Therapeutic strategies to improve drug delivery across the blood-brain barrier.
2015; 38 (3): E9-?
Glioblastoma antigen discovery-foundations for immunotherapy.
Journal of neuro-oncology
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
Improved capture of adverse events after spinal surgery procedures with a longitudinal administrative database.
Journal of neurosurgery. Spine
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
Nelson Syndrome - Update on Therapeutic Approaches.
OBJECT The significant medical and economic tolls of spinal disorders, increasing volume of spine surgeries, and focus on quality metrics have made it imperative to understand postoperative complications. This study demonstrates the utility of a longitudinal administrative database for capturing overall and procedure-specific complication rates after various spine surgery procedures. METHODS The Thomson Reuters MarketScan Commercial Claims and Encounters and the Medicare Supplemental and Coordination of Benefits database was used to conduct a retrospective analysis of longitudinal administrative data from a sample of approximately 189,000 patients. Overall and procedure-specific complication rates at 5 time points ranging from immediately postoperatively (index) to 30 days postoperatively were computed. RESULTS The results indicated that the frequency of individual complication types increased at different rates. The overall complication rate including all spine surgeries was 13.6% at the index time point and increased to 22.8% at 30 days postoperatively. The frequencies of wound dehiscence, infection, and other wound complications exhibited large increases between 10 and 20 days postoperatively, while complication rates for new chronic pain, delirium, and dysrhythmia increased more gradually over the 30-day period studied. When specific surgical procedures were considered, 30-day complication rates ranged from 8.6% in single-level anterior cervical fusions to 27.3% in multilevel combined anterior and posterior lumbar spine fusions. CONCLUSIONS This study demonstrates the usefulness of a longitudinal administrative database in assessing postoperative complication rates after spine surgery. Use of this database gave results that were comparable to those in prospective studies and superior to those obtained with nonlongitudinal administrative databases. Longitudinal administrative data may improve the understanding of overall and procedure-specific complication rates after spine surgery.
View details for DOI 10.3171/2014.12.SPINE14659
View details for PubMedID 26068273
Perspective on "The Role of Adjuvant Radiotherapy following Gross Total Resection of Atypical Meningiomas"
Anterior versus Posterior approach for Multilevel Degenerative Cervical Disease: A Retrospective Propensity Score-matched Study of the MarketScan database.
Nelson syndrome (NS) was first described in 1958 as an adrenocorticotropic hormone (ACTH)-producing pituitary tumor appearing after bilateral adrenalectomy for Cushing's disease. The syndrome is characterized by hyperpigmentation, a corticotroph pituitary adenoma, and increased plasma ACTH levels. The incidence of NS after bilateral adrenalectomy varies between 0 - 43% in the adult population; a rate of 21% was identified in a recent systematic review. Though management of Cushing's disease has evolved from the 1950s when adrenalectomy was a leading treatment option, removal of the adrenal glands for Cushing's disease remains necessary in certain clinical situations. For NS patients, surgical intervention is often the first line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited utility, though recent evidence supports the feasibility of a novel somatostatin analog for NS patients. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS. We describe the pathophysiology and discuss updates in surgical, radiotherapeutic, and pharmacologic management options for NS.
View details for DOI 10.1016/j.wneu.2015.01.038
View details for PubMedID 25683128
Glioblastoma stem cells and stem cell-targeting immunotherapies.
Journal of neuro-oncology
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
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
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
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