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The cerebrospinal fluid (CSF) is a key matrix for discovery of biomarkers relevant for prognosis and the development of therapeutic targets in pediatric central nervous system malignancies. However, the wide range of protein concentrations and age-related differences in children makes such discoveries challenging. In addition, pediatric CSF samples are often sparse and first prioritized for clinical purposes. The present work focused on optimizing each step of the proteome analysis workflow to extract the most detailed proteome information possible from the limited CSF resources available for research purposes. The strategy included applying sequential ultracentrifugation to enrich for extracellular vesicles (EV) in addition to analysis of a small volume of raw CSF, which allowed quantification of 1351 proteins (+55% relative to raw CSF) from 400 μL CSF. When including a spectral library, a total of 2103 proteins (+240%) could be quantified. The workflow was optimized for CSF input volume, tryptic digestion method, gradient length, mass spectrometry data acquisition method and database search strategy to quantify as many proteins a possible. The fully optimized workflow included protein aggregation capture (PAC) digestion, paired with data-independent acquisition (DIA, 21 min gradient) and allowed 2989 unique proteins to be quantified from only 400 μL CSF, which is a 340% increase in proteins compared to analysis of a tryptic digest of raw CSF.

Background: Treatment of patients with low-grade and high-grade gliomas is highly variable due to the large difference in survival expectancy. New non-invasive tools are needed for risk stratification prior to treatment. The urokinase plasminogen activator receptor (uPAR) is expressed in several cancers, associated with poor prognosis and may be non-invasively imaged using uPAR-PET. We aimed to investigate the uptake of the uPAR-PET tracer [ 68 Ga]Ga-NOTA-AE105 in primary gliomas and establish its prognostic value regarding overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the proportion of uPAR-PET positive tumors to estimate the potential number of candidates for future uPAR-PRRT., Methods: In a prospective phase II clinical trial, 24 patients suspected of primary glioma underwent a dynamic 60-min PET/MRI following the administration of approximately 200 MBq (range: 83-222 MBq) [ 68 Ga]Ga-NOTA-AE105. Lesions were considered uPAR positive if the tumor-to-background ratio, calculated as the ratio of TumorSUVmax-to-Normal-BrainSUVmean tumor-SUVmax-to-background-SUVmean, was ≥ 2.0. The patients were followed over time to assess OS and PFS and stratified into high and low uPAR expression groups based on TumorSUVmax., Results: Of the 24 patients, 16 (67%) were diagnosed with WHO grade 4 gliomas, 6 (25%) with grade 3, and 2 (8%) with grade 2. Two-thirds of all patients (67%) presented with uPAR positive lesions and 94% grade 4 gliomas. At median follow up of 18.8 (2.1-45.6) months, 19 patients had disease progression and 14 had died. uPAR expression dichotomized into high and low, revealed significant worse prognosis for the high uPAR group for OS and PFS with HR of 14.3 (95% CI, 1.8-112.3; P = 0.011), and HR of 26.5 (95% CI, 3.3-214.0; P = 0.0021), respectively. uPAR expression as a continuous variable was associated with worse prognosis for OS and PFS with HR of 2.7 (95% CI, 1.5-4.8; P = 0.0012), and HR of 2.5 (95% CI, 1.5-4.2; P = 0.00073), respectively., Conclusions: The majority of glioma patients and almost all with grade 4 gliomas displayed uPAR positive lesions underlining the feasibility of 68 Ga-NOTA-AE105 PET/MRI in gliomas. High uPAR expression is significantly correlated with worse survival outcomes for patients. Additionally, the high proportion of uPAR positive gliomas underscores the potential of uPAR-targeted radionuclide therapy in these patients., Trail Registration: EudraCT No: 2016-002417-21; the Scientific Ethics Committee: H-16,035,303; the Danish Data Protection Agency: 2012-58-0004; clinical trials registry: NCT02945826, 26Oct2016, URL: https://classic., Clinicaltrials: gov/ct2/show/NCT02945826 ., (© 2024. The Author(s).)

Hyperlactatemia is common during tumor craniotomy, but the underlying pathophysiology is unclear. This study measured simultaneous arterial and jugular-bulb lactate concentrations in patients undergoing brain tumor craniotomy to investigate the hypothesis that hyperlactatemia was associated with a net cerebrovascular lactate input. In 20 patients, arterial and jugular-bulb blood was collected hourly from the start of surgery to 6 h postoperatively for measurement of lactate, glucose, and oxygen concentration. For each marker, data were analyzed using a linear mixed-effects model with jugular-bulb concentration as dependent variable, arterial concentration as fixed effect, and patient as random effect. Furthermore, we generated regression lines between arterial and jugular-bulb concentrations. The slope of the regression line between arterial and jugular-bulb lactate was 0.95 (95% CI 0.93-0.97, R 2  = 0.98), indicating that increasing arterial lactate levels were associated with an increasingly positive net cerebrovascular balance (net input). The line crossed the identity line at 2.86 (95% CI 0.57-5.16) mmol/L, indicating that lower levels of lactate were associated with a negative net cerebrovascular balance (net output). This suggests a switch from net lactate output during normolactatemia towards net input during hyperlactatemia. Hyperlactatemia in tumor-craniotomy patients probably does not originate from the brain., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available. Immunotherapies have shown limited responses in unselected patients, and there is an urgent need to identify mechanisms of treatment resistance to design novel therapy strategies., Methods: Here we investigated the phenotypic and transcriptional dynamics at single-cell resolution during nivolumab immune checkpoint treatment of glioblastoma patients., Results: We present the integrative paired single-cell RNA-seq analysis of 76 tumor samples from patients in a clinical trial of the PD-1 inhibitor nivolumab and untreated patients. We identify a distinct aggressive phenotypic signature in both tumor cells and the tumor microenvironment in response to nivolumab. Moreover, nivolumab-treatment was associated with an increased transition to mesenchymal stem-like tumor cells, and an increase in TAMs and exhausted and proliferative T cells. We verify and extend our findings in large external glioblastoma dataset (n = 298), develop a latent immune signature and find 18% of primary glioblastoma samples to be latent immune, associated with mesenchymal tumor cell state and TME immune response. Finally, we show that latent immune glioblastoma patients are associated with shorter overall survival following immune checkpoint treatment (P = .0041)., Conclusions: We find a resistance mechanism signature in one fifth of glioblastoma patients associated with a tumor-cell transition to a more aggressive mesenchymal-like state, increase in TAMs and proliferative and exhausted T cells in response to immunotherapy. These patients may instead benefit from neuro-oncology therapies targeting mesenchymal tumor cells., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Several prognostic factors are known to influence survival for patients treated with IDH-wildtype glioblastoma, but unknown factors may remain. We aimed to investigate the prognostic implications of early postoperative MRI findings. A total of 187 glioblastoma patients treated with standard therapy were consecutively included. Patients either underwent a biopsy or surgery followed by an early postoperative MRI. Progression-free survival (PFS) and overall survival (OS) were analysed for known prognostic factors and MRI-derived candidate factors: resection status as defined by the response assessment in neuro-oncology (RANO)-working group (no contrast-enhancing residual tumour, non-measurable contrast-enhancing residual tumour, or measurable contrast-enhancing residual tumour) with biopsy as reference, contrast enhancement patterns (no enhancement, thin linear, thick linear, diffuse, nodular), and the presence of distant tumours. In the multivariate analysis, patients with no contrast-enhancing residual tumour or non-measurable contrast-enhancing residual tumour on the early postoperative MRI displayed a significantly improved progression-free survival compared with patients receiving only a biopsy. Only patients with non-measurable contrast-enhancing residual tumour showed improved overall survival in the multivariate analysis. Contrast enhancement patterns were not associated with survival. The presence of distant tumours was significantly associated with both poor progression-free survival and overall survival and should be considered incorporated into prognostic models., (© 2024. The Author(s).)

Background: This Danish cohort study aims to (1) compare patterns of care (POC) and survival of patients with multifocal glioblastoma (mGBM) to those with unifocal glioblastoma (uGBM), and (2) explore the association of patient-related factors with treatment assignment and prognosis, respectively, in the subgroup of mGBM patients., Methods: Data on all adults with newly diagnosed, pathology-confirmed GBM between 2015 and 2019 were extracted from the Danish Neuro-Oncology Registry. To compare POC and survival of mGBM to uGBM, we applied multivariable logistic and Cox regression analysis, respectively. To analyze the association of patient-related factors with treatment assignment and prognosis, we established multivariable logistic and Cox regression models, respectively., Results: In this cohort of 1343 patients, 231 had mGBM. Of those, 42% underwent tumor resection and 41% were assigned to long-course chemoradiotherapy. Compared to uGBM, mGBM patients less often underwent a partial (odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2-0.6), near-total (OR 0.1, 95% CI 0.07-0.2), and complete resection (OR 0.1, 95% CI 0.07-0.2) versus biopsy. mGBM patients were furthermore less often assigned to long-course chemoradiotherapy (OR 0.6, 95% CI 0.4-0.97). Median overall survival was 7.0 (95% CI 5.7-8.3) months for mGBM patients, and multifocality was an independent poor prognostic factor for survival (hazard ratio 1.3, 95% CI 1.1-1.5). In mGBM patients, initial performance, O[6]-methylguanine-DNA methyltransferase promotor methylation status, and extent of resection were significantly associated with survival., Conclusions: Patients with mGBM were treated with an overall less intensive approach. Multifocality was a poor prognostic factor for survival with a moderate effect. Prognostic factors for patients with mGBM were identified., Competing Interests: CAH reports personal fees from Bristol Myers Squibb and GlaxoSmithKline, outside the submitted work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The reliability of near-infrared spectroscopy (NIRS) for measuring cerebral oxygenation (ScO 2 ) is controversial due to the possible contamination from extracranial tissues. We compared ScO 2 measured with the NIRS optode on the forehead, the skull and the dura mater in anaesthetised patients undergoing craniotomy. We hypothesised that ScO 2 measured directly on the skull and the dura mater would differ from ScO 2 measured on the skin., Methods: This prospective observational study included 17 adult patients scheduled for elective craniotomy. After induction of general anaesthesia, ScO 2 was measured on the forehead skin, as well as on the skull and on the dura mater in the surgical field. The primary comparison was the difference in ScO 2 measured on the dura mater and on ScO 2 measured on the skin; secondary comparisons were the differences in ScO 2 on the skull and ScO 2 on the skin and the dura mater, respectively. Data were described with median (5%-95% range) and analysed with the Wilcoxon signed-rank test., Results: ScO 2 values on the dura mater were obtained in 11 patients, and median ScO 2 (48%, 29%-95%) did not differ significantly from ScO 2 on the skin (73%, 49%-92%; p = .052), median difference -25% (-35.6% to -1.2%). ScO 2 on the skull (N = 16) was lower than that on the skin (63% [43%-79%] vs. 75% [61%-94%]; p = .0002), median difference -10% (-20.8 to -3.0)., Conclusion: In adults undergoing craniotomy, NIRS-based ScO 2 measured on the dura mater did not reach statistically significantly lower values than ScO 2 measured on the skin, whereas values on the skull were lower than on the skin, indicating a contribution from scalp tissue to the signal., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Objective: Pediatric neuro-oncological surgery is often associated with significant risk; however, comprehensive data on surgical morbidity remain limited. The purpose of this study was therefore to provide national population-based data on both the incidence and characteristics of poor postoperative outcomes following pediatric intracranial neuro-oncological surgery. Additionally, the authors aimed to evaluate key risk factors for poor postoperative outcomes including overall morbidity, significant morbidity, and the most frequent types of morbidity., Methods: The authors conducted a registry-based, nationwide, retrospective study including all children receiving surgical treatment for a CNS tumor over a 10-year period. Patients were identified using the Danish Childhood Cancer Registry, and 30-day morbidity was assessed through manual review of electronic health records. Significant morbidity was defined as complications in need of treatment under general anesthesia, ICU admission, or persistent neurological deficits at 30 days following surgery or death. Risk factors including sex, age, tumor location, tumor malignancy grade, and preoperative hydrocephalus were investigated using multivariate logistic regression analysis., Results: A total of 349 children undergoing 473 tumor procedures were included, with an overall morbidity rate of 66.0% and a significant morbidity rate of 34.2%. The most frequent complications included neurological deficits (41.4%) and CSF-related morbidity consisting of CSF leaks, pseudomeningoceles, and postoperative hydrocephalus. Highly significant associations between infratentorial tumor location and both significant morbidity (OR 1.26, 95% CI 1.11-1.43; p < 0.001) and neurological deficits (OR 1.38, 95% CI 1.21-1.57; p < 0.001) were identified. In addition, younger age was revealed as a major risk factor of both postoperative CSF leakage and CSF-related morbidity in general., Conclusions: In this large, population-based cohort, the authors show that postoperative morbidity is frequent, occurring in about two-thirds of all patients, largely driven by neurological deficits and CSF-related complications. In addition, infratentorial tumor location and younger age emerged as key risk factors for poor postoperative outcomes.

Purpose: To assess the performance of the risk-predicting Milan Complexity Scale (MCS) on postoperative morbidity in pediatric neuro-oncological surgery., Methods: A retrospective dual-center review of children undergoing primary brain tumor resection in Denmark over a 10-year period. MCS scoring was performed based on preoperative imaging, blinded to individual outcomes. Surgical morbidity was registered according to existing complication scales and dichotomized as significant or nonsignificant morbidity. The MCS was evaluated using logistic regression modeling., Results: 208 children (50% female, mean age 7.9 y, and SD 5.2) were included. Of the original "Big Five" predictors included in the MCS, only posterior fossa (OR: 2.31, 95% CI: 1.25-4.34, p-value = 0.008) and eloquent area (OR: 3.32, 95% CI: 1.50-7.68, p-value = 0.004) locations were significantly associated with increased risk of significant morbidity in our pediatric cohort. The absolute MCS score correctly classified 63.0% of cases. Its accuracy increased to 69.2% when mutually adjusting for each of the "Big Five" predictors with corresponding positive and negative predictive values of 66.2% and 71.0%, using a predicted probability cutoff of 0.5., Conclusion: The MCS is predictive of postoperative morbidity also in pediatric neuro-oncological surgery, although only two of its original five variables were significantly associated with poor outcome in children. The clinical value of the MCS is likely limited for the experienced pediatric neurosurgeon. Future clinically impactful risk-prediction tools should include a larger number of relevant variables and be tailored to the pediatric population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Despite considerable research effort, causes of brain cancer are largely unknown. Male brain cancer predominance and reduced brain cancer risk with increasing parity among women, however, support a favourable role of pregnancy. We set out to determine whether fetal-origin microchimerism, namely the presence and long-term persistence of fetal cells, likely obtained via natural trafficking across the placenta during pregnancy, associates with reduced risk of brain cancer in women., Methods: Using a case-cohort design, we sampled 505 middle-aged women randomly at baseline in the Diet, Cancer and Health cohort (controls), and 73 women with incident brain cancer diagnosed during follow-up in the Danish Cancer Registry (cases). Male origin microchimerism was determined by presence of Y chromosome sequences in female blood samples. Data were analysed using weighted proportional Hazards regression, yielding Hazard Ratios with 95% confidence intervals., Results: Compared with male origin microchimerism negative women, positive women had half the risk of developing brain cancer (Hazard Ratio = 0.50 [0.33-0.77]). Sensitivity analyses support that our findings are unlikely due to bias or chance., Conclusion: Here, for the first time, we demonstrate half the risk of brain cancer in male origin microchimerism positive compared with negative women. Our findings resemble those of previous studies of male origin microchimerism and other female cancers., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Significance: This third biennial intraoperative molecular imaging (IMI) conference shows how optical contrast agents have been applied to develop clinically significant endpoints that improve precision cancer surgery., Aim: National and international experts on IMI presented ongoing clinical trials in cancer surgery and preclinical work. Previously known dyes (with broader applications), new dyes, novel nonfluorescence-based imaging techniques, pediatric dyes, and normal tissue dyes were discussed., Approach: Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center's third clinical trials update on IMI were selected to discuss their clinical trials and endpoints., Results: Dyes that are FDA-approved or currently under clinical investigation in phase 1, 2, and 3 trials were discussed. Sections on how to move benchwork research to the bedside were also included. There was also a dedicated section for pediatric dyes and nonfluorescence-based dyes that have been newly developed., Conclusions: IMI is a valuable adjunct in precision cancer surgery and has broad applications in multiple subspecialties. It has been reliably used to alter the surgical course of patients and in clinical decision making. There remain gaps in the utilization of IMI in certain subspecialties and potential for developing newer and improved dyes and imaging techniques., (© 2023 The Authors.)

Background: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking., Methods: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives., Results: Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e-4) and all other genes (P = 5e-17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity-raising the question of the role of other highly constrained gene alterations detected., Conclusions: Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

MR-guided laser interstitial thermal therapy (LITT) is feasible and safe in the awake patient. Awake LITT may be performed with analgesics for head fixation in a head-ring, no sedation during laser ablation, and with continuous neurological testing in patients with brain tumors and epilepsy. In the LITT treatment of lesions near eloquent areas and subcortical fiber tracts, neurological function can potentially be preserved by monitoring the patient during laser ablation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

An early postoperative MRI is recommended following Glioblastoma surgery. This retrospective, observational study aimed to investigate the timing of an early postoperative MRI among 311 patients. The patterns of the contrast enhancement (thin linear, thick linear, nodular, and diffuse) and time from surgery to the early postoperative MRI were recorded. The primary endpoint was the frequencies of the different contrast enhancements within and beyond the 48-h from surgery. The time dependence of the resection status and the clinical parameters were analysed as well. The frequency of the thin linear contrast enhancements significantly increased from 99/183 (50.8%) within 48-h post-surgery to 56/81 (69.1%) beyond 48-h post-surgery. Similarly, MRI scans with no contrast enhancements significantly declined from 41/183 (22.4%) within 48-h post-surgery to 7/81 (8.6%) beyond 48-h post-surgery. No significant differences were found for the other types of contrast enhancements and the results were robust in relation to the choice of categorisation of the postoperative periods. Both the resection status and the clinical parameters were not statistically different in patients with an MRI performed before and after 48 h. The findings suggest that surgically induced contrast enhancements are less frequent when an early postoperative MRI is performed earlier than 48-h, supporting the recommendation of a 48-h window for an early postoperative MRI.

Purpose: To investigate the risk of central nervous system (CNS) infections in children undergoing neurosurgery for brain tumors., Methods: Single-center retrospective cohort study including all children with brain tumors undergoing neurosurgical treatment over an 11-year period., Results: A total of 274 patients undergoing 733 neurosurgical procedures were included. Overall, 12.8% of patients were diagnosed with a CNS infection during their course of treatment. CNS infections were more frequent among children treated with CSF diversion (p < 0.001) and independently associated with low age (OR/y 0.9 (CI 95% 0.769-0.941), intraventricular (OR 2.8, CI 95% 1.2-6.5), and high-grade tumors (OR 2.7, CI 95% 1.1-6.5). The majority of CNS infections occurred within 30 days of surgery, resulting in a postoperative CNS infection rate of 5.3%. Postoperative CNS infections were significantly more frequent following adjunct EVD placement during tumor resection compared to a stand-alone craniotomy (30.4% vs. 1.5%, RR 20.6, CI 95% 5.7-72.2)., Conclusion: CNS infections affect at least 12% of children with brain tumors and are associated with age, tumor location, and grade. Adding EVD to tumor surgery increases the risk of postoperative CNS infection, and reconsidering routine adjunct EVD placement is therefore advocated., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Oxygen supply to the brain is of special importance during intracranial surgery because it may be compromised by intracranial pathology. A high arterial blood pressure (mean arterial pressure above 80 mmHg) and a high arterial oxygen tension (PaO 2 above 12 kPa) is therefore often targeted in these patients, when for example intracranial pressure is increased or when a mass effect on brain tissue from a tumour is present, and it is pursued by administering vasopressors such as phenylephrine and by increasing inspiratory oxygen fraction (FiO 2 ). However, whether these interventions increase cerebral oxygenation remains uncertain. We aimed to investigate the effect of hyperoxia and phenylephrine on brain tissue oxygen tension (PbtO 2 ) in patients undergoing craniotomy., Methods: In this experimental study, we included 17 adult patients scheduled for elective craniotomy. After securing a stable baseline of the oxygen probe, PbtO 2 was measured in white matter peripherally in the surgical field during general anaesthesia. Primary comparisons were PbtO 2 before versus after an increase in FiO 2 from 0.30 to 0.80 as well as before versus after a bolus dose of phenylephrine (0.1-0.2 mg depending on patient haemodynamics). Data were analysed with the Wilcoxon signed rank test., Results: We obtained complete data sets in 11 patients undergoing the FiO 2 increase and six patients receiving the phenylephrine bolus. PbtO 2 was 22 (median; 5%-95% range, 4.6-54) mmHg during 30% oxygen, 68 (8.4-99) mmHg during 80% oxygen (p = .004 compared to 30% oxygen), 21 (4.5-81) mmHg before phenylephrine, and 19 (4.2-56) mmHg after phenylephrine (p = .56 compared to before phenylephrine)., Conclusion: In patients undergoing craniotomy under general anaesthesia, brain tissue oxygen tension increased with a high inspiratory oxygen fraction but remained unchanged after a bolus dose of phenylephrine., (© 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Purpose: Both amino acid positron emission tomography (PET) and magnetic resonance imaging (MRI) blood volume (BV) measurements are used in suspected recurrent high-grade gliomas. We compared the separate and combined diagnostic yield of simultaneously acquired dynamic contrast-enhanced (DCE) perfusion MRI and O-(2-[ 18 F]-fluoroethyl)-L-tyrosine ([ 18 F]FET) PET in patients with anaplastic astrocytoma and glioblastoma following standard therapy., Methods: A total of 76 lesions in 60 hybrid [ 18 F]FET PET/MRI scans with DCE MRI from patients with suspected recurrence of anaplastic astrocytoma and glioblastoma were included retrospectively. BV was measured from DCE MRI employing a 2-compartment exchange model (2CXM). Diagnostic performances of maximal tumour-to-background [ 18 F]FET uptake (TBR max ), maximal BV (BV max ) and normalised BV max (nBV max ) were determined by ROC analysis using 6-month histopathological (n = 28) or clinical/radiographical follow-up (n = 48) as reference. Sensitivity and specificity at optimal cut-offs were determined separately for enhancing and non-enhancing lesions., Results: In progressive lesions, all BV and [ 18 F]FET metrics were higher than in non-progressive lesions. ROC analyses showed higher overall ROC AUCs for TBR max than both BV max and nBV max in both lesion-wise (all lesions, p = 0.04) and in patient-wise analysis (p < 0.01). Combining TBR max with BV metrics did not increase ROC AUC. Lesion-wise positive fraction/sensitivity/specificity at optimal cut-offs were 55%/91%/84% for TBR max , 45%/77%/84% for BV max and 59%/84%/72% for nBV max . Combining TBR max and best-performing BV cut-offs yielded lesion-wise sensitivity/specificity of 75/97%. The fraction of progressive lesions was 11% in concordant negative lesions, 33% in lesions only BV positive, 64% in lesions only [ 18 F]FET positive and 97% in concordant positive lesions., Conclusion: The overall diagnostic accuracy of DCE BV imaging is good, but lower than that of [ 18 F]FET PET. Adding DCE BV imaging did not improve the overall diagnostic accuracy of [ 18 F]FET PET, but may improve specificity and allow better lesion-wise risk stratification than [ 18 F]FET PET alone., (© 2022. The Author(s).)

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.)

Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene., (© 2022. The Author(s).)

Hyperlactatemia occurs frequently after brain tumor surgery. Existing studies are scarce and predominantly retrospective, reporting inconsistent associations to new neurological deficits and prolonged hospital stay. Here we describe a protocol for a prospective observational study of hyperlactatemia during and after elective tumor craniotomy and the association with postoperative outcome, as well as selected pathophysiological aspects, and possible risk factors. We will include 450 brain tumor patients scheduled for elective craniotomy. Arterial blood samples for lactate and glucose measurement will be withdrawn hourly during surgery and until six hours postoperatively. To further explore the association of hyperlactatemia with perioperative insulin resistance, additional blood sampling measuring markers of insulin resistance will be done in 100 patients. Furthermore, in a subgroup of 20 patients, blood from a jugular bulb catheter will be drawn simultaneously with blood from the radial artery to measure the arterial to jugular venous concentration difference of lactate, in order to study the direction of cerebrovascular lactate flux. Functional clinical outcome will be determined by the modified Rankin Scale, length of stay and mortality at 30 days, 6 months, 1 year and 5 years. Clinical outcome will be compared between patients with and without hyperlactatemia. Multivariate logistic regression will be used to identify risk factors for hyperlactatemia. A statistical analysis plan will be publicized to support transparency and reproducibility. Results will be published in a peer-reviewed journal and presented at international conferences., Competing Interests: There are no competing interests related to any patents, patent applications, or products in development or for market. The authors have declared that no competing interests exist.

Germline pathogenic variants in CDKN2A predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, whereas CDKN2B variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both CDKN2A and CDKN2B associated with a cancer predisposition syndrome (CPS) that constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a de novo germline 9p21 microdeletion involving the CDKN2A / CDKN2B genes , who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with CDKN2A / CDKN2B deletion., (© 2022 Jensen et al.; Published by Cold Spring Harbor Laboratory Press.)

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.)

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.

Treatment of glioblastoma (GBM) remains a challenging task, with limited treatment options, none offering a cure. Immune therapy has proven effective across different cancers with remarkable response rates. Tumor mutational burden (TMB) is a marker of response, but technical and methodological differences in TMB estimates have made a proper assessment and comparison challenging. Here, we analyzed a prospective collection of paired samples from 35 patients with newly diagnosed GBM, all of whom were wild-type (WT) for isocitrate dehydrogenase, before and after treatment with radiotherapy and temozolomide. Seven patients (20%) had O6-methylguanine-DNA methyltransferase-methylated tumors. Six patients (17%) had two relapse surgeries, and tissue from all three surgeries was collected. We found that accurate evaluation of TMB was confounded by high variability in the cancer cell fraction of relapse samples. To ameliorate this, we developed a model to adjust for tumor purity based on the relative density distribution of variant allele frequencies in each primary-relapse pair. Additionally, we examined the mutation spectra of shared and private mutations. After tumor purity adjustment, we found TMB comparison reliable in tumors with tumor purity between 15% and 40%, resulting in 27/35 patients (77.1%). TMB remained unchanged from 0.65 mutations per megabase (Mb) to 0.67/Mb before and after treatment, respectively. Examination of the mutation spectra revealed a dominance of C > T transitions at CpG sites in both shared and relapse-private mutations, consistent with cytosine deamination and the clock-like mutational signature 1. We present and apply a cellularity correction approach that enables more accurate assessment of TMB in paired tumor samples. We did not find a significant increase in TMB after correcting for cancer cell fraction. Our study raises significant concerns when determining TMB. Although a small sample size, corrected TMB can have a clinical significance when stratifying patients to experimental treatment, for example, immune checkpoint therapy., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Meningiomas are benign lesion although anot insignificant number experiences recurrences despite Simpson grade 1 removal. FG001 is a compound with a fluorophore (ICG) that binds to a urokinase-type plasminogen activator receptor (uPAR) and is currently investigated at our institution in a first-in-human trial. The patient presented with a plausible malignant glioma but proved to be a grade 1 meningioma. FG001 could delineated the tumor not only on the surface but supplementary in the cavity to remove safely the dural attachment. We present FG001 as a new promising tool for improved surgical radicality beyond the intended indication, provided that a prospective validation in a consecutive meningioma cohort demonstrates similar results., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [18F]FET PET to MRI in children with CNS tumors., Methods: A total of 169 [18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse., Results: Adding [18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4%-13%] of all scans (n = 151) and in 33% [CI: 17%-53%] of scans deemed clinically indicated due to difficult decision making on MRI alone (n = 30). Using pathology or follow-up as reference standard, the addition of [18F]FET PET increased specificity (1.00 [0.82-1.00] vs 0.48 [0.30-0.70], P = .0001) and accuracy (0.91 [CI: 0.87-0.96] vs 0.81 [CI: 0.75-0.89], P = .04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI: 0.91-1.00] vs 0.90 [CI: 0.82-0.92], P < .001). Further, in a subset of patients (n = 15) [18F]FET uptake correlated positively with genomic proliferation index., Conclusions: The addition of [18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

For the radiological assessment of resection of high-grade gliomas, a 72-h diagnostic window is recommended to limit surgically induced contrast enhancements. However, such enhancements may occur earlier than 72 h post-surgery. This systematic review aimed to assess the evidence on the timing of the postsurgical MRI. PubMed, Embase, Web of Science and Cochrane were searched following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only original research articles describing surgically induced contrast enhancements on MRI after resection for high-grade gliomas were included and analysed. The frequency of different contrast enhancement patterns on intraoperative MRI (iMRI) and early postoperative MRI (epMRI) was recorded. The search resulted in 1443 studies after removing duplicates, and a total of 12 studies were chosen for final review. Surgically induced contrast enhancements were reported at all time points after surgery, including on iMRI, but their type and frequency vary. Thin linear contrast enhancements were commonly found to be surgically induced and were less frequently recorded on postoperative days 1 and 2. This suggests that the optimal time to scan may be at or before this time. However, the evidence is limited, and higher-quality studies using larger and consecutively sampled populations are needed.

MR-guided laser interstitial thermal therapy (LITT) is a minimally invasive neurosurgical procedure, which in the last decade has gained significant momentum of the treatment of intracranial tumours and epileptic foci. In brief, LITT utilises the heat from a stereotactically placed laser catheter to selectively ablate a lesion or a structure under real-time MRI guidance, which is summarised and discussed in this review. The first LITT system gained FDA approval in 2007 and was CE-marked in 2018. In December 2020, the first patient with recurrent glioblastoma was treated at the Department of Neurosurgery at Rigshospitalet, Copenhagen.

Background: CNS immune privilege has been challenged in recent years. Glioblastoma (GBM) immune dysfunction includes complex interactions with the immune system outside the CNS. The aim of this study was to determine diagnostic and prognostic potential of immune-related proteins in plasma in GBM and interrogate biomarker presence in the brain tumor microenvironment (TME)., Methods: One hundred and fifty-eight patients with glioma WHO grade II-IV were included. Plasma collected at surgery was screened for 92 proteins using proximity extension assay technology and related to clinical outcome. Secretion and expression of candidate prognostic biomarkers were subsequently analyzed in 8 GBM cell lines and public RNAseq data., Results: Plasma levels of 20 out of 92 screened proteins were significantly different in patients with GBM compared to patients with astrocytoma WHO grade II-III. High plasma interleukin-8 (IL-8) (hazard ratio [HR] = 1.52; P = .0077) and low CD244 (HR = 0.36; P = .0004) were associated with short progression-free survival and high plasma IL-8 (HR = 1.40; P = .044) and low ICOS ligand (ICOSLG) (HR = 0.17; P = .0003) were associated with short overall survival (OS) in newly diagnosed patients with GBM. A similar trend was found for ICOSLG (HR = 0.34; P = .053) in recurrent GBM. IL-8 was mostly secreted and expressed by mesenchymal GBM cell lines and expressed by vascular cells and immune cells in the TME. This was also the case for ICOSLG, although less consistent, and with additional expression in tumor-associated oligodendrocytes., Conclusions: High plasma IL-8 and low ICOSLG at surgery are associated with short OS in newly diagnosed GBM. Source of plasma ICOSLG may be found outside the TME., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Glioblastoma (GBM) is a devastating cancer with basically no curative treatment. Even with aggressive treatment, the median survival is disappointing 14 months. Surgery remains the key treatment and the postoperative survival is determined by the extent of resection. Unfortunately, the invasive growth with irregular infiltrating margins complicates an optimal surgical resection. Precise intraoperative tumor visualization is therefore highly needed and molecular targeted near-infrared (NIR) fluorescence imaging potentially constitutes such a tool. The urokinase-type Plasminogen Activator Receptor (uPAR) is expressed in most solid cancers primarily at the invading front and the adjacent activated peritumoral stroma making it an attractive target for targeted fluorescence imaging. The purpose of this study was to develop and evaluate a new uPAR-targeted optical probe, IRDye800CW-AE344, for fluorescence guided surgery (FGS). Methods: In the present study we characterized the fluorescent probe with regard to binding affinity, optical properties, and plasma stability. Further, in vivo imaging characterization was performed in nude mice with orthotopic human patient derived glioblastoma xenografts, and we performed head-to-head comparison within FGS between our probe and the traditional procedure using 5-ALA. Finally, the blood-brain barrier (BBB) penetration was characterized in a 3D BBB spheroid model. Results: The probe effectively visualized GBM in vivo with a tumor-to-background ratio (TBR) above 4.5 between 1 to 12 h post injection and could be used for FGS of orthotopic human glioblastoma xenografts in mice where it was superior to 5-ALA. The probe showed a favorable safety profile with no evidence of any acute toxicity. Finally, the 3D BBB model showed uptake of the probe into the spheroids indicating that the probe crosses the BBB. Conclusion: IRDye800CW-AE344 is a promising uPAR-targeted optical probe for FGS and a candidate for translation into human use., Competing Interests: Competing Interests: AK is a co-founder and KJ is an employee of FluoGuide A/S that seeks to commercialize uPAR-targeted optical probes., (© The author(s).)

Glioblastomas (GBM) are heterogeneous highly vascular brain tumors exploiting the unique microenvironment in the brain to resist treatment and anti-tumor responses. Anti-angiogenic agents, immunotherapy, and targeted therapy have been studied extensively in GBM patients over a number of decades with minimal success. Despite maximal efforts, prognosis remains dismal with an overall survival of approximately 15 months.Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, underwent accelerated approval by the U.S. Food and Drug Administration in 2009 for the treatment of recurrent GBM based on promising preclinical and early clinical studies. Unfortunately, subsequent clinical trials did not find overall survival benefit. Pursuing pleiotropic targets and leaning toward multitarget strategies may be a key to more effective therapeutic intervention in GBM, but preclinical evaluation requires careful consideration of model choices. In this study, we discuss bevacizumab resistance, dual targeting of pro-angiogenic modulators VEGF and YKL-40 in the context of brain tumor microenvironment, and how model choice impacts study conclusions and its translational significance.

Glioblastoma (GBM) is an incurable brain tumor for which new treatment strategies are urgently needed. Next-generation sequencing of GBM has most often been performed retrospectively and on archival tissue from both diagnostic and relapse surgeries with limited knowledge of clinical information, including treatment given. We sought to investigate the genomic composition prospectively in treatment-naïve patients, searched for possible targetable aberrations, and investigated for prognostic and/or predictive factors. A total of 108 newly diagnosed GBM patients were included. Clinical information, progression-free survival, and overall survival (OS) were noted. Tissues were analyzed by whole-exome sequencing, single nucleotide polymorphism (SNP) and transcriptome arrays, and RNA sequencing; assessed for mutations, fusions, tumor mutational burden (TMB), and chromosomal instability (CI); and classified into GBM subgroups. Each genomic report was discussed at a multidisciplinary tumor board meeting to evaluate for matching trials. From 111 consecutive patients, 97.3% accepted inclusion in this study. Eighty-six (77%) were treated with radiation therapy/temozolomide (TMZ) and adjuvant TMZ. One NTRK2 and three FGFR3-TACC3 fusions were identified. Copy number alterations in GRB2 and SMYD4 were significantly correlated with worse median OS together with known clinical variables like age, performance status, steroid dose, and O6-methyl-guanine-DNA-methyl-transferase status. Patients with CI-median or TMB-high had significantly worse median OS compared to CI-low/high or TMB-low/median. In conclusion, performing genomic profiling at diagnosis enables evaluation of genomic-driven therapy at the first progression. Furthermore, TMB-high or CI-median patients had worse median OS, which can support the possibility of offering experimental treatment already at the first line for this group., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: Complex local and systemic immune dysfunction in glioblastoma (GBM) may affect survival. Interleukin (IL)-6 and YKL-40 are pleiotropic biomarkers present in the tumor microenvironment and involved in immune regulation. We therefore analyzed plasma IL-6, YKL-40, and genetic variation in YKL-40 and explored their ability to distinguish between glioma subtypes and predict survival in GBM. Methods: One hundred fifty-eight patients with glioma WHO grade II-IV were included in the study. Plasma collected at surgery was analyzed for IL-6 and YKL-40 (CHI3L1) by ELISA. CHI3L1 rs4950928 genotyping was analyzed on whole-blood DNA. Results: Neither plasma IL-6 nor YKL-40 corrected for age or rs4950928 genotype could differentiate GBM from lower grade gliomas. GC and GG rs4950928 genotype were associated with lower plasma YKL-40 levels (CC vs. GC, p = 0.0019; CC vs. GG, p = 0.01). Only 10 and 14 out of 94 patients with newly diagnosed GBM had elevated IL-6 or YKL-40, respectively. Most patients received corticosteroid treatment at time of blood-sampling. Higher pretreatment plasma IL-6 was associated with short overall survival (OS) [HR = 1.19 (per 2-fold change), p = 0.042] in univariate analysis. The effect disappeared in multivariate analysis. rs4950928 genotype did not associate with OS [HR = 1.30, p = 0.30]. In recurrent GBM, higher YKL-40 [HR = 2.12 (per 2-fold change), p = 0.0005] but not IL-6 [HR = 0.99 (per 2-fold change), p = 0.92] were associated with short OS in univariate analysis. Conclusion: In recurrent GBM high plasma YKL-40 may hold promise as a prognostic marker. In newly diagnosed GBM perioperative plasma IL-6, YKL-40, and genetic variation in YKL-40 did not associate with survival. Corticosteroid use may complicate interpretation of results., (Copyright © 2020 Holst, Christensen, Skjøth-Rasmussen, Hamerlik, Poulsen and Johansen.)

Background: Diagnostic accuracy in previous studies of O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) PET in patients with suspected recurrent glioma may be influenced by prolonged dynamic PET acquisitions, heterogeneous populations, different non-standard-of-care therapies, and PET scans performed at different time points post radiotherapy. We investigated the diagnostic accuracy of a 20-minute 18F-FET PET scan in MRI-suspected recurrent glioblastoma 6 months after standard radiotherapy and its ability to prognosticate overall survival (OS)., Methods: In total, 146 glioblastoma patients with 168 18F-FET PET scans were reviewed retrospectively. Patients with MRI responses to bevacizumab or undergoing re-irradiation or immunotherapy after 18F-FET PET were excluded. Maximum and mean tumor-to-background ratios (TBRmax, TBRmean) and biological tumor volume (BTV) were recorded and verified by histopathology or clinical/radiological follow-up. Thresholds of 18F-FET parameters were determined by receiver operating characteristic (ROC) analysis. Prognostic factors were investigated in Cox proportional hazards models., Results: Surgery was performed after 104 18F-FET PET scans, while clinical/radiological surveillance was used following 64, identifying 152 glioblastoma recurrences and 16 posttreatment changes. ROC analysis yielded thresholds of 2.0 for TBRmax, 1.8 for TBRmean, and 0.55 cm3 for BTV in differentiating recurrent glioblastoma from posttreatment changes with the best performance of TBRmax (sensitivity 99%, specificity 94%; P < 0.0001) followed by BTV (sensitivity 98%, specificity 94%; P < 0.0001). Using these thresholds, 166 18F-FET PET scans were correctly classified. Increasing BTV was associated with shorter OS (P < 0.0001)., Conclusion: A 20-minute 18F-FET PET scan is a powerful tool to distinguish posttreatment changes from recurrent glioblastoma 6-month postradiotherapy, and predicts OS., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Complete resection is the treatment of choice for most pediatric brain tumors, but early postoperative MRI for detection of residual tumor may be misleading because of MRI signal changes caused by the operation. PET imaging with amino acid tracers in adults increases the diagnostic accuracy for brain tumors, but the literature in pediatric neurooncology is limited. A hybrid PET/MRI system is highly beneficial in children, reducing the number of scanning procedures, and this is to our knowledge the first larger study using PET/MRI in pediatric neurooncology. We evaluated if additional postoperative 18 F-fluoro-ethyl-tyrosine ( 18 F-FET) PET in children and adolescents would improve diagnostic accuracy for the detection of residual tumor as compared with MRI alone and would assist clinical management. Methods: Twenty-two patients (7 male; mean age, 9.5 y; range, 0-19 y) were included prospectively and consecutively in the study and had 27 early postoperative 18 F-FET PET exams performed preferentially in a hybrid PET/MRI system (NCT03402425). Results: Using follow-up (93%) or reoperation (7%) as the reference standard, PET combined with MRI discriminated tumor from treatment effects with a lesion-based sensitivity/specificity/accuracy (95% confidence intervals) of 0.73 (0.50-1.00)/1.00 (0.74-1.00)/0.87 (0.73-1.00) compared with MRI alone: 0.80 (0.57-1.00)/0.75 (0.53-0.94)/0.77 (0.65-0.90); that is, the specificity for PET/MRI was 1.00 as compared with 0.75 for MRI alone ( P = 0.13). In 11 of 27 cases (41%), results from the 18 F-FET PET scans added relevant clinical information, including one scan that directly influenced clinical management because an additional residual tumor site was identified. 18 F-FET uptake in reactive changes was frequent (52%), but correct interpretation was possible in all cases. Conclusion: The high specificity for detecting residual tumor suggests that supplementary 18 F-FET PET is relevant in cases where reoperation for residual tumor is considered., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Glioblastoma (GB) is an incurable brain cancer with limited treatment options. The aim was to test the feasibility of using cell-free DNA (cfDNA) to support evaluation of treatment response, pseudo-progression and whether progression could be found before clinical and/or radiologic progression. Results: CfDNA fluctuated during treatment with the highest levels before diagnostic surgery and at progression. An increase was seen in 3 out of 4 patients at the time of progression while no increase was seen in 3 out of 4 patients without progression. CfDNA levels could aid in 3 out of 3 questionable cases of pseudo-progression. Methods: Eight newly diagnosed GB patients were included. Blood samples were collected prior to diagnosis, before start and during oncologic treatment until progression. Seven patients received concurrent radiotherapy/Temozolomide with adjuvant Temozolomide with one of the patients included in a clinical trial with either immunotherapy or placebo as add-on. One patient received radiation alone. CfDNA concentration was determined for each blood sample. Conclusions: It was feasible to measure cfDNA concentration. Despite the limited cohort size, there was a good tendency between cfDNA and treatment course and -response, respectively with the highest levels at progression., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Background: Glioblastoma ranks among the most lethal cancers, with current therapies offering only palliation. Paracrine vascular endothelial growth factor (VEGF) signaling has been targeted using anti-angiogenic agents, whereas autocrine VEGF/VEGF receptor 2 (VEGFR2) signaling is poorly understood. Bevacizumab resistance of VEGFR2-expressing glioblastoma cells prompted interrogation of autocrine VEGF-C/VEGFR2 signaling in glioblastoma., Methods: Autocrine VEGF-C/VEGFR2 signaling was functionally investigated using RNA interference and exogenous ligands in patient-derived xenograft lines and primary glioblastoma cell cultures in vitro and in vivo. VEGF-C expression and interaction with VEGFR2 in a matched pre- and post-bevacizumab treatment cohort were analyzed by immunohistochemistry and proximity ligation assay., Results: VEGF-C was expressed by patient-derived xenograft glioblastoma lines, primary cells, and matched surgical specimens before and after bevacizumab treatment. VEGF-C activated autocrine VEGFR2 signaling to promote cell survival, whereas targeting VEGF-C expression reprogrammed cellular transcription to attenuate survival and cell cycle progression. Supporting potential translational significance, targeting VEGF-C impaired tumor growth in vivo, with superiority to bevacizumab treatment., Conclusions: Our results demonstrate VEGF-C serves as both a paracrine and an autocrine pro-survival cytokine in glioblastoma, promoting tumor cell survival and tumorigenesis. VEGF-C permits sustained VEGFR2 activation and tumor growth, where its inhibition appears superior to bevacizumab therapy in improving tumor control.

Background: Balancing survival versus risk of inducing functional deficits is a challenge when resecting gliomas in or near eloquent areas. Our objectives were to assess deficits prior to and at 6 and 12 months after awake craniotomies with cortical and subcortical mapping in patients with suspected grade 2 gliomas in eloquent areas. We analyzed whether pre- and intraoperative factors were linked to an increased risk of postoperative deficits., Method: Retrospective study of 92 consecutive patients operated between January 2010 and June 2014. All deficits reported by any healthcare professional and KPS-score preoperatively, immediately postoperatively (day 1-10), at 6 months and 12 months, were analyzed., Results: A decrease in neurological and or cognitive function was common in the first days after surgery, with a significant improvement at 6 months after surgery and further improvement at 12 months. Immediately after surgery, 33% of the patients had severe deficits compared to 2% prior to surgery; this improved to 9% at 6 months and 3% at 12 months. However, at 12 months, 18% of the patients had new or worsened minor or moderate deficits and only 10% had no deficits compared to 39% prior to surgery. There were only minor changes in KPS. None of the recorded pre/intraoperative factors were found significantly to influence the risk of moderate/severe late postoperative deficits., Conclusion: A significant amount of the patients in this study experienced new or worsened neurological and or cognitive deficits during follow-up. We found a higher frequency of deficits than normally reported. This is due to the inclusion of mild deficits, the use of patient-reported data, and our focus on cognitive deficits. Our study indicates that the impact of awake craniotomy with mapping on patient outcome is larger than expected. This in no way negates the use of the technique.

Purpose: Pediatric cancers are often difficult to classify and can be complex to treat. To ensure precise diagnostics and identify relevant treatment targets, we implemented comprehensive molecular profiling of consecutive pediatric patients with cancer relapse. We evaluated the clinical impact of extensive molecular profiling by assessing the frequency of identified biological onco-drivers, altered diagnosis, and/or identification of new relevant targeted therapies. Patients and Methods: Forty-six tumor samples (44 fresh-frozen; two formalin-fixed paraffin embedded), two bone marrow aspirates, three cerebrospinal fluid samples, and one archived DNA were obtained from 48 children (0-17 years; median 9.5) with relapsed or refractory cancer, where the disease was rapidly progressing in spite of their current treatment or they had exhausted all treatment options. The samples were analyzed by whole-exome sequencing (WES), RNA sequencing (RNAseq), transcriptome arrays, and SNP arrays. Final reports were available within 3-4 weeks after patient inclusion and included mutation status, a description of copy number alterations, differentially expressed genes, and gene fusions, as well as suggestions for targeted treatment. Results: Of the 48 patients, 33 had actionable findings. The most efficient method for the identification of actionable findings was WES (39%), followed by SNP array (37%). Of note, gene fusions were identified by RNAseq in 21% of the samples. Eleven findings led to clinical intervention, i.e., oncogenetic counseling, targeted treatment, and treatment based on changed diagnosis. Four patients received compassionate use targeted therapy. Six patients experienced direct benefits in the form of stable disease or response. Conclusion: The application of comprehensive genetic diagnostics in children with recurrent cancers allowed for discovery and implementation of effective targeted therapies and hereby improvement of outcome in some patients.

Introduction: In 2016, the WHO classification of diffuse astrocytoma began to include isocitrate dehydrogenase (IDH) mutation in addition to histology., Results: We here demonstrate a case where a 14-year-old boy presented with a parietal tumor with no histological evidence of neoplasia but with an IDH1 mutation. Due to the IDH1 R132H mutation, the patient was diagnosed with diffuse astrocytoma WHO grade II and underwent successful gross total resection of this near-eloquently located tumor., Conclusion: This case exemplifies how inclusion of immunohistochemistry in tumor classification alters surgical strategy and might improve accuracy and time to diagnosis.

Background and Purpose: Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage. Treatments with convincing effect are lacking and the pathophysiology behind DCI remains poorly understood. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor and a role of NPY in the development of DCI has been proposed. This study investigated the relationship between plasma-NPY and cerebral blood flow (CBF), cerebral vasospasm, DCI, and clinical outcome., Methods: In 90 patients with subarachnoid hemorrhage, NPY was measured in peripheral blood days 2 to 11. Any occurrence of DCI was recorded and CBF was quantified day 3 and day 8 using computed tomography (CT) perfusion. CT angiography was performed day 8. Clinical outcome was assessed after 3 months., Results: No correlation was found between plasma-NPY and CBF or angiographic vasospasm. The correlation between reduced plasma-NPY and DCI reached borderline statistical significance (P=0.05). Increased levels of NPY measured on days 2 to 4 were correlated to good outcome (P=0.006)., Conclusions: Our findings in peripheral blood were not supportive of a causal relationship between NPY secretion and DCI. Although high levels of plasma-NPY were correlated with good clinical outcome, NPY did not show promise as a clinically useful biomarker.

A 17-year-old female with migraine with aura complained of fatigue and was diagnosed with anemia. Three years later, changes in her headache pattern prompted hospital referral. Brain MRI showed a bi-lobed extra-axial intracerebral tumor encroaching both parieto-occipital regions. The resection specimen yielded a rare diagnosis of primary intracranial angiomatoid fibrous histiocytoma (AFH). Tumor removal resulted in cessation of her migraine and anemia. AFH may cause systemic symptoms--in this case fatigue and anemia--long before focal neurological symptoms are present. This is the first report of an intracranial AFH presenting as migraine with visual aura and anemia., (© International Headache Society 2015.)

Purpose: Medulloblastoma is the most common malignant brain tumor in childhood. Radical surgery in the non-metastatic stage is an important factor with respect to overall survival. In this case, 5-aminolevulinic acid (5-ALA) was used at second-look surgery in order to improve surgical results., Methods: The child was pretreated with 3 × 4 mg dexamethasone for 4 days prior to the second surgery. At 5 a.m. on the day of surgery, a freshly prepared solution of 5-ALA (20 mg/kg body weight; Medac, Germany) was given orally., Results: At surgery, through the original opening, the vague red fluorescence of the tumor was clearly distinctive from the cerebellum with no tumor infiltration. All fluorescent tissue was removed. Postoperative MRI gave suspicion of yet at small tumor residue, but this structure is less than 1.5 ml in calculated volume, and consequently the recommended adjuvant therapy of the child changed from the high-risk medulloblastoma regimen to the standard-risk regimen., Conclusions: In this particular difficult case of non-contrast-enhancing tumor, 5-ALA was of vital importance to improve rate of resection and change the aggressiveness needed in postsurgery radiation therapy.

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

Background: Frame-based stereotactic procedures are the gold standard because of their superior stereotactic accuracy. The procedure used to be in multiple steps and was especially cumbersome and hazardous in intubated patients. A single-step procedure using intraoperative CT was created to optimize the procedures., Methods: A combined fixation and low profile frame holder was designed for the operating table, allowing positioning for the scanning procedure immediately followed by the surgical biopsy procedure with the same positioning and head fixation. For placement of depth electrodes immediate CT control of positioning was feasible., Results: In the first 8 months the procedure was successfully used 65 times including 8 times in pediatric cases. The procedure duration in awake patients was on average 81 min (range 33 to 202) and in intubated patients (children) on average 89 min (median 89, 78-100)., Discussion: This study demonstrates that frame-based stereotactic procedures in all brain locations are a feasible and practical technique with improved workflow and added patient safety and comfort.

The use of endovascular intervention to treat cerebral vasospasm after subarachnoid hemorrhage has increased. Although the effect on angiographic vasospasm can be easily demonstrated, the effect on cerebral blood flow and clinical outcome is still controversial. In this report, we investigate minute-by-minute changes in brain tissue oxygen during balloon angioplasty and intraarterial administration of vasodilators in three patients.Our results confirm that endovascular intervention is capable of not only resolving angiographic vasospasm, but also of normalizing values of brain tissue oxygen pressure (PtiO₂) in target parenchyma. However, during the intervention, dangerously low levels of brain tissue oxygen, leading to cerebral infarction, may occur. Thus, no clinical improvement was seen in two of the patients and a dramatic worsening was observed in the third patient. Because the decrease in brain tissue oxygen was seen after administration of vasopressor agents, this may be a contributing factor.

Background and Purpose: Delayed ischemic neurological deficits (DINDs) are a major contributing factor for poor outcome in patients with subarachnoid hemorrhage. In this trial, we investigated the therapeutic potential of prostacyclin, an endogen substance with known effect on vascular tone and blood flow regulation, on factors related to DIND., Methods: This trial is a single-center, randomized, blinded, clinical, pilot trial with 3 arms. Ninety patients were randomized to continuous infusion of prostacyclin 1 ng/kg per minute, prostacyclin 2 ng/kg per minute, or placebo. The intervention was initiated day 5 after subarachnoid hemorrhage and discontinued day 10. Primary outcome was the difference in change from baseline in global cerebral blood flow. Secondary outcome measures were occurrence of DIND, angiographic vasospasm, and clinical outcome at 3 months., Results: No statistically significant difference in change of global cerebral blood flow was found between the intervention groups. The observed incidence of DIND and angiographic vasospasm was markedly higher in the placebo group, although this difference was not statistically significant. No statistically significant differences in safety parameters or clinical outcome were found between the 3 groups., Conclusions: Administration of prostacyclin to patients with subarachnoid hemorrhage may be safe and feasible. Global cerebral blood flow after subarachnoid hemorrhage is not markedly affected by administration of prostacyclin in the tested dose range. It may be possible that the observed reduction in the point estimates of DIND and vasospasm in the prostacyclin groups represents an effect of prostacyclin as this trial was not powered to investigate the effect of prostacyclin on these outcomes., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT01447095., (© 2014 American Heart Association, Inc.)

Background: Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. Case reports indicate that 5-ALA can be used for children, yet no prospective study has been conducted as of yet. As a basis for a study, we conducted a survey among certified European Gliolan users to collect data on their experiences with children., Methods: Information on patient characteristics, MRI characteristics of tumors, histology, fluorescence qualities, and outcomes were requested. Surgeons were further asked to indicate whether fluorescence was "useful", i.e., leading to changes in surgical strategy or identification of residual tumor. Recursive partitioning analysis (RPA) was used for defining cohorts with high or low likelihoods for useful fluorescence., Results: Data on 78 patients <18 years of age were submitted by 20 centers. Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III (80 %). Fluorescence was found inconsistently useful in PNETs (three of seven; 43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %) and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors showed tumors with supratentorial location, strong contrast enhancement and first operation to have a likelihood of useful fluorescence of 64.3 %, as opposed to infratentorial tumors with first surgery (23.1 %)., Conclusions: Our survey demonstrates 5-ALA as being used in pediatric brain tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial tumors. These data indicate controlled studies to be necessary and also provide a basis for planning such a study.