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Background: The harm-benefit balance for early out-of-bed mobilisation of patients with severe acquired brain injury (ABI) in neurointensive care units (neuro-ICUs) is unclear, and there are no clinical guidelines. This study aimed to survey the current clinical practice and perceptions among clinicians involved in first out-of-bed mobilisation in Scandinavian neuro-ICUs., Methods: This was a cross-sectional, anonymous, web-based survey; the reporting follows the recommended CROSS checklist. Clinicians involved in the first out-of-bed mobilisation in all 14 Scandinavian neuro-ICUs were eligible to participate. The questionnaire was distributed to local contact persons. Respondents were asked about their clinical practice regarding the first out-of-bed mobilisation, and perceived harms and benefits of early mobilisation., Results: One hundred eighty clinicians (53% nurses, 31% physicians, and 14% therapists) completed the questionnaire. Eighty-one percent indicated that more than half of patients underwent their first out-of-bed mobilisation in the neuro-ICU. More respondents from Denmark than the remaining countries indicated that both physicians, nurses and physiotherapists contributed to the decision on when to mobilise. Intracranial pressure, cerebral perfusion pressure, sedation, presence of vasospasm and arterial blood pressure were the most used safety clinical indicators for deciding about mobilisation. Clinicians stated several positive effects of mobilisation, for example, improved bowel movements, level of consciousness, motor function, and reduced risk of pneumonia, contractures, delirium, and deep vein thrombosis., Conclusions: Mobilisation out of bed is frequently performed in patients with severe ABI in Scandinavian neuro-ICUs. The perceived clinical safety indicators for mobilisation were ICP, CPP, level of sedation, presence of vasospasms, and ABP., (© 2025 Acta Anaesthesiologica Scandinavica Foundation.)

In recent decades, there has been increasing interest in measuring the quality of care across all medical fields, including neurosurgery. This interest aims not only to optimize care but also to reduce healthcare costs. For this purpose, different quality indicators (QIs) have been developed. We performed a systematic review according to the PRISMA guidelines aiming at identifying studies that critically evaluate QIs applied in cranial neurosurgery. A total of 34 studies, suggesting 22 indicators, were identified. The most discussed indicator was the 30-day readmission rate, followed by the 30-day reoperation rate. The majority of QIs are influenced by baseline and underlying patient characteristics, reflecting the severity of the patient`s underlying disease, rather than adherence to best available evidence of treatment. Therefore, it is crucial to implement adequate risk adjustment strategies when applying QIs to compensate for differences in patient complexity and to ensure that departments that are treating high-risk patients do not have worse results. The review revealed several limitations of the currently used quality indicators. Most suggested indicators are attractive from a payer point of view, easy to measure and therefore convenient for reimbursement purposes. However, from a clinician's point of view, most indicators were considered poor performance markers as they do not correlate with meaningful outcome and do not reflect treatment quality. In addition, there is a lack of disease- and neurosurgery specific indicators. This highlights the need for clinicians to actively participate in developing more clinically relevant QIs tailored to neurosurgical practice., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: A tumor-to-tumor metastasis (TTM) is a rare metastatic process where a primary malignant tumor metastasizes to another tumor, most commonly a benign tumor such as a meningioma. Here, we present two recent cases of tumor-to-meningioma metastases (TMM) from our clinical practice and review of recent literature. The primary cancers were prostate and breast cancer, respectively., Material and Methods: We reviewed the electronic medical records of the two patients and conducted a literature review of TTM, focusing on biological mechanisms related to TMM., Results: Our first patient, a man with a history of stable prostate cancer, underwent resection of two WHO grade 1 meningiomas, and the largest tumor was found to have TMM. Our second patient, a woman with progressive breast cancer, was operated for a WHO grade II meningioma, and the meningioma harbored breast cancer metastases. TMM is a rare occurrence, but breast cancer is a much more frequent cause than prostate cancer and we reviewed 50 cases. Only 15 of cases of TMM from prostate cancer have been described., Discussion and Conclusion: TMM is a rare phenomenon, but it is important to be aware of this as more and more patients live with cancer and meningiomas have a high prevalence, The possibility of TMM may impact not only both the surgical and oncological treatment but also surveillance of incidental meningiomas., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V. on behalf of EUROSPINE, the Spine Society of Europe, EANS, the European Association of Neurosurgical Societies.)

Background: Ethiopia is a fast-growing economy with rapid urbanization and poor occupational safety measures. Fall injuries are common and frequently result in traumatic brain injury (TBI) or spinal cord injury (SCI)., Methods: We prospectively included fall victims who were hospital-treated for neurotrauma or forensically examined in 2017 in Addis Ababa, Ethiopia. We registered sociodemographic factors, fall types, injuries, treatment, and outcome., Results: We included 117 treated and 51 deceased patients (median age 27 vs. 40 years). Most patients were injured at construction sites (39.9%) and only one in three used protective equipment. TBI (64.7%) and SCI (27.5%) were the most common causes of death among the deceased patients, of which most died at the accident site (90.2%). Many patients suffered significant prehospital time delays (median 24 h). Among treated patients, SCI was more frequent than TBI (50.4% vs. 39.3%), and 10.3% of the patients had both SCI and TBI. Most SCIs were complete (49.3%), whereas most TBIs were mild (55.2%). Less than half of TBI patients and less than one in five SCI patients were operated. There were twice as many deaths among TBI patients as SCI patients. Among those discharged alive, at a median of 33 weeks, 50% of TBI patients had a good recovery whereas 35.5% of SCI patients had complete injuries., Conclusion: Falls at construction sites with inadequate safety measures were common causes of SCI and TBI resulting in severe disability and death. These results support further development of prevention strategies and neurotrauma care in Ethiopia., (© 2024 Published by Elsevier B.V. on behalf of EUROSPINE, the Spine Society of Europe, EANS, the European Association of Neurosurgical Societies.)

Background: Surveillance of incidence and survival of central nervous system tumors is essential to monitor disease burden and epidemiological changes, and to allocate health care resources. Here, we describe glioma incidence and survival trends by histopathology group, age, and sex in the Norwegian population., Material and Methods: We included patients with a histologically verified glioma reported to the Cancer Registry of Norway from 2002 to 2021 (N = 7,048). Population size and expected mortality were obtained from Statistics Norway. Cases were followed from diagnosis until death, emigration, or 31 December 2022, whichever came first. We calculated age-standardized incidence rates (ASIR) per 100,000 person-years and age-standardized relative survival (RS).  Results: The ASIR for histologically verified gliomas was 7.4 (95% CI: 7.3-7.6) and was higher for males (8.8; 95% CI: 8.5-9.1) than females (6.1; 95% CI: 5.9-6.4). Overall incidence was stable over time. Glioblastoma was the most frequent tumor entity (ASIR = 4.2; 95% CI: 4.1-4.4). Overall, glioma patients had a 1-year RS of 63.6% (95% CI: 62.5-64.8%), and a 5-year RS of 32.8% (95% CI: 31.6-33.9%). Females had slightly better survival than males. For most entities, 1- and 5-year RS improved over time (5-year RS for all gliomas 29.0% (2006) and 33.1% (2021), p < 0.001). Across all tumor types, the RS declined with increasing age at diagnosis., Interpretation: The incidence of gliomas has been stable while patient survival has increased over the past 20 years in Norway. As gliomas represent a heterogeneous group of primary CNS tumors, regular reporting from cancer registries at the histopathology group level is important to monitor disease burden and allocate health care resources in a population.

Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR-146a-5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR-146a-5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour-promoting cytokines (IL-6, IL-8, MCP-1 and CXCL1). Brain metastases were significantly reduced following miR-146a-5p knockdown. Corroborating these findings, miR-146a-5p inhibition led to a reduction of IL-6, IL-8, MCP-1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR-146a-5p inhibitor, both in vitro and in vivo. Our results highlight the pro-metastatic function of miR-146a-5p in EVs and identifies deserpidine for targeted adjuvant treatment., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Glioblastoma is the most common form of primary brain cancer in adults, and the disease has a serious prognosis. Although great progress has been made in molecular characteristics, no major breakthroughs in treatment have been achieved for many years. In this article we present a clinical review of current diagnostics and treatment, as well as the challenges and opportunities inherent in developing improved and more personalised treatment.

Background: Chronic subdural hematoma (CSDH) is one of the most common neurosurgical conditions. Here, we studied differences in demographics, treatment, and outcome for CSDH patients in low-income (Ethiopia) and high-income (Norway) countries and assessed potential outcome determinants., Methods: We included patients from Addis Ababa University Hospitals (AAUH) and Haukeland University Hospital (HUH) who had surgery for CSDH (2013-2017). Patients were included prospectively in Ethiopia and retrospectively in Norway., Results: We enrolled 314 patients from AAUH and 284 patients from HUH, with a median age of 60 and 75 years, respectively. Trauma history was more common in AAUH (72%) than in HUH patients (64.1%). More patients at HUH (45.1%) used anticoagulants/antiplatelets than at AAUH (3.2%). Comorbidities were more frequent in HUH (77.5%) than in AAUH patients (30.3%). Burr hole craniostomy under local anesthesia and postoperative drainage was the standard treatment in both countries. Postoperative CT scanning was more common at HUH (99.3%) than at AAUH (5.2%). Reoperations were more frequent at HUH (10.9%) than at AAUH (6.1%), and in both countries, mostly due to hematoma recurrence. Medical complications were more common at HUH (6.7%) than at AAUH (1.3%). The 1-year mortality rate at HUH was 7% and at AAUH 3.5%. At the end of follow-up (> 3 years), the Glasgow Outcome Scale Extended (GOSE) score was 8 in 82.9% of AAUH and 46.8% of HUH patients., Conclusion: The surgical treatment was similar at AAUH and HUH. The poorer outcome in Norway could largely be explained by age, comorbidity, medication, and complication rates., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Importance: The use of spinal cord stimulation for chronic pain after lumbar spine surgery is increasing, yet rigorous evidence of its efficacy is lacking., Objective: To investigate the efficacy of spinal cord burst stimulation, which involves the placement of an implantable pulse generator connected to electrodes with leads that travel into the epidural space posterior to the spinal cord dorsal columns, in patients with chronic radiculopathy after surgery for degenerative lumbar spine disorders., Design, Setting, and Participants: This placebo-controlled, crossover, randomized clinical trial in 50 patients was conducted at St Olavs University Hospital in Norway, with study enrollment from September 5, 2018, through April 28, 2021. The date of final follow-up was May 20, 2022., Interventions: Patients underwent two 3-month periods with spinal cord burst stimulation and two 3-month periods with placebo stimulation in a randomized order. Burst stimulation consisted of closely spaced, high-frequency electrical stimuli delivered to the spinal cord. The stimulus consisted of a 40-Hz burst mode of constant-current stimuli with 4 spikes per burst and an amplitude corresponding to 50% to 70% of the paresthesia perception threshold., Main Outcomes and Measures: The primary outcome was difference in change from baseline in the self-reported Oswestry Disability Index (ODI; range, 0 points [no disability] to 100 points [maximum disability]; the minimal clinically important difference was 10 points) score between periods with burst stimulation and placebo stimulation. The secondary outcomes were leg and back pain, quality of life, physical activity levels, and adverse events., Results: Among 50 patients who were randomized (mean age, 52.2 [SD, 9.9] years; 27 [54%] were women), 47 (94%) had at least 1 follow-up ODI score and 42 (84%) completed all stimulation randomization periods and ODI measurements. The mean ODI score at baseline was 44.7 points and the mean changes in ODI score were -10.6 points for the burst stimulation periods and -9.3 points for the placebo stimulation periods, resulting in a mean between-group difference of -1.3 points (95% CI, -3.9 to 1.3 points; P = .32). None of the prespecified secondary outcomes showed a significant difference. Nine patients (18%) experienced adverse events, including 4 (8%) who required surgical revision of the implanted system., Conclusions and Relevance: Among patients with chronic radicular pain after lumbar spine surgery, spinal cord burst stimulation, compared with placebo stimulation, after placement of a spinal cord stimulator resulted in no significant difference in the change from baseline in self-reported back pain-related disability., Trial Registration: ClinicalTrials.gov Identifier: NCT03546738.

An ageing population as well as improved diagnostics, monitoring and treatment mean that an increasing incidence of brain metastases can be expected. Patients with brain metastases were previously regarded as a homogenous group with a very poor prognosis. However, the current picture is more complex. The development of new treatment methods, better molecular understanding and personalised medicine require a focus on multidisciplinary collaboration to provide optimal treatment for individual patients. This clinical review article provides an overview of important factors related to the diagnosis and treatment of patients with brain metastases.

Purpose: Risk of cancer has been associated with body or organ size in several studies. We sought to investigate the relationship between intracranial volume (ICV) (as a proxy for lifetime maximum brain size) and risk of IDH-mutant low-grade glioma., Methods: In a multicenter case-control study based on population-based data, we included 154 patients with IDH-mutant WHO grade 2 glioma and 995 healthy controls. ICV in both groups was calculated from 3D MRI brain scans using an automated reverse brain mask method, and then compared using a binomial logistic regression model., Results: We found a non-linear association between ICV and risk of glioma with increasing risk above and below a threshold of 1394 ml (p < 0.001). After adjusting for ICV, sex was not a risk factor for glioma., Conclusion: Intracranial volume may be a risk factor for IDH-mutant low-grade glioma, but the relationship seems to be non-linear with increased risk both above and below a threshold in intracranial volume., (© 2022. The Author(s).)

Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/threonine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18-2.6 μM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B-Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis., Competing Interests: The authors declare that no competing interests exist.

Background: Bicyclists are vulnerable road users. The aim of this paper was to describe all bicycle-related traumatic cervical spine injuries (CSIs) in the South-East region of Norway (2015-2019), and to investigate whether certain types of CSIs are typical for bicyclists., Methods: Retrospective cohort study of prospectively collected registry data of all CSIs in the South-East region of Norway (3.0 million inhabitants), from 2015 to 2019. Patient characteristics, injury types, and treatment were summarized with descriptive statistics. Bayesian multivariable logistic regression was used to identify potential factors associated with occipital condyle fractures (OC-Fx) or odontoid fractures (OFx)., Results: During the five-year study period, 2,162 patients with CSIs were registered, and 261 (12%) were bicycle-related. The incidence of bicycle-related CSIs was 1.7/100,000 person-years. The median age of the patients with bicycle-related CSIs was 55 (IQR: 22) years, 83% were male, 71% used a helmet, 16% were influenced by ethanol, 12% had a concomitant cervical spinal cord injury (SCI), and 64% sustained multiple traumas. The three most common bicycle-related CSIs were C6/C7 fracture (Fx) (28%), occipital condyle Fx (OC-Fx) (23%) and C5/C6 Fx (19%). Patients with bicycle-related CSIs compared to patients with non-bicycle related CSIs were younger, more often male, had fewer comorbidities, more likely multiple traumas, more often had OC-Fx, and less often sustained an odontoid fracture (OFx). Multivariable logistic regression of potential risk factors for OC-Fx demonstrated a significantly increased risk of OC-Fx for bicyclists compared to non-bicyclists (OR=2.8).The primary treatment for bicycle-related CSIs was external immobilization in 187/261 (71.6%) cases, open surgical fixation in 44/261 (16.8%), and no treatment in 30/261 (11.5%)., Conclusion: Bicycle crashes are a frequent cause of CSIs in the Norwegian population and should be of concern to the public society. The three most common bicycle-related CSIs were C6/C7 fracture, occipital condyle fracture and C5/C6 fracture., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Craniotomy involves procedures with high incidences of postoperative pain. Dexmedetomidine, a highly selective a 2 -adrenoreceptor agonist, has been shown to be beneficial in neuroanaesthesia. The purpose of this narrative review was to assess the effect and safety of dexmedetomidine given intraoperatively during anaesthesia compared to placebo and demonstrate the effect on acute postoperative pain in adult patients undergoing craniotomy. Literature published from 1996 until 2021 were analysed through a search of PubMed, Medline and Embase. Randomised controlled trials investigating intraoperative administration of Dexmedetomidine with evaluation of postoperative pain were included. Medical Subject Headings terms and free-text words were used to identify articles related to the intraoperative use of Dexmedetomidine and postcraniotomy pain. Thirteen distinct randomized controlled trials with 882 recruited patients undergoing craniotomy were identified as eligible for final inclusion. Intraoperative administration of dexmedetomidine is associated with decreased postoperative pain and opioid consumption, and it assures haemodynamic stability. Dexmedetomidine is an efficacious adjunct in craniotomy in adults, showing benefits in reduction of postoperative pain and analgesic consumption. Dexmedetomidine also offers haemodynamic stability. However, widespread methodological heterogeneity of the papers prohibits a valid meta-analysis.

Melanomas have a high potential to metastasize to the brain. Recent advances in targeted therapies and immunotherapies have changed the therapeutical landscape of extracranial melanomas. However, few patients with melanoma brain metastasis (MBM) respond effectively to these treatments and new therapeutic strategies are needed. Cabozantinib is a receptor tyrosine kinase (RTK) inhibitor, already approved for the treatment of non-skin-related cancers. The drug targets several of the proteins that are known to be dysregulated in melanomas. The anti-tumor activity of cabozantinib was investigated using three human MBM cell lines. Cabozantinib treatment decreased the viability of all cell lines both when grown in monolayer cultures and as tumor spheroids. The in vitro cell migration was also inhibited and apoptosis was induced by cabozantinib. The phosphorylated RTKs p-PDGF-Rα, p-IGF-1R, p-MERTK and p-DDR1 were found to be downregulated in the p-RTK array of the MBM cells after cabozantinib treatment. Western blot validated these results and showed that cabozantinib treatment inhibited p-Akt and p-MEK 1/2. Further investigations are warranted to elucidate the therapeutic potential of cabozantinib for patients with MBM.

Background: Traumatic brain injury (TBI) is an important cause of trauma-related mortality and morbidity in Ethiopia. There are significant resource limitations along the entire continuum of care, and little is known about the neurosurgical activity and patient outcomes., Methods: All surgically treated TBI patients at the 4 teaching hospitals in Addis Ababa, Ethiopia were prospectively registered from October 2012 to December 2016. Data registration included surgical procedures, complications, reoperations, discharge outcomes, and mortality., Results: A total of 1087 patients were included. The most common procedures were elevation of depressed skull fractures (49.5%) and craniotomies (47.9%). Epidural hematoma was the most frequent indication for a craniotomy (74.7%). Most (77.7%) patients were operated within 24 hours of admission. The median hospital stay for depressed skull fracture operations or craniotomies was 4 days. Decompressive craniectomy was only done in 10 patients. Postoperative complications were seen in 17% of patients, and only 3% were reoperated. Cerebrospinal fluid leak was the most common complication (7.9%). The overall mortality was 8.2%. Diagnosis, admission Glasgow Coma Scale (GCS) score, surgical procedure, and complications were significant predictors of discharge GCS score (P < 0.01). Age, admission GCS score, and length of hospital stay were significantly associated with mortality (P ≤ 0.005)., Conclusions: The injury panorama, surgical activity, and outcome are significantly influenced by patient selection due to deficits within both prehospital and hospital care. Still, the neurosurgical services benefit a large number of patients in the greater Addis region and are qualitatively comparable with reports from high-income countries., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Traumatic brain injury (TBI) is a public health problem in Ethiopia. More knowledge about the epidemiology and neurosurgical management of TBI patients is needed to identify possible focus areas for quality improvement and preventive efforts., Methods: This prospective cross-sectional study (2012-2016) was performed at the 4 teaching hospitals in Addis Ababa, Ethiopia. All surgically treated TBI patients were included, and data on clinical presentation, injury types, and trauma causes were collected., Results: We included 1087 patients (mean age 29 years; 8.7% females; 17.1% <18 years old). Only 15.5% of TBIs were classified as severe (Glasgow Coma Scale score 3-8). Depressed skull fracture (44.9%) and epidural hematoma (39%) were the most frequent injuries. Very few patients had polytrauma (3.1%). Assault was the most common injury mechanism (69.9%) followed by road traffic accidents (15.8%) and falls (8.1%). More than 80% of patients came from within 200 km of the hospitals, but the median time to admission was 24 hours. Most assault victims (80.4%) were injured >50 km from the hospitals, whereas 46% of road traffic accident victims came from the urban area. Delayed admission was associated with higher Glasgow Coma Scale scores and nonsevere TBI (P < 0.01)., Conclusions: The injury panorama, delayed admission, and small number of operations performed for severe TBI are linked to a substantial patient selection bias both before and after hospital admission. Our results also suggest that there should be a geographical framework for tailored guidelines, preventive efforts, and development of prehospital and hospital services., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Patients with melanoma have a high risk of developing brain metastasis, which is associated with a dismal prognosis. During early stages of metastasis development, the blood-brain barrier (BBB) is likely intact, which inhibits sufficient drug delivery into the metastatic lesions. We investigated the ability of the peptide, K16ApoE, to permeabilize the BBB for improved treatment with targeted therapies preclinically. Dynamic contrast enhanced MRI (DCE-MRI) was carried out on NOD/SCID mice to study the therapeutic window of peptide-mediated BBB permeabilization. Further, both in vivo and in vitro assays were used to determine K16ApoE toxicity and to obtain mechanistic insight into its action on the BBB. The therapeutic impact of K16ApoE on metastases was evaluated combined with the mitogen-activated protein kinase pathway inhibitor dabrafenib, targeting BRAF mutated melanoma cells, which is otherwise known not to cross the intact BBB. Our results from the DCE-MRI experiments showed effective K16ApoE-mediated BBB permeabilization lasting for up to 1 hour. Mechanistic studies showed a dose-dependent effect of K16ApoE caused by induction of endocytosis. At concentrations above IC 50 , the peptide additionally showed nonspecific disturbances on plasma membranes. Combined treatment with K16ApoE and dabrafenib reduced the brain metastatic burden in mice and increased animal survival, and PET/CT showed that the peptide also facilitated the delivery of compounds with molecular weights as large as 150 kDa into the brain. To conclude, we demonstrate a transient permeabilization of the BBB, caused by K16ApoE, that facilitates enhanced drug delivery into the brain. This improves the efficacy of drugs that otherwise do not cross the intact BBB., (©2019 American Association for Cancer Research.)

Melanoma patients carry a high risk of developing brain metastases, and improvements in survival are still measured in weeks or months. Durable disease control within the brain is impeded by poor drug penetration across the blood-brain barrier, as well as intrinsic and acquired drug resistance. Augmented mitochondrial respiration is a key resistance mechanism in BRAF-mutant melanomas but, as we show in this study, this dependence on mitochondrial respiration may also be exploited therapeutically. We first used high-throughput pharmacogenomic profiling to identify potentially repurposable compounds against BRAF-mutant melanoma brain metastases. One of the compounds identified was β-sitosterol, a well-tolerated and brain-penetrable phytosterol. Here we show that β-sitosterol attenuates melanoma cell growth in vitro and also inhibits brain metastasis formation in vivo. Functional analyses indicated that the therapeutic potential of β-sitosterol was linked to mitochondrial interference. Mechanistically, β-sitosterol effectively reduced mitochondrial respiratory capacity, mediated by an inhibition of mitochondrial complex I. The net result of this action was increased oxidative stress that led to apoptosis. This effect was only seen in tumor cells, and not in normal cells. Large-scale analyses of human melanoma brain metastases indicated a significant role of mitochondrial complex I compared to brain metastases from other cancers. Finally, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either β-sitosterol or a functional knockdown of mitochondrial complex I. In conclusion, based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, β-sitosterol represents a promising adjuvant to BRAF inhibitor therapy in patients with, or at risk for, melanoma brain metastases.

Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14-15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome-wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late-stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy-lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM., (© 2018 UICC.)

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma., Competing Interests: Authors have no conflict of interest to disclose

Background: The key metabolic enzyme lactate dehydrogenase A (LDHA) is overexpressed in many cancers, and several preclinical studies have shown encouraging results of targeted inhibition. However, the mechanistic importance of LDHA in melanoma is largely unknown and hitherto unexplored in brain metastasis., Methods: We investigated the spatial, temporal, and functional features of LDHA expression in melanoma brain metastasis across multiple in vitro assays, in a robust and predictive animal model employing MRI and PET imaging, and in a unique cohort of 80 operated patients. We further assessed the genomic and proteomic landscapes of LDHA in different cancers, particularly melanomas., Results: LDHA expression was especially strong in early and small brain metastases in vivo and related to intratumoral hypoxia in late and large brain metastases in vivo and in patients. However, LDHA expression in human brain metastases was not associated with the number of tumors, BRAF(V600E) status, or survival. Moreover, LDHA depletion by small hairpin RNA interference did not affect cell proliferation or 3D tumorsphere growth in vitro or brain metastasis formation or survival in vivo. Integrated analyses of the genomic and proteomic landscapes of LDHA indicated that LDHA is present but not imperative for tumor progression within the CNS, or predictive of survival in melanoma patients., Conclusions: In a large patient cohort and in a robust animal model, we show that although LDHA expression varies biphasically during melanoma brain metastasis formation, tumor progression and survival seem to be functionally independent of LDHA., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The cervical collar has been routinely used for trauma patients for more than 30 years and is a hallmark of state-of-the-art prehospital trauma care. However, the existing evidence for this practice is limited: Randomized, controlled trials are largely missing, and there are uncertain effects on mortality, neurological injury, and spinal stability. Even more concerning, there is a growing body of evidence and opinion against the use of collars. It has been argued that collars cause more harm than good, and that we should simply stop using them. In this critical review, we discuss the pros and cons of collar use in trauma patients and reflect on how we can move our clinical practice forward. Conclusively, we propose a safe, effective strategy for prehospital spinal immobilization that does not include routine use of collars.

Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting d-luciferin (molecular weight (MW) 320 D) suggested that tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200 μm after contrast injection at week 5. PET imaging showed that (18)F-FLT (MW 244 Da) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559 Da and 2.066 kDa) extravasated after 5 weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27 × 10(-5)cm/s versus 1.12 × 10(-5)cm/s). PET imaging further demonstrated tumor permeability to (64)Cu-BSA (MW 65.55 kDa) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to d-luciferin and the amphipathic small molecule (18)F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies., (© 2013. Published by Elsevier B.V. All rights reserved.)

BACKGROUND In 2000, the Scandinavian Neurotrauma Committee (SNC) published evidence-based guidelines for the management of minimal, mild or moderate head injuries. Since then, considerable new evidence has emerged on the clinical use of these guidelines and on the radiation risks associated with computer tomographic (CT) examinations. The SNC has recently published updated Scandinavian guidelines. Here we present the Norwegian version of the updated guidelines with emphasis on the professional recommendations and the reasons the new guidelines were necessary, plus comments from the Norwegian authors.MATERIALS AND METHODS A task force appointed by the SNC compiled recommendations based on a systematic, evidence-based review. These recommendations were revised through consensus in the SNC and through consultation with relevant clinical experts.RESULTS A blood test of the brain injury biomarker S100B is for the first time recommended as an initial diagnostic measure for mild head injury patients with low risk. Of these patients, CT examination is only recommended for those who show a pathologically elevated S100B. CT examination is still the recommended routine for moderate head injury patients and for mild head injury patients with medium to high risk. An updated information sheet on head injuries has also been compiled for patients and their relatives.CONCLUSION The SNC recommends the implementation of these guidelines in Norway.

Objective: The aim of this study was to investigate the influence of age on mortality and 3-month outcome in a Norwegian cohort of patients with severe traumatic brain injury (TBI)., Methods: Norwegian residents ≥ 16 years of age who were admitted with a severe TBI to the country's 4 major trauma centres in 2009 and 2010 were included, as were adults (16- 64 years) and elderly patients (≥ 65 years)., Results: Half of the adult subjects and 84% of the elderly subjects were injured by falls. One-third of the adults and half of the elderly subjects were admitted to a local hospital before being transported to a regional trauma hospital. Subdural haematomas were more frequent in the elderly subjects. One-quarter of adults and two-thirds of the elderly subjects died within 3 months. At 3 months, 41% of the adult survivors were still in-patients, mainly in rehabilitation units (92%). Of the surviving elderly subjects, 14% were in-patients and none were in rehabilitation units. There was no difference in functional level for survivors at the 3-month follow-up., Conclusion: Old age is associated with fall-induced severe TBI and high mortality rates. Less intensive treatment strategies were applied to elderly patients in the present study despite high rates of haemorrhage. Few surviving elderly patients received rehabilitation at 3 months post-injury.

Brain metastasis is associated with a particular poor prognosis. Novel insight into the brain metastatic process is therefore warranted. Several preclinical models of brain tumor metastasis have been developed during the last 60 years, and they have in part revealed some of the mechanisms underlying the metastatic process. This review discusses mechanisms of brain metastasis with a key focus of the development of animal model systems. This includes the use of rodent, syngeneic brain metastasis models (spontaneous, chemically induced and genetically engineered models) and human xenotransplantation models (ectopic inoculation and orthotopic models). Current information indicates that none of these fully reflect tumor development seen in patients with metastatic disease. The various model systems used, however, have provided important insight into specific mechanisms of the metastatic process related to the brain. By combining the knowledge obtained from animal models, new important information on the molecular mechanisms behind metastasis will be obtained, leading to the future development of new therapeutic strategies.

Biologic and therapeutic advances in melanoma brain metastasis are hampered by the paucity of reproducible and predictive animal models. In this work, we developed a robust model of brain metastasis that empowers quantitative tracking of cellular dissemination and tumor progression. Human melanoma cells labeled with superparamagnetic iron oxide nanoparticles (SPION) were injected into the left cardiac ventricle of mice and visualized by MRI. We showed that SPION exposure did not affect viability, growth, or migration in multiple cell lines across several in vitro assays. Moreover, labeling did not impose changes in cell-cycle distribution or apoptosis. In vivo, several SPION-positive cell lines displayed similar cerebral imaging and histologic features. MRI-based automated quantification of labeled cells in the brain showed a sigmoid association between metastasis frequency and doses of inoculated cells. Validation of this fully automated quantification showed a strong correlation with manual signal registration (r(2) = 0.921, P < 0.001) and incidence of brain metastases (r(2) = 0.708, P < 0.001). Metastasis formation resembled the pattern seen in humans and was unaffected by SPION labeling (histology; tumor count, P = 0.686; survival, P = 0.547). In summary, we present here a highly reproducible animal model that can improve the predictive value of mechanistic and therapeutic studies of melanoma brain metastasis., (©2013 AACR.)

Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

Surgery for chronic subdural hematoma (CSDH) is performed to relieve brain displacement and high intracranial pressure (ICP). However, the intraoperative impression is often that the pressure inside the CSDH is low, despite marked clinical symptoms. We wanted to quantify the CSDH pressure and relate this to radiological and clinical characteristics. This prospective, population-based study of unilateral CSDHs was conducted over a 3-year period. CSDHs that were secondary to other conditions, re-operations, or CSDHs requiring other procedures than burr hole craniostomy under local anesthesia were excluded. Subdural pressure registration was performed via a simple manometric technique, and full compliance with a standardized protocol was mandatory. Sixty patients were included (mean age 76.2 years; for men, 77.4, and for women, 72.9). The mean pressure in the CSDHs was 15.2 cm H(2)O (range, 0-40) with no gender difference. Men had significantly larger volumes (mean 158.1 vs. 103.2 cm(3)) and midline shifts (mean 1.04 vs. 0.68 cm) than did women. Large hematomas with large midline shifts had higher pressures and more often required repeat surgery. With a patient's increasing age, the volumes and midline shifts seemed to become larger, whereas the pressures became lower. We did not find an association between repeat surgery and pressure or age. Our results are generally in line with those of previous studies reporting quantitative pressure registrations. However, there are important disparities regarding methodology, not least when comparing with various subjective scales that are widely used in clinical practice. A mean subdural pressure of 15.2 cm H(2)O is probably within the range of a normal ICP.

Objectives: We have previously determined the incidence and prevalence of idiopathic normal pressure hydrocephalus (iNPH) in the county of Vestfold in Norway. This study aimed at determining the incidence of surgeries for iNPH., Materials and Methods: Information about age, sex, operation year and operation type was collected retrospectively for all patients hospitalized from 2002 to 2006 with any diagnosis of iNPH and operated with insertion of a ventriculo-peritoneal or ventriculoatrial shunt system, or with endoscopic third ventriculostomy in any of Norway's five regional neurosurgical centers., Results: Two hundred fifty-two patients were operated during the 5-year period, making the total incidence 1.09/100,000/year. The yearly incidence ranged from a minimum of 0.84/100,000 in 2006 to a maximum of 1.47/100,000 in 2004. The incidence was highest in the age group 70-79 years. There were little regional differences regarding incidence, sex, and age and operation type., Conclusions: The data suggest that too few patients are being offered surgical treatment for iNPH in Norway.

Objective: The aim of this study is to map and evaluate the available resources and the premises of traumatic head injury management in the Nordic countries, before the implementation of a Nordic adaption of the Brain Trauma Foundation guidelines for prehospital management., Methods: The study is a synthesis of two cross-sectional surveys. Questionnaires were used to collect data on the annual number of acute head injury operations, the infrastructure, the level of education, the use of trauma protocols and the management of traumatic head injury at Nordic hospitals., Results: The proportion of acute head injury operations performed outside a neurosurgical department was 0% in Denmark, 16% in Finland, 19% in Norway and 33% in Sweden. Eighty-four per cent of Nordic hospitals had written protocols for the assessment and treatment of trauma patients and 78% had regular training in trauma management; 67% had specific protocols for the treatment of traumatic head injury. Computed tomography (CT) was available in 93% of the hospitals, and 59% of the hospitals could link CT scans to the regional neurosurgical department., Conclusions: Most Nordic hospitals are well prepared to manage patients with acute traumatic head injury. A substantial proportion of the operations are performed at local and central hospitals without neurosurgical expertise, despite an efficient pre and interhospital transport system. The Nordic adaption of the Brain Trauma Foundation guidelines recommends that this practice is terminated.

Head trauma is the cause the death for many young persons. The number of fatalities can be reduced through systematic management. Prevention of secondary brain injury combined with the fastest possible transport to a neurosurgical unit, have been shown to effectively reduce mortality and morbidity. Evidence-based guidelines already exist that focus on all steps in the process. In the present article members of the Scandinavian Neurotrauma Committee present recommendations on prehospital management of traumatic brain injury adapted to the infrastructure of the Nordic region.

Head trauma causes the death of many young persons. The number of fatalities can be reduced through systematic management. Preventing secondary brain injury together with the fastest possible transport to a neurosurgical unit has been shown to be effective in reducing mortality and morbidity. Evidence-based guidelines already exist that focus on all steps in the management. This article, which was written by members of the Scandinavian Neurotrauma Committee, presents recommendations on the pre-hospital management of traumatic brain injury adapted to the infrastructure of Scandinavia.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in Western countries. Effective management planning for these patients requires knowledge of TBI epidemiology. The purpose of this study was to describe and analyze the development of TBI mortality in the Nordic countries during the period 1987-2001. Data on TBI deaths were retrieved from the national official statistical agencies according to specified diagnostic codes. We also collected data on the number of operations for acute TBI in the year 2000 from all Nordic hospitals admitting trauma patients. Finland had about twice as high a TBI mortality rate as the other countries. Similarly, the Finnish incidence of acute TBI operations was nearly twice that of the other countries. The median TBI death rate for Finland was 21.2 per 100,000 per year, and for Denmark, Norway, and Sweden 11.5, 10.4, and 9.5, respectively. There were more male than female deaths in all countries. The mortality rate from extracranial injuries was relatively equal between the countries. We observed a sizeable reduction in TBI mortality rates for all countries, except in Finland. Younger age groups had the most pronounced decrease in TBI mortality rates. The oldest age group had the least favorable development of TBI mortality rates, and the mean age of TBI casualties increased substantially during the study period. This study demonstrates considerable differences in and between the Nordic countries regarding TBI mortality. Preventive measures and implementation of regional guidelines are needed to assure a positive development in the future.

Background: Traumatic brain injury (TBI) is the major cause of death among young adults in western countries. In the context of a joint Nordic initiative regarding future management of patients with severe TBI, it was of interest to look into the magnitude of the problem and the most recent developments., Material and Methods: We have conducted a survey of the epidemiological aspects of TBI deaths in Denmark, Finland, Norway and Sweden for the period 1987-2000. Data were retrieved from the official statistical agencies in the four countries. We have also collected data on the number of operations for acute TBI in the year 2000 from all Nordic hospitals admitting trauma patients., Results: There were almost twice as many deaths from TBI in Finland as in the other Nordic countries. The median mortality rate in Finland was 21.2 per 100,000 per year. The corresponding figures for Denmark were 12.8, Norway 10.5 and Sweden 9.8. Finland also had almost twice as many operations for acute TBI with 10.0 per 100,000 per year, versus 5.1 in Denmark, 4.8 in Norway and 5.7 in Sweden. The mortality rate was about three times higher among males than among females. All countries except Finland had a significant reduction in TBI deaths during the study period. The mortality rate from injuries other than TBI was more or less the same in all four countries., Interpretation: Our findings imply that there are twice as many severe TBIs and related deaths in Finland compared with the other Nordic countries.