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.

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.

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.

Patterns of care and survival for glioblastoma patients in the Veterans population.

Survival outcomes and patterns of care for brain tumor patients in the USA Veterans population have not been previously published and the extent of variation in outcomes between Veterans and the rest of the USA is currently unknown. The Veterans healthcare administration (VA) provides comprehensive care to Veterans and their families and maintains the Veterans affairs central cancer registry (VACCR). This was a retrospective review of microscopically-confirmed, supratentorial glioblastoma multiforme in male Veterans actively followed by the VACCR; survival was analyzed and compared to a national cohort from the surveillance, epidemiology and end results program. We analyzed 1,219 Veterans with glioblastomas diagnosed between 1997 and 2006. Median survival was 6.5 months and 1, 2, and 5 years survival rates were 26.8, 5.4, and 0.5%, respectively. Patients receiving all three treatment modalities (surgical resection, radiotherapy, and chemotherapy) did best; these findings remained true among patients aged 70 and older such that these patients had an overall survival similar to those age <70. A comparable national cohort had longer median survival (9.0 months) and greater 1, 2, and 5 years survival rates (37.8, 12.8, and 4.1%) than the VA cohort. Survival and patterns of care are presented for the first time for Veterans with glioblastoma multiforme. In conclusion, we found that more aggressive therapy was associated with better survival, even among elderly Veterans and whether compared overall or by age group, VA patients showed decreased survival relative to a national cohort. We believe this potential disparity warrants further investigation.

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.

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.

Cargo areas of pickup trucks: an avoidable mechanism for neurological injuries in children.

OBJECT: Falls from pickup truck cargo areas represent a unique mode of injury in children and adolescents. The goal of this study was to identify the neurological spectrum of injuries resulting from children riding in the back of pickup trucks. METHODS: The authors undertook a retrospective review of the University of New Mexico Hospital trauma registry of data compiled over a 7-year period. Their goal was to identify instances in which a fall or ejection from a pickup truck cargo area was the mechanism of injury. The charts of pediatric patients (< or = 16 years of age) with neurological injuries were reviewed and analyzed. Seventy-three pediatric patients with injuries related to riding in the cargo areas of trucks were identified, of which 53 children (73%) had sustained neurological injuries. Among these 53 children, 64% sustained isolated head injuries, 15% isolated spine injuries, 9.4% combined spine and head injuries, 2% combined peripheral nerve, spine, and head injuries, 4% isolated peripheral nerve injuries, and 5.6% concussive events. In 53.4% of patients with neurological injuries the results of computed tomography (CT) examination were abnormal. In 36% of patients with Glasgow Coma Scale (GCS) scores of 14 to 15 there was evidence of intracranial hemorrhage on head CT scans. Injury Severity Scores were similar in the patients who were ejected and those who fell from cargo areas, but patients who were ejected had a lower mean GCS score than those who suffered falls (GCS score 12.5 and 14.3, respectively). CONCLUSIONS: Falls or ejections from pickup truck cargo areas result in a relatively high incidence of traumatic head, spine, and peripheral nerve injury. Head CT scanning should therefore be considered in pediatric patients with this mechanism of injury. Cargo area occupancy poses an unacceptable risk of injury and should be avoided.

Pituitary adenomas can appear as hypermetabolic lesions in (18) F-FDG PET imaging.

OBJECTIVE: The 2-deoxy-2-[(18) F] fluoro-D-glucose positron emission tomography (FDG-PET) scan is commonly used in detection and staging of many malignant neoplasms. However, several benign or non-neoplastic conditions avidly accumulate (18) F-FDG, causing ambiguity in interpretation of results. It is unknown whether pituitary adenomas uptake (18) F-FDG and appear positive in PET imaging. Here, we present 2 cases of benign pituitary adenoma with elevated metabolic activity in (18) F-FDG PET scan. METHODS: Medical, neurologic, and psychiatric histories; physical examination findings; laboratory work up results; and pathologic and imaging studies were documented. RESULTS: The (18) F-FDG-PET images revealed foci of marked FDG uptake in pituitary adenomas of 2 patients. CONCLUSION: Pituitary micro- and macro-adenomas may present as hypermetabolic foci on (18) F-FDG PET scan.

An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation.

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.