Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects.

Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-ß as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.

Atopic Dermatitis: A Guide to Transitioning to Janus Kinase Inhibitors.

Janus kinase inhibitors (JAKis) are promising medications that the Food and Drug Administration recently approved for treatment of atopic dermatitis in January 2022. These medications offer a novel therapeutic mechanism and may be an additional treatment avenue for patients who are currently reliant on conventional immunosuppressants, such as cyclosporine A, methotrexate, or mycophenolate mofetil, or newer medications, such as dupilumab. However, redundant treatment puts patients at risk for excessive toxicity and polypharmacy, whereas abrupt tapering of a preexisting regimen may cause flares of the disease. Thus, transitioning to JAKis should be implemented strategically to retain the therapeutic benefit and minimize the risk of flares. Herein, we outline gradual transition schemas for patients needing to transition to JAKis from conventional immunosuppressants or dupilumab. There is no evidence-based guideline to instruct this transition to JAKis, and our recommendations are based on expert experience and the review of efficacy data from pivotal trials.

Allergen Composition, Marketing Claims, and Affordability of Pediatric Sunscreens.

BACKGROUND: Childhood sun exposure is associated with development of future skin cancers. Sunscreens are an important tool to prevent harmful ultraviolet rays. OBJECTIVES: The aims of the study are to evaluate sunscreens targeted to children and to analyze cost, marketing claims, ingredients, and allergens to help consumers select products. METHODS: The top 50 pediatric sunscreens across retailers were analyzed for their cost, marketing claims, ingredients, vehicles, and containers. Ingredients were compared with the American Contact Dermatology Society 2020 Core Allergen List. RESULTS: The mean price was $6.20 per ounce (range, $0.25-$39.98). The mean sun protection factor was 48.5 (range, 30-100; SD, 48.5). There was a mean of 17.5 ingredients and a mean of 1.1 allergens in products. On average, products marketed as "sensitive skin" were not only significantly more expensive ($8.90 vs $3.50 per ounce, P = 0.01) but also were significantly more likely to not contain any allergens (36.0%, n = 18 vs 12%, n = 6; P = 0.05). Products with mineral-only UV blockers were significantly less likely to have any allergen when compared with products that had chemical UV blockers (5.6%, n = 1 vs 94.4%, n = 17; P = 0.02). CONCLUSIONS: The current market of pediatric sunscreens varies significantly in price, marketing claims, and active ingredients. Products marked as suitable for sensitive skin had significantly fewer allergens, but a majority of these products still had at least one allergen. Many sunscreens contain contact allergens, which is an important selection consideration.

Sarcopenia as a Prognostic Factor for 90-Day and Overall Mortality in Patients Undergoing Spine Surgery for Metastatic Tumors: A Multicenter Retrospective Cohort Study.

BACKGROUND: Novel methods in predicting survival in patients with spinal metastases may help guide clinical decision-making and stratify treatments regarding surgery vs palliative care. OBJECTIVE: To evaluate whether the frailty/sarcopenia paradigm is predictive of survival and morbidity in patients undergoing surgery for spinal metastasis. METHODS: A total of 271 patients from 4 tertiary care centers who had undergone surgery for spinal metastasis were identified. Frailty/sarcopenia was defined by psoas muscle size. Survival hazard ratios were calculated using multivariate analysis, with variables from demographic, functional, oncological, and surgical factors. Secondary outcomes included improvement of neurological function and postoperative morbidity. RESULTS: Patients in the smallest psoas tertile had shorter overall survival compared to the middle and largest tertile. Psoas size (PS) predicted overall mortality more strongly than Tokuhashi score, Tomita score, and Karnofsky Performance Status (KPS). PS predicted 90-d mortality more strongly than Tokuhashi score, Tomita score, and KPS. Patients with a larger PS were more likely to have an improvement in deficit compared to the middle tertile. PS was not predictive of 30-d morbidity. CONCLUSION: In patients undergoing surgery for spine metastases, PS as a surrogate for frailty/sarcopenia predicts 90-d and overall mortality, independent of demographic, functional, oncological, and surgical characteristics. The frailty/sarcopenia paradigm is a stronger predictor of survival at these time points than other standards. PS can be used in clinical decision-making to select which patients with metastatic spine tumors are appropriate surgical candidates.

Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.

Fibronectin in malignancy: Cancer-specific alterations, protumoral effects, and therapeutic implications.

Initial studies on cancer primarily focused on malignant cells themselves. The overarching narrative of cancer revolved around unchecked and rapidly proliferating cells. Special attention was given to the molecular, genetic, and metabolic profiles of isolated cancer cells in hopes of elucidating a critical factor in malignancy. However, the scope of cancer research has broadened over the past few decades to include the local environment around cancer. It has become increasingly apparent that the immune cells, vascular networks, and the extracellular matrix all have a part in cancer progression. The impact of the extracellular matrix is particularly fascinating and key stromal changes have been identified in various cancers. Pioneering work studying laminin and hyaluronate has shown that these molecules have vital roles in cancer progression. More recently, fibronectin has been included as an extracellular driver of malignancy. Fibronectin is thought to play a considerable, albeit poorly understood, role in cancer pathogenesis. In this review, we present fundamental studies that have investigated the impact of fibronectin in cancer. As an abundant component of the extracellular matrix, understanding the effect of this molecule has the potential to elucidate cancer biology.

From bench to bedside: trends in National Institutes of Health funding for neurosurgeons from 1991 to 2015.

OBJECTIVE: Neurosurgeons play an important role in advancing medicine through research, the funding of which is historically linked to the National Institutes of Health (NIH). The authors defined variables associated with neurosurgical NIH funding, prevalence of funded topics by neurosurgical subspecialty, and temporal trends in NIH neurosurgical funding. METHODS: The authors conducted a retrospective review of NIH-funded American Association of Neurological Surgeons members using NIH RePORTER (http://report.nih.gov/) for the years 1991-2015. RESULTS: The authors followed 6515 neurosurgeons from 1991 to 2015, including 6107 (94%) non-MD-PhD physicians and 408 (6%) MD-PhDs. NIH grants were awarded to 393 (6%) neurosurgeons, with 23.2% of all first-time grants awarded to the top 5 funded institutions. The average total funded grant-years per funded neurosurgeon was 12.5 (range 1-85 grant-years). A higher percentage of MD-PhDs were NIH funded than MDs (22% [n = 91] vs 5% [n = 297], p < 0.0001). The most common grants awarded were R01 (128, 33%), K08 (69, 18%), F32 (60, 15%), M01 (50, 13%), and R21 (39, 10%). F32 and K08 recipients were 9-fold (18% vs 2%, p < 0.001) and 19-fold (38% vs 2%, p < 0.001) more likely to procure an R01 and procured R01 funding earlier in their careers (F32: 7 vs 12 years after residency, p = 0.03; K08: 9 vs 12 years, p = 0.01). Each year, the number of neurosurgeons with active grants linearly increased by 2.2 (R2 = 0.81, p < 0.001), whereas the number of total active grants run by neurosurgeons increased at nearly twice the rate (4.0 grants/year) (R2 = 0.91, p < 0.001). Of NIH-funded neurosurgical grants, 33 (9%) transitioned to funded clinical trial(s). Funded neurosurgical subspecialties included neuro-oncology (33%), functional/epilepsy (32%), cerebrovascular (17%), trauma (10%), and spine (6%). Finally, the authors modeled trends in the number of active training grants and found a linear increase in active R01s (R2 = 0.95, p < 0.001); however, both F32 (R2 = 0.36, p = 0.01) and K08 (R2 = 0.67, p < 0.001) funding had a significant parabolic rise and fall centered around 2003. CONCLUSIONS: The authors observed an upward trend in R01s awarded to neurosurgeons during the last quarter century. However, their findings of decreased K08 and F32 training grant funding to neurosurgeons and the impact of these training grants on the ultimate success and time to success for neurosurgeons seeking R01 funding suggests that this upward trend in R01 funding for neurosurgeons will be difficult to maintain. The authors' work underscores the importance of continued selection and mentorship of neurosurgeons capable of impacting patient care through research, including the MD-PhDs, who are noted to be more represented among NIH-funded neurosurgeons.

Systemic therapy for brain metastases.

Metastases from cells outside of the central nervous system are the most common cancer found in the brain and are commonly associated with poor prognosis. Although cancer treatment is improving overall, central nervous system metastases are becoming more prevalent and require finesse to properly treat. Physicians must consider the biology of the primary tumor and the complex neurological environment that the metastasis resides in. This can be further complicated by the fact that the practice of cancer management is constantly evolving and therapy that works outside of the blood-brain barrier may not be effective inside of it. Therefore, this review seeks to update the reader on recent advancements made on the three most common sources of brain metastases: lung cancer, breast cancer, and melanoma. Each of these malignancies has been the subject of intriguing and novel avenues of therapy which are reviewed here.

Insurance type impacts the economic burden and survival of patients with newly diagnosed glioblastoma.

OBJECTIVE: Glioblastoma (GBM) carries a high economic burden for patients and caregivers, much of which is associated with initial surgery. The authors investigated the impact of insurance status on the inpatient hospital costs of surgery for patients with GBM. METHODS: The authors conducted a retrospective review of patients with GBM (2010-2015) undergoing their first resection at the University of California, San Francisco, and corresponding inpatient hospital costs. RESULTS: Of 227 patients with GBM (median age 62 years, 37.9% females), 31 (13.7%) had Medicaid, 94 (41.4%) had Medicare, and 102 (44.9%) had private insurance. Medicaid patients had 30% higher overall hospital costs for surgery compared to non-Medicaid patients ($50,285 vs $38,779, p = 0.01). Medicaid patients had higher intensive care unit (ICU; p < 0.01), operating room (p < 0.03), imaging (p < 0.001), room and board (p < 0001), and pharmacy (p < 0.02) costs versus non-Medicaid patients. Medicaid patients had significantly longer overall and ICU lengths of stay (6.9 and 2.6 days) versus Medicare (4.0 and 1.5 days) and privately insured patients (3.9 and 1.8 days, p < 0.01). Medicaid patients had similar comorbidity rates to Medicare patients (67.8% vs 68.1%), and both groups had higher comorbidity rates than privately insured patients (37.3%, p < 0.0001). Only 67.7% of Medicaid patients had primary care providers (PCPs) versus 91.5% of Medicare and 86.3% of privately insured patients (p = 0.009) at the time of presentation. Tumor diameter at diagnosis was largest for Medicaid (4.7 cm) versus Medicare (4.1 cm) and privately insured patients (4.2 cm, p = 0.03). Preoperative (70 vs 90, p = 0.02) and postoperative (80 vs 90, p = 0.03) Karnofsky Performance Scale (KPS) scores were lowest for Medicaid versus non-Medicaid patients, while in subgroup analysis, postoperative KPS score was lowest for Medicaid patients (80, vs 90 for Medicare and 90 for private insurance; p = 0.03). Medicaid patients had significantly shorter median overall survival (10.7 months vs 12.8 months for Medicare and 15.8 months for private insurance; p = 0.02). Quality-adjusted life year (QALY) scores were 0.66 and 1.05 for Medicaid and non-Medicaid patients, respectively (p = 0.036). The incremental cost per QALY was $29,963 lower for the non-Medicaid cohort. CONCLUSIONS: Patients with GBMs and Medicaid have higher surgical costs, longer lengths of stay, poorer survival, and lower QALY scores. This study indicates that these patients lack PCPs, have more comorbidities, and present later in the disease course with larger tumors; these factors may drive the poorer postoperative function and greater consumption of hospital resources that were identified. Given limited resources and rising healthcare costs, factors such as access to PCPs, equitable adjuvant therapy, and early screening/diagnosis of disease need to be improved in order to improve prognosis and reduce hospital costs for patients with GBM.

Efficacy of decompressive craniectomy in the management of intracranial pressure in severe traumatic brain injury.

Traumatic brain injury (TBI) is a common cause of permanent disability for which clinical management remains suboptimal. Elevated intracranial pressure (ICP) is a common sequela following TBI leading to death and permanent disability if not properly managed. While clinicians often employ stepwise acute care algorithms to reduce ICP, a number of patients will fail medical management and may be considered for surgical decompression. Decompressive craniectomy (DC) involves removing a component of the bony skull to allow cerebral tissue expansion in order to reduce ICP. However, the impact of DC, which is performed in the setting of neurological instability, ongoing secondary injury, and patient resuscitation, has been challenging to study and outcomes are not well understood. This review summarizes historical and recent studies to elucidate indications for DC and the nuances, risks and complications in its application. The pathophysiology driving ICP elevation, and the corresponding medical interventions for their temporization and treatment, are thoroughly described. The current state of DC - including appropriate injury classification, surgical techniques, concurrent medical therapies, mortality and functional outcomes - is presented. We also report on the recent updates from large randomized controlled trials in severe TBI (Decompressive Craniectomy [DECRA] and Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of ICP [RESCUEicp]), and recommendations for early DC to treat refractory ICP elevations in malignant middle cerebral artery syndrome. Limitations for DC, such as the equipoise between immediate reduction in ICP and clinically meaningful functional outcomes, are discussed in support of future investigations.

Preinjury employment status as a risk factor for symptomatology and disability in mild traumatic brain injury: A TRACK-TBI analysis.

BACKGROUND: Preinjury employment status may contribute to disparity, injury risk, and recovery patterns following mild traumatic brain injury (MTBI). OBJECTIVE: To characterize associations between preinjury unemployment, prior comorbidities, and outcomes following MTBI. METHODS: MTBI patients from TRACK-TBI Pilot with complete six-month outcomes were extracted. Preinjury unemployment, comorbidities, injury factors, and intracranial pathology were considered. Multivariable regression was performed for employment and outcomes, correcting for demographic and injury factors. Mean-differences (B) and 95% CIs are reported. Statistical significance was assessed at p < 0.05. RESULTS: 162 MTBI patients were aged 39.8±15.4-years and 24.6% -unemployed. Unemployed patients demonstrated increased psychiatric comorbidities (45.0% -vs.- 23.8%; p = 0.010), drug use (52.5% -vs.- 21.3%; p < 0.001), smoking (62.5% -vs.- 27.0%; p < 0.001), prior TBI (78.4% -vs.- 55.0%; p = 0.012), and lower education (15.0% -vs.- 45.1% college degree; p = 0.003). On multivariable analysis, unemployment associated with decreased six-month functional outcome (Glasgow Outcome Scale-Extended: B = - 0.50, 95% CI [- 0.88, - 0.11]), increased psychiatric disturbance (Brief Symptom Inventory-18: B = 6.22 [2.33, 10.10]), postconcussional symptoms (Rivermead Questionnaire: B = 4.91 [0.38, 9.44]), and post-traumatic stress disorder (PTSD Checklist-Civilian: B = 5.99 [0.76, 11.22]). No differences were observed for cognitive measures or satisfaction with life. CONCLUSIONS: Unemployed patients are at risk for preinjury psychosocial comorbidities, poorer six-month functional recovery and increased psychiatric/postconcussional/PTSD symptoms. Resource allocation and return precautions should be implemented to mitigate and/or prevent the decline of at-risk patients.

Disparities in health care determine prognosis in newly diagnosed glioblastoma.

OBJECTIVE Glioblastoma (GBM) is an aggressive brain malignancy with a short overall patient survival, yet there remains significant heterogeneity in outcomes. Although access to health care has previously been linked to impact on prognosis in several malignancies, this question remains incompletely answered in GBM. METHODS This study was a retrospective analysis of 354 newly diagnosed patients with GBM who underwent first resection at the authors' institution (2007-2015). RESULTS Of the 354 patients (median age 61 years, and 37.6% were females), 32 (9.0%) had no insurance, whereas 322 (91.0%) had insurance, of whom 131 (40.7%) had Medicare, 45 (14%) had Medicaid, and 146 (45.3%) had private insurance. On average, insured patients survived almost 2-fold longer (p < 0.0001) than those who were uninsured, whereas differences between specific insurance types did not influence survival. The adjusted hazard ratio (HR) for death was higher in uninsured patients (HR 2.27 [95% CI 1.49-3.33], p = 0.0003). Age, mean household income, tumor size at diagnosis, and extent of resection did not differ between insured and uninsured patients, but there was a disparity in primary care physician (PCP) status-none of the uninsured patients had PCPs, whereas 72% of insured patients had PCPs. Postoperative adjuvant treatment rates with temozolomide (TMZ) and radiation therapy (XRT) were significantly less in uninsured (TMZ in 56.3%, XRT in 56.3%) than in insured (TMZ in 75.2%, XRT in 79.2%; p = 0.02 and p = 0.003) patients. Insured patients receiving both agents had better prognosis than uninsured patients receiving the same treatment (9.1 vs 16.34 months; p = 0.025), suggesting that the survival effect in insured patients could only partly be explained by higher treatment rates. Moreover, having a PCP increased survival among the insured cohort (10.7 vs 16.1 months, HR 1.65 [95% CI 1.27-2.15]; p = 0.0001), which could be explained by significant differences in tumor diameter at initial diagnosis between patients with and without PCPs (4.3 vs 4.8 cm, p = 0.003), and a higher rate of clinical trial enrollment, suggesting a critical role of PCPs for a timelier diagnosis of GBM and proactive cancer care management. CONCLUSIONS Access to health care is a strong determinant of prognosis in newly diagnosed patients with GBM. Any type of insurance coverage and having a PCP improved prognosis in this patient cohort. Higher rates of treatment with TMZ plus XRT, clinical trial enrollment, fewer comorbidities, and early diagnosis may explain survival disparities. Lack of health insurance or a PCP are major challenges within the health care system, which, if improved upon, could favorably impact the prognosis of patients with GBM.

Petrous Face Meningiomas: Classification, Clinical Syndromes, and Surgical Outcomes.

BACKGROUND: Petrous face meningiomas (PFMs) are challenging tumors because of their proximity to the cranial nerves, brainstem, and critical vasculature. The objective of this study is to present surgical outcomes and support an anatomic classification for PFM based on clinical presentation. METHODS: A retrospective chart review was performed, and 51 PFMs were identified. Tumors were classified by location along the petrous face into anterior, middle, and posterior. Presentation and outcomes were analyzed with logistic regression. RESULTS: The median follow-up was 31.6 months. Tumors were World Health Organization grade I (n = 50), with 1 World Health Organization grade II tumor. Location was anterior (22%), middle (14%), posterior (53%), and overlapping (12%). Median tumor diameter was 3.0 cm (range, 0.8-6.2 cm). Anterior location was associated with facial pain/numbness on presentation (P < 0.0001), middle location with hearing loss/vestibular dysfunction (P = 0.0035), and posterior with hydrocephalus (P = 0.0190), headache (P = 0.0039), and vertigo (P = 0.0265). Extent of resection was gross total (63%), near total (14%), and subtotal (25%). The observed radiographic recurrence rate was 15%. Mean progression-free survival after diagnosis was 9.1 years with 2-year, 5-year, and 10-year progression-free survival of 91.8%, 78.6%, and 62.9%, respectively. The complication rate was 27%. Age, location, and approach were not associated with complications. CONCLUSIONS: PFMs present with distinct clinical syndromes based on their location along the petrous face: anterior with trigeminal symptoms, middle with auditory/vestibular symptoms, and posterior with symptoms of mass effect/hydrocephalous. Surgical resection is associated with excellent long-term survival and a low rate of recurrence, which can be managed with radiotherapy.

Correction: Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.

[This corrects the article DOI: 10.1371/journal.ppat.1006753.].

Reduction of shunt dependency rates following aneurysmal subarachnoid hemorrhage by tandem fenestration of the lamina terminalis and membrane of Liliequist during microsurgical aneurysm repair.

OBJECTIVEShunt-dependent hydrocephalus is an important cause of morbidity following aneurysmal subarachnoid hemorrhage (aSAH) in excess of 20% of cases. Hydrocephalus leads to prolonged hospital and ICU stays, well as to repeated surgical interventions, readmissions, and complications associated with ventriculoperitoneal (VP) shunts, including shunt failure and infection. Whether variations in surgical technique at the time of aneurysm treatment may modify rates of shunt dependency remains a matter of debate. Here, the authors report on their experience with tandem fenestration of the lamina terminalis (LT) and membrane of Liliequist (MoL) at the time of open microsurgical repair of the ruptured aneurysm.METHODSThe authors conducted a retrospective review of 663 consecutive patients with aSAH treated from 2005 to 2015 by open microsurgery via a pterional or orbitozygomatic craniotomy by the senior author (M.T.L.). Data collected from review of the electronic medical record included age, Hunt and Hess grade, Fisher grade, need for an external ventricular drain, and opening pressure. Patients were stratified into those undergoing no fenestration and those undergoing tandem fenestration of the LT and MoL at the time of surgical repair. Outcome variables, including VP shunt placement and timing of shunt placement, were recorded and statistically analyzed.RESULTSIn total, shunt-dependent hydrocephalus was observed in 15.8% of patients undergoing open surgical repair following aSAH. Tandem microsurgical fenestration of the LT and MoL was associated with a statistically significant reduction in shunt dependency (17.9% vs 3.2%, p < 0.01). This effect was confirmed with multivariate analysis of collected variables (multivariate OR 0.09, 95% CI 0.03-0.30). Number-needed-to-treat analysis demonstrated that tandem fenestration was required in approximately 6.8 patients to prevent a single VP shunt placement. A statistically significant prolongation in days to VP shunt surgery was also observed in patients treated with tandem fenestration (26.6 ± 19.4 days vs 54.0 ± 36.5 days, p < 0.05).CONCLUSIONSTandem fenestration of the LT and MoL at the time of open microsurgical clipping and/or bypass to secure ruptured anterior and posterior circulation aneurysms is associated with reductions in shunt-dependent hydrocephalus following aSAH. Future prospective randomized multicenter studies are needed to confirm this result.

Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.

Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model.

Update on critical care for acute spinal cord injury in the setting of polytrauma.

Traumatic spinal cord injury (SCI) often occurs in patients with concurrent traumatic injuries in other body systems. These patients with polytrauma pose unique challenges to clinicians. The current review evaluates existing guidelines and updates the evidence for prehospital transport, immobilization, initial resuscitation, critical care, hemodynamic stability, diagnostic imaging, surgical techniques, and timing appropriate for the patient with SCI who has multisystem trauma. Initial management should be systematic, with focus on spinal immobilization, timely transport, and optimizing perfusion to the spinal cord. There is general evidence for the maintenance of mean arterial pressure of > 85 mm Hg during immediate and acute care to optimize neurological outcome; however, the selection of vasopressor type and duration should be judicious, with considerations for level of injury and risks of increased cardiogenic complications in the elderly. Level II recommendations exist for early decompression, and additional time points of neurological assessment within the first 24 hours and during acute care are warranted to determine the temporality of benefits attributable to early surgery. Venous thromboembolism prophylaxis using low-molecular-weight heparin is recommended by current guidelines for SCI. For these patients, titration of tidal volumes is important to balance the association of earlier weaning off the ventilator, with its risk of atelectasis, against the risk for lung damage from mechanical overinflation that can occur with prolonged ventilation. Careful evaluation of infection risk is a priority following multisystem trauma for patients with relative immunosuppression or compromise. Although patients with polytrauma may experience longer rehabilitation courses, long-term neurological recovery is generally comparable to that in patients with isolated SCI after controlling for demographics. Bowel and bladder disorders are common following SCI, significantly reduce quality of life, and constitute a focus of targeted therapies. Emerging biomarkers including glial fibrillary acidic protein, S100ß, and microRNAs for traumatic SCIs are presented. Systematic management approaches to minimize sources of secondary injury are discussed, and areas requiring further research, implementation, and validation are identified.

Improved Survival with Decreased Wait Time to Surgery in Glioblastoma Patients Presenting with Seizure.

BACKGROUND: Preoperative seizure is reported to confer favorable prognosis in glioblastoma patients, but studies to date have not investigated how broadly applicable seizure is as a prognostic factor. OBJECTIVE: To investigate if prompter surgical intervention affects the relationship between preoperative seizure and prognosis in glioblastoma patients, focusing on the development of tumor growth and/or additional preoperative symptoms after seizure. METHODS: Retrospective analysis of 443 patients (mean age = 60.2; 60% male) undergoing first glioblastoma resection at our institution (2005-2011). RESULTS: Preoperative seizure(s) occurred in 28% of patients (n = 124), of which 63 (51%) had only seizure at presentation. Patients experiencing seizure as their only preoperative symptom ("seizure-only"; n = 45) survived over twice as long as patients who presented with seizure and then later developed additional preoperative symptoms (n = 18; "other symptoms postseizure"; 26.8 vs 10.2 months, P < .001) and patients without preoperative seizure ("no seizure"; 26.8 vs 13.1 months, P < .001). Multivariate stepwise analysis revealed preoperative seizures only (hazard ratio 0.54 [0.37-0.75]; P < .001) to be independently associated with increased survival. Longer wait time from presentation (ie, diagnostic magnetic resonance imaging) to surgery was a risk factor for developing additional symptoms. Eleven "other symptoms postseizure" patients (69%) vs 6 of the "seizure-only" patients (15%) had wait times >45 days (P < .001). CONCLUSION: Seizure as the only preoperative symptom independently improved survival, however, when patients developed additional preoperative symptoms, typically due to surgical delay, no prognostic benefit was observed. Prompt diagnosis and neurosurgical intervention is warranted in patients with seizures without other preoperative symptoms to preserve their favorable prognosis.

Factors Associated With Pre- and Postoperative Seizures in 1033 Patients Undergoing Supratentorial Meningioma Resection.

BACKGROUND: Risk factors for pre- and postoperative seizures in supratentorial meningiomas are understudied compared to other brain tumors. OBJECTIVE: To report seizure frequency and identify factors associated with pre- and postoperative seizures in a large single-center population study of patients undergoing resection of supratentorial meningioma. METHODS: Retrospective chart review of 1033 subjects undergoing resection of supratentorial meningioma at the author's institution (1991-2014). Multivariate regression was used to identify variables significantly associated with pre- and postoperative seizures. RESULTS: Preoperative seizures occurred in 234 (22.7%) subjects. At 5 years postoperative, probability of seizure freedom was 89.9% among subjects without preoperative seizures and 62.2% with preoperative seizures. Multivariate analysis identified the following predictors of preoperative seizures: presence of ≥1 cm peritumoral edema (odds ratio [OR]: 4.45, 2.55-8.50), nonskull base tumor location (OR: 2.13, 1.26-3.67), greater age (OR per unit increase: 1.03, 1.01-1.05), while presenting symptom of headache (OR: 0.50, 0.29-0.84) or cranial nerve deficit (OR: 0.36, 0.17-0.71) decreased odds of preoperative seizures. Postoperative seizures after discharge were associated with preoperative seizures (OR: 5.70, 2.57-13.13), in-hospital seizure (OR: 4.31, 1.28-13.67), and among patients without preoperative seizure, occurrence of medical or surgical complications (OR 3.39, 1.09-9.48). Perioperative anti-epileptic drug use was not associated with decreased incidence of postoperative seizures. CONCLUSIONS: Nonskull base supratentorial meningiomas with surrounding edema have the highest risk for preoperative seizure. Long-term follow-up showing persistent seizures in meningioma patients with preoperative seizures raises the possibility that these patients may benefit from electrocorticographic mapping of adjacent cortex and resection of noneloquent, epileptically active cortex.

Patients cured of acromegaly do not experience improvement of their skull deformities.

PURPOSE: Acromegaly is a rare disease that is associated with many co-morbidities. This condition also causes progressive deformity of the skull which includes frontal bossing and cranial thickening. Surgical and/or medical management can cure this condition in many patients, but it is not understood if patients cured of acromegaly experience regression of their skull deformities. METHODS: We performed a retrospective analysis on patients treated at our dedicated pituitary center from 2009 to 2014. We looked at all MRI images taken during the treatment of these patients and recorded measurements on eight skull dimensions. We then analyzed these measurements for changes over time. RESULTS: 29 patients underwent curative treatment for acromegaly within our timeframe. The mean age for this population was 45.0 years old (range 19-70) and 55.2 % (n = 16) were female. All of these patients were treated with a transsphenoidal resection for a somatotropic pituitary adenoma. 9 (31.1%) of these patients required further medical therapy to be cured. We found statically significant variation in the coronal width of the sella turcica after therapy, which is likely attributable to changes from transsphenoidal surgery. None of the other dimensions had significant variation over time after cure. CONCLUSION: Patients cured of acromegaly should not expect natural regression of their skull deformities. Our study suggests that both frontal bossing and cranial thickening do not return to normal after cure.