Stable glioma incidence and increased patient survival over the past two decades in Norway: a nationwide registry-based cohort study.

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.

Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes.

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.

[Glioblastoma in adults]. / Glioblastom hos voksne.

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.

Surgical treatment and outcome of chronic subdural hematoma: a comparative study between Ethiopia and Norway.

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.

[Brain metastases ­ diagnostics and treatment] / Hjernemetastasar ­ diagnostikk og behandling.

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.

Effect of Spinal Cord Burst Stimulation vs Placebo Stimulation on Disability in Patients With Chronic Radicular Pain After Lumbar Spine Surgery: A Randomized Clinical Trial.

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.

CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells.

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.

Is intracranial volume a risk factor for IDH-mutant low-grade glioma? A case-control study.

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.

Bicycle-related cervical spine injuries.

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.

Effects of Intraoperative Dexmedetomidine Infusion on Postoperative Pain after Craniotomy: A Narrative Review.

Craniotomy involves procedures with high incidences of postoperative pain. Dexmedetomidine, a highly selective a2-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.

Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways.

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.

Prospective Study of Surgery for Traumatic Brain Injury in Addis Ababa, Ethiopia: Surgical Procedures, Complications, and Postoperative Outcomes.

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.

Prospective Study of Surgery for Traumatic Brain Injury in Addis Ababa, Ethiopia: Trauma Causes, Injury Types, and Clinical Presentation.

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.

Improved Drug Delivery to Brain Metastases by Peptide-Mediated Permeabilization of the Blood-Brain Barrier.

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 IC50, 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.

Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis.

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 ß-sitosterol, a well-tolerated and brain-penetrable phytosterol. Here we show that ß-sitosterol attenuates melanoma cell growth in vitro and also inhibits brain metastasis formation in vivo. Functional analyses indicated that the therapeutic potential of ß-sitosterol was linked to mitochondrial interference. Mechanistically, ß-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 ß-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, ß-sitosterol represents a promising adjuvant to BRAF inhibitor therapy in patients with, or at risk for, melanoma brain metastases.

Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide.

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.