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Baseline clinical characteristics of all patients by cohort

Purpose Developmental gene expression data from medulloblastoma (MB) supported by retrospective MR imaging studies suggest that WNT-MB originate from the region of the embryonic lower rhombic lip (LRL), whereas SHH-MB and non-WNT/non-SHH-activated MB arise from cerebellar precursor matrix regions. This study aims to analyze detailed intraoperative data with regard to the site of origin (STO) and compare these findings with the hypothesized regions of origin associated with the molecular group. Methods A review of the institutional database identified 58 pediatric patients who were operated on a MB at our department between 1996 and 2020 and had a detailed operative report, surgical video as well as clinical and genetic classification data available for analysis. The STO was assessed based on intraoperative findings of an expert neurosurgeon blinded to the molecular group information. Results Using the intraoperatively defined STO, “correct” prediction of molecular groups was feasible in 20% of WNT-MB, 60% of SHH-MB and 71% of non-WNT/non-SHH activated MB. The positive predictive values of the neurosurgical inspection to detect the molecular group were 0.21 (95% CI 0.08–0.48) for WNT-MB, 0.86 (95% CI 0.49–0.97) for SHH-MB and 0.73 (95% CI 0.57–0.85) for non-WNT/non-SHH activated MB. Conclusions The present study demonstrated a limited predictive value of the intraoperatively observed STO for the prediction of the molecular group of MB. Thus, our findings challenge the current concept of the molecular group-specific origins based on developmental gene expression data and neuroradiological STO definitions.

OBJECTIVE The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity. Standards are lacking for surgical decision-making, and previous studies indicate treatment variations. These shortcomings reflect the need to evaluate larger populations from different care teams. In this study, the authors used probability maps to quantify and compare surgical decision-making throughout the brain by 12 neurosurgical teams for patients with glioblastoma. METHODS The study included all adult patients who underwent first-time glioblastoma surgery in 2012–2013 and were treated by 1 of the 12 participating neurosurgical teams. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to identify and compare patient treatment variations. Brain regions with different biopsy and resection results between teams were identified and analyzed for patient functional outcome and survival. RESULTS The study cohort consisted of 1087 patients, of whom 363 underwent a biopsy and 724 a resection. Biopsy and resection decisions were generally comparable between teams, providing benchmarks for probability maps of resections and biopsies for glioblastoma. Differences in biopsy rates were identified for the right superior frontal gyrus and indicated variation in biopsy decisions. Differences in resection rates were identified for the left superior parietal lobule, indicating variations in resection decisions. CONCLUSIONS Probability maps of glioblastoma surgery enabled capture of clinical practice decisions and indicated that teams generally agreed on which region to biopsy or to resect. However, treatment variations reflecting clinical dilemmas were observed and pinpointed by using the probability maps, which could therefore be useful for quality-of-care discussions between surgical teams for patients with glioblastoma.

Purpose: To investigate the prognostic relevance of temporal muscle thickness (TMT) as a surrogate parameter of skeletal muscle status in patients with newly diagnosed glioblastoma. Experimental Design: We assessed TMT in cranial MRI of 755 patients enrolled in the CENTRIC EORTC 26071–22072 study (n = 508) and CORE study (n = 247). We used predefined sex-specific TMT cut-off values to categorize “patients at risk of sarcopenia” and “patients with normal muscle status” at baseline. Furthermore, we categorized patients according to the extent of TMT loss over time. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using the Cox model adjusted for other exploratory variables. Results: Patients at risk of sarcopenia (CENTRIC; n = 158/508, 31.1%; CORE; n = 87/247, 35.2%) at baseline had significantly higher risk of progression and death than patients with normal muscle status in both study cohorts [CENTRIC: PFS = HR 0.16; 95% confidence interval (CI), 0.12–0.21; P < 0.001; OS = HR 0.341; 95% CI, 0.27–0.44; P < 0.001; CORE: PFS = HR 0.29; 95% CI, 0.21–0.39; P < 0.001; OS = HR, 0.365; 95% CI, 0.27–0.49; P < 0.001]. Similar results were obtained in multivariate Cox models adjusted for other important prognostic parameters. The extent of TMT loss over time showed a significant inverse correlation with median OS times in patients at risk for sarcopenia (CENTRIC: P < 0.001; CORE: P = 0.005), but not in patients with normal baseline muscle mass (CENTRIC: P = 0.538; CORE: P = 0.28). Conclusions: TMT identifies ambulatory patients with newly diagnosed glioblastoma at risk for progressive sarcopenia and adverse outcomes. Early intervention may prevent skeletal muscle loss and improve patient outcome.

The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and the publication of practice-changing randomized trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for the treatment of PCNSL, including intraocular manifestations and specific management of the elderly. The main changes from the previous guideline include strengthened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.

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 100mg 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.

Background A growing body of evidence has supported alternatives to sedation and general anesthesia for increasing treatment compliance of children during MRI examinations. Particularities in children with a brain tumor (frequency of examinations, neuropsychological deficits (attention, memory)) have a significant impact on methods and are given special consideration in this study. The aim of the present study was to (1) evaluate the effectiveness of an MRI training program and to investigate the moderating factors for successful MRI examination for a group of young patients with pediatric brain tumors and/or NF1 and (2) to examine the effect of the training on the patient’s well-being. Methods A total of 87 patients of the neuro-oncology unit (mean age: 6.83 years) underwent a two-step program to prepare children for MRI, including an in vitro strategy training inside the scanner and were recorded using a process-oriented screening (emotional wellbeing and level of information), which was developed for this purpose. All data was analyzed retrospectively and the data of a subgroup of 17 patients was also analyzed prospectively (ClinicalTrials.gov: NCT04474678). Results 81% of the children who had received MRI training managed to successfully undergo the MRI scan without sedation and/or anesthesia making the success rate almost five times as high as in the group that did not receive the intervention. Memory, attentional difficulties, and hyperactivity were significant neuropsychological moderators for successful or unsuccessful scanning. Furthermore, the training was effective in improving the psychological well-being of the patients. Conclusion Based on the results, the MRI training is an effective alternative to sedation of young patients for MRI examinations and a promising tool for improving patient well-being related to the diagnostic procedure. However, specialized psychological staff and an interdisciplinary approach are required to adapt the intervention to the children’s individual neuropsychological needs. Trial registration number: ClinicalTrials.gov Identifier: NCT04474678

OBJECTIVE Decisions in glioblastoma surgery are often guided by presumed eloquence of the tumor location. The authors introduce the “expected residual tumor volume” (eRV) and the “expected resectability index” (eRI) based on previous decisions aggregated in resection probability maps. The diagnostic accuracy of eRV and eRI to predict biopsy decisions, resectability, functional outcome, and survival was determined. METHODS Consecutive patients with first-time glioblastoma surgery in 2012–2013 were included from 12 hospitals. The eRV was calculated from the preoperative MR images of each patient using a resection probability map, and the eRI was derived from the tumor volume. As reference, Sawaya’s tumor location eloquence grades (EGs) were classified. Resectability was measured as observed extent of resection (EOR) and residual volume, and functional outcome as change in Karnofsky Performance Scale score. Receiver operating characteristic curves and multivariable logistic regression were applied. RESULTS Of 915 patients, 674 (74%) underwent a resection with a median EOR of 97%, functional improvement in 71 (8%), functional decline in 78 (9%), and median survival of 12.8 months. The eRI and eRV identified biopsies and EORs of at least 80%, 90%, or 98% better than EG. The eRV and eRI predicted observed residual volumes under 10, 5, and 1 ml better than EG. The eRV, eRI, and EG had low diagnostic accuracy for functional outcome changes. Higher eRV and lower eRI were strongly associated with shorter survival, independent of known prognostic factors. CONCLUSIONS The eRV and eRI predict biopsy decisions, resectability, and survival better than eloquence grading and may be useful preoperative indices to support surgical decisions.

Despite the fact that the diagnosis of dementia is mainly based on clinical criteria, the role of neuroimaging is still expanding. Among other imaging techniques, magnetic resonance imaging (MRI) plays a core role in assisting with the differentiation between various dementia syndromes and excluding other underlying pathologies that cause dementia, such as brain tumors and subdural hemorrhages. This article gives an overview of the standard MRI protocol and of structural radiological reporting systems in patients who suffer from dementia. Moreover, it presents characteristic MRI features of the most common dementia subtypes.Trotz der Tatsache, dass Demenzdiagnostik vor allem auf klinischen Kriterien basiert, erhält die Bildgebung einen immer höheren Stellenwert. Neben diversen weitern bildgebenden Verfahren spielt die Magnetresonanztomographie (MRT) eine zentrale Rolle bei der Differenzierung zwischen den unterschiedlichen Demenzsyndromen bzw. zum Ausschluss etwaiger anderer zugrunde liegender Pathologien, die eine Demenz verursachen können, wie Hirntumoren und subdurale Blutungen. Dieser Artikel gibt einerseits einen Überblick über standardisierte MRT-Protokolle sowie andererseits über eine strukturierte radiologische Befundung im Rahmen einer bildgebenden Demenzabklärung. Darüber hinaus werden charakteristische MRT-Merkmale der häufigsten Demenz-Subtypen vorgestellt.

PDGFRA has been shown to be commonly altered in high-grade gliomas (HGGs), including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a disease with almost no long-term survivors. Here, we performed comprehensive genomic and transcriptomic analysis of 260 high-grade glioma cases, which revealed PDGFRA genomic alterations (mutations and/or amplifications) in 13% of patients. H3K27M DMGs had significantly higher PDGFRA expression compared to H3 wild-type tumors, and PDGFRA gene amplification resulted in even higher expression levels in H3K27M DMGs as well as H3 wild-type HGGs. We tested a panel of patient- derived pHGG/H3K27M DMG models against a range of PDGFRA inhibitors, including avapritinib, a potent small molecule inhibitor with relatively selective activity against both wild-type and mutant PDGFRA. Avapritinib showed supra-micromolar blood-brain barrier penetration in our pre-clinical models and demonstrated significant survival impact in an aggressive patient-derived H3K27M DMG mouse xenograft model. Finally, building on this preclinical activity, we report here the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib has thus far been well tolerated with no significant acute toxicities. Most importantly, our preliminary data reveal radiographic response evaluated by RAPNO criteria in 50% of patients, a striking outcome rarely seen in this patient population. In summary, we report that avapritinib is a selective, CNS-penetrant small molecule inhibitor of PDGFRA that shows potent activity in preclinical models and produces promising clinical responses with good tolerability in patients with high-grade glioma. This suggests a promising role for avapritinib therapy in this population with previously dismal outcomes. Citation Format: Lisa Mayr, Maria Trissal, Kallen Schwark, Jenna Labelle, Andrew Groves, Julia Furtner-Srajer, Jeffrey Supko, Liesa Weiler-Wichtl, Olivia Hack, Jacob Rozowsky, Joana G. Marques, Eshini Pandatharatna, Ulrike Leiss, Verena Rosenmayr, Frank Dubois, Noah F. Greenwald, Sibylle Madlener, Armin S. Guntner, Hana Pálová, Natalia Stepien, Daniela Lötsch-Gojo, Christian Dorfer, Karin Dieckmann, Andreas Peyrl, Amedeo A. Azizi, Alicia Baumgartner, Ondřej Slabý, Petra Pokorná, Pratiti Bandopadhayay, Rameen Beroukhim, Keith Ligon, Christof Kramm, Annika Bronsema, Simon Bailey, Ana Guerreiro Stücklin, Sabine Mueller, David T. Jones, Natalie Jäger, Jaroslav Štěrba, Leonhard Müllauer, Christine Haberler, Chandan Kumar-Sinha, Arul Chinnaiyan, Rajen Mody, Mary Skrypek, Nina Martinez, Daniel C. Bowers, Carl Koschmann, Johannes Gojo, Mariella Filbin. Clinical response to the PDGFRα inhibitor avapritinib in high-grade glioma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5719.

Trastuzumab deruxtecan is an antibody–drug conjugate with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. We conducted the prospective, open-label, single-arm, phase 2 TUXEDO-1 trial. We enrolled patients aged ≥18 years with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy. Patients received trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg per kg bodyweight once every 3 weeks. The primary endpoint was intracranial response rate measured according to the response assessment in neuro-oncology brain metastases criteria. A Simon two-stage design was used to compare a null hypothesis of

Patient positioning is an integral part of surgical planning, and numerous variations have been suggested to optimize the prone position. So far, however, little attention has been given to address the restrictions and special needs in an intraoperative MRI suite.To share our experience of transforming the modified prone position from the conventional operating room to the intraoperative MRI suite.Two-room 3T intraoperative MRI suite. Detailed description of the technical pearls is provided.Ten procedures in 9 consecutive patients (2 female and 7 male) were performed. The median age was 8 years ranging from 4 to 71 years. We experienced no complication from patient positioning. Neither size (range 104-182 cm) nor weight (range 18-98 kg) of the patients was a limiting factor. In none of them, the surgeon experienced an adverse event from inadequate patient positioning and the surgical goals could be achieved without restrictions. An intraoperative MRI could be acquired in all of them with the same image quality as observed for standard positions.A transition of the modified prone position from the conventional operating room to the intraoperative MRI suite is feasible, if some crucial steps are considered. We provide a detailed technical description that could be used as a guide by others.

Perioperative stroke is a devastating complication after coronary artery bypass graft (CABG) surgery, with atherosclerosis of the ascending aorta as important risk factor. During surgical manipulation, detachment of plaques can lead to consecutive embolization into brain-supplying arteries. High-pitch computed tomography angiography (HP-CTA) represents a non-invasive imaging modality, which provides the opportunity for comprehensive imaging of the ascending aorta, including plaque detection and advanced characterization. In our present retrospective study on 719 individuals, who had undergone HP-CTA within 6 months prior to CABG, atherosclerotic disease of the ascending aorta was evaluated with respect to perioperative stroke rates. For image analysis, the ascending aorta was divided into a proximal and distal part, consisting of four segments, and evaluated for presence and distribution of calcified and mixed plaques. All patients with perioperative stroke presented with atherosclerotic disease of the ascending aorta. The stroke rate was significantly associated with the presence and extent of atherosclerotic disease. Patients burdened with mixed plaques presented with significantly higher perioperative stroke rates. This study demonstrates that HP-CTA allows accurate evaluation of plaque extent and composition in the ascending aorta, and therefore may improve risk stratification of stroke prior to CABG.

Introduction Pilocytic astrocytoma (PA) is the most common primary brain neoplasm in children and treated in curative intent with gross total resection (GTR). However, PA is rare in adults, resulting in limited knowledge on the natural clinical course. This study aimed to describe the clinical course and identify prognostic factors of adult patients with PA. Methods 46 patients ≥ 18 years at diagnosis of PA and neurosurgical resection or biopsy between 2000 and 2018 were identified from the Neuro-Biobank of the Medical University of Vienna. In two cases with differing histopathological diagnosis at recurrence, DNA methylation analysis was performed using Illumina Infinium HumanMethylation850 BeadChip (850 k) arrays and the Molecular Neuropathology classifier. Clinico-pathological features were correlated with patient outcomes. Results Median age at diagnosis was 32.5 years (range: 19–75) and median Ki67 proliferation index was 2.8% (0.5–13.4%). Tumor location significantly correlated with resectability (p 40 and higher body mass index (BMI) were associated with impaired progression-free and overall survival (p Conclusions Tumor recurrence or progression in adult PA patients was higher than the one reported in pediatric patients. Higher age and BMI were associated with impaired prognosis.

Background No systemic treatment has been established for meningioma progressing after local therapies. Methods This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. Results Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. Conclusions Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

Brain tumours that are refractory to treatment have a poor prognosis and constitute a major challenge in offering effective treatment strategies. By targeting molecular alterations, precision cancer medicine may be a viable option for the treatment of brain tumours. In this retrospective analysis of our PCM platform, we describe the molecular profiling of primary brain tumours from 50 patients. Tumour samples of the patients were examined by a 161-gene next-generation sequencing panel, immunohistochemistry, and fluorescence in situ hybridization (FISH). We identified 103 molecular aberrations in 36 (72%) of the 50 patients. The predominant mutations were TP53 (14.6%), IDH1 (9.7%) and PIK3CA (6.8%). No mutations were detected in 14 (28%) of the 50 patients. IHC demonstrated frequent overexpression of EGFR and mTOR, in 38 (76%) and 35 (70%) patients, respectively. Overexpression of PDGFRa and PDGFRb were less common and detected in 16 and four patients, respectively. For 35 patients a targeted therapy was recommended. In our database, the majority of patients displayed mutations, against which targeted therapy could be offered. Based on our observations, PCM may be a feasible novel treatment approach in neuro-oncology.

BACKGROUND Validation of the 2016 LANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. The objective of this joint EORTC Brain Tumor Group and RANO effort was to validate the feasibility of the revised MRI scorecard for assessing response in leptomeningeal metastasis. METHODS Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The kappa coefficient (K) was used to evaluate inter-observer pairwise agreement. Statistical analyses were performed using SAS V9.4 software (Cary, NC). The sponsor of the study was the University Hospital Zurich (2018-00192). RESULTS Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among leptomeningeal metastases-related items at baseline, the best median concordance was noted for hydrocephalus (K=0.63), and the worst median for spinal linear enhancing disease (K=0.46). The median concordance for overall response was moderate (K=0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was minimal (K=0.29). Significant differences were observed when considering the specialty of the raters. Only 394 of 700 ratings (56%) were fully completed. Among 394 fully completed ratings, perfect concordance was noted in 293 ratings (74%) when comparing the overall response according to the guidelines provided in the scorecard and the overall response provided by the raters. The main discordances were noted for partial response according to the rater versus stable disease according to the guidelines (n=44), followed by progression according to the raters versus stable disease according to the guidelines (n=23). CONCLUSION Electronic case report forms with "blocking solutions" are probably required to enforce completeness and quality of scoring. These results confirm the necessity of central review and the need for training of MRI assessment in clinical trials.

Pediatric high-grade glioma (pHGG) is an incurable disease with a median survival of less than 6 months post-progression and no effective targeted therapy. PDGFRA is commonly altered in pHGG, but targeting PDGFRA in this disease has been unsuccessful, likely due to poor central nervous system (CNS) penetrance. Avapritinib is a novel and CNS-penetrant PDGFRA/KIT inhibitor that is FDA-approved for adults with unresectable or metastatic PDGFRA exon 18-mutant gastrointestinal stromal tumor (GIST) and is being studied in CNS tumors. We performed a pre-clinical and clinical assessment to determine the potential suitability of avapritinib therapy in PDGFRA-driven glioma. A multi-institutional cohort genetic analysis revealed PDGFRA amplification and mutation in 10.2% and 6.1% of pHGG, respectively. Additionally, PDGFRA expression in the absence of genetic events was significantly increased in H3K27-altered diffuse midline glioma (DMG) compared to H3-wildtype pHGG. Avapritinib performed well in: (i) mutant PDGFRA enzyme inhibition and wildtype inhibition at high dose, (ii) minimal off-target kinase inhibition, (iii) brain penetration (peak 10 µM), and (iv) proliferation/pPDGFRA reduction in PDGFRA-amplified and mutant pHGG cell lines. Avapritinib treatment in an aggressive PDX model of pHGG resulted in significant survival benefit. We pursued treatment of eight pediatric and young adult HGG patients with avapritinib across seven institutions. Patients were a mixture of local (N = 4) and metastatic disease (N = 4); all patients were post-initial radiation, with 7/8 having progressed on prior treatment. 7/8 patients had PDGFRA amplifications or mutations, and 7/8 had H3K27M mutations. Therapy was generally well-tolerated. 4/8 patients showed radiographic response to avapritinib, with one patient demonstrating complete response of target lesion and remains on therapy. Avapritinib levels in patients’ CSF and brain tumor tissue reached micromolar levels. These results demonstrate that avapritinib is a potent, selective, and CNS-penetrant PDGFRA/KIT inhibitor that is promising for further study in pHGG with relevant alterations.

Background: Blood-based biomarkers may add a great benefit in detecting the earliest neuropathological changes in patients with Alzheimer’s disease (AD). We examined the utility of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) regarding clinical diagnosis and amyloid positivity in an outpatient memory clinic - based cohort. Methods: In this retrospective analysis, we included a total of 185 patients, 141 patients along clinical the AD continuum, i.e. subjective cognitive decline (SCD, n=18), mild cognitive impairment (MCI, n=63), AD (n=60) and 44 age-matched healthy controls (HC). CSF and plasma concentrations of NfL and GFAP were measured with single molecule array (SIMOAâ) technology using the Neurology 2-Plex B kit from Quanterix. Amyloid-PET was performed in 75 patients and graded as amyloid positive and negative by visual rating. To assess the discriminatory potential of different biomarkers, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong’s test for correlated AUC curves.Results: We constructed a panel combining plasma NfL and GFAP with known AD risk factors (age+sex+APOE4+GFAP+NfL panel). Using this panel, AUC was 91.6% for HC vs. AD, 81.7% for HC vs. MCI, 85% for SCD vs. AD, 81.3% for SCD vs. MCI, 77.7% for HC vs. SCD and 72.3% for MCI vs. AD. In terms of predicting amyloid PET status, we computed an AUC of 88.4%. Conclusion: The combination of plasma GFAP and NfL with well-established risk factors could contribute crucially to the identification of patients at risk, and thereby facilitate inclusion of patients in clinical trials for disease modifying therapies.

Simple Summary Neurosurgical decisions for patients with glioblastoma depend on tumor characteristics in the preoperative MR scan. Currently, this is based on subjective estimates or manual tumor delineation in the absence of a standard for reporting. We compared tumor features of 1596 patients from 13 institutions extracted from manual segmentations by a human rater and from automated segmentations generated by a machine learning model. The automated segmentations were in excellent agreement with manual segmentations and are practically equivalent regarding tumor features that are potentially relevant for neurosurgical purposes. Standard reports can be generated by open access software, enabling comparison between surgical cohorts, multicenter trials, and patient registries. Abstract Treatment decisions for patients with presumed glioblastoma are based on tumor characteristics available from a preoperative MR scan. Tumor characteristics, including volume, location, and resectability, are often estimated or manually delineated. This process is time consuming and subjective. Hence, comparison across cohorts, trials, or registries are subject to assessment bias. In this study, we propose a standardized Glioblastoma Surgery Imaging Reporting and Data System (GSI-RADS) based on an automated method of tumor segmentation that provides standard reports on tumor features that are potentially relevant for glioblastoma surgery. As clinical validation, we determine the agreement in extracted tumor features between the automated method and the current standard of manual segmentations from routine clinical MR scans before treatment. In an observational consecutive cohort of 1596 adult patients with a first time surgery of a glioblastoma from 13 institutions, we segmented gadolinium-enhanced tumor parts both by a human rater and by an automated algorithm. Tumor features were extracted from segmentations of both methods and compared to assess differences, concordance, and equivalence. The laterality, contralateral infiltration, and the laterality indices were in excellent agreement. The native and normalized tumor volumes had excellent agreement, consistency, and equivalence. Multifocality, but not the number of foci, had good agreement and equivalence. The location profiles of cortical and subcortical structures were in excellent agreement. The expected residual tumor volumes and resectability indices had excellent agreement, consistency, and equivalence. Tumor probability maps were in good agreement. In conclusion, automated segmentations are in excellent agreement with manual segmentations and practically equivalent regarding tumor features that are potentially relevant for neurosurgical purposes. Standard GSI-RADS reports can be generated by open access software.

BackgroundThe impact of time-to-surgery on clinical outcome for patients with glioblastoma has not been determined. Any delay in treatment is perceived as detrimental, but guidelines do not specify acceptable timings. In this study, we relate the time to glioblastoma surgery with the extent of resection and residual tumor volume, performance change, and survival, and we explore the identification of patients for urgent surgery.MethodsAdults with first-time surgery in 2012–2013 treated by 12 neuro-oncological teams were included in this study. We defined time-to-surgery as the number of days between the diagnostic MR scan and surgery. The relation between time-to-surgery and patient and tumor characteristics was explored in time-to-event analysis and proportional hazard models. Outcome according to time-to-surgery was analyzed by volumetric measurements, changes in performance status, and survival analysis with patient and tumor characteristics as modifiers.ResultsIncluded were 1033 patients of whom 729 had a resection and 304 a biopsy. The overall median time-to-surgery was 13 days. Surgery was within 3 days for 235 (23%) patients, and within a month for 889 (86%). The median volumetric doubling time was 22 days. Lower performance status (hazard ratio [HR] 0.942, 95% confidence interval [CI] 0.893–0.994) and larger tumor volume (HR 1.012, 95% CI 1.010–1.014) were independently associated with a shorter time-to-surgery. Extent of resection, residual tumor volume, postoperative performance change, and overall survival were not associated with time-to-surgery.ConclusionsWith current decision-making for urgent surgery in selected patients with glioblastoma and surgery typically within 1 month, we found equal extent of resection, residual tumor volume, performance status, and survival after longer times-to-surgery.

Introduction Adult brainstem gliomas (BSGs) are rare central nervous system tumours characterized by a highly heterogeneous clinical course. Median survival times range from 11 to 84 months. Beyond surgery, no treatment standard has been established. We investigated clinical and radiological data to assess prognostic features providing support for treatment decisions. Methods 34 BSG patients treated between 2000 and 2019 and aged ≥ 18 years at the time of diagnosis were retrospectively identified from the databases of the two largest Austrian Neuro-Oncology centres. Clinical data including baseline characteristics, clinical disease course, applied therapies, the outcome as well as neuroradiological and neuropathological findings were gathered and analysed. The tumour apparent diffusion coefficient (ADC), volumetry of contrast-enhancing and non-contrast-enhancing lesions were determined on magnetic resonance imaging scans performed at diagnosis. Results The median age at diagnosis was 38.5 years (range 18–71 years). Tumour progression occurred in 26/34 (76.5%) patients after a median follow up time of 19 months (range 0.9–236.2). Median overall survival (OS) and progression-free survival (PFS) was 24.1 months (range 0.9–236.2; 95% CI 18.1–30.1) and 14.5 months (range 0.7–178.5; 95% CI 5.1–23.9), respectively. Low-performance status, high body mass index (BMI) at diagnosis and WHO grading were associated with shorter PFS and OS at univariate analysis (p p = 0.018). Conclusion ECOG, BMI, WHO grade and ADC values were associated with the survival prognosis of BSG patients and should be included in the prognostic assessment.

The prediction of the individual prognosis of low-grade glioma (LGG) patients is limited in routine clinical practice. Nowadays, 5-aminolevulinic acid (5-ALA) fluorescence is primarily applied for improved intraoperative visualization of high-grade gliomas. However, visible fluorescence is also observed in rare cases despite LGG histopathology and might be an indicator for aggressive tumor behavior. The aim of this study was thus to investigate the value of intraoperative 5-ALA fluorescence for prognosis in LGG patients. We performed a retrospective analysis of patients with newly diagnosed histopathologically confirmed LGG and preoperative 5-ALA administration at two independent specialized centers. In this cohort, we correlated the visible intraoperative fluorescence status with progression-free survival (PFS), malignant transformation-free survival (MTFS) and overall survival (OS). Altogether, visible fluorescence was detected in 7 (12%) of 59 included patients in focal intratumoral areas. At a mean follow-up time of 5.3 ± 2.9 years, patients with fluorescing LGG had significantly shorter PFS (2.3 ± 0.7 vs. 5.0 ± 0.4 years, p = 0.01), MTFS (3.9 ± 0.7 vs. 8.0 ± 0.6 years, p = 0.03), and OS (5.4 ± 1.0 vs. 10.3 ± 0.5 years, p = 0.01) than non-fluorescing tumors. Our data indicate that visible 5-ALA fluorescence during surgery of pure LGG might be an already intraoperatively available marker of unfavorable patient outcome and thus close imaging follow-up might be considered.

Background: Intraoperative semiquantitative classification of different visible 5-aminolevulinic acid (5-ALA) fluorescence levels by the neurosurgeon is subjective. Recently, handheld spectroscopic probes were introduced enabling quantitative analysis of 5-ALA induced fluorescence intensity (FI). The aim of this ex-vivo study was to correlate the FI in gliomas of different grades with histopathology, proliferation and microvasular density (MVD). Patients and Methods: Patients with suspected World Health Organization (WHO) grade II-IV gliomas were included and tissue samples from different visible fluorescence levels (strong, vague or none) were intraoperatively collected. After resection, the FI of each sample was investigated ex-vivo by a handheld spectroscopic probe. The FI values were correlated with visible fluorescence, histopathology (WHO grade, quality of tissue, histopathological parameters of anaplasia), proliferation (MIB-1) and MVD. Results: Altogether, 143 tumor samples with strong (n = 61), vague (n = 21) and no fluorescence (n = 61) were collected in 68 patients. We found significantly different median FI values between all three visible fluorescence levels. Moreover, the median FI value was significantly higher in WHO grade III/IV samples and compact tumor tissue compared to WHO grade II samples and infiltrated tumor tissue. Further, significant differences in median FI values were observed in specific histopathological parameters of anaplasia (mitotic rate, cell density, nuclear pleomorphism and microvascular proliferation) in multivariable analysis. Finally, a significant correlation between the proliferation rate and FI, but not between MVD and FI was noted. Conclusion: Our data indicate that handheld spectroscopic probes are capable of visualizing intratumoral glioma heterogeneity by objective assessment of fluorescence and may thus optimize future glioma surgery.

PURPOSE: Using conventional magnetic resonance imaging (MRI) techniques, the imaging features of meningiomas and dural metastases overlap and a differentiation between these tumor entities therefore remains difficult, particularly in patients with a known primary neoplasm. The purpose of this study was to explore the potential role of normalized vascular intratumoral signal intensity values (nVITS) obtained from pulsed arterial spin labeling (PASL) to differentiate between meningiomas and dural metastases. METHODS: In this study PASL was performed in 46 patients with meningiomas (n = 30) and dural metastases (n = 16) on a 3T scanner, in addition to the routine diagnostic imaging protocol. The ratio between the vascular signal intensity of the tumor and the contralateral normal white matter obtained by PASL images was defined as nVITS. RESULTS: Meningiomas showed significantly higher nVITS values compared to dural metastases (p < 0.001). The optimal nVITS cut-off value to differentiate between the 2 tumor entities was 1.989, with 100% sensitivity and 81.2% specificity. CONCLUSION: The nVITS values obtained by PASL provide a fast and noninvasive MRI technique with which to differentiate between meningiomas and dural metastases in a routine clinical setting based on tumor vascularity.

Background Despite strongly overlapping patterns of clinical and histopathologic findings in primary and secondary progressive multiple sclerosis, differences concerning motor symptoms, central nervous system inflammation, atrophy, and demyelination that cannot be accounted for by lesion load alone remain to be elucidated. Purpose To evaluate the normal-appearing deep gray matter in patients with primary and secondary progressive multiple sclerosis, diffusion tensor imaging was used in this study. Material and Methods In 14 multiple sclerosis patients with primary and secondary progressive multiple sclerosis, axial echo-planar single-shot diffusion tensor imaging sequences with 32 diffusion-encoding directions and axial FLAIR sequences were acquired on a 3T system using an eight-channel SENSE head coil. FLAIR hyperintense multiple sclerosis lesions were outlined semi-automatically and normal-appearing deep gray matter was outlined manually (caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus). Fractional anisotropy and mean diffusivity values within the normal-appearing deep gray matter for the two groups were compared. Results Interhemispheric differences in mean diffusivity values (but not in fractional anisotropy), were significantly higher in primary progressive multiple sclerosis than in secondary progressive multiple sclerosis for the substantia nigra ( P = 0.04) and the putamen ( P = 0.021). Volumes, mean diffusivity, or fractional anisotropy of the remaining normal-appearing deep gray matter did not differ significantly. Conclusion This study showed a higher interhemispheric difference in the mean diffusivity in the substantia nigra and putamen in patients with primary progressive multiple sclerosis than in those with secondary progressive multiple sclerosis. These changes may represent edema, as well as axonal and myelin loss that can affect the normal-appearing deep gray matter of the two hemispheres differently and may point to differences in the laterality of motor symptoms.

Objectives To demonstrate the feasibility of 7 T magnetic resonance spectroscopic imaging (MRSI), combined with patch-based super-resolution (PBSR) reconstruction, for high-resolution multi-metabolite mapping of gliomas. Materials and methods Ten patients with WHO grade II, III and IV gliomas (6/4, male/female; 45 ± 9 years old) were prospectively measured between 2014 and 2018 on a 7 T whole-body MR imager after routine 3 T magnetic resonance imaging (MRI) and positron emission tomography (PET). Free induction decay MRSI with a 64 × 64-matrix and a nominal voxel size of 3.4 × 3.4 × 8 mm³ was acquired in six minutes, along with standard T1/T2-weighted MRI. Metabolic maps were obtained via spectral LCmodel processing and reconstructed to 0.9 × 0.9 × 8 mm³ resolutions via PBSR. Results Metabolite maps obtained from combined 7 T MRSI and PBSR resolved the density of metabolic activity in the gliomas in unprecedented detail. Particularly in the more heterogeneous cases (e.g. post resection), metabolite maps enabled the identification of complex metabolic activities, which were in topographic agreement with PET enhancement. Conclusions PBSR-MRSI combines the benefits of ultra-high-field MR systems, cutting-edge MRSI, and advanced postprocessing to allow millimetric resolution molecular imaging of glioma tissue beyond standard methods. An ideal example is the accurate imaging of glutamine, which is a prime target of modern therapeutic approaches, made possible due to the higher spectral resolution of 7 T systems.

BACKGROUND: A growing body of evidence has supported alternatives to sedation and general anesthesia for increasing treatment compliance of children during MRI examinations. Particularities in children with a brain tumor (frequency of examinations, neuropsychological deficits (attention, memory)) have a significant impact on methods of treatment and are given special consideration in this study. OBJECTIVE: The aim of the present study was to (1) evaluate the effectiveness of an MRI training program and to investigate the moderating factors for successful MRI examination for a group of young patients with pediatric brain tumors and/or NF1 and (2) to examine the effect of the training on the patient’s well-being. METHODS: A total of 87 in the retrospective analyses (Study 1) and a subgroup of 17 patients in the prospective analyses (Study 2, ClinicalTrials.gov: NCT04474678) of the neuro-oncology unit with a mean age of 6.83 years underwent a two-step program to prepare children for MRI, including an in vitro strategy training inside the scanner and were recorded using a process-oriented screening. RESULTS: 81 % of the children who had received MRI training managed to successfully undergo the MRI scan. Hence, the rate of successful MRI examinations without anesthesia was almost five times as high in the group that received MRI training compared to the group that did not. Memory, attentional difficulties and hyperactivity were significant neuropsychological moderators for successful or unsuccessful scanning. Furthermore, the training was effective in improving the psychological well-being of the patients. CONCLUSION: Based on the results, the MRI training is an effective alternative to sedation of young patients for MRI examinations and a promising tool for improving patient well-being related to the diagnostic procedure. However, the intervention needs to be customized according to the children’s individual neuropsychological difficulties, which requires specialized psychological staff and an interdisciplinary approach.

H3K27M-mutated diffuse midline glioma (H3K27M DMG) are an almost universally fatal disease with a median survival of less than 6 months post progression and no effective therapy. PDGFRA-signaling has shown to promote and sustain a subset of oligodendrocyte precursor-like tumor cells that are responsible for tumor propagating potential and high proliferation rates. However, first attempts to target PDGFRA in adult glioblastoma with dasatinib/imatinib or pediatric refractory brain tumors with sunitinib were not successful. We report on the first experience in two patients receiving avapritinib, a highly potent, selective, brain penetrant PDGFRA/KIT inhibitor under a compassionate use program. Our first patient with spinal H3K27M DMG developed supratentorial metastases ten months after initial diagnosis. Molecular profiling revealed de novo PDGFRA and KIT amplifications and treatment with dasatinib was initiated. Due to disease progression and novel metastases, therapy was switched to avapritinib showing near complete resolution of the previously unirradiated frontal lesion with additional disease stabilization of other metastatic sites. Following re-resection and irradiation of progressing cerebellar lesions, the patient remains clinically stable on avapritinib therapy over 12 months. The second patient with diffuse intrinsic pontine glioma showed disease progression nine months after diagnosis and was treated with focal re-irradiation (30Gy). As the tumor harbored a PDGFRA R841del alteration, avapritinib was initiated seven weeks after radiation upon further tumor progression resulting in partial response. Pharmacokinetic sampling of cerebrospinal fluid (CSF) detected an increasing CSF/plasma ratio over time and up to 4 µM avapritinib in tumor tissue. Avapritinib CSF levels in both patients were distinctly higher than dasatinib levels. Avapritinib was generally well tolerated besides lower limb edema, elevated LDH and liver enzymes. Hence, effective CNS penetration of avapritinib at pharmacologically relevant brain tumor concentrations resulted in clinical response in two patients with rapidly progressive H3K27M DMG.

Objective: In surgery for meningiomas tumor location and extension is currently the only MRI characteristic used to predict the feasibility and difficulty of the resection. Key surgical tumor characteristics such as consistency and vascularity remain obscured until the tumor is exposed. We therefore aimed to identify MRI sequences able to predict these crucial meningioma features.Methods: We retrospectively reviewed our imaging database on cranial meningiomas and correlated MRI T2W, T1W, and FLAIR images with the consistency and vascularity reported by the surgeon in the operative notes. The reported consistency was classified into three grades [°I (soft) to °III (hard)]. Vascularity was grouped into little (°I) versus strong (°II). MRI signal intensity (SI) ratios were calculated with ROIs in the meningioma, the buccinator muscle and the frontal white matter.Results: Of the 172 reviewed patients, 44 met the strict inclusion criteria with respect to the quality of the OR notes. The included meningiomas were located at the convexity (11/44), falcine (3/44), skull base (14/44), and posterior fossa (16/44). Twenty-four meningiomas (54.5%) were classified as consistency grade (°)I, seven (15.9%) °II, and thirteen (29.5%) °III. The grade of vascularization was little in 12 and strong in 14. The higher the ratio on T2W images the softer (p = 0.020) and the more vascularized (p = 0.001) the tumor presented.Discussion: T2W MR images may be helpful to characterize meningiomas with regard to the expected consistency and grade of vascularization.

Summary Objective The purpose of our functional magnetic resonance imaging (fMRI) study was to examine brain activity using a “1-back” paradigm as working memory task in drug-naïve subjects with first episode schizophrenia before and after cognitive remediation training. Methods In this study 15 drug-naïve first episode subjects who met DSM-IV criteria for schizophrenia were randomized to receive either atypical antipsychotics (AP, n = 8) or atypical antipsychotics in combination with cognitive remediation therapy (AP + CR, n = 7), 11 subjects had a follow-up fMRI examination after therapy (AP, n = 5; AP + CR, n = 6). Results In 4 of the 6 AP + CR subjects the number of activation clusters increased, whereas in 4 out of the 5 AP subjects the number of clusters decreased (mean number of clusters: AP + CR = 5.53, SD 12.79, AP = −5.8, SD 6.9). Conclusion In this randomized study the number of activation clusters during a working memory task increased after cognitive remediation training. Our data show that neurobiological effects of cognitive remediation can be identified in the very early course of schizophrenia.

Meningiomas are classified based on histological features, but genetic and epigenetic features are emerging as relevant biomarkers for outcome prediction and may supplement histomorphological evaluation. We investigated meningioma-relevant mutations and their correlation with DNA methylation clusters and patient survival times. Formalin-fixed and paraffin-embedded samples of 126 meningioma patients (WHO grade I 52/126; 41.3%; WHO grade II: 48/126; 38.1%; WHO grade III: 26/126; 20.6%) were investigated. We analyzed NF2, TRAF7, KLF4, ARID, SMO, AKT, TERT promotor, PIK3CA, and SUFU mutations using panel sequencing and correlated them to DNA methylation classes (MC) determined using 850k EPIC arrays. The TRAKL mutation genotype was characterized by the presence of any of the following mutations: TRAF7, AKT1, and KLF4. Survival data including progression-free survival (PFS) and overall survival (OS) was retrieved from chart review. Mutations were evident in 90/126 (71.4%) specimens with mutations in NF2 (39/126; 31.0%), TRAF7 (39/126; 31.0%) and KLF4 (25/126; 19.8%) being the most frequent ones. Two or more mutations were observed in 35/126 (27.8%) specimens. While TRAKL was predominantly found in benign MC, NF2 was associated with malign MC (p 0.05). TRAF7, KLF4, and TRAKL mutation genotype were associated with improved PFS and OS (p 0.05). TERT promotor methylation, intermediate, and malign MC were associated with impaired PFS and OS (p 0.05). Methylation cluster showed better prognostic discrimination for PFS and OS (c-index 0.77/0.75) than each of the individual mutations (c-index 0.63/0.68). In multivariate analysis correcting for age, gender, MC, and WHO grade, none of the individual mutations except TERT remained an independent significant prognostic factor for PFS. Molecular profiling including mutational analysis and DNA methylation classification may facilitate more precise prognostic assessment and identification of potential targets for personalized therapy in meningioma patients.

BackgroundSome sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma.Patients and methodsWe retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data.Results35 patients (median age of 50 (23–81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)–receptor interaction.ConclusionsOur data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma.

In this study, we assessed the prognostic relevance of temporal muscle thickness (TMT), likely reflecting patient’s frailty, in patients with primary central nervous system lymphoma (PCNSL). In 128 newly diagnosed PCNSL patients TMT was analyzed on cranial magnetic resonance images. Predefined sex-specific TMT cutoff values were used to categorize the patient cohort. Survival analyses, using a log-rank test as well as Cox models adjusted for further prognostic parameters, were performed. The risk of death was significantly increased for PCNSL patients with reduced muscle thickness (hazard ratio of 3.189, 95% CI: 2–097–4.848, p &lt, 0.001). Importantly, the results confirmed that TMT could be used as an independent prognostic marker upon multivariate Cox modeling (hazard ratio of 2.504, 95% CI: 1.608–3.911, p &lt, 0.001) adjusting for sex, age at time of diagnosis, deep brain involvement of the PCNSL lesions, Eastern Cooperative Oncology Group (ECOG) performance status, and methotrexate-based chemotherapy. A TMT value below the sex-related cutoff value at the time of diagnosis is an independent adverse marker in patients with PCNSL. Thus, our results suggest the systematic inclusion of TMT in further translational and clinical studies designed to help validate its role as a prognostic biomarker.

Simple Summary In a recent study, we observed 5-ALA fluorescence not only in brain metastases (BM) but also in the peritumoral brain tissue. However, the histopathological correlate of visible 5-ALA fluorescence in the peritumoral brain tissue is not fully understood. Therefore, we safely collected and analyzed tissue samples from fluorescing and non-fluorescing peritumoral brain tissue. Surprisingly, 5-ALA fluorescence in the peritumoral brain tissue did not correlate with tumor cell infiltration but did show a significant relation with angiogenesis. Moreover, the presence of angiogenesis significantly correlated with shorter time to local progression/recurrence and one-year survival. Consequently, angiogenesis in the peritumoral brain tissue might be a novel prognostic marker in BM. This represents the first study in the literature describing the prognostic impact of angiogenesis in fluorescent peritumoral brain tissue of BM, which might support individualized perioperative treatment concepts in the future. Abstract Complete resection is an indispensable treatment option in the management of brain metastases (BM). 5-aminolevulinic acid (5-ALA) fluorescence is used for improved intraoperative visualization of tumor tissue in gliomas and was recently observed in BM. We investigated the potential of 5-ALA fluorescence to visualize the infiltrative growth of BM in the peritumoral brain tissue and its histopathological correlate. Patients with BM resection after 5-ALA administration and collection of tissue samples from peritumoral brain tissue were included. Each tissue sample was histopathologically investigated for tumor cell infiltration and angiogenesis. Altogether, 88 samples were collected from the peritumoral brain tissue in 58 BM of 55 patients. Visible 5-ALA fluorescence was found in 61 (69%) of the samples, tumor infiltration in 19 (22%) and angiogenesis in 13 (15%) of samples. Angiogenesis showed a significant correlation with presence of fluorescence (p = 0.008). Moreover, angiogenesis was related to visible 5-ALA fluorescence and showed an association with patient prognosis since it was significantly correlated to shorter time to local progression/recurrence (p = 0.001) and lower one-year survival (p = 0.031). Consequently, angiogenesis in the peritumoral brain tissue of BM might be a novel prognostic marker for individualized perioperative treatment concepts in the future.

Simple Summary Neurosurgical decisions for patients with glioblastoma depend on visual inspection of a preoperative MR scan to determine the tumor characteristics. To avoid subjective estimates and manual tumor delineation, automatic methods and standard reporting are necessary. We compared and extensively assessed the performances of two deep learning architectures on the task of automatic tumor segmentation. A total of 1887 patients from 14 institutions, manually delineated by a human rater, were compared to automated segmentations generated by neural networks. The automated segmentations were in excellent agreement with the manual segmentations, and external validity, as well as generalizability were demonstrated. Together with automatic tumor feature computation and standardized reporting, our Glioblastoma Surgery Imaging Reporting And Data System (GSI-RADS) exhibited the potential for more accurate data-driven clinical decisions. The trained models and software are open-source and open-access, enabling comparisons among surgical cohorts, multicenter trials, and patient registries. Abstract For patients with presumed glioblastoma, essential tumor characteristics are determined from preoperative MR images to optimize the treatment strategy. This procedure is time-consuming and subjective, if performed by crude eyeballing or manually. The standardized GSI-RADS aims to provide neurosurgeons with automatic tumor segmentations to extract tumor features rapidly and objectively. In this study, we improved automatic tumor segmentation and compared the agreement with manual raters, describe the technical details of the different components of GSI-RADS, and determined their speed. Two recent neural network architectures were considered for the segmentation task: nnU-Net and AGU-Net. Two preprocessing schemes were introduced to investigate the tradeoff between performance and processing speed. A summarized description of the tumor feature extraction and standardized reporting process is included. The trained architectures for automatic segmentation and the code for computing the standardized report are distributed as open-source and as open-access software. Validation studies were performed on a dataset of 1594 gadolinium-enhanced T1-weighted MRI volumes from 13 hospitals and 293 T1-weighted MRI volumes from the BraTS challenge. The glioblastoma tumor core segmentation reached a Dice score slightly below 90%, a patientwise F1-score close to 99%, and a 95th percentile Hausdorff distance slightly below 4.0 mm on average with either architecture and the heavy preprocessing scheme. A patient MRI volume can be segmented in less than one minute, and a standardized report can be generated in up to five minutes. The proposed GSI-RADS software showed robust performance on a large collection of MRI volumes from various hospitals and generated results within a reasonable runtime.

Background: Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown. Methods: Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into ‘TP’, ‘other-HER2-targeted therapy’ and ‘no-HER2-targeted therapy’ according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM). Results: A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p Conclusion: First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.

BACKGROUNDS We aimed to evaluate the potential of radiomics as an imaging biomarker for GBM patients and explore the molecular rationale behind radiomics by radio-genomics approach. METHODS A total of 144 primary GBM patients were included in this study as a training cohort. Using multi-parametric MR images, radiomics features were extracted from multi-habitats of the tumor. We applied Cox-LASSO algorithm to build a survival prediction model and validated this model using an independent validation cohort (56 patients from Vienna). With the selected radiomics features, GBM patients were consensus clustered to reveal inherent phenotypic subtypes. The subtypes were further explored in terms of genomic signatures. RESULTS GBM patients were successfully stratified by the radiomics risk score, a weighted sum of radiomics features, corroborating the potential of radiomics as a prognostic biomarker. Using consensus clustering, we identified three distinct subtypes which significantly differed in the prognosis (‘heterogenous enhancing’, ‘rim-enhancing necrotic’, and ‘cystic’ subtype). Multi-variate cox regression analysis confirmed that radiomics subtype as an independent prognostic factor. Transcriptomic traits enriched in individual subtypes were in accordance with imaging phenotypes summarized by radiomics. For example, rim-enhancing necrotic subtype was well described by radiomics profiling (T2 autocorrelation & flat shape) and highlighted by the inflammatory genomic signatures, which well correlated to its phenotypic peculiarity (necrosis). CONCLUSIONS The present study confirmed the feasibility of radiomics as an imaging biomarker for GBM patients with comprehensible biologic annotation. Imaging subtypes derived from radiomics successfully recapitulate the genomic underpinnings of GBM tumors and in turn reinforce their potential as a prognostic biomarker.

Glioblastoma might have widespread effects on the neural organization and cognitive function, and even focal lesions may be associated with distributed functional alterations. However, functional changes do not necessarily follow obvious anatomical patterns and the current understanding of this interrelation is limited. In this study, we used resting-state functional magnetic resonance imaging to evaluate changes in global functional connectivity patterns in 15 patients with glioblastoma. For six patients we followed longitudinal trajectories of their functional connectome and structural tumour evolution using bi-monthly follow-up scans throughout treatment and disease progression. In all patients, unilateral tumour lesions were associated with inter-hemispherically symmetric network alterations, and functional proximity of tumour location was stronger linked to distributed network deterioration than anatomical distance. In the longitudinal subcohort of six patients, we observed patterns of network alterations with initial transient deterioration followed by recovery at first follow-up, and local network deterioration to precede structural tumour recurrence by two months. In summary, the impact of focal glioblastoma lesions on the functional connectome is global and linked to functional proximity rather than anatomical distance to tumour regions. Our findings further suggest a relevance for functional network trajectories as a possible means supporting early detection of tumour recurrence.

Purpose To improve the robustness of deep learning–based glioblastoma segmentation in a clinical setting with sparsified datasets. Materials and Methods In this retrospective study, preoperative T1-weighted, T2-weighted, T2-weighted fluid-attenuated inversion recovery, and postcontrast T1-weighted MRI from 117 patients (median age, 64 years; interquartile range [IQR], 55–73 years; 76 men) included within the Multimodal Brain Tumor Image Segmentation (BraTS) dataset plus a clinical dataset (2012–2013) with similar imaging modalities of 634 patients (median age, 59 years; IQR, 49–69 years; 382 men) with glioblastoma from six hospitals were used. Expert tumor delineations on the postcontrast images were available, but for various clinical datasets, one or more sequences were missing. The convolutional neural network, DeepMedic, was trained on combinations of complete and incomplete data with and without site-specific data. Sparsified training was introduced, which randomly simulated missing sequences during training. The effects of sparsified training and center-specific training were tested using Wilcoxon signed rank tests for paired measurements. Results A model trained exclusively on BraTS data reached a median Dice score of 0.81 for segmentation on BraTS test data but only 0.49 on the clinical data. Sparsified training improved performance (adjusted P < .05), even when excluding test data with missing sequences, to median Dice score of 0.67. Inclusion of site-specific data during sparsified training led to higher model performance Dice scores greater than 0.8, on par with a model based on all complete and incomplete data. For the model using BraTS and clinical training data, inclusion of site-specific data or sparsified training was of no consequence. Conclusion Accurate and automatic segmentation of glioblastoma on clinical scans is feasible using a model based on large, heterogeneous, and partially incomplete datasets. Sparsified training may boost the performance of a smaller model based on public and site-specific data. Supplemental material is available for this article. Published under a CC BY 4.0 license.

Background Salvage treatment for recurrent brain metastases (BM) of solid cancers is challenging due to the high symptomatic burden and the limited local treatment options. Methods Patients with recurrent BM with no option for further local therapies were retrospectively identified from BM databases. Bevacizumab-based treatment was initiated as a salvage treatment. Radiological imaging before and after bevacizumab-based treatment was reevaluated for treatment response using the Response Assessment in Neuro-Oncology (RANO) BM criteria. Results Twenty-two patients (36.4% male) with recurrent BM from breast cancer (40.9%), colorectal cancer (31.8%), or lung cancer (27.3%) were identified. Previous BM-directed therapies were radiosurgery in 16/22 (72.7%) patients, whole-brain radiotherapy in 8/22 (36.4%), and neurosurgical resection in 11/22 (50.0%). Time since BM diagnosis to initiation of bevacizumab treatment was 16.5 months. Of 22 patients 14 (63.6%) received concurrent systemic therapies. Neurological symptom improvement could be achieved in 14/22 (63.6%) and stabilization in 6/22 (27.3%) patients, resulting in a clinical benefit in 20/22 (90.9%) patients. Steroids could be reduced or stopped in 15/22 (68.2%) patients. Rate of improvement on T1-weighted imaging was 15/19 (78.9%; median reduction: −26.0% ± 32.9) and 19/20 (95%; median reduction: −36.2% ± 22.2) on T2-weighted FLAIR imaging. According to RANO-BM best response was partial response in 7/19 (36.8%), stable disease in 9/19 (47.3%), and progressive disease in 3/19 (15.7%) patients. Median CNS-specific progression-free survival was 8 months and median overall survival after initiation of bevacizumab treatment was 17 months. Conclusions Bevacizumab-based treatment had clinically relevant intracranial activity in the vast majority of patients suffering from recurrent, symptomatic BM. The data supports a prospective clinical trial of bevacizumab as a salvage treatment in BM.

Sex-specific differences have been increasingly recognized in many human diseases including brain cancer, namely glioblastoma. Primary CNS lymphoma (PCNSL) is an exceedingly rare type of brain cancer that tends to have a higher incidence and worse outcomes in male patients. Yet, relatively little is known about the reasons that contribute to these observed sex-specific differences. Using a population-representative cohort of patients with PCNSL with dense magnetic resonance (MR) imaging and digital pathology annotation (n = 74), we performed sex-specific cluster and survival analyses to explore possible associations. We found three prognostically relevant clusters for females and two for males, characterized by differences in (i) patient demographics, (ii) tumor-associated immune response, and (iii) MR imaging phenotypes. Upon a multivariable analysis, an enhanced FoxP3+ lymphocyte-driven immune response was associated with a shorter overall survival particularly in female patients (HR 1.65, p = 0.035), while an increased extent of contrast enhancement emerged as an adverse predictor of outcomes in male patients (HR 1.05, p &lt, 0.01). In conclusion, we found divergent prognostic constellations between female and male patients with PCNSL that suggest differential roles of tumor-associated immune response and MR imaging phenotypes. Our results further underline the importance of continued sex-specific analyses in the field of brain cancer.

Background Neurosurgical resection represents an important treatment option in the modern, multimodal therapy approach of brain metastases (BM). Guidelines for perioperative imaging exist for primary brain tumors to guide postsurgical treatment. Optimal perioperative imaging of BM patients is so far a matter of debate as no structured guidelines exist. Methods A comprehensive questionnaire about perioperative imaging was designed by the European Association of Neuro-Oncology (EANO) Youngsters Committee. The survey was distributed to physicians via the EANO network to perform a descriptive overview on the current habits and their variability on perioperative imaging. Chi square test was used for dichotomous variables. Results One hundred twenty physicians worldwide responded to the survey. MRI was the preferred preoperative imaging method (93.3%). Overall 106/120 (88.3%) physicians performed postsurgical imaging routinely including MRI alone (62/120 [51.7%]), postoperative CT (29/120 [24.2%]) and MRI + CT (15/120 [12.5%]). No correlation of postsurgical MRI utilization in academic vs. non-academic hospitals (58/89 [65.2%] vs. 19/31 [61.3%], p = 0.698) was found. Early postoperative MRI within ≤72 h after resection is obtained by 60.8% of the participants. The most frequent reason for postsurgical imaging was to evaluate the extent of tumor resection (73/120 [60.8%]). In case of residual tumor, 32/120 (26.7%) participants indicated to adjust radiotherapy, 34/120 (28.3%) to consider re-surgery to achieve complete resection and 8/120 (6.7%) to evaluate both. Conclusions MRI was the preferred imaging method in the preoperative setting. In the postoperative course, imaging modalities and timing showed high variability. International guidelines for perioperative imaging with special focus on postoperative MRI to assess residual tumor are warranted to optimize standardized management and adjuvant treatment decisions for BM patients.

Background Extent of resection (EOR) constitutes a crucial factor for patient prognosis in surgery of brain metastases (BMs). According to early studies using postoperative magnetic resonance imaging (MRI), an unexpected residual tumor was not uncommon. Knowledge of potential risk factors for incomplete BM resection would be of major importance to optimize surgical strategies. The aim of this study was to evaluate EOR in a large cohort and analyze potential risk factors for incomplete BM resection. Methods Patients with BM resection and available postoperative MRI were included. Intraoperative estimation of EOR by the neurosurgeon was noted. Additionally, EOR was determined by postoperative MRI. Potential risk factors for incomplete resection were investigated. Results There were 145 patients with 163 BMs included. According to postoperative MRI, complete resection was achieved in 103 (63%) BMs, and resection was incomplete in 44 (27%) BMs. Postoperative MRI detected unexpected residual tumor in 32 (25%) BMs, and a misjudgment of the EOR by the neurosurgeon was found in 29% of cases. Regarding risk factors for incomplete resection, preoperative tumor volume was significantly larger in incompletely resected BMs compared with completely resected BMs (P = 0.011). All other analyzed risk factors had no significant influence on EOR. Conclusions Our data indicate that postoperative MRI is able to detect a high portion of unexpected residual tumors after surgery of BMs. Preoperative tumor volume in particular represents an important risk factor for incomplete resection, and hence neurosurgeons should pay special attention to avoid residual tumor tissue.

OBJECTIVEGross-total resection (GTR) is the treatment of choice in the majority of patients suffering from spinal ependymal tumors. In such tumors, the extent of resection (EOR) is considered the key factor for tumor recurrence and thus patient prognosis. However, incomplete resection is not uncommon and leads to increased risk of tumor recurrence. One important cause of incomplete resection is insufficient intraoperative visualization of tumor tissue as well as residual tumor tissue. Therefore, the authors investigated the value of 5-aminolevulinic acid (5-ALA)–induced fluorescence in a series of spinal ependymal tumors for improved tumor visualization.METHODSAdult patients who underwent preoperative 5-ALA administration and surgery for a spinal ependymal tumor were included in this study. For each tumor, a conventional white-light microsurgical resection was performed. Additionally, the fluorescence status (strong, vague, or no fluorescence) and fluorescence homogeneity (homogenous or inhomogeneous) of the spinal ependymal tumors were evaluated during surgery using a modified neurosurgical microscope. In intramedullary tumor cases with assumed GTR, the resection cavity was investigated for potential residual fluorescing foci under white-light microscopy. In cases with residual fluorescing foci, these areas were safely resected and the corresponding samples were histopathologically screened for the presence of tumor tissue.RESULTSIn total, 31 spinal ependymal tumors, including 27 intramedullary tumors and 4 intradural extramedullary tumors, were included in this study. Visible fluorescence was observed in the majority of spinal ependymal tumors (n = 25, 81%). Of those, strong fluorescence was noted in 23 of these cases (92%), whereas vague fluorescence was present in 2 cases (8%). In contrast, no fluorescence was observed in the remaining 6 tumors (19%). Most ependymal tumors demonstrated an inhomogeneous fluorescence effect (17 of 25 cases, 68%). After assumed GTR in intramedullary tumors (n = 15), unexpected residual fluorescing foci within the resection cavity could be detected in 5 tumors (33%). These residual fluorescing foci histopathologically corresponded to residual tumor tissue in all cases.CONCLUSIONSThis study indicates that 5-ALA fluorescence makes it possible to visualize the majority of spinal ependymal tumors during surgery. Unexpected residual tumor tissue could be detected with the assistance of 5-ALA fluorescence in approximately one-third of analyzed intramedullary tumors. Thus, 5-ALA fluorescence might be useful to increase the EOR, particularly in intramedullary ependymal tumors, in order to reduce the risk of tumor recurrence.

Temporal muscle thickness (TMT) was investigated as a novel surrogate marker on MRI examinations of the brain, to detect patients who may be at risk for sarcopenia. TMT was analyzed in a retrospective, normal collective cohort (n = 624), to establish standard reference values. These reference values were correlated with grip strength measurements and body mass index (BMI) in 422 healthy volunteers and validated in a prospective cohort (n = 130) of patients with various neurological disorders. Pearson correlation revealed a strong association between TMT and grip strength (retrospective cohort, &rho, = 0.746, p &lt, 0.001, prospective cohort, &rho, = 0.649, 0.001). A low or no association was found between TMT and age (retrospective cohort, R2 correlation coefficient 0.20, = &minus, 0.199, p = 0.023), or BMI (retrospective cohort, &rho, = 0.116, p = 0.042, = 0.227, p = 0.009), respectively. Male patients with temporal wasting and unintended weight loss, respectively, showed significantly lower TMT values (p = 0.04 and p = 0.015, unpaired t-test). TMT showed a high correlation with muscle strength in healthy individuals and in patients with various neurological disorders. Therefore, TMT should be integrated into the diagnostic workup of neurological patients, to prevent, delay, or treat sarcopenia.

We document the case of a young adult female patient who presented with multiple intracerebral and extracerebral bone lesions, the latter most prominently along the vertebral column. The spatially distinct intracerebral lesions included a superficial frontal tumor nodule as well as diffuse enlargement of the pons. Differential diagnoses ranged from neoplastic to inflammatory conditions. Repeated bone biopsies yielded uncharacteristic reactive changes whereas cerebrospinal fluid cytology pointed towards a neoplastic disease. Resection of the superficial frontal tumor nodule prompted the diagnosis of an unusual "gliofibroma" with anaplastic features, WHO grade III. TMZ chemotherapy was initiated and led to intracranial disease stabilization, whereas the bone lesions were progressive. At 16 months after diagnosis, new brain lesions occurred, and further progression of the brain stem lesion led to clinical deterioration and patient death. Postmortem examination confirmed extensively disseminated intracranial disease with unusually striking morphologic heterogeneity across the various lesions ranging from diffuse spindle-celled areas to perivascular rosettes and embryonal-like areas. The morphologic heterogeneity was in contrast to shared epigenomic and copy number profiles supporting a common origin. Of note, molecular markers and DNA methylation-based classifier scores did not allow for unequivocal glioma classification. Ultimately, the bone lesions revealed scattered nests of GFAP-positive cells, thus confirming them as glioma-derived metastases. No other systemic organ involvement was found. In summary, this case 1) illustrates the strikingly heterogeneous morphological landscape of malignant gliomas, 2) serves as an example for rare cases that do not fit in any diagnostic category despite extensive molecular profiling, and 3) highlights the potential of gliomas for early systemic metastases - in the present case with selectivity for the bones.