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Background Oligodendrogliomas are glial tumors with a relatively favorable survival prognosis of >10 years. While immediate postoperative treatment prolongs survival, long-term toxicities of adjuvant radio-chemotherapy remain a concern. Predictive biomarkers guiding postoperative treatment decisions are limited. Material and Methods In this retrospective study, we included patients treated for a newly diagnosed oligodendroglioma (isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted, CNS WHO grades 2 and 3) in 1992 - 2019 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria). Early treatment was defined as radiotherapy, chemotherapy, or both within 6 months after resection, whereas benefit from early treatment was defined as progression-free survival (PFS) above the median in the overall cohort. DNA methylation analysis was performed using Illumina MethylationEPIC 850k microarrays. Results Of all 201 eligible patients, sufficient tumor tissue for DNA methylation analysis was available in 46 patients. Of these, 25/46 (54.3%) were diagnosed with CNS WHO grade 2 and 21/46 (45.6%) with grade 3 oligodendroglioma. Median age at diagnosis was 41 years (range: 23-70). In total, 21/46 (45.6%) patients received early treatment, of whom 13/21 (61.9%) received radio-chemotherapy, 6/21 (28.6%) radiotherapy only and 2/21 (9.5%) chemotherapy only. Median PFS was 134.0 months (95%CI: 78.3 - not reached) in patients receiving early treatment versus 87.2 months (95%CI: 66.8 - 150) in patients who did not. In patients receiving early treatment, differences in DNA methylation profiles could be detected between patients who drew benefit from postoperative treatment (group 1) versus those who did not (group 2). Based on the top 1000 differentially methylated CpG sites between both groups, two clusters were detected which comprised either patients of group 1 or 2. Clustering was independent from gender, WHO grade, extent of resection, type of postoperative treatment, treating center, and O6-methylguanine-methyltransferease (MGMT) promoter methylation status. Gene set enrichment analysis of the top 1000 differentially methylated gene sites mapped to 694 genes showed differential methylation in genes involved in fibroblast growth receptor 1 (FGFR1) signaling, Wnt signaling, integrin signaling, and actin cytoskeleton regulation. Conversely, in patients not receiving early treatment, PFS did neither correlate with DNA methylation clustering nor with MGMT promoter methylation. Conclusion In our cohort, whole genome DNA methylation was associated with PFS in patients who received early postoperative treatment, suggesting a predictive but not prognostic role. As the predictive value of MGMT promoter methylation is limited in oligodendroglioma, whole genome DNA methylation should be considered in future clinical trials.

Background Glioblastoma is associated with a high risk of epileptic seizures ranging from 40% to 60%. Before the advent of modern imaging techniques, electroencephalography (EEG) was a critical component in evaluating patients with space-occupying lesions. In this retrospective single-center study, we aimed (1) to characterize a cohort of patients with glioblastoma with regards to EEG monitoring, seizure frequency and the frequency of prescribed anti-seizure medications (ASM) and (2) to assess the value of EEG as a localizing technique in patients with glioblastoma. Material and Methods We reviewed the charts of 179 patients with glioblastomas between January 1st, 2020 and January 1st, 2022, treated at the Medical University of Vienna. The diagnosis was based on MRI and/or confirmed by biopsy according to the 2016 World Health Organization Classification of Tumors of the Central Nervous System. Patients who received an in-house EEG as part of their diagnostic work-up were included if an MRI/CT scan was available (within an average time of +/-60 days). For localization, focal slowing (theta/delta activity) and/or epileptiform discharges were considered. EEG rating was performed by a board-certified electrophysiologist blinded for the diagnosis and MRI/biopsy findings. Results We included 52 patients (29.05% of screened cohort) with at least one EEG and MRI or CT scan performed before or after EEG, following inclusion criteria (median: 2 days; mean: 6 days; range: -29 to 52), in the final analysis. Clinical seizure activity and/or epileptiform discharges on EEG were detected in 46 patients (88.46%), and 48 patients (92.31%) were on ASM. An IDH-wildtype glioblastoma was diagnosed in 45 patients (86.54%), 4 had an IDH-mutant glioblastoma (7.69%), and in 3 patients, IDH-status was unknown (5.77%). In 22 patients (42.31%), biopsy revealed a positive MGMT promoter methylation status, while 28 were unmethylated (53.84%), and two patients had an unknown MGMT promoter methylation status (3.85%). Intermittent and/or continuous focal slow-wave activity was registered in 45 patients (86.54%). In comparison, epileptiform discharges could only be found in 13 patients (25%). When compared to MRI/CT scans, the hemispheric tumor localization could be determined in 42 cases (80.77%). Moreover, the affected brain lobe was accurately predicted in 35 patients (67.31%). Three patients had diffuse EEG changes (5.77%), and EEG was unremarkable in 7 patients (13.46%). Conclusion Overall, our presented data indicate that the hemispheric localization of glioblastoma can be reliably predicted by EEG recordings, while a precise (brain lobe-specific) localization was only possible in around two-thirds of cases.

Background Levetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap. Patients and Methods In a retrospective analysis of individual patient data using a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment. Results Of 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, p Conclusion Any association of psychiatric adverse events with LEV did not persist beyond the concomitant treatment phase. Antiemetic properties of LEV may be beneficial during the maintenance temozolomide.

Background Brain metastases (BM) constitute the most common central nervous system tumors. The treatment options of BM consist of surgery, radiotherapy, radiosurgery, chemotherapy, and immunotherapy. Regarding surgery in BM, the extent of resection (EOR) represents a crucial factor for patient prognosis. However, first studies using postoperative MRI demonstrated that an unexpected residual tumor after surgery of BM is not uncommon despite these tumors were considered to be well-demarcated. The aim of this study was thus to investigate in a large cohort including multiple neurosurgical centers the EOR following BM resection, potential risk factors for incomplete resection and postsurgical follow-up data. Material and Methods In the current retrospective study conducted at 5 specialized neurosurgical centers in Austria, we included patients with BM resection and available postoperative MRI. The EOR following BM resection was determined by postoperative MRI (complete vs incomplete resection). Additionally, the data on the intraoperative judgement of the EOR of the performing neurosurgeon were collected. Moreover, potential factors for incomplete resection including tumor localization, tumor volume, primary tumor, pattern of contrast media enhancement on imaging and tumor eloquence were investigated. Finally, the rate of local progression of BM after initial surgery was analyzed in the follow-up period and overall survival data were collected. Results Altogether, 548 patients with 649 surgically treated BM were included. According to postoperative MRI, complete resection was achieved in 407 (66%) of 649 BM and incomplete resection in 176 (29%) of 649 BM. Misjudgment of the EOR by the neurosurgeon was found in 25% of cases and resulted in an unexpected residual tumor which was evident on postoperative MRI in 122 (22%) BM. Preoperative tumor volume was significantly larger in incompletely resected BM. Moreover, local progression was significantly more common in cases with incompletely resected BM and was also associated with shorter overall survival. Conclusion Our data of this study including multiple centers indicate that postoperative MRI is capable to detect a relatively high rate of unexpected residual tumors following resection of BM. Since local progression was more common in BM with residual tumors and this was associated with shorter survival, special attention should be paid to achieve a complete tumor resection.

Background T-DXd is a novel antibody-drug conjugate with high activity in HER2-positive metastatic breast cancer. The prospective, single-arm, single-centre phase II TUXEDO-1 trial showed clinically relevant activity of T-DXd in HER2-positive BC pts with active BM with an intracranial response rate of 73.3%. This biomarker sub-study of TUXEDO-1 aimed to investigate changes in the extent of metastases-induced brain damage in patients with and without response to therapy by measuring the serum levels of two proteins constitutively expressed in the human brain and measurable upon brain damage in the blood serum: NSE and S100. Material and Methods We assessed serum NSE (sNSE) and serum S100 (sS100) levels in a total of 37 blood samples drawn at cycles 1, 4 and end of treatment (EOT) in all patients of the intent-to-treat population of the TUXEDO-1 trial using commercially available ELISA assays. Intracranial radiological response was centrally assessed by a board-certified neuro-radiologist using RANO criteria. sNSE and sS100 levels were compared between responders and non-responders using the Mann Whitney U test and a significance level of 0.05. Results At baseline, we detected no significant difference of sNSE or sS100 levels between T-DXd responders and non-responders, respectively. Baseline median sNSE level was 10.6 ng/ml (interquartile range (IQR) 8.6-12.2) in T-DXd responders as compared with median 12.5 ng/ml (IQR 12.2-12.9) in the non-responder group (n.s.). At cycle 4, corresponding numbers were 8.1 ng/ml in responding patients (IQR 7-11.2) and 12.7 ng/ml (IQR 12.2-12.9) in non-responders, respectively (p=0.009). No differences in sS100 levels were observed between the groups at any time point. Conclusion In patients showing intracranial objective response to T-Dxd, sNSE levels were significantly lower at cycle 4 as compared with non-responders, suggesting a reduction in metastases-induced brain damage as a direct treatment effect. sNSE may be a clinically useful biomarker for longitudinal assessment of brain metastasis burden.

Background The incidence of brain metastases (BM) in patients with thyroid cancer (TC) depends on the histological subtype. About 1% of patients with differentiated (DTC), 3% with medullary (MTC) and up to 10% with anaplastic thyroid cancer (ATC) develop BM. The diagnosis of BM drastically worsens the prognosis of TC. Given the rare incidence, little is known about the presentation and outcome of this cohort. Material and Methods Patients with a histologically verified diagnosis of TC and BM were identified from the Vienna Brain Metastasis Registry, a comprehensive database managed by the Division of Oncology, Medical University of Vienna, including patients with cerebral metastasis since 1990. Data were obtained from medical records comprising clinicopathological features, treatment, BM-specific characteristics and outcome. Results 20/6074 patients included in the registry had a diagnosis of TC and radiologically verified BM. 13/20 (65%) were female and the median age at diagnosis of TC and manifestation of BM was 56 years (range 21-75) and 68 years (range 45-75), respectively. In terms of histology, 18/20 (90%) had DTC, one MTC and one ATC. Interestingly, 10/18 DTC presented with follicular histology which underlines the more aggressive course of this rare subtype. 6/20 (30%) had BM at primary diagnosis (DTC n=5, ATC n=1), while the remaining developed BM during follow-up. The median time to diagnosis of BM was 2.6 years for DTC (range 0-42), 22 years in the MTC patient and 2 months for ATC. Regarding BM-specific characteristics, all but one patient had symptoms due to BM (neurological deficits n=11, increased intracranial pressure n=5, seizures n=3). Most patients (13/20) had a singular BM, commonly located in the left hemisphere (8/13), and only one had more than three BMs. Upfront treatment for BM was local therapy (resection n=9, stereotactic radiosurgery n=7, whole brain radiotherapy n=3); one patient received supportive care only. The median overall survival (mOS) from diagnosis of TC was 6 years for DTC (range 2.5 months-42 years), 33 years for the MTC and 9 months for the ATC. The mOS from diagnosis of BM was 14 months for DTC (1.8 months-16 years), 22 years for the MTC and 3 months for the ATC. Conclusion Few patients with TC develop BM, which present commonly as single lesion. While in general BM constitute a poor prognostic factor, individual patients experience long-term survival following local therapy. More information about the optimal management of BM in TC is needed to enable guideline recommendations.

Background New approaches for 7 Tesla magnetic resonance spectroscopic imaging (MRSI) allow the simultaneous imaging of multiple neuro-oncological biomarkers with 3-4 mm resolution in clinically feasible measurement times. Specifically, the amino acids glutamine (Gln) and Glycine (Gly), were previously limited to single voxel detection at lower fields. Both could add to our capabilities to resolve heterogeneous tumour metabolism. Purpose To progress the validation of Gln and Gly as neuro-oncological markers by conducting the first comparison to amino acid PET in a cohort of glioma patients. Material and Methods In 24 glioma patients (WHO 2021 classification), we quantitatively compared 7T MRSI (3D, 3.4 mm isotropic resolution, 15 min scan time) and routine PET (FET or MET). Within manual tumour segmentations, we defined hotspot volumes of interest (VOI) for the ratios of total choline (tCho, clinical standard reference), Gln, Gly to total N-acetylaspartate (tNAA) and PET tumour-to-brain ratios (TBR), all with a cut-off threshold of 1.6. For these VOIs, we calculated VOI volumes and median ratios as well as Dice similarity coefficients (DSC) and centre of intensity distance (CoI), between MRSI and PET ratios. Results We found that Gln and Gly ratios to tNAA had a higher correspondence to PET-based amino acid metabolism than tCho. Our resulting median VOI volumes were 19.08±23.10 cm³ for tCho/tNAA, 33.68±24.60 cm³ for Gln/tNAA, and 22.38±18.49 cm³ for Gly/tNAA compared to 24.33±30.46 cm³ for PET, with correlation coefficients >0.5 for all MRSI hotspot values in relation to PET volumes. Median ratios were 0.52±0.13 for tCho/tNAA, 0.61±0.25 for Gln/tNAA, 0.33±0.15 for Gly/tNAA and 2.11±0.42 for PET. The median DSCs to PET amounted to 0.53±0.36 for tCho/tNAA, 0.66±0.40 for Gln/tNAA, and 0.57±0.36 for Gly/tNAA, while the median CoI distances were 0.56±0.43 cm for tCho/tNAA, 0.39±0.22 cm for Gln/tNAA, and 0.45±0.48 cm for Gly/tNAA. Conclusion With this first study that compared high-resolution 3D-MRSI at 7 Tesla to amino acid PET and a quantitative evaluation, we demonstrated that Gln and Gly corresponded better to PET than tCho, which is the main marker used in clinical MR, both within the study and compared to previous literature. Future research is needed to clearly define the benefits of 7T MRSI for neuro-oncology such as the identification of tumour microenvironments or non-invasive determination of molecular-pathologic markers. Gln could be further explored by the application of Gln-based PET tracers to MR-PET. We still see further developments of MRSI methods, such as motion correction or absolute quantification of concentrations instead of ratios, as necessary to obtain such goals.

Background Immunotherapy (IO) has changed the treatment landscape of metastatic cancer patients, however, treatment resistance is frequent. We aimed to characterize the inflammatory tumor microenvironment in brain metastases (BM) after IO to gain a deeper understanding of immunologic escape mechanisms. Material and Methods Solid cancer patients who had BM resection after IO progression (IO cohort) were retrospectively identified. We analyzed tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) by immunohistochemistry. A control cohort of BM tissue samples without prior IO served for comparison (no immunotherapy cohort, NIO). Results Twenty-eight IO patients (12/28, 42.9% females; 16/28, 57.1% males; median 61 years; 14/28, 50% lung cancer; 5/28, 17.9% melanoma; 4/28, 14.3% renal cell carcinoma; 1/28, 3.6% breast cancer; 4/28, 14.3% other cancer entities) and 57 NIO patients (28/57, 49.1% females; 29/57, 50.9% males; median 58 years; 35/57, 61.4% lung cancer; 9/57, 15.8% breast cancer; 4/57, 7.0% melanoma; 3/57, 5.3% renal cell carcinoma; 6/57, 10.5% other cancer entities) were included. IO patients had a median of one (range 0-4) systemic therapy line prior to IO. Median time from last IO application until BM resection was 5.6 months (range 0.2-49.8 months). Patients received a median number of 7 (range 1-56) IO applications (14/28, 50% PD-1-targeting IO; 8/28, 28.6% PD-L1; 2/28, 7.1% CTLA4; 4/28, 14.3% CTLA4+PD-1; 3/28, 10.7% IO+chemotherapy). No statistically significant differences in the densities of investigated TILs or PD-L1 expression between the IO and the NIO cohort were observed. Patients of the IO cohort showed higher PD-L1 expression compared to the NIO cohort (57.1 vs. 42.1%, Chi-square, p>0.05). Overall survival (OS) was similar in both cohorts, with a median OS of 11.0 months (range 5.0-17.0) in the IO cohort and 11.0 months (range 5.5-16.5) in the NIO cohort. Conclusion Our findings show an upregulation of PD-L1 in BM occurring after prior IO therapy in the absence of other overt changes in the inflammatory microenvironment. Ongoing analyses in this cohort are investigating possible molecular driver of resistance by analyzing DNA methylation profiles of pre-and post-IO tissue samples of the IO cohort to potentially gain insights on inflammatory IO resistance mechanisms in BM patients.

Background Based on the the rising detection of asymptomatic brain metastases (BM) and the remarkable intracranial responses of targeted- and immunotherapy in specific subgroups of asymptomatic BM patients, we aimed to evaluate the clinical characteristics and prognostic value of neurological symptoms in BM from melanoma. Material and Methods 670 patients with newly diagnosed melanoma BM were identified from the Vienna Brain Metastasis Registry. We performed retrospective chart review and statistical outcome analyses. Results 370/670 (55.2%) patients presented with neurological symptoms including neurological deficits (316/370; 85.4%), signs of increased intracranial pressure (126/370; 34.1%) and epileptic seizures (53/370; 14.3%). 57.6% (80/139) of patients with BRAF mutated melanoma presented with asymptomatic BM at diagnosis. Absence of neurological symptoms at BM diagnosis was associated with a longer median overall survival after time of BM diagnosis (7 vs. 5 months; p< 0.001; log-rank test). In multivariate analysis with the diagnosis-specific graded prognostic assessment (DS-GPA: HR:1.4; 95% CI, 1.25-1.48; p Conclusion: Neurological symptoms at the time of BM diagnosis are an independent and strong prognostic factor in melanoma BM patients. Our results argue for the integration of neurological symptoms into the prognostic assessment of patients with BM from melanoma.

Introduction A new generation of MR spectroscopic imaging (MRSI) methods using 7T scanners have demonstrated the capability to resolve more neuro- and oncometabolites at higher resolutions than clinical routine MRSI. In a cohort of glioma patients, we explored the automated preoperative and noninvasive classification of IDH-mutation status and tumor grade based on 7T MRSI. Methods This retrospective study included 36 patients (15 female) with histologically confirmed diffusely infiltrating glioma WHO grade 2-4 (9 grade 2, 9 grade 3 and 18 grade 4) and known IDH status (21 IDH1-mut, 15 IDH-wt) with an available 7T MRSI scan of sufficient data quality. The 3D MRSI scan had a 3.4 mm isotropic resolution and 15 minutes acquisition time. 12 spectral components were classified voxel-wise, including choline, glutamine and glycine. Within a tumor segmentation based on routine 3T imaging, we used a random forest algorithm for the voxel-wise classification of IDH mutation and grade (into low or high grade). Training used the leave-one-out cross validation method (i.e., for every patient data set, the other 35 datasets were used as training set) and feature selection out of the available combinations for metabolite ratios (e.g., glutamine to choline). The resulting voxel classifications were aggregated into a mean probability per patient that was the base for receiver-operator characteristic (ROC) curves both for grade and IDH status. Results The classification algorithm obtained an area under the curve (AUC) for IDH determination of 0.85 (e.g., 75% sensitivity and 95% specificity). For grade determination, the AUC was 0.88 (e.g., 87% sensitivity and 89% specificity). In comparison, the AUC per voxel would have resulted in an AUC of 0.66 for both. Further, classification by individual metabolite ratios resulted in lower AUCs in all cases. Conclusions According to our preliminary data, preoperative 7T MRSI is capable to determine the correct glioma grade and IDH status with high sensitivity and specificity by leveraging the extended metabolic panel width and voxel amount. By increasing this cohort in future, we intend to confirm our initial results and we also plan to extend classification to more molecular-pathological features (e.g., TERT). Thus, even a voxel-wise classification of tumor microenvironments could be attempted. Further improvements in 7T MRSI methodology such as absolute instead of relative quantification would also aid these attempts. In summary, 7T MRSI has shown its potential for improved preoperative characterization of gliomas.