Probing the glioma micro-environment: analysis using biopsy in combination with ultra-fast cyclic immunolabeling.

The interaction between gliomas and the immune system is poorly understood and thus hindering development of effective immunotherapies for glioma patients. The immune response is highly variable during tumor development, and affected by therapies such as surgery, radiation, and chemotherapy. Currently, analysis of these local changes is difficult due to poor accessibility of the tumor and high-morbidity of sampling. In this study, we developed a model for repeat-biopsy in mice to study these local immunological changes over time. Using fine needle biopsy we were able to safely and repeatedly collect cells from intracranial tumors in mice. Ultra-fast cycling technology (FAST) was used for multi-cycle immunofluorescence of retrieved cells, and provided insights in the changing immune response over time. The combination of these techniques can be utilized to study changes in the immune response in glioma or other intracranial diseases over time, and in response to treatment within the same animal.

Electrical and Magnetic Neuromodulation Technologies and Brain-Computer Interfaces: Ethical Considerations for Enhancement of Brain Function in Healthy People - A Systematic Scoping Review.

INTRODUCTION: This scoping review aimed to synthesize the fragmented evidence on ethical concerns related to the use of electrical and magnetic neuromodulation technologies, as well as brain-computer interfaces for enhancing brain function in healthy individuals, addressing the gaps in understanding spurred by rapid technological advancements and ongoing ethical debates. METHODS: The following databases and interfaces were queried: MEDLINE (via PubMed), Web of Science, PhilPapers, and Google Scholar. Additional references were identified via bibliographies of included citations. References included experimental studies, reviews, opinion papers, and letters to editors published in peer-reviewed journals that explored the ethical implications of electrical and magnetic neuromodulation technologies and brain-computer interfaces for enhancement of brain function in healthy adult or pediatric populations. RESULTS: A total of 23 articles were included in the review, of which the majority explored expert opinions in the form of qualitative studies or surveys as well as reviews. Two studies explored the view of laypersons on the topic. The majority of evidence pointed to ethical concerns relating to a lack of sufficient efficacy and safety data for these new technologies, with the risks of invasive procedures potentially outweighing the benefits. Additionally, concerns about potential socioeconomic consequences were raised that could further exacerbate existing socioeconomic inequalities, as well as the risk of changes to person and environment. CONCLUSION: This scoping review highlights a critical shortage of ethical research on electrical and magnetic neuromodulation technologies and brain-computer interfaces for enhancement of brain function in healthy individuals, with key concerns regarding the safety, efficacy, and socioeconomic impacts of neuromodulation technologies. It underscores the urgent need for integrating ethical considerations into neuroscientific research to address significant gaps and ensure equitable access and outcomes.

Caffeine, alcohol, and drug use as work adjuncts among neurosurgeons. Prevalence, contributing factors, and proposed strategies.

BACKGROUND: Neurosurgeons may resort to caffeine, alcohol, and various drugs to maintain peak performance as they grapple with work demands and escalated stress. The prevalence of this controversial strategy remains largely unexplored. METHODS: An anonymous survey of 23 questions formulated by our research group was distributed through personal contacts and neurosurgical societies. Inquiries revolved around the use of medications and other substances for job-related reasons. Data were analyzed via regression and descriptive statistics in python. RESULTS: In total, 215 neurosurgeons (43 residents) were included, with 213 disclosing their gender (94 females). Out of all, 9.3% were <30, 38.1% were 30-39, 44.6% were 40-59 and 7.9% were >60 years old. Most (70.7%) practiced in Europe, 18.6% in Asia, 6.5% in North and South America and the rest in Africa or Australia. While 132 participants stated they consume caffeine to manage challenging schedules, drugs for cognitive and mood enhancement were utilized by 18 and 35 respectively. Alcohol was employed for stress relief by 28 with 4 reporting as heavy drinkers. Drugs posed a solution to sleep disorders for 82, and helped 8 others in strengthening their hand dexterity. Notably, 12 of those claiming drug use, initiated it in medical school. Exercise, self-care activities and relational support were the main alternatives sought. Ultimately, most responders recommended extending mental health assistance and raising awareness about drug use. CONCLUSIONS: Reflecting on our results on job-associated drug use by neurosurgeons, we propose the judicious use of pharmacological or non- adjuncts, alongside the prioritization of neurosurgeons' well-being.

Medical Malpractice in Neurosurgery: An Analysis of Claims in the Netherlands.

BACKGROUND AND OBJECTIVES: Studying malpractice claims is important to improve quality of health care and patient safety and to educate the individual healthcare providers. The objective of this study was to describe characteristics of neurosurgical claims in the Netherlands. METHODS: A nationwide retrospective observational study of neurosurgery-related claims closed by Centramed and MediRisk, 2 major insurance companies in the Netherlands, was performed. Relevant data, including type of neurosurgical pathology, theme and category of the claim, type and severity of injury, outcome, and financial burden, were extracted from anonymized claim files. The estimated annual risk was used to determine the risk for claims by adjusting for the number of annually practicing neurosurgeons in the Netherlands. RESULTS: A total of 388 claims against neurosurgeons were closed between 2007 and 2021. Liability was denied in a slight majority of claims (n = 230; 59%). The total burden during this period was €6 165 000 (amount paid out to patients: €5 497 000). The estimated annual risk per Dutch neurosurgeon for a claim was 15.5%, meaning 1 claim per 6.5 years. The case-level analysis of 238 available anonymized claims revealed that most claims were related to spinal pathology (81.5%), followed by cranial pathology (10.9%) and peripheral nerve (7.6%). The motivations for filing claims were mostly related to alleged surgical (56.3%) or diagnostic errors (22.3%). Most of these claims were denied (151/238; 63.4%), and fewer were settled (42/238; 17.6%), sustained (31/238; 13.0%), or closed without final decision (14/238; 5.9%). CONCLUSION: Neurosurgery-related malpractice claims primarily involved spinal pathology and were mostly related to alleged treatment errors. Most claims did not result in compensation because there seemed to be no liability or culpable injury. However, the annual risk for a claim for Dutch neurosurgeons is considerable.

Whole genome sequencing in (recurrent) glioblastoma: challenges related to informed consent procedures and data sharing.

Increased use of whole genome sequencing (WGS) in neuro-oncology for diagnostics and research purposes necessitates a renewed conversation about informed consent procedures and governance structures for sharing personal health data. There is currently no consensus on how to obtain informed consent for WGS in this population. In this narrative review, we analyze the formats and contents of frameworks suggested in literature for WGS in oncology and assess their benefits and limitations. We discuss applicability, specific challenges, and legal context for patients with (recurrent) glioblastoma. This population is characterized by the rarity of the disease, extremely limited prognosis, and the correlation of the stage of the disease with cognitive abilities. Since this has implications for the informed consent procedure for WGS, we suggest that the content of informed consent should be tailor-made for (recurrent) glioblastoma patients.

Overcoming Barriers in Glioblastoma-Advances in Drug Delivery Strategies.

The world of cancer treatment is evolving rapidly and has improved the prospects of many cancer patients. Yet, there are still many cancers where treatment prospects have not (or hardly) improved. Glioblastoma is the most common malignant primary brain tumor, and even though it is sensitive to many chemotherapeutics when tested under laboratory conditions, its clinical prospects are still very poor. The blood-brain barrier (BBB) is considered at least partly responsible for the high failure rate of many promising treatment strategies. We describe the workings of the BBB during healthy conditions and within the glioblastoma environment. How the BBB acts as a barrier for therapeutic options is described as well as various approaches developed and tested for passing or opening the BBB, with the ultimate aim to allow access to brain tumors and improve patient perspectives.

External validation of the lung-molGPA to predict survival in patients treated with stereotactic radiotherapy for brain metastases of non-small cell lung cancer.

BACKGROUND: In the era of personalized medicine, individualized prognostic models with tumor characteristics are needed to inform patients about survival. Before clinical use, external validation of such models by an independent group is needed. An updated version of the graded prognostic assessment (GPA) estimates survival in patients with brain metastases (BMs) of non-small cell lung cancer (NSCLC). This is the first external validation of the updated Lung-molGPA in patients treated with stereotactic radiotherapy (SRT) for one or more BMs. MATERIALS AND METHODS: Patients treated with SRT for BMs from NSCLC adenocarcinoma were retrospectively included. GPA score was calculated for each patient based on six prognostic factors including age, Karnofsky Performance Status, number of BMs, extracranial metastases, EGFR/ALK status, and PD-L1 expression. Kaplan-Meier analysis evaluated survival probability. Impact of individual prognostic factors on survival was assessed by univariate and multivariate analyses using the Cox proportional hazard model. Predictive performance was evaluated using discrimination (C-statistic) and calibration (Brier test). RESULTS: The cohort (n = 241) was divided into four prognostic groups. Overall median survival was 15 months. Predicted and observed median survival were similar between the original and validation cohorts, apart from the most favorable prognostic group. With adequate C-statistics and Brier scores, the Lung-molGPA provided accurate survival predictions. CONCLUSION: The Lung-molGPA accurately predicted survival in our European population, except for an overestimation of survival in the small most favorable prognostic group. This prognostic model was externally validated and is therefore useful for counseling of patients with BMs of NSCLC adenocarcinoma.

Developer perspectives on the ethics of AI-driven neural implants: a qualitative study.

Convergence of neural implants with artificial intelligence (AI) presents opportunities for the development of novel neural implants and improvement of existing neurotechnologies. While such technological innovation carries great promise for the restoration of neurological functions, they also raise ethical challenges. Developers of AI-driven neural implants possess valuable knowledge on the possibilities, limitations and challenges raised by these innovations; yet their perspectives are underrepresented in academic literature. This study aims to explore perspectives of developers of neurotechnology to outline ethical implications of three AI-driven neural implants: a cochlear implant, a visual neural implant, and a motor intention decoding speech-brain-computer-interface. We conducted semi-structured focus groups with developers (n = 19) of AI-driven neural implants. Respondents shared ethically relevant considerations about AI-driven neural implants that we clustered into three themes: (1) design aspects; (2) challenges in clinical trials; (3) impact on users and society. Developers considered accuracy and reliability of AI-driven neural implants conditional for users' safety, authenticity, and mental privacy. These needs were magnified by the convergence with AI. Yet, the need for accuracy and reliability may also conflict with potential benefits of AI in terms of efficiency and complex data interpretation. We discuss strategies to mitigate these challenges.

SUPRAMAX-study: supramaximal resection versus maximal resection for glioblastoma patients: study protocol for an international multicentre prospective cohort study (ENCRAM 2201).

INTRODUCTION: A greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might yield even better survival outcomes (supramaximal resection, SMR). Therefore, this study evaluates the efficacy and safety of SMR with and without mapping techniques in high-grade glioma (HGG) patients in terms of survival, functional, neurological, cognitive and quality of life outcomes. Furthermore, it evaluates which patients benefit the most from SMR, and how they could be identified preoperatively. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of observational nature. Consecutive glioblastoma patients will be operated with SMR or maximal resection at a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months postoperatively. Secondary endpoints are (1) residual CE and NCE tumour volume on postoperative T1-contrast and FLAIR (Fluid-attenuated inversion recovery) MRI scans; (2) progression-free survival; (3) receipt of adjuvant therapy with chemotherapy and radiotherapy; and (4) quality of life at 6 weeks, 3 months and 6 months postoperatively. The total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.

Parenthood and neurosurgery in Europe, a white paper from the European association of neurosurgical societies' diversity in neurosurgery committee, part II - practice with children.

Introduction: In the first part of this White Paper, the European Association of Neurosurgical Societies (EANS) Diversity in Neurosurgery Committee (DC) addressed the obstacles faced by neurosurgeons when planning to have a family and practice during pregnancy, attempting to enumerate potential, easily implementable solutions for departments to be more family-friendly and retain as well as foster talent of parent-neurosurgeons, regardless of their gender identity and/or sexual orientation. Attrition avoidance amongst parent-neurosurgeons is at the heart of these papers. Research question: In this second part, we address the obstacles posed by practice with children and measures to mitigate attrition rates among parent-neurosurgeons. For the methodology employed to compose this White Paper, please refer to Supplementary Electronic Materials (SEM) 1. Materials and methods: For composing these white papers, the European Association of Neurosurgical Societies (EANS)'s Diversity Committee (DC) recruited neurosurgeon volunteers from all member countries, including parents, aspiring parents, and individuals without any desire to have a family to create a diverse and representative working group (WG). Results: In spite of the prevailing heterogeneity in policies across the continent, common difficulties can be identified for both mothers and fathers considering the utilization of parental leave. Discussion and conclusion: Reconciliation of family and a neurosurgical career is challenging, especially for single parents. However, institutional support in form of childcare facilities and/or providers, guaranteed lactation breaks and rooms, flexible schedule models including telemedicine, and clear communication of policies can improve working conditions for parent-neurosurgeons, avoid their attrition, and foster family-friendly work environments.

European Medical Students' Views on Neurosurgery, with Emphasis on South-East Europe (Albania, Greece, Serbia, and Turkey).

BACKGROUND: Neurosurgery, an intricate and dynamic surgical specialty, faces challenges in attracting medical graduates. Despite its potential appeal, a decreasing trend in medical students opting for surgical specialties, including neurosurgery, is noted. This study aims to assess European medical students' perceptions of neurosurgery, focusing on South-East Europe, and address concerns about the declining interest in this field. METHODS: A comprehensive digital survey, comprising 33 questions, was distributed to 1115 medical students across 17 European countries. The survey, conducted over 9 months, gathered responses through European neurosurgical societies, the European Association of Neurosurgical Societies (EANS), and university channels. Statistical analysis utilized IBM Statistical Package for the Social Sciences, presenting data through counts, proportions, and χ2 tests. RESULTS: The study reveals that, over the survey period, 834 medical students completed the questionnaire, with a predominant representation from South-East Europe. While 43.2% of participants were considering a surgical career, neurosurgery emerged as the most preferred specialty (26.37%). Despite this interest, 80.2% reported insufficient knowledge about pursuing a neurosurgical career, with limited exposure during medical education. Concerns about work-life balance, heavy workload, and hierarchical structures were prominent among respondents. CONCLUSIONS: The findings underscore the need for targeted interventions to address concerns influencing medical students' decisions regarding neurosurgery. Improving neurosurgical education, dispelling misconceptions, and creating a supportive work environment are crucial steps to attract and retain diverse talented individuals in neurosurgery. These efforts will be vital in narrowing the gap between the demand for neurosurgeons and the number of medical graduates entering the field, ensuring a sustainable future for this essential surgical specialty.

Next generation sequencing of high-grade adult-type diffuse glioma in the Netherlands: interlaboratory variation in the primary diagnostic and recurrent setting.

PURPOSE: Next generation sequencing (NGS) is an important tool used in clinical practice to obtain the required molecular information for accurate diagnostics of high-grade adult-type diffuse glioma (HGG). Since individual centers use either in-house produced or standardized panels, interlaboratory variation could play a role in the practice of HGG diagnosis and treatment. This study aimed to investigate the current practice in NGS application for both primary and recurrent HGG. METHODS: This nationwide Dutch survey used the expertise of (neuro)pathologists and clinical scientists in molecular pathology (CSMPs) by sending online questionnaires on clinical and technical aspects. Primary outcome was an overview of panel composition in the different centers for diagnostic practice of HGG. Secondary outcomes included practice for recurrent HGG and future perspectives. RESULTS: Out of twelve neuro-oncology centers, the survey was filled out by eleven (neuro)pathologists and seven CSMPs. The composition of the diagnostic NGS panels differed in each center with numbers of genes ranging from 12 to 523. Differences are more pronounced when tests are performed to find therapeutic targets in the case of recurrent disease: about half of the centers test for gene fusions (60%) and tumor mutational burden (40%). CONCLUSION: Current notable interlaboratory variations as illustrated in this study should be reduced in order to refine diagnostics and improve precision oncology. In-house developed tests, standardized panels and routine application of broad gene panels all have their own advantages and disadvantages. Future research would be of interest to study the clinical impact of variation in diagnostic approaches.

RNA-sequencing to discover genes and signaling pathways associated with venous thromboembolism in glioblastoma patients: A case-control study.

BACKGROUND: Glioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms remain incompletely understood. OBJECTIVES: To identify tumor-expressed genes and signaling pathways that associate with glioblastoma-related VTE by using next generation RNA-sequencing (RNA-Seq). METHODS: The tumor gene expression profile of 23 glioblastoma patients with VTE and 23 glioblastoma patients without VTE was compared using an unpaired analysis. Ingenuity Pathway Analysis (IPA) core analysis was performed on the top 50 differentially expressed genes to explore associated functions and pathways. Based on full RNA-Seq data, molecular glioblastoma subtypes were determined by performing cluster analysis. RESULTS: Of the 19,327 genes, 1246 (6.4 %) were differentially expressed between glioblastoma patients with and without VTE (unadjusted P < 0.05). The most highly overexpressed gene was GLI1, a classical target gene in the Sonic Hedgehog (Shh) signaling pathway (log2 fold change: 3.7; unadjusted P < 0.0001, adjusted P = 0.219). In line, Shh signaling was among the top canonical pathways and processes associated with VTE. The proportion of patients with the proneural/neural glioblastoma subtype was higher among those with VTE than controls. CONCLUSION: Shh signaling may be involved in the development of glioblastoma-related VTE.

Parenthood and neurosurgery in Europe a white paper from the European Association of Neurosurgical Societies' Diversity in Neurosurgery Committee Part I - Family Planning and Practice during Pregnancy.

Introduction: Family and work have immensely changed and become intertwined over the past half century for both men and women. Additionally, alongside to traditional family structures prevalent, other forms of families such as single parents, LGBTQ + parents, and bonus families are becoming more common. Previous studies have shown that surgical trainees regularly leave residency when considering becoming a parent due to the negative stigma associated with pregnancy during training, dissatisfaction with parental leave options, inadequate lactation and childcare support, and desire for greater mentorship on work-life integration. Indeed, parenthood is one of the factors contributing to attrition in surgical specialities, neurosurgery not being an exception. Research question: The Diversity in Neurosurgery Committee (DC) of the European Association of Neurosurgical Societies (EANS) recognizes the challenges individuals face in parenthood with neurosurgery and wishes to address them in this white paper. Materials and methods: In the following sections, the authors will focus on the issues pertaining to family planning and neurosurgical practice during pregnancy in itemized fashion based on an exhaustive literature search and will make recommendations to address the matters raised. Results: Potential solutions would be to further improve the work-family time ration as well as improving working conditions in the hospital. Discussion and conclusion: While many obstacles have been quoted in the literature pertaining to parenthood in medicine, and in neurosurgery specifically, initiatives can and should be undertaken to ensure not only retention of colleagues, but also to increase productivity and job satisfaction of those seeking to combine neurosurgery and a family life, regardless of their sexual identity and orientation.

Methodological and ethical challenges in the use of focused ultrasound for blood-brain barrier disruption in neuro-oncology.

BACKGROUND: Focused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), and it is increasingly used in the clinical setting to treat brain tumours. It remains however unclear whether FUS is being introduced in an ethically and methodologically sound manner. The IDEAL-D framework for the introduction of surgical innovations and the SYRCLE and ROBINS-I tools for assessing the risk of bias in animal studies and non-randomized trials, respectively, provide a comprehensive evaluation for this. OBJECTIVES AND METHODS: A comprehensive literature review on FUS in neuro-oncology was conducted. Subsequently, the included studies were evaluated using the IDEAL-D framework, SYRCLE, and ROBINS-I tools. RESULTS: In total, 19 published studies and 12 registered trials were identified. FUS demonstrated successful BBB disruption, increased drug delivery, and improved survival rates. However, the SYRCLE analysis revealed a high risk of bias in animal studies, while the ROBINS-I analysis found that most human studies had a high risk of bias due to a lack of blinding and heterogeneous samples. Of the 15 pre-clinical stage 0 studies, only six had formal ethical approval, and only five followed animal care policies. Both stage 1 studies and stage 1/2a studies failed to provide information on patient data confidentiality. Overall, no animal or human study reached the IDEAL-D stage endpoint. CONCLUSION: FUS holds promise for enhancing drug delivery to the brain, but its development and implementation must adhere to rigorous safety standards using the established ethical and methodological frameworks. The complementary use of IDEAL-D, SYRCLE, and ROBINS-I tools indicates a high risk of bias and ethical limitations in both animal and human studies, highlighting the need for further improvements in study design for a safe implementation of FUS in neuro-oncology.

Practice variation in re-resection for recurrent glioblastoma: A nationwide survey among Dutch neuro-oncology specialists.

Background: Despite current best treatment options, a glioblastoma almost inevitably recurs after primary treatment. However, in the absence of clear evidence, current guidelines on recurrent glioblastoma are not well-defined. Re-resection is one of the possible treatment modalities, though it can be challenging to identify those patients who will benefit. Therefore, treatment decisions are made based on multidisciplinary discussions. This study aimed to investigate the current practice variation between neuro-oncology specialists. Methods: In this nationwide study among Dutch neuro-oncology specialists, we surveyed possible practice variation. Via an online survey, 4 anonymized recurrent glioblastoma cases were presented to neurosurgeons, neuro-oncologists, medical oncologists, and radiation oncologists in The Netherlands using a standardized questionnaire on whether and why they would recommend a re-resection or not. The results were used to provide a qualitative analysis of the current practice in The Netherlands. Results: The survey was filled out by 56 respondents, of which 15 (27%) were neurosurgeons, 26 (46%) neuro-oncologists, 2 (4%) medical oncologists, and 13 (23%) radiation oncologists. In 2 of the 4 cases, there appeared to be clinical equipoise. Overall, neurosurgeons tended to recommend re-resection more frequently compared to the other specialists. Neurosurgeons and radiation oncologists showed opposite recommendations in 2 cases. Conclusions: This study showed that re-resection of recurrent glioblastoma is subject to practice variation both between and within neuro-oncology specialties. In the absence of unambiguous guidelines, we observed a relationship between preferred practice and specialty. Reduction of this practice variation is important; to achieve this, adequate prospective studies are essential.

External Ventricular Drains versus Intraparenchymal Pressure Monitors in the Management of Moderate to Severe Traumatic Brain Injury: Experience at Two Academic Centers over a Decade.

OBJECTIVE: The choice between external ventricular drain (EVD) and intraparenchymal monitor (IPM) for managing intracranial pressure in moderate-to-severe traumatic brain injury (msTBI) patients remains controversial. This study aimed to investigate factors associated with receiving EVD versus IPM and to compare outcomes and clinical management between EVD and IPM patients. METHODS: Adult msTBI patients at 2 similar academic institutions were identified. Logistic regression was performed to identify factors associated with receiving EVD versus IPM (model 1) and to compare EVD versus IPM in relation to patient outcomes after controlling for potential confounders (model 2), through odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of 521 patients, 167 (32.1%) had EVD and 354 (67.9%) had IPM. Mean age, sex, and Injury Severity Score were comparable between groups. Epidural hemorrhage (EDH) (OR 0.43, 95% CI 0.21-0.85), greater midline shift (OR 0.90, 95% CI 0.82-0.98), and the hospital with higher volume (OR 0.14, 95% CI 0.09-0.22) were independently associated with lower odds of receiving an EVD whereas patients needing a craniectomy were more likely to receive an EVD (OR 2.04, 95% CI 1.12-3.73). EVD patients received more intense medical treatment requiring hyperosmolar therapy compared to IPM patients (64.1% vs. 40.1%). No statistically significant differences were found in patient outcomes. CONCLUSIONS: While EDH, greater midline shift, and hospital with larger patient volume were associated with receiving an IPM, the need for a craniectomy was associated with receiving an EVD. EVD patients received different clinical management than IPM patients with no significant differences in patient outcomes.

Heparin interferes with the uptake of liposomes in glioma.

In glioblastoma, a malignant primary brain tumor, liposomes have shown promise in pre-clinical and early phase clinical trials as delivery vehicles for therapeutics. However, external factors influencing cellular uptake of liposomes in glioma cells are poorly understood. Heparin and heparin analogues are commonly used in glioma patients to decrease the risk of thrombo-embolic events. Our results show that heparin inhibits pegylated liposome uptake by U87 glioma and GL261 cells in a dose dependent manner in vitro, and that heparin-mediated inhibition of uptake required presence of fetal bovine serum in the media. In a subcutaneous model of glioma, Cy5.5 labeled liposomes could be detected with in vivo imaging after direct intra-tumoral injection. Ex-vivo analysis with flow cytometry showed a decreased uptake of liposomes into tumor cells in mice treated systemically with heparin compared to those treated with vehicle only.

Practice-Pattern Variation in Sedation of Neurotrauma Patients in the Intensive Care Unit: An International Survey.

Background: Analgo-sedation plays an important role during intensive care management of traumatic brain injury (TBI) patients, however, limited evidence is available to guide practice. We sought to quantify practice-pattern variation in neurotrauma sedation management, surveying an international sample of providers. Methods: An electronic survey consisting of 56 questions was distributed internationally to neurocritical care providers utilizing the Research Electronic Data Capture platform. Descriptive statistics were used to quantitatively describe and summarize the responses. Results: Ninety-five providers from 37 countries responded. 56.8% were attending physicians with primary medical training most commonly in intensive care medicine (68.4%) and anesthesiology (26.3%). Institutional sedation guidelines for TBI patients were available in 43.2%. Most common sedative agents for induction and maintenance, respectively, were propofol (87.5% and 88.4%), opioids (60.2% and 70.5%), and benzodiazepines (53.4% and 68.4%). Induction and maintenance sedatives, respectively, are mostly chosen according to provider preference (68.2% and 58.9%) rather than institutional guidelines (26.1% and 35.8%). Sedation duration for patients with intracranial hypertension ranged from 24 h to 14 days. Neurological wake-up testing (NWT) was routinely performed in 70.5%. The most common NWT frequency was every 24 h (47.8%), although 20.8% performed NWT at least every 2 h. Richmond Agitation and Sedation Scale targets varied from deep sedation (34.7%) to alert and calm (17.9%). Conclusions: Among critically ill TBI patients, sedation management follows provider preference rather than institutional sedation guidelines. Wide practice-pattern variation exists for the type, duration, and target of sedative management and NWT performance. Future comparative effectiveness research investigating these differences may help optimize sedation strategies to promote recovery.