Activity of a Novel Anti-Inflammatory Agent F-3,6'-dithiopomalidomide as a Treatment for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6'-dithiopomalidomide (F-3,6'-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6'-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6'-DP. F-3,6'-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6'-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6'-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

3,6'- and 1,6'-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation.

(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6'-dithiopomalidomide (3,6'-DP) and 1,6'-dithiopomalidomide (1,6'-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-ß levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6'- and 1,6'-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6'-DP did not lower Ikaros, Aiolos or SALL4 levels-critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6'-DP and 1,6'-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays -critical FDA regulatory tests. Finally, 3,6'- and 1,6'-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6'-DP and 1,6'-DP may prove valuable as stroke therapies and thus warrant further preclinical development.

Detection of tumor-specific DNA methylation markers in the blood of patients with pituitary neuroendocrine tumors.

BACKGROUND: DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases. METHODS: We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET. RESULTS: Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets. CONCLUSIONS: Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs.

Neurosurgery residency and fellowship education in the United States: 2 decades of system development by the One Neurosurgery Summit organizations.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

Early Experience With Virtual and Synchronized Augmented Reality Platform for Preoperative Planning and Intraoperative Navigation: A Case Series.

BACKGROUND: Virtual reality (VR) allows for presurgical planning. Intraoperatively, augmented reality (AR) enables integration of segmented anatomic information with neuronavigation into the microsurgical scene to provide guidance without workflow disruption. Combining VR and AR solutions may help guide microsurgical technique to improve safety, efficiency, and ergonomics. OBJECTIVE: To describe a VR/AR platform that provides VR planning and intraoperative guidance via microscope ocular injection of a comprehensive AR overlay of patient-specific 360°/3D anatomic model aligned and synchronized with neuronavigation. METHODS: Custom 360° models from preoperative imaging of 49 patients were utilized for preoperative planning using a VR-based surgical rehearsal platform. Each model was imported to SyncAR, the platform's intraoperative counterpart, which was coregistered with Medtronic StealthStation S8 and Zeiss or Leica microscope. The model was injected into the microscope oculars and referenced throughout by adjusting overlay opacity. For anatomic shifts or misalignment, the overlay was reregistered via manual realignment with known landmarks. RESULTS: No SyncAR-related complications occurred. SyncAR contributed positively to the 3D understanding of patient-specific anatomy and ability to operate. Preoperative planning and intraoperative AR with 360° models allowed for more precise craniotomy planning and execution. SyncAR was useful for guiding dissection, identifying critical structures including hidden anatomy, understanding regional anatomy, and facilitating resection. Manual realignment was performed in 48/49 surgeries. Gross total resection was achieved in 34/40 surgeries. All aneurysm clipping and microvascular decompression procedures were completed without complications. CONCLUSION: SyncAR combined with VR planning has potential to enhance surgical performance by providing critical information in a user-friendly, continuously available, heads-up display format.

N-Adamantyl Phthalimidine: A New Thalidomide-like Drug That Lacks Cereblon Binding and Mitigates Neuronal and Synaptic Loss, Neuroinflammation, and Behavioral Deficits in Traumatic Brain Injury and LPS Challenge.

Neuroinflammation contributes to delayed secondary cell death following traumatic brain injury (TBI), has the potential to chronically exacerbate the initial insult, and represents a therapeutic target that has largely failed to translate into human efficacy. Thalidomide-like drugs have effectively mitigated neuroinflammation across cellular and animal models of TBI and neurodegeneration but are complicated by adverse actions in humans. We hence developed N-adamantyl phthalimidine (NAP) as a new thalidomide-like drug to mitigate inflammation without binding to cereblon, a key target associated with the antiproliferative, antiangiogenic, and teratogenic actions seen in this drug class. We utilized a phenotypic drug discovery approach that employed multiple cellular and animal models and ultimately examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) TBI in mice. NAP mitigated LPS-induced inflammation across cellular and rodent models and reduced oligomeric α-synuclein and amyloid-ß mediated inflammation. Following CCI TBI, NAP mitigated neuronal and synaptic loss, neuroinflammation, and behavioral deficits, and is unencumbered by cereblon binding, a key protein underpinning the teratogenic and adverse actions of thalidomide-like drugs in humans. In summary, NAP represents a new class of thalidomide-like drugs with anti-inflammatory actions for promising efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

Drug Repurposing in the Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is the most common cause of morbidity among trauma patients; however, an effective pharmacological treatment has not yet been approved. Individuals with TBI are at greater risk of developing neurological illnesses such as Alzheimer's disease (AD) and Parkinson's disease (PD). The approval process for treatments can be accelerated by repurposing known drugs to treat the growing number of patients with TBI. This review focuses on the repurposing of N-acetyl cysteine (NAC), a drug currently approved to treat hepatotoxic overdose of acetaminophen. NAC also has antioxidant and anti-inflammatory properties that may be suitable for use in therapeutic treatments for TBI. Minocycline (MINO), a tetracycline antibiotic, has been shown to be effective in combination with NAC in preventing oligodendrocyte damage. (-)-phenserine (PHEN), an anti-acetylcholinesterase agent with additional non-cholinergic neuroprotective/neurotrophic properties initially developed to treat AD, has demonstrated efficacy in treating TBI. Recent literature indicates that NAC, MINO, and PHEN may serve as worthwhile repositioned therapeutics in treating TBI.

Cranial Surgical Site Infection Interventions and Prevention Bundles: A Systematic Review of the Literature.

BACKGROUND: Cranial surgical site infections (cSSIs) are associated with significant morbidity. Measures to reduce cSSI are necessary to reduce patient morbidity as well as hospital costs and resource utilization. OBJECTIVE: To identify and characterize interventions or bundled interventions aimed at reduction of the incidence of cranial surgical site infections. METHODS: A systematic review of the literature was conducted according to the PRISMA guidelines. The search strategy included randomized trials, quasi-experimental studies, cohort studies, and case series published between 2000 and 2020 that evaluated interventions implemented to reduce cSSI. Bias assessments and data extraction were performed on included studies. RESULTS: The initial search generated 1249 studies. Application of inclusion and exclusion criteria and review of references yielded 15 single-intervention and 6 bundled-intervention studies. The single interventions included handwashing protocols, use of vancomycin powder, hair washing and clipping practices, and incision closure techniques. Bundled interventions addressed a variety of preoperative, intraoperative, and postoperative changes. Despite a lack of strong evidence to support the adoption of statistically significant interventions, the use of vancomycin powder may be effective in reducing cSSI. In addition, bundled interventions that involved cultural changes, such as increased teaching/education, personal accountability, direct observation, and feedback, showed some success in decreasing SSI rates. CONCLUSIONS: The strength of the conclusions is limited by small sample sizes, study heterogeneity, relatively low cSSI incidence, and high case variability. Some evidence supports the use of intraoperative vancomycin powder in adult noncranioplasty cases and the application of accountability, teaching, and surveillance of faculty, particularly those early in training.

A Comprehensive Multicomponent Neurosurgical Course with use of Virtual Reality: Modernizing the Medical Classroom.

OBJECTIVE: Surgical education has constantly evolved and has been recently severely impacted by the COVID-19 pandemic. While virtual reality (VR) has been utilized for resident training and neuroanatomy education, application of VR has been limited for neurosurgical education in medical school. This is the first report of a comprehensive, multicomponent teaching model with VR as a primary component to neurosurgical and neuroanatomy education for pre-clerkship medical students. DESIGN: Twelve second-year medical students were included in this prospective survey study that was conducted to evaluate a year-long neurosurgery elective course with an interactive VR platform as a primary teaching tool for neuroanatomy and neurosurgical procedures. The course had 4 components: (1) didactic/lecture-based learning, (2) problem-based learning, (3) hands-on skills lab, and (4) VR-based learning through Surgical Theater's Precision VR visualization platform. Outcome measures were based on confidence levels measured on pre- and post-course competency confidence surveys in students' ability to identify neuroanatomical structures, interpret neuroradiological imaging, and analyze neurosurgical cases, and student feedback on their experience with VR on a postcourse survey. SETTING: The survey study was conducted in the neurosurgery library and conference room at University Hospitals Cleveland Medical Center in Cleveland, Ohio, USA. PARTICIPANTS: All 12 second-year medical students who enrolled in the neurosurgery zero-credit hour course completed the course. RESULTS: At course conclusion, 100% of students reported significantly higher competency confidence levels on all topics, and 100% agreed utilizing VR helped them gain a deeper understanding of neuroanatomy/neurosurgery. 92% agreed that using VR helped them better retain the anatomical/functional details of the brain/spine, and 69% better understand neurosurgical skills taught, respectively. 100% of students found the course to be a valuable learning experience and VR a useful learning tool. CONCLUSION: A comprehensive multi-component neurosurgery elective course using VR as a primary teaching tool may improve neurosurgical education in medical school.

Association of metabolic syndrome with glioblastoma: a retrospective cohort study and review.

BACKGROUND: Metabolic syndrome is identified as a risk factor for the development of several systemic cancers, but its frequency among patients with glioblastoma and its association with clinical outcomes have yet to be determined. The aim of this study was to investigate metabolic syndrome as a risk factor for and affecting survival in glioblastoma patients. METHODS: A retrospective cohort study, consisting of patients with diagnoses at a single institution between 2007 and 2013, was conducted. Clinical records were reviewed, and clinical and laboratory data pertaining to 5 metabolic criteria were extrapolated. Overall survival was determined by time from initial surgical diagnosis to date of death or last follow-up. RESULTS: The frequency of metabolic syndrome among patients diagnosed with glioblastoma was slightly greater than the frequency of metabolic syndrome among the general population. Within a subset of patients (n = 91) receiving the full schedule of concurrent radiation and temozolomide and adjuvant temozolomide, median overall survival was significantly shorter for patients with metabolic syndrome compared with those without. In addition, the presence of all 5 elements of the metabolic syndrome resulted in significantly decreased median survival in these patients. CONCLUSIONS: We identified the metabolic syndrome at a slightly higher frequency in patients with diagnosed glioblastoma compared with the general population. In addition, metabolic syndrome with each of its individual components is associated with an overall worse prognosis in patients receiving the standard schedule of radiation and temozolomide after adjustment for age.

Back to the future: surgical rehearsal platform technology as a means to improve surgeon-patient alliance, patient satisfaction, and resident experience.

OBJECTIVE: Informed consent, when performed appropriately, serves many roles beyond simply obtaining the prerequisite medicolegal paperwork to perform a surgery. Prior studies have suggested that patient understanding is poor when verbal communication is the sole means of education. Virtual reality platforms have proven effective in enhancing medical education. No studies exist that have demonstrated the utility of virtual reality-facilitated informed consent (VR-IC) in improving the physician-patient alliance. The aim of this study was to determine the utility of VR-IC among patients providing consent for surgery and the impact of this educational and information technology-based strategy on enhancing the physician-patient alliance, patient satisfaction, and resident-physician perception of the consent process. METHODS: Prospective, single-site, pre- and postconsent surveys were administered to assess patient and resident perception of informed consent performed with the aid of VR-IC at a large tertiary academic medical center in the US. Participants were adult patients (n = 50) undergoing elective surgery for tumor resection and neurosurgical residents (n = 19) who obtained patient informed consent for these surgical procedures. Outcome measures included scores on the Patient-Doctor Relationship Questionnaire (PDRQ-9), the modified Satisfaction with Simulation Experience Scale, and the Maslach Burnout Inventory. Patient pre- and postconsent data were recorded in real time using a secure online research data platform (REDCap). RESULTS: A total of 48 patients and 2 family members provided consent using VR-IC and completed the surveys pre- and postconsent; 47.9% of patients were women. The mean patient age was 57.5 years. There was a statistically significant improvement from pre- to post-VR-IC consent in patient satisfaction scores. Measures of patient-physician alliance, trust, and understanding of their illness all increased. Among the 19 trainees, perceived comfort and preparedness with the informed consent process significantly improved. CONCLUSIONS: VR-IC led to improved patient satisfaction, patient-physician alliance, and patient understanding of their illness as measured by the PDRQ-9. Using VR-IC contributed to residents' increased comfort in the consent-gathering process and handling patient questions. In an era in which satisfaction scores are directly linked with hospital and service-line outcomes and reimbursement, positive results from VR-IC may augment physician and hospital satisfaction scores in addition to increasing measures of trust between physicians and patients.

Subdural Hematoma in Patients with Hematologic Malignancies: An Outcome Analysis and Examination of Risk Factors of Operative and Nonoperative Management.

BACKGROUND: Patients with hematologic disorders who present with subdural hematomas (SDH) present a surgical decision-making challenge. Because of intrinsic coagulopathy, platelet dysfunction, and immunosuppression, surgical intervention poses a unique set of risks. OBJECTIVE: To describe a clinical sample of patients with hematologic disorders and concurrent SDH, to compare baseline and outcome variables, including complication rates and survival, in surgical versus nonsurgical management, and to identify clinical variables that may predict outcomes. METHODS: A 12-year retrospective case-control study was carried out of 50 adult patients with hematologic malignancies and SDH. Patients underwent surgical evacuation for SDH. Controls did not. Outcomes included discharge disposition, Glasgow Outcome Scale score, 30-day mortality, and overall survival. Complications included seizure, reoperation, and readmission. A Fisher exact test or χ2 analysis compared categorical variables; continuous outcomes were compared with a Student t test. A Kaplan-Meier survival analysis was performed and multivariable Cox logistic regression evaluated variables associated with overall mortality. RESULTS: Surgical and nonsurgical groups differed only by Glasgow Coma Scale score, with slightly lower Glasgow Coma Scale scores in the surgical group. Complication rates did not differ; however, the 30-day reoperation rate was 35% for the surgical cohort. Overall, seizure incidence was 18%, readmission was 30%, 30-day mortality was 38%, median survival was 140.5 days, and 75% had a Glasgow Outcome Scale score of 1-3 at censorship. Increased age, low hemoglobin levels, and low platelet levels were associated with increased risk of mortality. CONCLUSIONS: Low platelet and hemoglobin levels are consistent markers of poor prognosis and surgical intervention, either as a proxy of or as a cause for clinical deterioration, is associated with increased mortality risk.

(-)-Phenserine Ameliorates Contusion Volume, Neuroinflammation, and Behavioral Impairments Induced by Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer's disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateral ventricular size increase, motor asymmetry, motor coordination, and balance function, suggesting the improvement of these histological and behavioral tests by Phen treatment occur via pathways other than anti-acetylcholinesterase inhibition. However, the reduction of lesion size and improvement of sensorimotor function by Posiphen were much smaller than with equivalent doses of Phen. Taken together, these results show that post-injury treatment with Phen over 5 days significantly ameliorates severity of TBI. These data suggest a potential development of this compound for clinical use in TBI therapy.

Impact of Dual-Layer Duraplasty During Hemicraniectomy on Morbidity and Operative Metrics of Cranioplasty: A Retrospective Case-Control Study Comparing a Single-Layer with a Dual-Layer Technique.

BACKGROUND: Dural substitutes used during hemicraniectomy provide a barrier and dissection plane during subsequent cranioplasty. A recent review by our group showed that use of dural substitutes in hemicraniectomy is associated with reduction in estimated blood loss (EBL) and operative time (OT). In our experience, the use of a dual-layer technique facilitates a dissection plane with minimal adhesions. We hypothesized that use of this dual-layer technique would show decreased OT and EBL in patients undergoing cranioplasty. METHODS: We conducted a retrospective case-control study comparing use of single-layer versus dual-layer duraplasty on cranioplasty operative outcomes. Data on dual-layer cases were collected from patients who underwent cranioplasty from 2013 to 2017. These data were matched to controls from 2008 to 2012. Patients were identified by query of a neurosurgical database of all procedures performed at our institution. Patients were included if they had complete surgical records for cranioplasty. Cases and controls were compared with a Student t test, χ2 test, or Fisher exact test. RESULTS: A total of 78 controls and 45 cases met inclusion criteria. All baseline characteristics between cohorts were similar except for surgical indication. Mean OT (102.97 minutes vs. 102.18 minutes) and mean EBL were not significantly different (204.66 mL vs. 190 mL) between cohorts. CONCLUSIONS: In this study, we did not detect any significant difference between EBL and OT with use of single-layer versus dual-layer duraplasty. Mean EBL was slightly higher in the controls compared with cases but this difference was not statistically or clinically significant. This concept would benefit from a prospective randomized study.

Intratumoral Rathke's Cleft Cyst Remnants Within Craniopharyngioma, Pituitary Adenoma, Suprasellar Dermoid, and Epidermoid Cysts: A Ubiquitous Signature of Ectodermal Lineage or a Transitional Entity?

BACKGROUND: The authors present cystic epithelial masses in the suprasellar region which on histopathology revealed 4 mixed tumors having simple cuboidal epithelium of Rathke's Cleft Cyst (RCC) elements trapped within pituitary adenoma, epidermoid cyst, dermoid cyst, and papillary craniopharyngioma respectively. OBJECTIVE: To highlight the developmental theory of ectodermal continuum in the realm of suprasellar epithelial cystic lesions and examines the cardinal aspects that distinguish RCC from its confounder, ciliary craniopharyngioma. METHODS: The authors performed a medical chart review on 4 patients who had coexisting RCC with craniopharyngioma, pituitary adenoma, suprasellar dermoid, and epidermoid cysts. RESULTS: This series of unique suprasellar lesions elucidate the spectrum of cases from Rathke's cyst to other suprasellar epithelial cysts including a recently identified clinical entity called ciliary craniopharyngioma, which authors feel is a misnomer. The authors also report the first case of ruptured dermoid cyst admixed with elements of Rathke's cyst elements and xanthogranuloma in neurosurgical literature. CONCLUSION: We propose that the new entity of ciliary craniopharyngioma could be just another variant of RCC elements nested within a typical papillary or adamantinomatous lesion. Further study is warranted to understand the implications of natural history with tumors containing RCC elements.

Sequential combined Treatment of Pifithrin-α and Posiphen Enhances Neurogenesis and Functional Recovery After Stroke.

OBJECTIVE: Although cerebral ischemia can activate endogenous reparative processes, such as proliferation of endogenous neural stem cells (NSCs) in the subventricular zone (SVZ) and subgranular zone (SGZ), the majority of these new cells die shortly after injury and do not appropriately differentiate into neurons, or migrate and functionally integrate into the brain. The purpose of this study was to examine a novel strategy for treatment of stroke after injury by optimizing the survival of ischemia-induced endogenous NSCs in the SVZ and SGZ. METHODS: Adult SVZ and SGZ NSCs were grown as neurospheres in culture and treated with a p53 inactivator, pifithrin-α (PFT-α), and an amyloid precursor protein (APP)-lowering drug, posiphen, and effects on neurosphere number, size and neuronal differentiation were evaluated. This combined sequential treatment approach was then evaluated in mice challenged with middle cerebral artery occlusion (MCAo). Locomotor behavior and cognition were evaluated at 4 weeks, and the number of new surviving neurons was quantified in nestin creERT2-YFP mice. RESULTS: PFT-α and posiphen enhanced the self-renewal, proliferation rate and neuronal differentiation of adult SVZ and SGZ NSCs in culture. Their sequential combination in mice challenged with MCAo-induced stroke mitigated locomotor and cognitive impairments and increased the survival of SVZ and SGZ NSCs cells. PFT-α and the combined posiphen+PFT-α treatment similarly improved locomotion behavior in stroke challenged mice. Notably, however, the combined treatment provided significantly more potent cognitive function enhancement in stroke mice, as compared with PFT-α single treatment. INTERPRETATION: Delayed combined sequential treatment with an inhibitor of p53 dependent apoptosis (PFT-α) and APP synthesis (posiphen) proved able to enhance stroke-induced endogenous neurogenesis and improve the functional recovery in stroke animals. Whereas the combined sequential treatment provided no further improvement in locomotor function, as compared with PFT-α alone treatment, suggesting a potential ceiling in the locomotion behavioral outcome in stroke animals, combined treatment more potently augmented cognitive function recovery after stroke.

Impact of Resident Involvement in Neurosurgery: An American College of Surgeons' National Surgical Quality Improvement Program Database Analysis of 33,977 Patients.

OBJECTIVE: There is conflicting and limited literature on the effect of intraoperative resident involvement on surgical outcomes. Our study assessed effects of resident involvement on outcomes in patients undergoing neurosurgery. METHODS: We identified 33,977 adult neurosurgical cases from 374 hospitals in the 2006-2012 National Surgical Quality Improvement Program, a prospectively collected national database with established reproducibility and validity. Outcomes were compared according to resident involvement before and after 1:1 matching on procedure and perioperative risk factors. RESULTS: Resident involvement was documented in 13,654 cases. We matched 10,170 resident-involved cases with 10,170 attending-alone. In the matched sample, resident involvement was associated with increased surgery duration (average, 34 minutes) and slight increases in odds for prolonged hospital stay (odds ratio, 1.2; 95% confidence interval [CI], 1.2-1.3) and complications (odds ratio, 1.2; 95% CI, 1.1-1.3) including infections (odds ratio, 1.4; 95% CI, 1.2-1.7). Increased risk for infections persisted after controlling for surgery duration (odds ratio, 1.3; 95% CI, 1.1-1.5). The majority of cases were spine surgeries, and resident involvement was not associated with morbidity or mortality for malignant tumor and aneurysm patients. Training level of residents was not associated with differences in outcomes. CONCLUSION: Resident involvement was more common in sicker patients undergoing complex procedures, consistent with academic centers undertaking more complex cases. After controlling for patient and intraoperative characteristics, resident involvement in neurosurgical cases continued to be associated with longer surgical duration and slightly higher infection rates. Longer surgery duration did not account for differences in infection rates.

The Value of Perioperative Levels of ACTH, DHEA, and DHEA-S and Tumor Size in Predicting Recurrence of Cushing Disease.

Context and Objectives: Despite the development of hypocortisolemia after corticotroph surgical adenomectomy, 15% to 20% patients have recurrence of Cushing disease (CD). In this study, we investigated the effect of tumor size and the value of perioperative assessment of corticotropin (ACTH) and adrenal steroid levels in predicting recurrence. Design: Perioperatively, no glucocorticoids were administered until the serum cortisol was ≤3 µg/dL. Blood samples were obtained before and repeatedly after adenomectomy in 79 patients with CD. Of these, 66 had a nadir serum cortisol of ≤3.0 µg/dL and clinical and biochemical remissions. During a median follow-up of 131 months, 11 of 66 had disease recurrence (REC), whereas 55 of 66 did not (NO-REC). Results: Preoperative hormone levels in the REC and NO-REC groups were similar. After adenomectomy, a brief and similar increase in ACTH, cortisol, and dehydroepiandrosterone (DHEA) levels was observed in both groups followed by gradual decline in those levels. Although REC and NO-REC patients had similar cortisol levels (3.4 ± 1.7 µg/dL vs 2.9 ± 2.2 µg/dL) at the 36th postoperative hour, their respective ACTH (33 ± 7.1 ng/L vs 12.1 ± 5.4 ng/L; P < 0.0001), DHEA (3.8 ± 1.7 ng/mL vs 1.2 ± 1.1 ng/mL; P = 0.005), and dehydroepiandrosterone sulphate (DHEA-S) (143.9 ± 45.2 µg/dL vs 48.9 ± 38.2 µg/dL; P < 0.0001) were higher. At nadir hypocortisolemia, perioperative ACTH levels were >20 in all REC patients and <20 ng/L in the NO-REC group. Patients with REC had larger tumors than those with NO-REC. Conclusion: Recurrent CD is characterized by persistent perioperative ACTH secretion after adenomectomy. Higher perioperative levels of ACTH, DHEA, and DHEA-S are highly predictive of future disease recurrence, particularly in those with profound hypocortisolemia.