Bhargav, Adip G.

Abstract Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.

AbstractBrain cancer persists as a difficult‐to‐treat condition. In particular, metastatic brain cancer and malignant primary brain tumors such as glioblastoma (GBM) are among the most deadly and still carry a dismal prognosis despite current standard of care with surgery and chemo‐radiation. Recent advances in nanotechnology have led to innovative nanomedicine strategies for the treatment of brain cancers and specifically for GBM. These strategies represent promising alternative or adjunctive therapies for conventional treatment modalities and are increasingly designed to target specific cell types such as brain tumor‐initiating cells and immune cells. This review provides an update on emerging insights into these nanomedicine strategies with a focus on nanoparticles as tools that facilitate 1) drug delivery 2) gene therapy, and 3) engineered‐cellular therapy for GBM and future directions for brain cancer treatment.

OBJECTIVEThe sitting or semisitting position in neurosurgery allows for several technical advantages, including improved visualization of the surgical field. However, it has also been associated with an increased risk of venous air embolisms and positioning-related complications that limit its commonplace adoption. The authors report a large, single-center series of cervical spine procedures performed with patients in the sitting or prone position in order to assess the perceived risk of intraoperative and postoperative complications associated with the sitting position.METHODSNoninstrumented, single-level posterior cervical spine procedures performed with patients in the sitting/semisitting or prone position from 2000 to 2016 at a single institution were reviewed. Institutional abstraction tools (DataMart and Chart Plus) were used to collect data from the medical records. The two positions were compared with regard to preoperative factors, intraoperative variables, and postoperative outcomes. Multivariable logistic regression models were fitted for 30-day readmission, 30-day return to the operating room, and complication rates.RESULTSA total of 750 patients (sitting, n = 480; prone, n = 270) were analyzed. The median age was 53 years for those who underwent surgery in the prone position and 50 years for those who underwent surgery in the sitting position (IQRs 45–62 years and 43–60 years, respectively), and 35% of the patients were female. Sitting cases were associated with significantly longer anesthetic times (221 minutes [range 199–252 minutes] vs 205 minutes [range 179–254 minutes]) and operative times (126 minutes [range 101–163 minutes] vs 149 minutes [120–181 minutes]). Cardiorespiratory events in the postanesthesia care unit (PACU) were comparable between the two groups, with the exception of episodes of apnea (2.6% vs 0.6%, p = 0.041) and hypoventilation (4.4% vs 0.8%, p < 0.003), which were more frequent in the prone-position cohort. On multivariable analysis, the effect of the sitting versus the prone position was not significant for 30-day readmission (OR 0.77, 95% CI 0.34–1.71, p = 0.52) or reoperation (OR 0.71, 95% CI 0.31–1.60, p = 0.40). The sitting position was associated with lower odds of developing any complication (OR 0.31, 95% CI 0.16–0.62, p < 0.001).CONCLUSIONSBased on the intraoperative and postoperative complications chosen in this study, the sitting position confers a similar safety profile to the prone position. This can be explained by a more anatomic positioning accounting for reduced temporary neurological deficits and reduced PACU-associated hypoventilation noted in this series. Nevertheless, the findings may also reflect institutional familiarity, experience, and mastery of this position type, and outcomes may not reflect practices in general.

OBJECTIVE Cushing’s disease arises from functioning adrenocorticotropic hormone (ACTH)–secreting pituitary adenomas. These tumors can be very small and evade detection by MRI. Empty sella syndrome is a phenomenon by which an arachnoid outpouching of CSF into the sella leads to compression of the pituitary, likely due to intracranial hypertension (a common issue in Cushing’s disease), further leading to difficulty in visualizing the pituitary gland that may contribute to difficulty in finding a tumor on MRI, so-called MRI-negative Cushing’s disease. The authors sought to examine the association between empty sella syndrome and MRI-negative Cushing’s disease. METHODS A single-institution database of Cushing’s disease cases from 2000 to 2017 was reviewed, and 197 cases were included in the analysis. One hundred eighty patients had a tissue diagnosis of Cushing’s disease and 17 had remission with surgery, but no definitive tissue diagnosis was obtained. Macroadenomas (tumors > 1 cm) were excluded. The degree of empty sella syndrome was graded on the degree of CSF visualized in the sella on midline sagittal T1-weighted MRI. RESULTS Of the 197 cases identified, 40 (20%) presented with MRI-negative disease, and empty sella syndrome was present in 49 cases (25%). MRI-negative disease was found in 18 (37%) of 49 empty sella cases versus 22 (15%) of 148 cases without empty sella syndrome present. Empty sella syndrome was significantly associated with MRI-negative disease (OR 3.32, 95% CI 1.61–6.74, p = 0.0018). Decreased thickness of the pituitary gland was also associated with MRI-negative disease (mean thickness 5.6 vs 6.8 mm, p = 0.0002). CONCLUSIONS Empty sella syndrome is associated with an increased rate of MRI-negative Cushing’s disease. Pituitary compression causing a relative reduction in the volume of the pituitary for imaging is a plausible cause for not detecting the tumor mass with MRI.

Abstract PURPOSE: Preoperative stereotactic radiosurgery (SRS) for symptomatic brain metastases has arisen as a therapeutic option for patients with brain lesions, potentially reducing radionecrosis risk, leptomeningeal disease risk, as well as delays in systemic therapy after craniotomy. The purpose of our work is to analyze the current evidence regarding 1-year local control (LC) and RN rates in the preoperative and postoperative settings. METHODS AND MATERIALS: Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were used to select articles in which patients had “large” brain metastases (&gt;4 cm3 or &gt;2 cm in diameter) solely treated with preoperative or postoperative SRS and 1-year LC and/or rates of RN reported. Radiosurgery was stratified by timing: preoperatively or postoperatively. Random effects meta-analyses using timing of SRS relative to surgery as covariates were conducted. Meta-regression and Wald-type tests were used to determine the effect of increasing tumor size on the summary estimate, where the null hypothesis was rejected for p &lt; 0.05. RESULTS: Fifteen studies were included (of 314 screened), published between 2012 and 2018 with 854 brain metastases. Preoperative SRS was delivered in 229 lesions. The 1-year LC random effects estimate was 79.1% (95% confidence interval [CI]: 55.9–95.0%; I 2 = 80%) for preoperative SRS and 80.5% (95% CI: 66.3–91.5%; I 2 = 93%) for postoperative SRS (p=0.9). Radionecrosis incidence random effects estimate was 2.1% (95% CI: 0.1–8.6%; I 2 = 36%) for preoperative SRS and 6.3% (95% CI: 1.1–15.4%; I 2 = 90%) for postoperative SRS (p=0.52). CONCLUSIONS: Rates of 1-year LC and RN incidence are similar after preoperative SRS as compared to postoperative SRS for large brain metastases. Results from ongoing prospective clinical trials studying preoperative SRS are important to further investigate these two techniques.

OBJECTIVEAlthough ventricular shunting is an effective therapy for idiopathic normal pressure hydrocephalus (iNPH), the effect of shunt valve type on the incidence of revision surgery is not well defined. To address this issue, shunt revision rates between patients with iNPH receiving a fixed-setting valve (FSV) versus a programmable valve (PV) were compared.METHODSPatients with iNPH treated with ventricular shunting between 2001 and 2017 were included for analysis. The incidence of shunt revision was noted and risk factors for revision were identified using a Cox proportional hazards model. Costs associated with admission for ventricular shunt procedures were obtained from the Vizient national database.RESULTSThere were 348 patients included for analysis, with 98 patients (28.1%) receiving a PV. Shunt revision occurred in 73 patients (21.0%), with 12 patients (3.4%) undergoing multiple revisions. Overall revision rates were lower in patients receiving a PV (13.3% vs 24.0%; p = 0.027), as was the incidence of multiple revisions (0.0% vs 4.8%; p = 0.023). Patients with initial placement of an FSV were also more likely to undergo valve exchange during follow-up (12.4% vs 2.0%; p = 0.003). Patients with a PV were less likely to undergo revision due to persistent symptoms without obstruction (2.0% vs 8.8%; p = 0.031) and distal obstruction (1.0% vs 6.8%; p = 0.030). In a multivariate Cox proportional hazards model, initial placement of a PV was associated with reduced risk of revision due to persistent symptoms without obstruction (OR 0.27, 95% CI 0.04–0.93; p = 0.036). PVs were associated with more frequent shunt series (1.3 vs 0.6; p < 0.001) and head CT scans (3.6 vs 2.7; p = 0.038) during follow-up. There was no significant difference in mean total costs between patients receiving an FSV and a PV ($24,282.50 vs $24,396.90; p = 0.937).CONCLUSIONSThe authors’ results suggest that PVs lead to reduced rates of shunt revision in patients with iNPH, and decreased risk of revision due to persistent symptoms of iNPH, thereby justifying the higher upfront cost of PVs despite similar overall treatment costs between these devices.

Pilocytic astrocytomas (PA) are highly vascular tumors with vascular endothelial growth factor (VEGF)–vascular endothelial growth factor receptor-2 (VEGFR-2) signaling present in the tumor vasculature. PA may, therefore, be responsive to VEGF blockade with bevacizumab (BEV). Data regarding the use of BEV in refractory PA in adults are limited primarily to case reports and case series of patients with recurrent PA. We conducted a single-center, retrospective cohort study from 2009 to 2018. We screened 426 patients with pathologically confirmed PA. We identified 5 adult patients with PA who received BEV at our institution with sufficient clinical follow-up to derive evidence of the efficacy and toxicity. All 5 patients experienced tumor progression after initial therapies which included surgery, radiation, and chemotherapy. Four patients received BEV as monotherapy, whereas 1 received BEV with the continuation of previously initiated alkylating chemotherapy (temozolomide). The average duration of BEV therapy was 10.2 months (range, 1 to 20 mo) with an average follow-up of 47 months (range, 6 to 112 mo). One patient had a severe necrotizing rash in areas of skin contact and discontinued after 1 cycle of BEV. All patients had stabilization per RANO criteria, with 1 patient experiencing progression after 10 months on treatment. One patient had disease progression 5 years after completion of BEV, but the tumor responded to repeat treatment with BEV. Our institution’s experience with the use of BEV in recurrent PA is in line with previous reports of therapeutic benefit in recurrent adult PA.

OBJECTIVEThe authors sought to investigate the incidence and predictors of venous thromboembolic events (VTEs) after craniotomy for tumor resection, which are not well established, and the efficacy of and risks associated with VTE chemoprophylaxis, which remains controversial.METHODSThe authors investigated the incidence of VTEs in a consecutive series of patients presenting to the authors’ institution for resection of an intracranial lesion between 2012 and 2017. Information on patient and tumor characteristics was collected and independent predictors of VTEs were determined using stepwise multivariate logistic regression analysis. Review of the literature was performed by searching MEDLINE using the keywords “venous thromboembolism,” “deep venous thrombosis,” “pulmonary embolism,” “craniotomy,” and “brain neoplasms.”RESULTSThere were 1622 patients included for analysis. A small majority of patients were female (52.6%) and the mean age of the cohort was 52.9 years (SD 15.8 years). A majority of intracranial lesions were intraaxial (59.3%). The incidence of VTEs was 3.0% and the rates of deep venous thromboses and pulmonary emboli were 2.3% and 0.9%, respectively. On multivariate analysis, increasing patient age (unit OR 1.02, 95% CI 1.00–1.05; p = 0.018), history of VTE (OR 7.26, 95% CI 3.24–16.27; p < 0.001), presence of motor deficit (OR 2.64, 95% CI 1.43–4.88; p = 0.002), postoperative intracranial hemorrhage (OR 4.35, 95% CI 1.51–12.55; p < 0.001), and prolonged intubation or reintubation (OR 3.27, 95% CI 1.28–8.32; p < 0.001) were independently associated with increased odds of a VTE. There were 192 patients who received VTE chemoprophylaxis (11.8%); the mean postoperative day of chemoprophylaxis initiation was 4.6 (SD 3.8). The incidence of VTEs was higher in patients receiving chemoprophylaxis than in patients not receiving chemoprophylaxis (8.3% vs 2.2%; p < 0.001). There were 30 instances of clinically significant postoperative hemorrhage (1.9%), with only 1 hemorrhage occurring after initiation of VTE chemoprophylaxis (0.1%).CONCLUSIONSThe study results show the incidence and predictors of VTEs after craniotomy for tumor resection in this patient population. The incidence of VTE within this cohort appears low and comparable to that observed in other institutional series, despite the lack of routine prophylactic anticoagulation in the postoperative setting.