioblastoma multiforme: Treatment patterns, outcomes and cost.

The Surveillance, Epidemiology and End Results (SEER) database was used to determine the treatment patterns, outcomes and cost of therapy in elderly patients with glioblastoma multiforme (GBM). The SEER-Medicare linked database was used to identify patients aged >66 years with GBM diagnosed between 1997 and 2009. The patients were stratified by initial treatment following diagnostic surgery (resection or biopsy) into 6 groups as follows: No treatment, standard radiation therapy (SRT) with and without concurrent temozolomide (TMZ), hypofractionated RT (HRT) with and without concurrent TMZ, or TMZ alone. The 3,759 patients identified had a median age of 74 years (range, 66-97 years). A total of ~48% of the patients received SRT without TMZ; ~10% received SRT with concurrent TMZ; ~29% received no treatment; ~10% received HRT without TMZ; ~1% received HRT with TMZ; and <1% received TMZ alone. Untreated patients had a median survival of 2 months (range, 0-89 months). Patients treated with SRT with and without concurrent TMZ had a median survival of 11 and 9 months, respectively (P=0.01). Patients treated with HRT with and without TMZ or TMZ alone had a median survivals of 3 months [adjusted hazard ratio (AHR)=0.48; 95% confidence interval (CI): 0.36-0.66], 4 months (AHR=0.55; 95% CI: 0.49-0.62) and 6 months (AHR=0.43; 95% CI: 0.29-0.62), respectively. The median post-surgery total treatment cost for patients receiving HRT with and without TMZ or TMZ alone was 63,915, 42,834 and 48,298 USD, respectively. Standard RT with concurrent TMZ was associated with improved survival, even in patients aged >75 years. HRT with and without concurrent TMZ and TMZ alone improved survival compared to the no treatment group. Therefore, in certain cases, HRT or TMZ alone may be more cost-effective, with similar survival outcomes. The various treatment options highlight the need for geriatric assessment tools to aid in therapeutic decision making.

Materials used in cranioplasty: a history and analysis.

Cranioplasty, one of the oldest surgical procedures used to repair cranial defects, has undergone many revolutions over time to find the ideal material to improve patient prognosis. Cranioplasty offers cosmetic and protective benefits for patients with cranial defects. The first primitive cranioplasty procedures date back to 7000 bc and used metal and gourds to repair cranial defects. Cranioplasty was first documented by Fallopius who described repair using gold plates; the first bone graft was documented by van Meekeren. The first significant improvement for this procedure began with experimentation involving bone grafts in the late 19th century as a more natural approach for repairing cranial defects. The next impetus for advancement came because of wartime injuries incurred during World Wars I and II and involved experimentation with synthetic materials to counter the common complications associated with bone grafts. Methyl methacrylate, hydroxyapatite, ceramics, and polyetheretherketone implants among other materials have since been researched and used. Research now has shifted toward molecular biology to improve the ability of the patient to regenerate bone using bone growth factors. This paper reviews the evolution of materials used over time in addition to the various advantages and pitfalls associated with each change. It is important for neurosurgeons to be mindful of how these techniques have evolved in order to gain a better understanding of this procedure and how it has been adapted.

Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III.

The relationship between mutated proteins and the cancer stem-cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGF receptor (EGFR) variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here, we show that EGFRvIII is highly coexpressed with CD133 and that EGFRvIII(+)/CD133(+) defines the population of cancer stem cells (CSC) with the highest degree of self-renewal and tumor-initiating ability. EGFRvIII(+) cells are associated with other stem/progenitor markers, whereas markers of differentiation are found in EGFRvIII(-) cells. EGFRvIII expression is lost in standard cell culture, but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII(+)/CD133(+) coexpression, self-renewal, and tumor initiating abilities. Elimination of the EGFRvIII(+)/CD133(+) population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC-specific expression and be used to specifically target this population.

Health-related quality-of-life status in Veterans with spinal disorders.

PURPOSE: To measure the impact of spinal disorders on health-related quality of life (HRQOL) among Veterans, to describe demographic patterns of Veterans with spinal disorders, and to quantify HRQOL scores as they relate to demographics, medical comorbidities, pain severity, and depressive symptoms. METHODS: From 2009 to 2010, 112 lumbar and 56 cervical spinal disorder patients completed SF-12, Oswestry Disability Index, visual analog pain scale, and Beck Depression Inventory surveys. Multivariate analysis identified predictors of HRQOL, disability, and depressive symptoms. RESULTS: A total of 168 patients completed surveys for this study. The median age of all patients was 60. Nearly 30% of lumbar and 16% of cervical patients were aged 65 or older. Approximately 96% of patients were men. Sixty percent of patients were currently receiving or had pending disability compensation. Nearly 60% of patients were current smokers, approximately 26% reported alcoholism or intravenous drug use, and 26% self-reported post-traumatic stress disorder. The most common lumbar spine diagnoses were disk herniation (36.6%) and stenosis (34.8%), and most common cervical spine diagnoses were stenosis (50.0%) and disk herniation (23.2%). Back pain was reported by 93.8% of lumbar patients and leg pain by 83.0%. Neck pain was reported by 96.4% of cervical patients and arm pain by 69.6%. Median SF-12 physical component scores were more than two standard deviations below the US average. Ninety percent of patients had at least moderate physical disability. Sixty-four percent met criteria for depressive symptoms. Visual analog pain score was the strongest predictor of SF-12 physical (ß = -1.32, P < 0.001) and mental (ß = -1.63, P < 0.001) HRQOL and was the prime determinant of depressive symptoms (ß = 1.52, P < 0.001) and disability index score (ß = 4.39, P < 0.0001). Charlson Comorbidity Score and smoking status had no significant impact on HRQOL or disability scores. Age was negatively correlated with depressive symptoms and positively correlated with SF-12 mental component scores. CONCLUSIONS: Spinal disorders have a severe impact on both physical and emotional HRQOL of Veterans and are associated with severe disability and an unusually high prevalence of depressive symptoms. Therapeutic interventions should be targeted to reduce pain, which is a prime determinant of HRQOL, disability, and depressive symptoms. Given high prevalence of multiple risk factors for poor outcomes, studies of spine surgery outcomes in Veterans are needed.