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Thorbjørn Søren Rønn Jensen,1 Emilia Myrup Thiesson,2 Kåre Fugleholm,1 Jan Wohlfahrt,2,3 Tina Nørgaard Munch1,2 1Department of Neurosurgery, Copenhagen University Hospital, Copenhagen, DK-2100, Denmark; 2Department of Epidemiology Research, Statens Serum Institute, Copenhagen, DK-2300, Denmark; 3Danish Cancer Society Research Center, Copenhagen, DK-2100, DenmarkCorrespondence: Thorbjørn Søren Rønn Jensen, Email tjens07@gmail.comBackground: The discovery of biomarkers in chronic subdural haematomas (CSDH) suggests that inflammation is part of CSDH pathophysiology. It is unknown whether inflammation reflects an independent CSDH driver or haematoma degeneration. This knowledge holds a potential target for anti-inflammatory treatment in patients at risk of CSDH. This study investigated the association of pro- and anti-inflammatory factors with CSDH development.Methods: This cohort study included all individuals in Denmark over 50 years between 2007– 2018. The outcome was first-time CSDH surgery. Hazard ratios (HR) according to potential risk factors were estimated using Cox regression, with age as underlying time scale.Results: Among the 2,391,853 individuals, head trauma was registered in 427,612 individuals (17%), and among these, only 812 were operated for CSDH (0.18%). Among individuals without registered head trauma, the pro-inflammatory conditions of alcohol addiction, diabetes, anti-hypertensive treatment, and chronic hepatic disease were significantly associated with CSDH among individuals (50– 74 years). The use of glucocorticoids displayed a decreased risk in cohort members aged 75 and older. Non-steroid anti-inflammatory drugs and statins appeared to be risk factors for CSDH in individuals between the ages of 50– 64 and 65– 74.Conclusion: Although head trauma was a risk factor for CSDH, the absolute risk was low (0.18%), which does not support preventive measures after emergency room contacts for head trauma. Interestingly, pro-and anti-inflammatory factors were significantly associated with CSDH in patients without registered head trauma, and the pronounced age-dependency of the associations suggests that the pathophysiological mechanisms vary with age.Keywords: head trauma, inflammation, trauma, anti-inflammatory treatment, risk factors

Objective: This study aimed to investigate the immunological profile of Chronic Subdural Hematoma (CSDH) subtypes based on their radiological appearances, with a focus on comparing the membranous CSDH to other subtypes., Methods: We prospectively analyzed 170 CSDH cases from 138 patients, categorizing them into 'Membranous' and 'Other' subtypes based on computed tomography scans. Samples were collected from the subdural fluid and systemic blood and analyzed for a panel of inflammatory markers. Demographic data, clinical characteristics, and time since trauma were also assessed., Results: Time since trauma to diagnostic CT was significantly longer for the 'membranous' subtype (p=0.001). 'Membranous' CSDH exhibited a distinct immunoprofile, including lower hemoglobin levels (p=0.0002) and higher concentrations of MMP-9 (p=0.005) and IL-8 (p<0.0001). Additionally, 'Membranous' CSDH showed elevated levels of IP-10, MIG, and uPAR compared to 'Other' subtypes, with significant correlations between IP-10 and MCP-1 (p=0.013), MIG (p=0.002), and uPAR (p=0.006). IL-8 levels also correlated significantly with MCP-1 (p=0.02), suggesting distinct inflammatory pathways in the 'Membranous' subtype CONCLUSIONS: This study demonstrates that CSDH subtypes, particularly the 'Membranous' subtype, possess a distinct immunological profile. These findings provide novel insights into CSDH pathophysiology. The unique inflammatory landscape of 'Membranous' CSDH, marked by elevated MMP-9 and IL-8 levels, may contribute to its chronic nature., (Copyright © 2024. Published by Elsevier Inc.)

Abstract: Intracranial mesenchymal tumor, FET-CREB fusion positive, is a newly recognized and rare CNS tumor that occurs primarily in children and young adults. It is regarded as the intracranial variant of angiomatoid fibrous histiocytoma. Extracranial angiomatoid fibrous histiocytomas are typically located in the extremities and usually discernible on a 18 F-FDG PET/CT scanning. We present a 50-year-old man with recurrence of a primary intracranial mesenchymal tumor with equivocal 18 F-FDG PET/CT findings but with subsequent highly increased metabolic activity using 18 F-FET PET/CT confirming tumor recurrence. This case highlights the importance of 18 F-FET PET/CT, as opposed to 18 F-FDG, in the clinical evaluation of this rare intracranial mesenchymal tumor., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This 13-year consecutive case series aims to provide a comprehensive overview of all patients operated for clival chordomas and clival chondrosarcomas in Denmark since the centralization of treatment in 2010, comparing outcomes to international series., Methods: This was a retrospective review of 33 patients with clival tumors, comprising 22 chordomas and 11 chondrosarcomas, who were treated at Copenhagen University Hospital between years 2010 and 2023. Data were collected from digital patient records and pathology reports., Results: The symptoms leading to diagnosis primarily included double vision, headaches, and dizziness. In general, patients were in good health, with a mean Charlson Comorbidity Index score of 1.6. The complication rate of the index surgery was 51.5%. Adjuvant radiotherapy was applied in 51.5% of the cases. In patients with clival chordomas, the mean age was 51.1 years, ranging from 16 to 83 years. At the time of diagnosis, the mean tumor volume was 20.9 cm 3 and the five-year overall survival rates were 79.1% (95% confidence interval (CI): 62.4-100). In patients with chondrosarcomas, the mean age was 48.2 years, ranging from 15 to 76 years. At the time of diagnosis, the mean tumor volume was 22.3 cm 3 and the five-year overall survival 90% (95% CI: 73.2-100)., Conclusion: The centralized treatment of clival tumors in Denmark demonstrates incidence, survival, and complication rates comparable to those found in other international series. Given the variations in treatment strategies, tumor localizations across series, and small sample sizes, the further analysis of larger compiled multicenter datasets for clival tumors could provide more solid evidence regarding the management of these rare tumors., (© 2024. The Author(s).)

Background: Postoperative drainage after surgical evacuation of chronic subdural haematoma reduces the risk of recurrence, but the optimum drainage time is uncertain. We aimed to investigate the shortest possible drainage time without increasing the haematoma recurrence rate., Methods: We conducted a randomised, multi-arm and multistage non-inferiority trial at four neurosurgical centres in Denmark. We enrolled adult patients (aged ≥18 years) with symptomatic chronic subdural haematoma. All patients were treated according to the national standard practice with a burr hole above the maximum width of the haematoma. Patients were randomly assigned in a 1:1:1 ratio via a centralised web server to receive 6 h, 12 h, or 24 h of postoperative passive subdural drainage. Randomisation was done by an independent on-call neurosurgeon and was masked until 6 h after surgery. The primary outcome was symptomatic haematoma recurrence at 3 months after surgery; the rate of recurrence was assessed in a regression model for non-inferiority testing, with no missing data. Personnel assessing the primary outcome were masked to group allocation. Non-inferiority was assessed with a prespecified margin of 7%, in a modified intention-to-treat population-defined as patients with randomly assigned treatment excluding those withdrawing from study participation after randomisation, or experiencing acute rebleedings or accidental drain removal. This trial is registered with ISRCTN (number 15186366); the trial was stopped after the first interim analysis on the advice of an independent safety advisory committee., Findings: Between March 1, 2021, and June 30, 2022, 347 patients were enrolled and 331 were followed up to 3 months, 105 were assigned to 6 h of drainage, 111 to 12 h of drainage, and 115 to 24 h of drainage. At admission, 83 (25%) participants were women and 248 (75%) were men, mean age was 75·7 years (SD 10·5), median modified Rankin Scale score was 4 (IQR 3-5), and median Glasgow Coma Scale score was 15 (IQR 14-15). At 3 months after surgery, haematoma recurrence was reported in 28 (27%) of 105 patients who were assigned to 6 h drainage (predicted haematoma recurrence rate 27·0%, 95% CI 18·5 to 35·4), 22 (20%) of 111 assigned to 12 h drainage (19·5%, 12·0 to 27·0), and 12 (10%) of 115 assigned to 24 h drainage (10·4%, 4·8 to 16·0). The risk of haematoma recurrence was increased by 16·5 percentage points (95% CI 6·5 to 26·6) in patients drained for 6 h compared with 24 h, and by 9·1 percentage points (-0·4 to 18·5) in patients drained for 12 h compared with 24 h. Therefore, non-inferiority of 6 h and 12 h of drainage to 24 h of drainage was not established. 20 patients had died by 3 months, seven in the 6 h group, eight in the 12 h group, and five in the 24 h group. The most frequent known causes of death were haematoma recurrence (three in 12 h group), comorbidity (three in 12 h group), and pneumonia (one each in 6 h and 12 h groups, two in 24 h group). The most frequent complication was postoperative infection, reported in 20 (20%) patients in the 6 h group, 25 (23%) in the 12 h group, and 19 (17%) in the 24 h group. The most common infection source was the urinary tract., Interpretation: Patients surgically treated for symptomatic chronic subdural haematoma and postoperatively drained for 6 h or 12 h had higher rates of haematoma recurrence than did patients drained for 24 h. The findings from this non-inferiority trial provide evidence to support 24 h of postoperative drainage as the standard drain time when a fixed drain time approach is used. To provide solid evidence of generalisability of the results to countries other than Denmark, a multinational randomised controlled trial will be needed., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Chronic subdural hematoma (CSDH) development involves inflammatory, angiogenetic, and fibrinolytic mechanisms, several components of which are now unraveled through intensive research. The urokinase plasminogen activator receptor (uPAR) is part of the plasminogen activator system and possesses inflammatory, angiogenetic, and fibrinolytic capabilities. As a first, this study aims to identify uPAR in the hematoma fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH and, if present, to investigate if the uPAR level at the time of surgery may be a predictor for later developing recurrent CSDH. uPAR expression in the hematoma membrane and dura mater was analyzed using immunohistochemistry and presented as the H-score of the positive immunostaining. The uPAR levels in the hematoma fluid and systemic blood were determined using a multiplex antibody bead kit (Luminex). Samples were collected at the time of the first CSDH surgery, and in the case of recurrent CSDH within 90 days, the samples were again collected at reoperation. A comparison of uPAR expression between the hematoma membrane and dura mater, as well as uPAR levels in systemic blood and hematoma fluid, was performed using the Wilcoxon rank sum test. We included 112 patients, 26 of whom had recurrent CSDH. The median hematoma uPAR level was 22,125 (14,845-33,237) and significantly higher than the median systemic blood level of 789 pg/L (465-2,088) (p < 0.001). Similarly, the uPAR level of the hematoma membrane was 14.3 (7.54-44.8) and significantly higher than the dural uPAR level of 0.81 (0.3-1.98) (p < 0.001). For the first time, we identified uPAR in the subdural fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH. The high expression of uPAR in the subdural fluid and hematoma membrane indicates that the mechanisms of CSDH are predominantly in the subdural fluid collection and surrounding hematoma membrane., (© 2024. The Author(s).)

Introduction: The pathophysiology of chronic subdural hematoma (CSDH) remains to be fully understood. Basic knowledge of the composition and features of cells in the CSDH fluid may contribute to the understanding of the seemingly complex processes involved in CSDH formation and recurrence. This study is the first to examine the composition of cells and of cellular features in both systemic blood and subdural fluid from CSDH patients. We hypothesized that the cellular composition and features in the hematoma fluid may be; 1) different from that in the systemic blood; 2) different between patients with and without recurrence; 3) and different between the first and second operation in patients with recurrent CSDH., Methods: Systemic blood and subdural hematoma fluid were collected from CSDH patients with and without recurrent CSDH at the time of primary and secondary surgery. Analyses of cells and cellular features included total number of white blood cells, erythroblasts, reticulocytes, platelets, neutrophilocytes, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, immature granulocytes, mean corpuscular cell volume (MCV), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin and hematocrit., Results: Of the 85 included patients, 20 patients were operated for a recurrent CSDH within 90 days follow-up. All cells found in the systemic blood were present in the CSDH fluid, but the composition was different (p < 0.0001). MCV was higher in the hematoma fluid from the primary operation of patients later developing a recurrent CSDH compared to patients not developing recurrence (p = 0.009). Also, the percentage distribution of inflammatory cells in hematoma fluid from patients with recurrent CSDH was different between the first and second operation (p = 0.0017)., Conclusion: This study is the first to investigate the cellular composition of CSDH fluid. Compared to systemic blood and to a reference distribution, an increased number of immune cells were present in the hematoma fluid, supporting an inflammatory component of the CSDH pathophysiology. MCV was higher in the subdural fluid at time of the first operation of CSDH patients later developing recurrence., Clinical Trial Registration: The study was approved by the Scientific Ethical Committee of the Capital Region of Denmark (Journal no. H-20051073., (© 2024. The Author(s).)

Background and Objectives: Intraoperative orientation during microsurgery has a prolonged learning curve among neurosurgical residents. Three-dimensional (3D) understanding of anatomy can be facilitated with realistic 3D anatomic models created from photogrammetry, where a series of 2-dimensional images is converted into a 3D model. This study implements an algorithm that can create photorealistic intraoperative 3D models to exemplify important steps of the operation, operative corridors, and surgical perspectives., Methods: We implemented photograph-based and video-based scanning algorithms for uptakes using the operating room (OR) microscope, targeted for superficial structures, after surgical exposure, and deep operative corridors, in cranial microsurgery. The algorithm required between 30-45 photographs (superficial scanning), 45-65 photographs (deep scanning), or approximately 1 minute of video recording of the entire operative field to create a 3D model. A multicenter approach in 3 neurosurgical departments was applied to test reproducibility and refine the method., Results: Twenty-five 3D models were created of some of the most common neurosurgical approaches-frontolateral, pterional, retrosigmoid, frontal, and temporal craniotomy. The 3D models present important steps of the surgical approaches and allow rotation, zooming, and panning of the model, enabling visualization from different surgical perspectives. The superficial and medium depth structures were consistently presented through the 3D models, whereas scanning of the deepest structures presented some technical challenges, which were gradually overcome with refinement of the image capturing process., Conclusion: Intraoperative photogrammetry is an accessible method to create 3D educational material to show complex anatomy and demonstrate concepts of intraoperative orientation. Detailed interactive 3D models, displaying stepwise surgical case-based anatomy, can be used to help understand details of the operative corridor. Further development includes refining or automatization of image acquisition intraoperatively and evaluation of other applications of the resulting 3D models in training and surgical planning., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

A further rise in chronic subdural haematoma (CSDH) prevalence is expected with an ageing population, and evidence-based guidelines are needed to direct treatment, while creating a platform for research. The Danish Chronic Subdural Hematoma Study (DACSUHS) has implemented the first Danish national CSDH guidelines in 2018 and have standardised CSDH management on a national level. Based on CSDH literature published between 2016 and 2022, these guidelines were updated in 2022. The updated guidelines are presented in this review., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated., Methods: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions., Results: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions)., Conclusion: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions., (© 2024. The Author(s).)

Background and Objectives: In most neurosurgical centers, irrigation is an essential part of the surgical procedure for chronic subdural hematoma (CSDH). However, it is unknown whether the volume of irrigation fluid affects the risk of CSDH recurrence. This study aimed to investigate a potential association between the volume of irrigation fluid used during burr hole evacuation of CSDH and the risk of CSDH recurrence., Methods: This study is a subanalysis of 2 randomized trials (Drain Time & Drain Time 2) designed to investigate the effect of drainage duration on the recurrence of CSDH. Intraoperative irrigation volume was measured, and patients were followed for 90 days for recurrent CSDH., Results: A total of 525 patients with CSDH were included. There was no significant difference in the volume of irrigation fluid used between patients with recurrence (mean = 938 mL, SD = ±552) and without recurrence (mean = 852 mL, SD = ±454) ( P -value = .15). Patients with recurrent CSDH had larger primary CSDH volumes (mean = 134 cm 3 , SD = ±69) than patients without recurrence (mean = 119 cm 3 , SD = ±58) ( P = .04). Multiple logistic regression analysis revealed no association between irrigation volume and recurrence, also when stratified for hematoma size., Conclusion: There was no significant association between irrigation volume and recurrent CSDH within 90 days in patients undergoing burr hole surgery for CSDH., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Purpose: Cadaver dissections and X-ray based 3D angiography are considered gold standards for studying neurovascular anatomy. We sought to develop a model that utilize the combination of both these techniques to improve current tools for anatomical research, teaching and preoperative surgical planning, particularly addressing the venous system of the brain., Materials and Methods: Seven ethanol-fixed human cadaveric heads and one arm were injected with a latex-barium mixture into the internal jugular veins and the brachial artery. After the ethanol-based fixation, specimens were scanned by high-resolution cone-beam CT and images were post-processed on a 3D-workstation. Subsequent, microsurgical dissections were performed by an experienced neurosurgeon and venous anatomy was compared with relevant 3D venograms., Results: Latex-barium mixtures resulted in a homogenous cast with filling of the cerebral venous structures down to 150 μm in diameter. The ethanol-based preparation of the cadaveric brains allowed for near-realistic microsurgical maneuverability during dissection. The model improves assessment of the venous system for anatomical education and hands-on surgical training., Conclusion: To our knowledge we describe the first preparation method which combines near-realistic microsurgical dissection of human heads with high-resolution 3D imaging of the cerebral venous system in the same specimens., (© 2023. The Author(s).)

Background: Chronic subdural hematoma (CSDH) pathophysiology has undergone a paradigm shift from being regarded as solely traumatic to be driven mainly by inflammation. Human leucocyte antigen (HLA) is a gene complex involved in antigen processing and presentation to T lymphocytes, thereby mediating the adaptive immune responses. As specific HLA profiles are associated with inflammatory diseases, patients with a specific HLA profile may have a lower threshold for subdural inflammation, and therefore are predisposed for CSDH development. We hypothesized that (1) CSDH patients have a specific HLA profile compared to a Danish background population, and (2) patients with recurrent CSDH have a specific HLA profile compared to CSDH patients without recurrent CSDH., Methods: Three specific HLA class II haplotypes known to drive inflammatory-mediated diseases were determined in 68 patients with CSDH. The distribution of these three haplotypes in our CSDH population was compared to a Danish population of blood donors using Monte Carlo Pearson's chi-square test. Furthermore, the distribution of the haplotypes was compared between CSDH patients with and without recurrent CSDH., Results: We found no significant association between either of the haplotypes and the risk of CSDH, and neither of the haplotypes were associated with increased risk of CSDH recurrence., Conclusion: This study did not show an association between selected HLA class II haplotypes and the risk of CSDH or recurrence of CSDH compared with a healthy background population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background and Objectives: Smartphone-based photogrammetry (SMPhP) was recently presented as a practical and simple algorithm to create photorealistic 3-dimensional (3D) models that benefit from volumetric presentation of real anatomic dissections. Subsequently, there is a need to adapt the techniques for realistic depiction of layered anatomic structures, such as the course of cranial nerves and deep intracranial structures; the feasibility must be tested empirically. This study sought to adapt and test the technique for visualization of the combined intracranial and extracranial course of the facial nerve's complex anatomy and analyze feasibility and limitations., Methods: We dissected 1 latex-injected cadaver head to depict the facial nerve from the meatal to the extracranial portion. A smartphone camera alone was used to photograph the specimen, and dynamic lighting was applied to improve presentation of deep anatomic structures. Three-dimensional models were created with a cloud-based photogrammetry application., Results: Four 3D models were generated. Two models showed the extracranial portions of the facial nerve before and after removal of the parotid gland; 1 model showed the facial nerve in the fallopian canal after mastoidectomy, and 1 model showed the intratemporal segments. Relevant anatomic structures were annotated through a web-viewer platform. The photographic quality of the 3D models provided sufficient resolution for imaging of the extracranial and mastoid portions of the facial nerve, whereas imaging of the meatal segment only lacked sufficient precision and resolution., Conclusion: A simple and accessible SMPhP algorithm allows 3D visualization of complex intracranial and extracranial neuroanatomy with sufficient detail to realistically depict superficial and deeper anatomic structures., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Anti-inflammatory treatment reduces the risk of recurrent chronic subdural hematoma (CSDH), but clinical implementation is improper due to side effects. Exact knowledge of subdural molecules involved in recurrent CSDH may lead to targeted medical treatment and possibly improve the prospect of a personalized approach by eliminating the broad use of anti-inflammatory drugs on the entire CSDH population. With this study, we aim to (1) describe the associations between cytokine levels at the primary surgery and the risk of subsequent recurrence and (2) describe the association between cytokines in patients with recurrent CSDH between the first and second operations. Systemic and subdural levels of pro- and anti-inflammatory cytokines were measured and compared between patients with the first-time CSDH and recurrent CSDH. Cytokine levels were analyzed using a multiplex antibody bead kit. In case of recurrent CSDH within 90 days of follow-up, the samples were re-collected and analyzed. We included 101 adult CSDH patients of which 20 had a recurrence. The levels of cytokines in the CSDH fluid from patients who were operated on for the first-time CSDH were not associated with the risk of later developing a recurrence. We found interleukin-1 receptor antagonist (IL-1ra) to be elevated in subdural fluid in patients with recurrent CSDH at the time of their second operation (p = 0.0005). This study provides knowledge on cytokine composition in the subdural fluid in patients with CSDH with and without recurrence. IL-1ra is elevated in subdural fluid in patients with recurrent CSDH at the time of the second operation, identifying a possible medical target., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Subdural drainage reduces recurrence after evacuation of chronic subdural hematoma (CSDH). In the present study, the authors investigated the dynamics of drain production and potentially contributing factors for recurrence., Method: Patients treated with a single burr hole evacuation of CSDH between April 2019 and July 2020 were included. Patients were also participants in a randomized controlled trial. All patients included, had a passive subdural drain for exactly 24 hours. Drain production, Glasgow Coma Scale score, and degree of mobilization was recorded every hour for 24 hours. A CSDH successfully drained for 24 hours is referred to as a "case". Patients were followed for 90 days. Primary outcome was symptomatic recurrent CSDH requiring surgery., Results: A total of 118 cases from 99 patients were included in the study. Of the 118 cases, 34 (29%) had spontaneous drain cessation within the first 0-8 hours after surgery (Group A), 32 (27%) within 9-16 hours (Group B), and 52 (44%) within 17-24 hours (Group C). Hours of production (P < 0.000) and total drain volume (P = 0.001) were significantly different between groups. The recurrence rate was 26.5% in group A, 15.6% in group B, and 9.6% in group C (P = 0.037). Multivariable logistic regression analysis show that cases in group C (OR: 0.13, P = 0.005) are significantly less likely to recur compared to group A. Only in 8 of the 118 cases (6.8%), the drain started draining again after an interval of three consecutive hours., Conclusions: Early spontaneous cessation of subdural drain production seems to be associated with increased risk of recurrent hematoma. Patients with early cessation of drainage did not benefit from further drain time. Observations of the present study indicate personalized drainage discontinuation strategy as a potentially alternative to a specific discontinuation time for all CSDH patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hjortdal Grønhøj et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Decompressive hinge craniotomy (DHC) is an alternative treatment option to decompressive craniectomy (DC) for elevated intracranial pressure (ICP). The aim of this study was to characterize the difference in pressure-volume relationship between DHC and DC., Methods: We compared the intracranial pressure-volume relationship in a human cadaver model following either DHC, DC, or fixing of the bone plate by titanium clamps. We inserted an intracranial expandable device in two human cadaver specimens, performed either DHC, DC, or bone plate fixation, and gradually increased the intracranial volume while measuring ICP. Following DHC, we also performed CT-scans at pre-defined intervals., Results: Before ICP exceeded a threshold of 20 mmHg, a fixed bone plate tolerated an increase of 130 ml of intracranial volume, while DHC and DC allowed an increase of 190 ml and 290 ml, respectively. CT-derived calculations following DHC determined that the increase in intracranial volume at ICP 22 mmHg was 65 ml, the maximal increase of intracranial volume was 84 ml, the maximal bone displacement was 21 mm, and the bone plate volume to be 82 ml. Manual stress test of the hinged bone plate did not allow misalignment or intracranial displacement of the bone plate., Conclusion: DHC increases the intracranial volume by up to 84 ml and allows for approximately 60 ml increase of intracranial volume before ICP exceeds 20 mmHg. This indicates, when comparing with results from previous studies of herniation volumes, that DHC will be sufficient in many patients with head injury or cerebral infarction with treatment refractory intracranial hypertension., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Treatment of multiple recurrent chronic subdural hematomas (CSDH) is challenging. Identification of specific risk factors for multiple recurrences may allow a higher degree of personalized treatment, including closer postoperative follow-up, detailed prognostication, and a more aggressive initial surgical strategy, such as craniotomy, adjuvant embolization of the middle meningeal artery, or adjuvant medical treatment, such as steroids. The aim of this study was to identify pretreatment risk factors for a second recurrence of CSDH (re-re-CSDH) and risk factors for developing re-re-CSDH once operated for the first recurrence., Methods: Clinical and demographic data on all Danish patients admitted to a neurosurgical department with CSDH between 2010 and 2012 were retrospectively recorded. Data were retrieved before the evacuation of a primary CSDH, a first recurrent CSDH (re-CSDH), and a re-re-CSDH. We compared patients undergoing first, second, and third CSDH evacuation to identify risk factors for re-CSDH and re-re-CSDH., Results: The cohort comprised 1052 patients, with 172 patients with re-CSDH and 29 patients with re-re-CSDH. Risk factors for re-re-CSDH included radiological subtype, midline shift, and hematoma volume, while postoperative drainage lowered the risk of re-re-CSDH. These risk factors were not specific for re-re-CSDH., Conclusions: We found similar independent risk factors for re-CSDH and re-re-CSDH, and for re-re-CSDH once treated for re-CSDH. Hence, it was not possible to identify specific risk factors for patients at risk of re-re-CSDH at the time of the primary diagnosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Subfrontal meningiomas grow insidiously in areas with high cerebral compliance and a relative scarcity of eloquent function. Symptoms develop progressively, are nonspecific, and include anosmia, changes in personality and cognition, depressive symptoms, headaches, visual disturbances, and seizures. Patients with subfrontal meningiomas carry the highest risk of developing psychological symptoms, which makes patient-reported outcome in terms of long-term health-related quality of life (HRQOL), anxiety, and depression of particular importance. This observational study aimed to investigate long-term HRQOL, anxiety, and depression in patients with subfrontal meningiomas who underwent a bifrontal craniotomy (subfrontal) approach between 2008 and 2017 at a single tertiary center. Correlations between preoperative, perioperative, and postoperative factors and HRQOL, anxiety, and depression were analyzed to detect prognostic factors., Methods: Seventy-seven consecutive patients who underwent operations at Rigshospitalet, Copenhagen, Denmark, between 2008 and 2017 were retrospectively analyzed. Patients were prospectively invited to respond to the Functional Assessment of Cancer Therapy-General, Functional Assessment of Cancer Therapy-Brain, and Hospital Anxiety and Depression Scale. Information regarding preoperative, perioperative, and postoperative factors were collected from the patients' medical records and scans., Results: Patients with subfrontal meningiomas exhibited better HRQOL and lower levels of anxiety and depression than general populations and other meningioma and glioblastoma cohorts. The only statistically significant prognostic factors for long-term HRQOL were number of symptoms at diagnosis and whether patients were discharged home or to a local hospital postoperatively. Tumor and peritumoral brain edema volumes were not prognostic factors., Conclusions: Patients with subfrontal meningiomas exhibited better long-term postoperative HRQOL and were less likely to have anxiety or depression than the reference populations. This information on long-term prognosis is very valuable for patients, next of kin, and neurosurgeons and has not been previously studied in detail.

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Meningioma is the most common primary intracranial neoplasm. Only 1%-3% of meningiomas are malignant according to the 2016 WHO criteria (WHO grade III). High-grade meningiomas present specific gene expression signatures indicating aggressive growth or recurrence. However, changes in gene expression and in neuroinflammatory gene expression signatures in WHO grade III meningiomas and during progression from WHO grade I or II to grade III are unknown., Methods: The authors used a NanoString targeted gene expression panel with focus on 787 genes relevant in meningioma pathology and neuroinflammatory pathways to investigate patients with grade III meningiomas treated at Rigshospitalet from 2000 to 2020 (n = 51). A temporal dimension was added to the investigation by including samples from patients' earlier grade I and II meningiomas and grade III recurrences (n = 139 meningiomas). The authors investigated changes in neuroinflammatory gene expression signatures in 1) grade I meningiomas that later transformed into grade III meningiomas, and 2) grade III meningiomas compared with nonrecurrent grade I meningiomas., Results: The authors' data indicate that FOXM1, TOP2A, BIRC5, and MYBL2 were enriched and the HOTAIR regulatory pathway was enriched in grade III meningiomas compared with nonrecurrent grade I meningiomas. They discovered a separation of malignant and benign meningiomas based only on genes involved in microglia regulation with enrichment of P2RY12 in grade I compared with grade III meningiomas. Interestingly, FOXM1 was upregulated in premalignant grade I meningioma years before the grade III transformation., Conclusions: The authors found gene expression changes in low-grade meningiomas that predated histological transformation to grade III meningiomas. Neuroinflammation genes distinguished grade III from grade I meningiomas.

TERT promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. A main purpose of refining tumour classification is better predictions on the patient level. We compiled data from previous published cohorts to investigate patient-level predictions of recurrence based on TERTp-mut status. Implementation of TERTp-mut into the WHO grading led to better patient prognostication by improved prediction of recurrence. Our results support implementation of TERTp-mut into diagnostics and classification of meningiomas., (© 2021 British Neuropathological Society.)

Background and Objectives: The risks of postoperative risk of epilepsy after a craniotomy is widely believed to be raised. A study is warranted to quantify the risks for any neurosurgical indication. In this unselected register-based nationwide cohort study with virtually complete follow-up, the short-term and long-term cumulative risks of postoperative de novo epilepsy for all major neurosurgical indications were estimated., Methods: The study was based on 8948 first-time craniotomy patients in Denmark 1 January 2005 to 31 December 2015 with follow-up until 31 December 2016. The patients were classified according to their underlying neurosurgical pathology. Patients with preoperative epilepsy were excluded. The postcraniotomy risks of de novo epilepsy were estimated using the Aalen-Johansen estimator in a multistate model., Results: The overall cumulative 1-year risk of postcraniotomy de novo epilepsy was 13.9% (95% CI 13.2 to 14.6). For patients with intracranial tumour the cumulative 1-year risk was 15.4% (95% CI 14.4 to 16.5), for spontaneous intracranial haemorrhage 11.3% (95% CI 10.1 to 12.6), for traumatic intracranial haemorrhage 11.1% (95% CI 9.6 to 12.9), for cerebral abscess 27.6% (95% CI 22.8 to 33.5) and for congenital malformations 3.8% (95% CI 1.3 to 11.7). The 6-month, 1-year and 5-year risks for all major indications by specific subtypes are provided., Conclusions: The cumulative risk of de novo epilepsy following craniotomy is high for patients with any indication for craniotomy, as compared with the background population. The results provide comprehensive data to support future recommendations regarding prophylactic antiepileptic treatment and driving restrictions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chronic subdural hematoma (CSDH) is a common acute or subacute neurosurgical condition, typically treated by burr-hole evacuation and drainage. Recurrent CSDH occurs in 5-20% of cases and requires reoperation in symptomatic patients, sometimes repeatedly. Postoperative subdural drainage of maximal 48 h is effective in reducing recurrent hematomas. However, the shortest possible drainage time without increasing the recurrence rate is unknown., Methods: DRAIN-TIME 2 is a Danish multi-center, randomized controlled trial of postoperative drainage time including all four neurosurgical departments in Denmark. Both incapacitated and mentally competent patients are enrolled. Patients older than 18 years, free of other intracranial pathologies or history of previous brain surgery, are recruited at the time of admission or no later than 6 h after surgery. Each patient is randomized to either 6, 12, or 24 h of passive subdural drainage following single burr-hole evacuation of a CSDH. Mentally competent patients are asked to complete the SF-36 questionnaire. The primary endpoint is CSDH recurrence rate at 90 days. Secondary outcome measures include SF-36 at 90 days, length of hospital stay, drain-related complications, and complications related to immobilization and mortality., Discussion: This multi-center trial will provide evidence regarding the shortest possible drainage time without increasing the recurrence rate. The potential impact of this study is significant as we believe that a shorter drainage period may be associated with fewer drain-related complications, fewer complications related to immobilization, and shorter hospital stays-thus reducing the overall health service burden from this condition. The expected benefits for patients' lives and health costs will increase as the CSDH patient population grows., Trial Registration: ISRCTN Registry ISRCTN15186366 . Registered in December 2020 and updated in October 2021. This protocol was developed in accordance with the SPIRIT Checklist and by use of the structured study protocol template provided by BMC Trials., (© 2022. The Author(s).)

Objective: WHO grade III meningiomas, also known as malignant meningiomas (MMs), are rare, and the heterogenous clinical course in patients with MM is not well described. To characterize the clinical course of patients with MM, granular clinical data were gathered from 51 patients treated at the Department of Neurosurgery and Radiation Oncology, Rigshospitalet, in Copenhagen, Denmark, between 2000 and 2020., Methods: The authors investigated outcome and timing in terms of 1) tumor progression and grade transformation in patients previously diagnosed with WHO grade I or II meningiomas (patients with a secondary MM [sMM]); 2) performance status and complications following surgery; and 3) transition to noncurative treatment and ultimately death. Complications, time between recurrences, and outcome (modified Rankin Scale [mRS] score) for every surgery were analyzed, both malignant and premalignant., Results: Of the 51 patients, 24 (47%) had an sMM. The time to WHO grade III transformation in the sMM group varied widely (median 5.5 years, range 0.5-22 years), but after transformation to a WHO grade III tumor, patients with an sMM and those with a primary MM (pMM) did not differ significantly in overall survival and cumulative risk of progression. Median overall survival for all 51 patients was 4.2 years (95% CI 2.6-7.2 years). Time from the decision to shift from curative to noncurative treatment until death was 3.8 months and the 30-day mortality rate following surgery was 11.8%. From a cumulative number of 151 surgeries, 10 surgeries were followed by improvement on the mRS, mRS score was unchanged in 70, and it worsened in 71. The MM was the underlying cause of death in 30 of 31 patients who had died at the end of follow-up., Conclusions: Together, these findings clearly show a significant morbidity and mortality from the disease itself and from the treatment. These findings warrant studies of prognostic factors for earlier support and adjuvant measures in MM and identify a need for better palliative strategies in this patient group.

Introduction: Malignant peripheral nerve sheath tumor of the vestibulocochlear nerve (VN-MPNST) is exceedingly rare and carries a poor prognosis. Little is known about its underlying genetics and in particular the process of malignant transformation. There is an ongoing debate on whether the transformation is initiated by ionizing radiation. We present here the analysis and comparison of two post-radiation VN-MPNST and one undergoing spontaneous transformation., Methods: Four tumors from three patients (radiation-naïve vestibular schwannoma before (VS) and after (VN-MPNST) malignant transformation in addition to two post-radiation VN-MPNST) were subjected to DNA whole-genome microarray and whole-exome sequencing and tumor-specific mutations were called. Mutational signatures were characterized using MuSiCa., Results: The tumor genomes were characterized predominantly by copy-number aberrations with 36-81% of the genome affected. Even the VS genome was grossly aberrated. The spontaneous malignant transformation was characterized by a near-total whole-genome doubling, disappearance of NF2 mutation and new mutations in three cancer-related genes (GNAQ, FOXO4 and PDGFRB). All tumors had homozygous loss of the tumor suppressor CDKN2A. Neither mutational signature nor copy number profile was associated with ionizing radiation., Conclusion: The VN-MPNST genome in our cases is characterized by large copy-number aberrations and homozygous deletion of CDKN2A. Our study demonstrates a VS with genetic alterations similar to its malignant counterpart, suggesting the existence of premalignant VS. No consistent mutational signature was associated with ionizing radiation., (© 2021. The Author(s).)

Introduction: The extent of meningioma resection is the most fundamental risk factor for recurrence, and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between "gross total removal" and "subtotal removal," while the latter comprises a five-tiered differentiation of the surgeon's impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with 68 Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas., Objective: To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy, and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of 68 Ga DOTATOC PET, we propose "Copenhagen Grading" for meningiomas., Results: Copenhagen Grading was described for six pilot patients with examples of positive and negative findings on histopathology and DOTATOC PET scanning. The grading could be traceably implemented and parameters of grading appeared complementary. Copenhagen Grading is prospectively implemented as a clinical standard at Rigshospitalet, Copenhagen., Conclusion: Copenhagen Grading provided a comprehensive, logical, and reproducible definition of the extent of resection. It offers promise to be the most sensitive and specific imaging modality available for meningiomas. Clinical and cost-efficacy remain to be established during prospective implementation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: Placement of a subdural drain reduces recurrence and death after evacuation of chronic subdural hematoma (CSDH), but little is known about optimal drainage duration. In the present national trial, the authors investigated the effect of drainage duration on recurrence and death., Methods: In a randomized controlled trial involving all neurosurgical departments in Denmark, patients treated with single burr hole evacuation of CSDH were randomly assigned to 24 hours or 48 hours of postoperative passive subdural drainage. Follow-up duration was 90 days, and the primary study outcome was recurrent hematoma requiring reoperation. Secondary outcome was death. In addition, complications and length of hospital stay were recorded and analyzed., Results: Of the 420 included patients, 212 were assigned 24-hour drainage and 208 were assigned 48-hour drainage. The recurrence rate was 14% in the 24-hour group and 13% in the 48-hour group. Four patients died in the 24-hour group, and 8 patients died in the 48-hour group; this difference was not statistically significant. The ORs (95% CIs) for recurrence and mortality (48 hours vs 24 hours) were 0.94 (0.53-1.66) and 2.07 (0.64-7.85), respectively, in the intention-to-treat analysis. The ORs (95% CIs) for recurrence and mortality per 1-hour increase in drainage time were 1.0005 (0.9770-1.0244) and 1.0046 (0.9564-1.0554), respectively, in the as-treated sensitivity analysis that used the observed drainage times instead of the preassigned treatment groups. The rates of surgical and drain-related complications, postoperative infections, and thromboembolic events were not different between groups. The mean ± SD postoperative length of hospital stay was 7.4 ± 4.3 days for patients who received 24-hour drainage versus 8.4 ± 4.9 days for those who received 48-hour drainage (p = 0.14). The mean ± SD postoperative length of stay in the neurosurgical department was significantly shorter for the 24-hour group (2 ± 0.9 days vs 2.8 ± 1.6 days, p < 0.001)., Conclusions: No significant differences in the rates of recurrent hematoma or death during 90-day follow-up were identified between the two groups that randomly received either 24- or 48-hour passive subdural drainage after burr hole evacuation of CSDH.

Meningiomas are the most common intracranial tumor. During pregnancy, explosive growth of a known meningioma occasionally occurs, but the underlying reasons remain unknown. Prolactin has been suggested as a possible key contributor to pregnancy-related meningioma growth. This study sets out to investigate prolactin and prolactin receptor status in 29 patients with pregnancy-related meningiomas in Denmark, from January 1972 to December 2016, as compared to 68 controls aged 20-45 years, also undergoing resection of a meningioma. Furthermore, we investigated potential differences in the progesterone and estrogen receptor statuses, WHO grade, Ki-67 labeling indices, and locations of the resected meningiomas between the cases and controls. Immunohistochemical analyses were performed, and histopathology and intracranial location were assessed with the investigator blinded for the case-control status. None of the samples stained positive for prolactin and very few samples stained positive for prolactin receptors, equally distributed among cases and controls. Estrogen and progesterone receptors generally followed the same distributional pattern between groups, whereas above cut-point Ki-67 labeling indices for both groups were observed. In conclusion, our results did not support the notion of prolactin as a key contributor to pregnancy-related meningioma growth. Rather, the similarities between the cases and controls suggest that meningiomas early in life may comprise a distinct biological entity.

Loss of vision is a feared consequence of idiopathic intracranial hypertension (IIH). Optic nerve sheath fenestration (ONSF) may be an effective surgical approach to protect visual function in medically refractory IIH. In this study, we evaluate the impact of unilateral superomedial transconjunctival ONSF on bilateral visual outcome using a comprehensive follow-up program. A retrospective chart review of IIH patients who underwent unilateral ONSF between January 2016 and March 2021 was conducted. Patients fulfilling the revised Friedman criteria for IIH and who had exclusively received ONSF as a surgical treatment were included. Main outcomes were visual acuity (VA); perimetric mean deviation (PMD); papilledema grade; and optic nerve head elevation (maxONHE) 1 week, 2 weeks, and 1, 3, and 6 months after surgery. VA ( p < 0.05), PMD ( p < 0.05), papilledema grade ( p < 0.01), and maxOHNE ( p < 0.001) were improved after 6 months on both the operated and non-operated eye. Prolonged surgical delay impedes PMD improvement (r = -0.78, p < 0.01), and an increasing opening pressure initiates a greater ganglion cell loss (r = -0.79, p < 0.01). In this small case series, we demonstrate that unilateral superonasal transconjunctival ONSF is a safe procedure with an effect on both eyes. Optic nerve head elevation and PMD are feasible biomarkers for assessing early treatment efficacy after ONSF.

Purpose: PET with somatostatin receptor ligand [ 68 Ga]Ga-DOTA-D-Phe 1 -Tyr 3 -octreotide ([ 68 Ga]Ga-DOTA-TOC) is an established method in radiotherapy planning because of the improved detection and delineation of meningioma tissue. We investigated the diagnostic accuracy of supplementary [ 68 Ga]Ga-DOTA-TOC PET in patients with a 3-month postoperative MRI reporting gross-total resection (GTR)., Experimental Design: Thirty-seven patients with a histologically proven meningioma and GTR on postoperative MRI were prospectively referred to [ 68 Ga]Ga-DOTA-TOC PET. Detection and volume measurements of [ 68 Ga]Ga-DOTA-TOC-avid lesions in relation to the primary tumor site were recorded. Residual tumor in suspicious lesions suggested by [ 68 Ga]Ga-DOTA-TOC PET was verified by (i) tumor recurrence/progression on subsequent MRI scans according to the Response Assessment of Neuro-Oncology criteria, (ii) subsequent histology, and (iii) follow-up [ 68 Ga]Ga-DOTA-TOC PET scan., Results: Twenty-three PET scans demonstrated [ 68 Ga]Ga-DOTA-TOC-avid lesions suspicious of residual meningioma, where 18 could be verified by (i) tumor progression on subsequent MRI scans ( n = 6), (ii) histologic confirmation ( n = 3), and (iii) follow-up [ 68 Ga]Ga-DOTA-TOC PET scans confirming the initial PET findings ( n = 9) after an overall median follow-up time of 17 months (range, 9-35 months). In contrast, disease recurrence was seen in only 2 of 14 patients without [ 68 Ga]Ga-DOTA-TOC-avid lesions ( P < 0.0001). The sensitivity, specificity, and diagnostic accuracy of [ 68 Ga]Ga-DOTA-TOC PET in detecting meningioma residue was 90% [95% confidence interval (CI), 67-99], 92% (95% CI, 62-100), and 90% (95% CI, 74-98; P < 0.0001), respectively., Conclusions: The majority of patients with GTR on 3-month postoperative MRI may have small unrecognized meningioma residues that can be detected using [ 68 Ga]Ga-DOTA-TOC PET., (©2021 American Association for Cancer Research.)

Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas. Methods: We performed an individual patient data meta-analysis, including all published data on meningioma patients treated with SSTR-targeted PRRT. The main outcomes were toxicity, response to treatment, progression-free survival (PFS), and overall survival (OS). We applied the Kaplan-Meier method to estimate survival probabilities and report incidence rates per 100 person-years. We applied Cox proportional hazards models to determine the effect of covariates. Results: We screened 537 papers and identified 6 eligible cohort studies. We included a total of 111 patients who had treatment-refractory meningioma and received SSTR-targeted PRRT. Disease control was achieved in 63% of patients. The 6-mo PFS rates were 94%, 48%, and 0% for World Health Organization grades I, II, and III, respectively. The risk of disease progression decreased by 13% per 1,000-MBq increase in the total applied activity. The 1-y OS rates were 88%, 71%, and 52% for World Health Organization grades I, II, and III, respectively. The risk of death decreased by 17% per 1,000-MBq increase in the total applied activity. The main side effects comprised transient hematotoxicity, such as anemia in 22% of patients, leukopenia in 13%, lymphocytopenia in 24%, and thrombocytopenia in 17%. Conclusion: To our knowledge, this individual patient data meta-analysis represents the most comprehensive analysis of the benefits of and adverse events associated with SSTR-targeted PRRT for treatment-refractory meningioma. The treatment was well tolerated, achieved disease control in most cases, and showed promising results regarding PFS and OS., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The primary aim of chronic subdural haematoma (CSDH) treatment is to relieve pressure to improve neurological symptoms. The secondary aim is to avoid recurrence. The blood supply from the middle meningeal artery (MMA) to the haematoma membranes has recently become a research target, to enhance our understanding of the processes leading to growth and re-growth of a CSDH. Several studies indicate that endovascular embolization of the MMA (eMMA) reduces recurrence rates, but this effect must be confirmed in a randomized controlled setting. Endovascular embolization is an advanced and costly procedure carrying a significant risk of embolism in the elderly. The aim of this study was to assess anatomical and technical aspects of surgical occlusion of the MMA (soMMA) via a single same-procedure burr hole, as an alternative to eMMA., Method: Technical aspects of soMMA were assessed using cadaver head dissection. MMA anatomy was examined by mapping the branching pattern and distribution of MMA in dry skulls, and CSDH position was investigated by analysis of computed tomography (CT) of CSDHs. Finally, we evaluated the possibility of CT-guided navigation to mark the branching point of the anterior MMA division on the skin., Results: We established anatomical landmarks to locate the MMA and found that particularly the anterior MMA branch can be occluded through a single burr hole at the pterion during the same procedure as haematoma decompression. CT of 1454 CSDHs in 1162 patients showed that the CSDH was anteriorly located in 57.5% compared with posteriorly in only 3%. This correlated with the anterior branch of the MMA being dominant in 58% of dry skull samples examined. We further confirmed that the MMA can be localized by neuronavigation as an alternative to using anatomical landmarks and average measurements., Conclusion: A CSDH is mainly anteriorly located and supposedly primarily supplied by the anterior MMA branch. In a simulated setting, soMMA can be performed during the same procedure as haematoma decompression. A few reservations notwithstanding, we find that soMMA may be a viable alternative to eMMA in most CSDH cases and that soMMA should be further evaluated in a clinical setting.

We have previously reported that PET with 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) provides a non-invasive assessment of cell proliferation in vivo in meningiomas. The purpose of this prospective study was to evaluate the potential of 18F-FLT PET in predicting subsequent tumour progression in asymptomatic meningiomas. Forty-three adult patients harbouring 46 MRI-presumed (n = 40) and residual meningiomas from previous surgery (n = 6) underwent a 60-min dynamic 18F-FLT PET scan prior to radiological surveillance. Maximum and mean tumour-to-blood ratios (TBRmax, TBRmean) of tracer radioactivity were calculated. Tumour progression was defined according to the latest published trial end-point criteria for bidimensional (2D) and corresponding yet exploratory volumetric measurements from the Response Assessment of Neuro-Oncology (RANO) workgroup. Independent-sample t-test, Pearson correlation coefficient, Cox regression, and receiver operating characteristic (ROC) curve analyses were used whenever appropriate. The median follow-up time after 18F-FLT PET imaging was 18 months (range 5-33.5 months). A high concordance rate (91%) was found with regard to disease progression using 2D-RANO (n = 11) versus volumetric criteria (n = 10). Using 2D-RANO criteria, 18F-FLT uptake was significantly increased in patients with progressive disease, compared to patients with stable disease (TBRmax, 5.5 ± 1.3 versus 3.6 ± 1.1, P < 0.0001; TBRmean, 3.5 ± 0.8 versus 2.4 ± 0.7, P < 0.0001). ROC analysis yielded optimal thresholds of 4.4 for TBRmax [sensitivity 82%, specificity 77%, accuracy 78%, and area under curve (AUC) 0.871; P < 0.0001] and 2.8 for TBRmean (sensitivity 82%, specificity 77%, accuracy 78%, AUC 0.848; P = 0.001) for early differentiation of patients with progressive disease from patients with stable disease. Upon excluding patients with residual meningioma or patients with stable disease with less than 12 months follow-up, the thresholds remained unchanged with similar diagnostic accuracies. Moreover, positive correlations were found between absolute and relative tumour growth rates and 18F-FLT uptake (r < 0.513, P < 0.015) that remained similar when excluding patients with residual meningioma or patients with stable disease and shorter follow-up period. Diagnostic accuracies were slightly inferior at 76% when assessing disease progression using volumetric criteria, while the thresholds remained unchanged. Multivariate analysis revealed that TBRmax was the only independent predictor of tumour progression (P < 0.046), while age, gender, baseline tumour size, tumour location, peritumoural oedema, and residual meningioma had no influence. The study reveals that 18F-FLT PET is a promising surrogate imaging biomarker for predicting subsequent tumour progression in treatment-naïve and asymptomatic residual meningiomas., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: DOTA-D-Phe 1 -Tyr 3 -octreotide with gallium-68 ([ 68 Ga]Ga-DOTA-TOC) is one of the PET tracers that forms the basis for peptide receptor radionuclide therapy based on somatostatin receptor subtype 2 (SSTR2) expression in meningiomas. Yet, the quantitative relationship between [ 68 Ga]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [ 68 Ga]Ga-DOTA-TOC PET metric(s) as imaging surrogate(s) of the receptor binding in meningiomas by correlating the PET results with SSTR2 expression from surgical specimens. We additionally investigated possible influences of secondary biological factors such as vascularization, inflammation and proliferation., Methods: Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [ 68 Ga]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUV max , SUV mean ) with and without normalization to reference regions, and quantitative measurements derived from kinetic modelling using a reversible two-tissue compartment model with the fractional blood volume (V B ). Expressions of SSTR2 and proliferation (Ki-67, phosphohistone-H3, proliferating cell nuclear antigen) were determined by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR), while biomarkers of vascularization (vascular endothelial growth factor A (VEGFA), endothelial marker CD34) and inflammation (cytokine interleukin-18, microglia/macrophage-specific marker CD68) by qPCR., Results: Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [ 68 Ga]Ga-DOTA-TOC PET metrics showed significant associations with SSTR2 protein, while all PET metrics were positively correlated with SSTR2 mRNA with the best results for mean tumour-to-blood ratio (TBR mean ) (r = 0.757, P = 0.001) and SUV mean (r = 0.714, P = 0.003). Significant positive correlations were also found between [ 68 Ga]Ga-DOTA-TOC PET metrics, and VEGFA and V B . SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539, P = 0.038). Neither [ 68 Ga]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation., Conclusion: [ 68 Ga]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBR mean being the best PET metric for assessing SSTR2.

Strengths and limitations of subdural versus subperiosteal drain location after burr hole evacuation of chronic subdural hematoma (CSDH) are currently debated. The safety of subdural placement of a drain has been questioned in a recent study by Soleman et al. from 2019, showing a misplacement rate of 17%, and these results have been further highlighted by the same authors, with a slightly lower misplacement rate of 15.8%, in the recent paper "When the drain hits the brain." The safety of subdural drainage for CSDH depends to a high degree on type of drain and surgical technique. In this technical note, we describe drain type and technique for drain placement which is standardized in Denmark.

Introduction: Chronic subdural hematomas (CSDH) show different radiological characteristics on CT scans at the time of diagnosis. The reason for this is largely unknown. We hypothesize that the imaging characteristics reflect a time-linked pathophysiological evolution. We therefore conducted a retrospective study to examine a possible relation between the hematoma age and the radiological subtype of a CSDH., Methods: Demographic data on patients with CSDH were retrieved from a Danish national cohort from 2010 to 2012. CT scans obtained on admission to a neurosurgical department were categorized as homogenous, separated, mixed, or membranous hematoma subtypes. The time from a known date of head injury to time of diagnostic CT was defined as hematoma age. The hematoma age was correlated to radiological hematoma subtype at the time of diagnosis by analysis of variance testing., Results: In total, 543 patients were analyzed for hematoma age and classified in the following hematoma subtypes: 231 homogenous, 44 separated, 119 mixed, and 149 membranous. Patients with homogenous, separated, mixed, and membranous hematoma subtypes had a median interval of 37, 36, 40, and 60 days from head injury to diagnostic CT. We found that membranous hematoma is significantly older than other subtypes. Comparison between the other radiological subtypes showed no statistical hematoma age difference. The distribution of radiological subtypes in 590 patients without a known head injury was similar to that of patients with a known head injury. Additionally, we found that hematoma age was significantly younger for patients on antiplatelet medication., Conclusion: In this large national cohort, patients with membranous CSDH had a significantly longer interval between head injury and diagnosis compared to other radiological subtypes. This indicates that the radiological appearance of CSDH evolves over time, causing an alteration from different early radiological subtypes to a radiological subtype with membranes., Clinical Trial Registration Number: The study was approved by the Danish Data Protection Agency (journal no.30-1145).

Purpose: Positron emission tomography (PET) with 3'-deoxy-3'-[ 18 F]fluorothymidine ([ 18 F]FLT) provides a noninvasive assessment of tumour proliferation in vivo and could be a valuable imaging modality for assessing malignancy in meningiomas. We investigated a range of static and dynamic [ 18 F]FLT metrics by correlating the findings with cellular biomarkers of proliferation and angiogenesis., Methods: Seventeen prospectively recruited adult patients with intracranial meningiomas underwent a 60-min dynamic [ 18 F]FLT PET following surgery. Maximum and mean standardized uptake values (SUV max , SUV mean ) with and without normalization to healthy brain tissue and blood radioactivity obtained from 40 to 60 min summed dynamic images (PET 40-60 ) and ~ 60-min blood samples were calculated. Kinetic modelling using a two-tissue reversible compartmental model with a fractioned blood volume (V B ) was performed to determine the total distribution volume (V T ). Expressions of proliferation and angiogenesis with key parameters including Ki-67 index, phosphohistone-H3 (phh3), MKI67, thymidine kinase 1 (TK1), proliferating cell nuclear antigen (PCNA), Kirsten RAt Sarcoma viral oncogene homolog (KRAS), TIMP metallopeptidase inhibitor 3 (TIMP3), and vascular endothelial growth factor A (VEGFA) were determined by immunohistochemistry and/or quantitative polymerase chain reaction., Results: Immunohistochemistry revealed 13 World Health Organization (WHO) grade I and four WHO grade II meningiomas. SUV max and SUV mean normalized to blood radioactivity from PET 40-60 and blood sampling, and V T were able to significantly differentiate between WHO grades with the best results for maximum and mean tumour-to-whole-blood ratios (sensitivity 100%, specificity 94-95%, accuracy 99%; P = 0.003). Static [ 18 F]FLT metrics were significantly correlated with proliferative biomarkers, especially Ki-67 index, phh3, and TK1, while no correlations were found with VEGFA or V B . Using Ki-67 index with a threshold > 4%, the majority of [ 18 F]FLT metrics showed a high ability to identify aggressive meningiomas with SUV mean demonstrating the best performance (sensitivity 80%, specificity 81%, accuracy 80%; P = 0.024)., Conclusion: [ 18 F]FLT PET could be a useful imaging modality for assessing cellular proliferation in meningiomas.