Improved capture of adverse events after spinal surgery procedures with a longitudinal administrative database
JOURNAL OF NEUROSURGERY-SPINE
2015; 23 (3): 374-382
Glioblastoma antigen discovery--foundations for immunotherapy.
Journal of neuro-oncology
2015; 123 (3): 347-358
Therapeutic strategies to improve drug delivery across the blood-brain barrier.
2015; 38 (3): E9-?
Prognosis for patients with glioblastoma (GBM), the most common high-grade primary central nervous system (CNS) tumor, remains discouraging despite multiple discoveries and clinical advances. Immunotherapy has emerged as a promising approach to GBM therapy as the idea the human CNS is immunoprivileged is being challenged. Early clinical studies of vaccine-based approaches have been encouraging, but further investigation is required before these therapies become clinically meaningful. A key challenge in immunotherapy involves identification of target antigens that are specific and sensitive for GBM. Here we discuss tumor-associated antigens that have been targeted for GBM therapy, strategies for discovery of novel antigens, and the theory of epitope spreading as it applies to GBM immunotherapy.
View details for DOI 10.1007/s11060-015-1836-8
View details for PubMedID 26045361
Stereotactic radiosurgery for metastasis to the craniovertebral junction preserves spine stability and offers symptomatic relief.
Journal of neurosurgery. Spine
Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.
View details for DOI 10.3171/2014.12.FOCUS14758
View details for PubMedID 25727231
Building an electronic health record integrated quality of life outcomes registry for spine surgery.
Journal of neurosurgery. Spine
OBJECT Metastatic disease to the craniovertebral junction (CVJ) is rare but presents unique management challenges. To date, studies on using stereotactic radiosurgery (SRS) for CVJ metastases have been limited to case reports and small case series. The aim of this analysis was to evaluate the utility of SRS in the management of these secondary lesions. METHODS Clinical and radiological information from the charts of 25 patients with metastatic disease of the CVJ who were treated with SRS between 2005 and 2013 at the Stanford CyberKnife Center were retrospectively reviewed. RESULTS Seven male and 18 female patients with a median age of 58 years (range 34-94 years) were identified. The most common primary tumors were breast cancer (n = 5) and non-small cell lung cancer (n = 5), and the most frequent symptom was neck pain (n = 17). The average tumor volume treated was 15.9 cm(3) (range 0.16-54.1 cm(3)), with a mean marginal radiation dose of 20.3 Gy (range 15-25.5 Gy). The median follow-up was 18 months (range 1-81 months), though 1 patient was lost to follow-up. SRS provided radiographic tumor stability in over 80% of patients, offered pain alleviation in nearly two-thirds of patients, and produced no serious complications. Moreover, SRS preserved spinal stability in all but 1 patient, in whom pre-SRS stability was established. There was no evidence of radiation toxicity in the patient population. Median survival was 28 months (range 2-81 months), with survival of 13.3% at 5 years. CONCLUSIONS In the absence of unstable pathological fracture and spinal cord compression, metastatic tumors of the CVJ can be safely and effectively treated with SRS. This treatment option offers palliative pain relief and can halt tumor progression with only a low risk of complications or spinal instability.
View details for DOI 10.3171/2015.6.SPINE15190
View details for PubMedID 26516666
Neural Placode Tissue Derived From Myelomeningocele Repair Serves as a Viable Source of Oligodendrocyte Progenitor Cells.
2015; 77 (5): 794-802
OBJECT Demonstrating the value of spine care requires adequate outcomes assessment. Long-term outcomes are best measured as overall improvement in quality of life (QOL) after surgical intervention. Present registries often require parallel data entry, introducing inefficiencies and limiting compliance. The authors detail the methodology of constructing an integrated electronic health record (EHR) system to collect QOL metrics and demonstrate the effect of data collection on routine clinical workflow. A streamlined approach to collecting QOL data can capture patient data without requiring dual data entry and without increasing clinic visit times. METHODS Through extensive literature review, a combination of QOL assessments was selected, consisting of the Patient Health Questionnaire-2 and -9, Oswestry Disability Index, Neck Disability Index, and visual analog scale for pain. These metrics were used to provide assessment of QOL following spine surgery and were incorporated into standard clinic workflow by a multidisciplinary team of surgeons, advanced practice providers, and health care information technology specialists. A clinical dashboard tracking more than 25 patient variables was developed. Clinic flow was assessed and opportunities for improvement reviewed. Duration of clinic visits before and after initiation of QOL measure capture was recorded, with assessment of mean clinic visit times for the 12 months before and the 12 months after implementation. RESULTS The integrated QOL capture was instituted for 3 spine surgeons in a tertiary care academic center. In the 12-month period prior to initiating collection of QOL data, 806 new patient visits were completed with an average visit time of 127.9 ± 51.5 minutes. In the 12 months after implementation, 1013 new patient visits were recorded, with 791 providing QOL measures with an average visit time of 117.0 ± 45.7 minutes. Initially the primary means of collecting patient outcome data was via paper form, with gradual transition to collection via entry into the electronic medical records system. To improve electronic data capture, paper forms were eliminated and an online portal used as part of the patient rooming process. This improved electronic capture to nearly 98% without decreasing the number of patients enrolled in the process. CONCLUSIONS A systematic approach to collecting spine-related QOL data within an EHR system is feasible and offers distinct advantages over registries that require dual data entry. The process of data collection does not impact patients' clinical visit or providers' clinical workflow. This approach is scalable, and may form the foundation for a decentralized outcomes registry network.
View details for DOI 10.3171/2015.3.SPINE141127
View details for PubMedID 26431073
Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities.
Science translational medicine
2015; 7 (303): 303ra138-?
The presence, characteristics, and potential clinical relevance of neural progenitor populations within the neural placodes of myelomeningocele patients remain to be studied. Neural stem cells are known to reside adjacent to ependyma-lined surfaces along the central nervous system axis.Given such neuroanatomic correlation and regenerative capacity in fetal development, we assessed myelomeningocele-derived neural placode tissue as a potentially novel source of neural stem and progenitor cells.Nonfunctional neural placode tissue was harvested from infants during the surgical repair of myelomeningocele and subsequently further analyzed by in vitro studies, flow cytometry, and immunofluorescence. To assess lineage potential, neural placode-derived neurospheres were subjected to differential media conditions. Through assessment of platelet-derived growth factor α (PDGFRα) and CD15 cell marker expression, Sox2+Olig2+ putative oligodendrocyte progenitor cells were successfully isolated.PDGFRαCD15 cell populations demonstrated the highest rate of self-renewal capacity and multipotency of cell progeny. Immunofluorescence of neural placode-derived neurospheres demonstrated preferential expression of the oligodendrocyte progenitor marker, CNPase, whereas differentiation to neurons and astrocytes was also noted, albeit to a limited degree.Neural placode tissue contains multipotent progenitors that are preferentially biased toward oligodendrocyte progenitor cell differentiation and presents a novel source of such cells for use in the treatment of a variety of pediatric and adult neurological disease, including spinal cord injury, multiple sclerosis, and metabolic leukoencephalopathies.OPC, oligodendrocyte progenitor cellPDGFRα, platelet-derived growth factor receptor αSCI, spinal cord injury.
View details for DOI 10.1227/NEU.0000000000000918
View details for PubMedID 26225855
Glioblastoma stem cells and stem cell-targeting immunotherapies.
Journal of neuro-oncology
2015; 123 (3): 449-457
Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic "clusters" emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters-pre-multifocal, spherical, and rim-enhancing, names reflecting their image features-were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.
View details for DOI 10.1126/scitranslmed.aaa7582
View details for PubMedID 26333934
Anterior Versus Posterior Approach for Multilevel Degenerative Cervical Disease: A Retrospective Propensity Score-Matched Study of the MarketScan Database.
2015; 40 (13): 1033-1038
Advancements in immunotherapeutics promise new possibilities for the creation of glioblastoma (GBM) treatment options. Ongoing work in cancer stem cell biology has progressively elucidated the role of this tumor sub-population in oncogenesis and has distinguished them as prime therapeutic targets. Current clinical trials take a multifaceted approach with the intention of harnessing the intrinsic cytotoxic capabilities of the immune system to directly target glioblastoma cancer stem cells (gCSC) or indirectly disrupt their stromal microenvironment. Monoclonal antibodies (mAbs), dendritic cell (DC) vaccines, and chimeric antigen receptor (CAR) T cell therapies have emerged as the most common approaches, with particular iterations incorporating cancer stem cell antigenic markers in their treatment designs. Ongoing work to determine the comprehensive antigenic profile of the gCSC in conjunction with efforts to counter the immunosuppressive tumor microenvironment holds much promise in future immunotherapeutic strategies against GBM. Given recent advancements in these fields, we believe there is tremendous potential to improve outcomes of GBM patients in the continuing evolution of immunotherapies targeted to cancer stem cell populations in GBM.
View details for DOI 10.1007/s11060-015-1729-x
View details for PubMedID 25682090
Nelson Syndrome: Update on Therapeutic Approaches
2015; 83 (6): 1135-1140
Perspective on "the role of adjuvant radiotherapy after gross total resection of atypical meningiomas".
2015; 83 (5): 737-738
Estimate of the global volume of surgery in 2012: an assessment supporting improved health outcomes.
2015; 385: S11-?
Retrospective 2:1 propensity score-matched analysis on a national longitudinal database between 2006 and 2010.To compare rates of adverse events, revisions procedure rates, and payment differences in anterior cervical fusion procedures compared to posterior laminectomy and fusion procedures with at least 3 levels of instrumentation.The comparative benefits of anterior versus posterior approach to multilevel degenerative cervical disease remain controversial. Recent systematic reviews have reached conflicting conclusions. We demonstrate the comparative economic and clinical outcomes of anterior and posterior approaches for multilevel cervical degenerative disk disease.We identified 13,662 patients in a national billing claims database who underwent anterior or posterior cervical fusion procedures with three or more levels of instrumentation. Cohorts were balanced using 2:1 propensity score matching and outcomes were compared using bivariate analysis.With the exception of dysphagia (6.4% in anterior and 1.4% in posterior), overall 30-day complication rates were lower in the anterior approach group. The rate of any complication excluding dysphagia with anterior approaches was 12.3%, significantly lower (p < 0.0001) than that of posterior approaches, 17.8%. Anterior approaches resulted in lower hospital ($18,346 vs. $23,638) and total payments ($28,963 vs. $33,526). Patients receiving an anterior surgical approach demonstrated significantly lower rate of 30-day readmission (5.1% vs 9.9%, p < 0.0001), were less likely to require revision surgery (12.8% vs 18.1%, p < 0.0001), and had a shorter length of stay by 1.5 nights (p < 0.0001).Anterior approaches in the surgical management of multilevel degenerative cervical disease provide clinical advantages over posterior approaches, including lower overall complication rates, revision procedure rates, and decreased length of stay. Anterior approach procedures are also associated with decreased overall payments. These findings must be interpreted in light of limitations inherent to retrospective longitudinal studies including absence of subjective and radiographic outcomes.
View details for DOI 10.1097/BRS.0000000000000872
View details for PubMedID 25768690
Avoidable maternal and neonatal deaths associated with improving access to caesarean delivery in countries with low caesarean delivery rates: an ecological modelling analysis.
2015; 385: S33-?
It was previously estimated that 234·2 million operations were performed worldwide in 2004. The association between surgical rates and population health outcomes is not clear. We re-estimated global surgical volume to track changes over time and assess rates associated with healthy populations.We gathered demographic, health, and economic data for 194 WHO member states. Surgical volumes were obtained from published studies and other reports from 2005 onwards. We estimated rates of surgery for all countries without available data based on health expenditure in 2012 and assessed the proportion of surgery comprised by caesarean delivery. The rate of surgery was plotted against life expectancy to describe the association between surgical care and this health indicator.We identified 66 countries reporting surgical data between 2005 and 2013. We estimate that 312·9 million operations (95% CI 266·2-359·5) took place in 2012-a 33·6% increase over 8 years; the largest proportional increase occurred in countries spending US$400 or less per capita on health care. Caesarean delivery comprised 29·8% (5·8 million operations) of the total surgical volume in poor health expenditure countries compared with 10·8% (7·8 million operations) in low health expenditure countries and 2·7% (5·1 million operations) in high health expenditure countries. We noted a correlation between increased life expectancy and increased surgical rates up to 1533 operations per 100 000 people, with significant but less dramatic improvement above this rate.Surgical volume is large and continues to grow in all economic environments. A single procedure-caesarean delivery-comprised almost a third of surgical volume in the most resource-limited settings. Surgical care is an essential part of health care and is associated with increased life expectancy, yet many low-income countries fail to achieve basic levels of service. Improvements in capacity and delivery of surgical services must be a major component of health system strengthening.None.
View details for DOI 10.1016/S0140-6736(15)60806-6
View details for PubMedID 26313057
Pediatric Central Nervous System Tumors in Nepal: Retrospective Analysis and Literature Review of Low and Middle Income Countries.
Reducing maternal and neonatal deaths are important global health priorities. We have previously shown that up to a country-level caesarean delivery rate (CDRs) of roughly 19·0%, cesarean delivery rates and maternal mortality ratio (MMR) and neonatal mortality rate (NMR) were inversely correlated. We investigated the absolute reductions in maternal and neonatal deaths if countries with low CDR increased their rates to a range of greater than 7·2% but less than or equal to 19·1%.We calculated maternal and neonatal deaths in 2013 and 2012, respectively, for countries with CDR 7·2% or less (N=45) with available data from the World Bank Development Indicators. We modelled the expected reduction in deaths in these countries if they had the 25th and 75th MMR and NMR percentiles observed for countries (N=48) with CDRs ranging from greater than 7·2% but less than or equal to 19·1%. This model assumes that if countries with low CDRs increased their rates of caesarean delivery to greater than 7·2% but less than or equal to 19·1%, they would achieve levels of MMR and NMR observed in countries with those CDRs.We estimate 176 078 (95% CI 163 258-188 898) maternal and 1 117 257 (95% CI 1 033 611-1 200 902) neonatal deaths occurred in 45 countries with low CDRs in 2013 and 2012, respectively. If these countries had the 25th and 75th MMR and NMR percentiles (MMR, IQR 36-190; NMR, 9-24) observed in countries (N=48) with a CDR ranging from greater than 7·2% but less than or equal to 19·1%, there would be a potential reduction of 109 762-163 513 and 279 584-803 129 maternal and neonatal deaths, respectively.Increasing caesarean delivery in countries with low CDRs could avert as many as 163 513 maternal deaths and 803 129 neonatal deaths annually. These findings assume that as health systems develop the capacity to deliver surgical care, there is a concurrent improvement in the quality of care and in the ability to rescue women and neonates who would otherwise die. Improving access to safe caesarean delivery should be a central focus in surgical care globally.None.
View details for DOI 10.1016/S0140-6736(15)60828-5
View details for PubMedID 26313081
The Alzheimer's disease-8 and Montreal Cognitive Assessment as screening tools for neurocognitive impairment in HIV-infected persons.
Journal of neurovirology
2013; 19 (1): 109-116
Central nervous system (CNS) tumors are the most common cause of cancer-related death in children. Very little is known about the demographics and treatment of pediatric brain tumors in the low and middle-income countries (LMIC).We performed a retrospective chart review of all pediatric patients who presented to the neurosurgical service at Tribhuvan University Teaching Hospital in Kathmandu, Nepal from 2009-2014 and collected information on patients <18 years old who received a diagnosis of a CNS tumor. We analyzed age, gender, clinical presentation, extent of surgical resection, histopathology, and length of hospital stay. We also conducted a literature review using specific terminology to capture studies of pediatric neuro-oncologic epidemiology conducted in LMIC. Study location, length of study, sample size, study type, and occurrence of four common pediatric brain tumors were extracted RESULTS: We identified 39 cases of pediatric CNS tumors, with 62.5% observed in male children. We found that male children (median = 13 years) presented later than female children (median = 8 years). The most frequently observed pediatric brain tumor type was ependymoma (17.5%), followed by astrocytoma (15%) and medulloblastoma (15%). Surgical resection was performed for 80% of cases and gross total resection reported in 62.9% of all surgeries. 54.1% of patients had symptoms for more than 28 days prior to seeking treatment. Symptomatic hydrocephalus was noted in 57.1% of children who presented with CNS tumors. The literature review yielded studies from 18 countries. Study length ranged from 2-20 years and sample sizes varied from 35-1948. Overall, we found more pronounced variation in the relative frequencies of the most common pediatric brain tumors, compared to high-income countries.We present the first operative series of childhood CNS tumors in Nepal. Children often had delayed diagnosis and treatment of a tumor, despite symptoms.. More comprehensive data is required to develop improved treatment and management algorithms in the context of a given country's demographics and medical capabilities for childhood CNS tumors.
View details for DOI 10.1016/j.wneu.2015.07.074
View details for PubMedID 26283488
Learning Chronobiology by Improving Wikipedia
JOURNAL OF BIOLOGICAL RHYTHMS
2012; 27 (4): 333-336
The diagnosis of human immunodeficiency virus (HIV)-associated neurocognitive impairment is time-intensive and often omitted in busy outpatient settings. Brief screening tools are needed. The Montreal Cognitive Assessment (MoCA) and the Alzheimer's disease (AD)-8 have been used in neurodegenerative disorders. We evaluated the sensitivity and specificity of these brief screening tools in HIV-infected persons. The AD-8, MoCA, and formal neuropsychological testing were administered to 200 HIV-infected patients who were followed at a single institution. Normalized scores on formal neuropsychological testing were used to define neurocognitive impairment. The sensitivity and specificity of the MoCA and AD-8 were assessed to diagnose the impairment. Neurocognitive impairment was highly prevalent in this cohort: 127 persons (64 %) were diagnosed with neurocognitive impairment based on formal testing. Using the AD-8 and MoCA, 113 (57 %) and 101 (51 %) persons were identified with neurocognitive impairment, respectively. The sensitivity and specificity of MoCA were 63 % and 71 %, respectively. The sensitivity and specificity of AD-8 were 61 % and 51 %, respectively. Our findings highlight that brief screening tools correlate with formal neuropsychological testing. However, the sensitivities of these screening tools are lower than desired. Nevertheless, given their ease in administration, these tools could assist as a first line for identifying individuals who may subsequently require formal neuropsychological testing.
View details for DOI 10.1007/s13365-012-0147-5
View details for PubMedID 23345074
Endothelial Nitric Oxide Synthase Mediates Endogenous Protection Against Subarachnoid Hemorrhage-Induced Cerebral Vasospasm
2011; 42 (3): 776-782
Although chronobiology is of growing interest to scientists, physicians, and the general public, access to recent discoveries and historical perspectives is limited. Wikipedia is an online, user-written encyclopedia that could enhance public access to current understanding in chronobiology. However, Wikipedia is lacking important information and is not universally trusted. Here, 46 students in a university course edited Wikipedia to enhance public access to important discoveries in chronobiology. Students worked for an average of 9 h each to evaluate the primary literature and available Wikipedia information, nominated sites for editing, and, after voting, edited the 15 Wikipedia pages they determined to be highest priorities. This assignment (http://www.nslc.wustl.edu/courses/Bio4030/wikipedia_project.html) was easy to implement, required relatively short time commitments from the professor and students, and had measurable impacts on Wikipedia and the students. Students created 3 new Wikipedia sites, edited 12 additional sites, and cited 347 peer-reviewed articles. The targeted sites all became top hits in online search engines. Because their writing was and will be read by a worldwide audience, students found the experience rewarding. Students reported significantly increased comfort with reading, critiquing, and summarizing primary literature and benefited from seeing their work edited by other scientists and editors of Wikipedia. We conclude that, in a short project, students can assist in making chronobiology widely accessible and learn from the editorial process.
View details for DOI 10.1177/0748730412449578
View details for Web of Science ID 000307021800008
View details for PubMedID 22855578
Vasospasm-induced delayed cerebral ischemia remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH-induced vasospasm and neurological deficits and, secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS).Wild-type mice were subjected to hypoxic PC or normoxia followed 24 hours later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery Day 2. Nitric oxide availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, wild-type and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits.PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in nitric oxide availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in wild-type mice treated with the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and in eNOS-null mice.Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced by PC. eNOS-derived nitric oxide is a critical mediator of PC-induced neurovascular protection. These data provide strong "proof-of-principle" evidence that PC represents a promising new strategy to reduce vasospasm and delayed cerebral ischemia after SAH.
View details for DOI 10.1161/STROKEAHA.110.607200
View details for Web of Science ID 000287479402016
View details for PubMedID 21317271