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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 [68Ga]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) [68Ga]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 68Ga-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET in patients with anaplastic astrocytoma and glioblastoma following standard therapy. Methods: A total of 76 lesions in 60 hybrid [18F]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 [18F]FET uptake (TBRmax), maximal BV (BVmax) and normalised BVmax (nBVmax) 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 [18F]FET metrics were higher than in non-progressive lesions. ROC analyses showed higher overall ROC AUCs for TBRmax than both BVmax and nBVmax in both lesion-wise (all lesions, p = 0.04) and in patient-wise analysis (p < 0.01). Combining TBRmax with BV metrics did not increase ROC AUC. Lesion-wise positive fraction/sensitivity/specificity at optimal cut-offs were 55%/91%/84% for TBRmax, 45%/77%/84% for BVmax and 59%/84%/72% for nBVmax. Combining TBRmax 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 [18F]FET positive and 97% in concordant positive lesions. Conclusion: The overall diagnostic accuracy of DCE BV imaging is good, but lower than that of [18F]FET PET. Adding DCE BV imaging did not improve the overall diagnostic accuracy of [18F]FET PET, but may improve specificity and allow better lesion-wise risk stratification than [18F]FET PET alone. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Arteriovenous malformations are not a common disease in childhood. A national survey was conducted to reveal the Danish incidence of the disease, presentation, choice of treatment, and outcome. Materials and methods: Forty patients were admitted to any of the five neurosurgical centers during the years 2000-2008. A retrospective survey was conducted using hospital records. Results: Twenty-three males and 17 females presented with AVM with a mean age of 11.3 (1 month-18 years). The incidence was found to be 0.4/100,000. Early fatal outcome was seen in three patients. Treatment was surgery (12), endovascular (5), radiosurgery (6), or a combination of the above (10). Four patients were treated conservatively. Complications of the treatment were seen in 27%. Occlusion rate was 74%. Good or excellent outcome was seen in 65%. Conclusion: A national survey may give a lower rate of success than in the specialized centers accepting patients more eligible for treatment. Still, the low number of children could call for centralization and collaboration in this population. [ABSTRACT FROM AUTHOR]