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The gold standard for precise diagnostic classification of brain tumors requires tissue sampling, which carries relevant procedural risks. Brain biopsies often have limited sensitivity and fail to address tumor heterogeneity, because small tissue parts are being examined. This study aims to explore the detection and quantification of diagnostically relevant somatic copy number aberrations (SCNAs) in cell-free DNA (cfDNA) extracted from cerebrospinal fluid (CSF) in a real-world cohort of patients with defined brain tumor subtypes. A total of 33 CSF samples were collected from 30 patients for cfDNA extraction. Shallow whole-genome sequencing was conducted on CSF samples containing > 3ng of cfDNA and corresponding tissue DNA from nine patients. The sequencing cohort encompassed 26 samples of 23 patients, comprising 12 with confirmed CNS cancer as compared to 11 patients with either ambiguous CNS lesions (n = 5) or non-cancer CNS lesions (n = 6). After mapping and quality filtering SCNAs were called by depth-of-coverage analyses with a binning of 5.5 Mbp. SCNAs were exclusively identified in CSF cfDNA from brain tumor patients (10/12, 83%). In tumor patients, SCNAs were detectable in cfDNA from all patients with, but also in five of seven patients without tumor cells detected by CSF cytopathology. A substantial number of shared SCNAs were traceable between tissue and CSF in matched pair analyses. Additionally, some SCNAs unique to either CSF or tissue indicating spatial heterogeneity or tumor evolution. Also, diagnostically relevant genomic alterations as well as essential and desirable SCNAs as implemented in the current WHO classification of CNS tumors for certain primary brain tumor subtypes were traceable. In summary, this minimally invasive cfDNA-based LB approach employing shallow whole genome sequencing demonstrates potential for providing a molecularly informed diagnosis of CNS cancers, mapping tumor heterogeneity, tracking tumor evolution, and surveilling tumor patients. Further prospective trials are warranted., Competing Interests: Declarations. Ethics approval and consent to participate: This retrospective investigation and use of patient material and data was approved by the Ethics Committee of the University Hospital Frankfurt (SNO-9-2022). Consent for publication: Not applicable. Competing interests: NGS was conducted and analyzed at Chronix Biomedical by JB, KBK and ES, who are employees of Chronix Biomedical an Oncocyte Company. JPS has received honoraria for lectures, advisory board participation, consulting, and travel grants from Abbvie, Roche, Boehringer, Bristol-Myers Squibb, Medac, Mundipharma, and UCB. PJW has received consulting fees and honoraria for lectures by Bayer, Sanofi, Janssen-Cilag, Novartis, Roche, MSD, Astellas Pharma, Bristol-Myers Squibb, Thermo Fisher Scientific, Molecular Health, Guardant Health, Sophia Genetics, Qiagen, Eli Lilly, Myriad, Hedera Dx, and Astra Zeneca and research support was provided by Astra Zeneca and Roche. HR received honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chop GmbH, Diaceutics, GlaxoSmithKline, HUeG, Janssen-Cilag, MCI, Merck, Novartis, Roche Pharma, Sanofi and Wolfsburg Klinikum and funding from Bristol-Myers Squibb. MWR has received a research grant from UCB. PSZ has received a lecture honorarium from Bristol-Myers Squibb. The remaining authors declare that the research was carried out without any commercial or financial relationships that could potentially create a conflict of interest., (© 2024. The Author(s).)

Background: Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that are dependent on Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)., Methods: In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and postmortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcomes were analyzed in BM patients., Results: Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human BM negatively correlated with survival., Conclusions: Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevents the outgrowth of macrometastases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of AMP-activated protein kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity. Moreover, a spatially resolved multiomic analysis was employed to correlate the gene expression pattern of PGC-1α with the local metabolic and genetic architecture in human glioblastoma tissue sections. A switch from glucose to alternative nutrients triggered an activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs promoting mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under nonglucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with nonhypoxic tumour niches defining a specific metabolic compartment. Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data confirms the relevance of PGC-1α especially in nonhypoxic tumour regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma. KEY POINTS/HIGHLIGHTS: AMPK activation induces PGC-1α expression in glioblastoma during nutrient scarcity. PGC-1α enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma. PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Purpose: Reprogramming of amino acid metabolism is relevant for initiating and fueling tumor formation and growth. Therefore, there has been growing interest in anticancer therapies targeting amino acid metabolism. While developing personalized therapeutic approaches to glioma, in vivo proton magnetic resonance spectroscopy (MRS) is a valuable tool for non-invasive monitoring of tumor metabolism. Here, we evaluated MRS-detected brain amino acids and myo-inositol as potential diagnostic and prognostic biomarkers in glioma., Method: We measured alanine, glycine, glutamate, glutamine, and myo-inositol in 38 patients with MRI-suspected glioma using short and long echo-time single-voxel PRESS MRS sequences. The detectability of alanine, glycine, and myo-inositol and the (glutamate + glutamine)/total creatine ratio were evaluated against the patients' IDH mutation status, CNS WHO grade, and overall survival., Results: While the detection of alanine and non-detection of myo-inositol significantly correlated with IDH wildtype (p = 0.0008, p = 0.007, respectively) and WHO grade 4 (p = 0.01, p = 0.04, respectively), glycine detection was not significantly associated with either. The ratio of (glutamate + glutamine)/total creatine was significantly higher in WHO grade 4 than in 2 and 3. We found that the overall survival was significantly shorter in glioma patients with alanine detection (p = 0.00002)., Conclusion: Focusing on amino acids in MRS can improve its diagnostic and prognostic value in glioma. Alanine, which is visible at long TE even in the presence of lipids, could be a relevant indicator for overall survival., (© 2024. The Author(s).)

Measuring the intracellular pH (pHi) is of interest for brain tumor diagnostics. Common metrics of CEST imaging like the amide proton transfer-weighted (APTw) MTR asym are pHi sensitive and allow differentiating malignant tumor from healthy tissue. Yet, the image contrast also depends on additional magnetization transfer effects and T1. In contrast, the apparent exchange-dependent relaxation (AREX) provides a T1 corrected exchange rate of the amide protons. As AREX still depends on amide proton density, its pHi sensitivity remains ambiguous. Hence, we conducted this study to assess the influence of pathologic tissue changes on the pHi sensitivity of AREX in vivo. Patients with newly diagnosed intra-axial brain tumors were prospectively recruited and underwent conventional MRI, quantitative T1 relaxometry, APT-CEST and 31 P-MRS on a 3T MRI scanner. Tumors were segmented into contrast-enhancing tumor (CE), surrounding T2 hyperintensity (T2-H) and contralateral normal appearing white matter (CNAWM). T1 mapping and APT-CEST metrics were correlated with 31 P-MRS-derived pHi maps (Pearson's correlation). Without differentiating tissue subtypes, pHi did not only correlate significantly with MTR asym (r = 0.46) but also with T1 (r = 0.49). Conversely, AREX only correlated poorly with pHi (r = 0.17). Analyzing different tissue subtypes separately revealed a tissue dependency of the pHi sensitivity of AREX with a significant correlation (r = 0.6) in CNAWM and no correlation in T2-H or CE (r = -0.11/-0.24). CE showed significantly increased MTR asym , pHi, and T1 compared with CNAWM (p < 0.001). In our study, the pHi sensitivity of AREX was limited to CNAWM. The lack of sensitivity in CE and T2-H is probably attributable to altered amide and water proton concentrations in these tissues. Conversely, the correlation of pHi with MTR asym may be explained by the coincidental contrast increase through increased T1 and amide proton density. Therefore, limited structural deviations from CNAWM might be a perquisite for the use of CEST contrasts as pHi-marker., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Maximum tumor resection improves overall survival (OS) in patients with glioblastoma. The extent of resection (EOR) is historically dichotomized. The RANO resect group recently proposed criteria for volumetry-based EOR assessment in patients that were treated according to Stupp´s protocol. The purpose of this study was (1) to investigate the prognostic value of EOR in patients receiving combined chemotherapy with lomustine (CCNU)/temozolomide (TMZ), and (2) to analyse the prognostic performance of binary EOR assessment compared to volumetric assessment., Methods: 78 patients with newly diagnosed MGMT-methylated GBM undergoing tumor resection followed by radiochemotherapy with CCNU/TMZ were included in this study. Residual contrast-enhancing (CE) tumor volume after the first resection was measured and its influence on OS and PFS was analysed using uni- and multivariable Cox regression analysis as well as two-sided log rank test. Patients were divided into RTV ≤1 cm³, >1 cm³ - ≤5 cm³ and >5 cm³ following the proposed criteria of the RANO resect group., Results: Prolonged OS was associated with age <60 years, low RTV, and gross total resection (GTR). Residual tumor volume (RTV) had a superior prognostic value compared to binary EOR assessment. Patients with total or near total resection of CE tumor (≤1 cm³ RTV) showed prolonged OS (median 54.4 months, 95% CI 46.94-not reached), with a 5-year survival rate of 49%., Conclusion: Low RTV is associated with increased survival in glioblastoma patients undergoing radiochemotherapy with CCNU/TMZ. This study demonstrates the applicability of the recently proposed RANO resect criteria in this subgroup of patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In glioblastoma (GB) cells oxidative stress is induced by both, conditions of the tumor microenvironment as well as by therapeutic interventions. Upregulation of superoxide dismutase 1 (SOD1), a key enzyme for oxidative defense and downstream target of mammalian target of rapamycin complex 1 (mTORC1) is a candidate mechanism to sustain survival and proliferation of tumor cells. SOD1 was inhibited by shRNA mediated gene suppression, CRISPR/Cas9 knockout and pharmacological inhibition in human (primary) GB cells. SOD1 activity was determined by SOD1/2 activity assay. ROS levels, cell death and the NADPH/NADP-ratio were measured under normal and starvation conditions. To study the mTORC1-SOD1 axis, mTORC1 activated TSC2 knockdown cells (TSC2sh) were analyzed. Genetic and pharmacological inhibition of SOD1 correlated with decreased SOD1 activity, increased ROS and enhanced the sensitivity of glioma cells towards starvation- and hypoxia-induced cell death. This was accompanied by a decreased NADPH/NADP-ratio. Furthermore, combination therapy of SOD1 and mTORC1 inhibition partially rescued the protective effect of mTORC1 inhibitor monotherapy. SOD1 mediates adaptation of GB cells to stress conditions in the tumor microenvironment in a mTORC1-dependent manner. Moreover, SOD1 activation contributes to the cell death resistance conferred by mTORC1 inhibitors under hypoxic conditions., (© 2024. The Author(s).)

Competing Interests: All authors declare no conflicts of interest with the content of the present study.

For CNS lymphomas (CNSL), there is a high need for minimally invasive and easily obtainable diagnostic markers. Intrathecal IgM synthesis can easily be determined in routine CSF diagnostics. The aim of this study was to systematically investigate the diagnostic potential of intrathecal IgM synthesis in primary and secondary CNSL (PCNSL and SCNSL). In this retrospective study, patients with a biopsy-proven diagnosis of PCNSL or SCNSL were compared with patients with other neurological diseases in whom CNSL was initially the primary radiological differential diagnosis based on MRI. Sensitivity and specificity of intrathecal IgM synthesis were calculated using receiver operating characteristic curves. Seventy patients with CNSL were included (49 PCNSL and 21 SCNSL) and compared to 70 control patients. The sensitivity and specificity for the diagnosis of CNSL were 49% and 87%, respectively, for the entire patient population and 66% and 91% after selection for cases with tumor access to the CSF system and isolated intrathecal IgM synthesis. In cases with MRI-based radiological suspicion of CNSL, intrathecal IgM synthesis has good specificity but limited sensitivity. Because of its low-threshold availability, analysis of intrathecal IgM synthesis has the potential to lead to higher diagnostic accuracy, especially in resource-limited settings, and deserves further study., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: Emerging evidence suggests that fasting could play a key role in cancer treatment. Its metabolic effects on gliomas require further investigation., Purpose: To design a multi-voxel 1 H/ 31 P MR-spectroscopic imaging (MRSI) protocol for noninvasive metabolic monitoring of cerebral, fasting-induced changes on an individual patient/tumor level, and to assess its technical reliability/reproducibility., Study Type: Prospective., Population: MRS phantom. Twenty-two patients (mean age = 61, 6 female) with suspected WHO grade II-IV glioma examined before and after 72-hour-fasting prior to biopsy/resection., Field Strength/sequence: 3-T, 1 H decoupled 3D 31 P MRSI, 2D 1 H sLASER MRSI at an echo time of 144 msec, 2D 1 H MRSI (as water reference), T1-weighted, T1-weighted contrast-enhanced, T2-weighted, and FLAIR. sLASER and PRESS sequences were used for phantom measurements., Assessment: Phantom measurements and spectral simulations were performed with various echo-times for protocol optimization. In vivo spectral analyses were conducted using LCModel and AMARES, obtaining quality/fitting parameters (linewidth, signal-to-noise-ratio, and uncertainty measures of fitting) and metabolite intensities. The volume of glioma sub-regions was calculated and correlated with MRS findings. Ex-vivo spectra of necrotic tumor tissues were obtained using high-resolution magic-angle spinning (HR-MAS) technique., Statistical Tests: Wilcoxon signed-rank test, Bland-Altman plots, and coefficient of variation were used for repeatability analysis of quality/fitting parameters and metabolite concentrations. Spearman ρ correlation for the concentration of ketone bodies with volumes of glioma sub-regions was determined. A P-value <0.05 was considered statistically significant., Results: 1 H and 31 P repeatability measures were highly consistent between the two sessions. β-hydroxybutyrate and acetoacetate were detectable (fitting-uncertainty <50%) in glioma sub-regions of all patients who completed the 72-hour-fasting cycle. β-hydroxybutyrate accumulation was significantly correlated with the necrotic/non-enhancing tumor core volume (ρ = 0.81) and validated using ex-vivo 1 H HR-MAS., Data Conclusion: We propose a comprehensive MRS protocol that may be used for monitoring cerebral, fasting-induced changes in patients with glioma., Evidence Level: 1 TECHNICAL EFFICACY: Stage 4., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo ® and Caspase-3 activity assays, we generated dose-response curves and analyzed the gene and protein regulation of anti-apoptotic proteins via PCR and Western blots. Optimal drug combinations were examined for their impact on the cell cycle and apoptosis induction via FACS analysis, paralleled by the assessment of potential toxicity in healthy mouse brain slices. Ara-C and MTX proved to be 150- to 10,000-fold more potent in inducing apoptosis than TMZ. In response to inhibitors Eltanexor (XPO1; E), Venetoclax (Bcl-2; V), and A1210477 (Mcl-1; A), genes encoding for the corresponding proteins were upregulated in a compensatory manner. TMZ, MTX, and Ara-C combined with E, V, and A evidenced highly lethal effects when combined. As no significant cell death induction in mouse brain slices was observed, we conclude that this drug combination is effective in vitro and expected to have low side effects in vivo.

Objective: Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population., Methods: This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017., Results: The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1-57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1-46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p < 0.001). Mortality at discharge was 17.3% (n = 36), with the greatest occurring in patients with metastatic disease (26.4%, p = 0.031) and those that met the radiological criteria for tumor progression (25%, p < 0.001). Long-term mortality at one year (65.9%) was highest in those diagnosed with adult-type diffuse gliomas (68.1%) and metastatic disease (79.2%). Refractory status epilepticus cases showed lower survival rates than non-refractory SE patients (log-rank p = 0.02) and those with signs of tumor progression (log-rank p = 0.001)., Conclusions: SE occurrence contributed to a decline in functional status in all cases, regardless of tumor type, tumor progression status, and SE refractoriness, while long-term mortality was increased in those with malignant tumor entities, tumor progressions, and refractory SE. SE prevention may preserve functional status and improve survival in individuals with brain tumors., (© 2024. The Author(s).)

Glioblastoma is an incurable brain tumor with a median survival below two years. Trials investigating targeted therapy with inhibitors of the kinase mTOR have produced ambiguous results. Especially combination of mTOR inhibition with standard temozolomide radiochemotherapy has resulted in reduced survival in a phase II clinical trial. To date, this phenomenon is only poorly understood. To recreate the therapeutic setting in vitro, we exposed glioblastoma cell lines to co-treatment with rapamycin and temozolomide and assessed cell viability, DNA damage and reactive oxygen species. Additionally, we employed a novel translatomic based mass spectrometry approach ("mePROD") to analyze acute changes in translated proteins. mTOR inhibition with rapamycin protected glioblastoma cells from temozolomide toxicity. Following co-treatment of temozolomide with rapamycin, an increased translation of reactive oxygen species (ROS)-detoxifying proteins was detected by mass spectrometry. This was accompanied by improved ROS-homeostasis and reduced DNA damage. Additionally, rapamycin induced the expression of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT) in glioblastoma cells with an unmethylated MGMT gene promotor. Inhibition of mTOR antagonized the cytotoxic effects of temozolomide in vitro. The induction of antioxidant defences and MGMT are two underlying candidate mechanisms. Further functional experiments in vitro and in vivo are warranted to characterize this effect that appears relevant for combinatorial therapeutic strategies., (© 2024. The Author(s).)

Purpose: The prognosis of patients ≥ 75 years suffering from glioblastoma is poor. Novel therapies are usually reserved for patients ≤ 70 years. In an aging population, treatment of very elderly patients remains a challenge., Methods: Between 2010 and 2018, a total of 977 glioblastoma patients were treated at our institution. Of these, 143 patients were ≥ 75 years at diagnosis. Primary procedure was surgical resection or biopsy followed by adjuvant treatment, whenever possible. We retrospectively investigated overall survival (OS) and potential prognostic factors influencing survival, including Karnofsky Performance Status (KPS), surgical therapy, adjuvant therapy as well as MGMT promotor status., Results: In very elderly patients, median age was 79 years (range: 75-110). Biopsy only was performed in 104 patients; resection was performed in 39 patients. Median OS for the entire cohort was 5.9 months. Univariate analysis showed that KPS at presentation (≥ 70 vs. ≤60), surgery vs. biopsy, adjuvant chemotherapy and adjuvant radiotherapy were significantly associated with OS (6 vs. 3, p < 0.0111; 12 vs. 4, p = 0.0011; 11 vs. 4, p = 0.0003 and 10 vs. 1.5 months, p < 0.0001, respectively). Multivariate analysis confirmed adjuvant radiotherapy (p < 0.0001) and chemotherapy (p = 0.0002) as independent factors influencing OS., Conclusion: For very elderly patients, the natural course of disease without treatment is devastating. These patients benefit from multimodal treatment including adjuvant radiotherapy and chemotherapy. A beneficial effect of resection has not been demonstrated. Treatment options and outcomes should be thoughtfully discussed before treatment decisions are made., (© 2023. The Author(s).)

Background: Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated safety and feasibility of adoptive transfer of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2, which is expressed at elevated levels by a subset of glioblastomas., Methods: Nine patients with recurrent HER2-positive GB were treated with single doses of 1 × 107, 3 × 107, or 1 × 108 irradiated CAR-NK cells injected into the margins of the surgical cavity during relapse surgery. Imaging at baseline and follow-up, peripheral blood lymphocyte phenotyping and analyses of the immune architecture by multiplex immunohistochemistry and spatial digital profiling were performed., Results: There were no dose-limiting toxicities, and none of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Five patients showed stable disease after relapse surgery and CAR-NK injection that lasted 7 to 37 weeks. Four patients had progressive disease. Pseudoprogression was found at injection sites in 2 patients, suggestive of a treatment-induced immune response. For all patients, median progression-free survival was 7 weeks, and median overall survival was 31 weeks. Furthermore, the level of CD8+ T-cell infiltration in recurrent tumor tissue prior to CAR-NK cell injection positively correlated with time to progression., Conclusions: Intracranial injection of HER2-targeted CAR-NK cells is feasible and safe in patients with recurrent GB. 1 × 108 NK-92/5.28.z cells was determined as the maximum feasible dose for a subsequent expansion cohort with repetitive local injections of CAR-NK cells., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: The biological understanding of glioblastoma (GB) with gliomatosis cerebri (GC) pattern is poor due to the absence of GC-specific studies. Here, we aimed to identify molecular or clinical parameters that drive GC growth., Methods: From our methylome database of IDH (isocitrate dehydrogenase)-wildtype GB, we identified 158 non-GC and 65 GC cases. GC cases were subdivided into diffuse-infiltrative (subtype 1), multifocal (subtype 2), or tumors with 1 solid mass (subtype 3). We compared clinical, histological, and molecular parameters and conducted a reference-free tumor deconvolution of DNA methylation data based on latent methylation components (LMC)., Results: GC subtype 1 less frequently showed contrast-enhancing tumors, and more frequently lacked morphological GB criteria despite displaying GB DNA methylation profile. However, the tumor deconvolution did not deliver a specific LMC cluster for either of the GC subtypes. Employing the reference-based analysis MethylCIBERSORT, we did not identify significant differences in tumor cell composition. The majority of both GC and non-GC patients received radiochemotherapy as first-line treatment, but there was a major imbalance for resection. The entire GC cohort had significantly shorter overall survival (OS) and time to treatment failure (TTF) than the non-GC cohort. However, when filtering for cases in which only stereotactic biopsy was performed, the comparison of OS and TTF lost statistical significance., Conclusions: Our study offers clinically relevant information by demonstrating a similar outcome for GB with GC growth pattern in the surgically matched analysis. The limited number of cases in the GC subgroups encourages the validation of our DNA methylation analysis in larger cohorts., Competing Interests: J.P.S. has received honoraria for lectures or advisory board participation from Boehringer, Medac, Roche, Seagen, Med-Update, and Novocure. U.H. has received lecture and/or advisory board honoraria from Medac and Bayer. E. Fokas has received honoraria from Celgene, and trial funding support from AstraZeneca that are unrelated to the present study. All other authors declare that they have no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO)., Methods: We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T 1 -enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined., Results: Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T 1 -enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm., Conclusion: The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09., (© 2023. The Author(s).)

Purpose: The AVAglio trial reported a significant survival benefit for first line bevacizumab treatment in patients with IDH wildtype glioblastoma of the proneural gene expression subtype. We here aim to replicate these findings in an independent trial cohort., Methods: We evaluate the treatment benefit of bevacizumab according to gene expression subtypes of pretreatment tumor samples (n = 123) in the GLARIUS trial (NCT00967330) for MGMT unmethylated glioblastoma patients with Kaplan-Meier analyses, log-rank tests and Cox regression models., Results: Employing the Phillips classifier, bevacizumab conferred a significant PFS advantage in patients with proneural IDH wild-type tumors (10.4 vs. 6.0 months, p = 0.002), but no OS advantage (16.4 vs. 17.4 months, p = 0.6). Multivariable analysis adjusting for prognostic covariates confirmed the absence of a significant OS advantage from bevacizumab (hazard ratio, 1.05, 95% CI, 0.42 to 2.64; p = 0.14). Further, there was no interaction between the proneural subtype and treatment arm (p = 0.15). These results were confirmed in analyses of tumor subgroups according to the Verhaak classifier., Conclusion: In contrast to AVAglio, glioblastoma gene expression subgroups were not associated with a differential OS benefit from first-line bevacizumab in the GLARIUS trial., (© 2023. The Author(s).)

Background: Metastases are the most common malignant tumors affecting the central nervous system and occur in 20-40 percent of patients with solid systemic tumors. The aim of this review is to discuss the role of neurosurgical procedures in a modern, multidisciplinary treatment approach., Methods: An expert panel of neurosurgeons, neurologists, and radio-oncologists conducted a selective literature review on neu - rosurgical interventions for the diagnosis and treatment of cerebral metastases. Original articles, meta-analyses, and systematic reviews were included., Results: There is a lack of prospective randomized studies. Based on retrospective case series, international guidelines recommend the harvesting (if required, stereotactically guided) of tissue for histological and molecular diagnosis in cases of unknown or possibly competing underlying systemic malignant diseases, in cases of suspected tumor recurrence, and with regard to the evaluation of targeted therapies taking into account molecular heterogeneity of primary and secondary tumors. Surgical resection is particularly valuable for the treatment of up to three space-occupying cerebral metastases, especially to achieve clinical stabilization to allow further non-surgical treatment. For cystic metastasis, a combination of stereotactic puncture and radiotherapy may be useful. Meningeal carcinomatosis can be treated with intrathecal medication via an intraventricular catheter system. Ventriculo-peritoneal shunts represents an effective treatment option for patients with tumor-associated hydrocephalus., Conclusion: Neurosurgical procedures are of central importance in the multimodal treatment of cerebral metastases. The indications for neurosurgical interventions will be refined in the light of more effective radiation techniques and systemic treatments with new targeted therapeutic approaches and immunotherapies on the horizon.

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has changed the clinical day-to-day practice. The aim of this study was to evaluate the impact of the pandemic on patients with high-grade glioma (HGG) as well as to derive best practice recommendations. We compared a multi-institutional cohort with HGG (n = 251) from 03/2020 to 05/2020 (n = 119) to a historical cohort from 03/2019 to 05/2019 (n = 132). The endpoints were outcome (progression-free survival (PFS) and overall survival (OS)) as well as patterns of care and time intervals between treatment steps. The median OS for WHO grade 4 gliomas was 12 months in 2019 (95% Confidence Interval 9.7-14.3 months), and not reached in 2020 (p = .026). There were no other significant differences in the Kaplan-Meier estimates for OS and PFS between cohorts of 2019 and 2020, neither did stratification by WHO grade reveal any significant differences for OS, PFS or for patterns of care. The time interval between cranial magnetic resonance imaging (cMRI) and biopsy was significantly longer in 2020 cohort (11 versus 21 days, p = .031). Median follow-up was 10 months (range 0-30 months). Despite necessary disease containment policies, it is crucial to ensure that patients with HGG are treated in line with the recent guidelines and standard of care (SOC) algorithms. Therefore, we strongly suggest pursuing no changes to SOC treatment, a timely diagnosis and treatment with short time intervals between first symptoms, initial diagnosis, and treatment, as well as a guideline-based cMRI follow-up., (© 2023. The Author(s).)

Purpose: Non-invasive prediction of the tumour of origin giving rise to brain metastases (BMs) using MRI measurements obtained in radiological routine and elucidating the biological basis by matched histopathological analysis., Methods: Preoperative MRI and histological parameters of 95 BM patients (female, 50; mean age 59.6 ± 11.5 years) suffering from different primary tumours were retrospectively analysed. MR features were assessed by region of interest (ROI) measurements of signal intensities on unenhanced T1-, T2-, diffusion-weighted imaging and apparent diffusion coefficient (ADC) normalised to an internal reference ROI. Furthermore, we assessed BM size and oedema as well as cell density, proliferation rate, microvessel density and vessel area as histopathological parameters., Results: Applying recursive partitioning conditional inference trees, only histopathological parameters could stratify the primary tumour entities. We identified two distinct BM growth patterns depending on their proliferative status: Ki67 high BMs were larger (p = 0.02), showed less peritumoural oedema (p = 0.02) and showed a trend towards higher cell density (p = 0.05). Furthermore, Ki67 high BMs were associated with higher DWI signals (p = 0.03) and reduced ADC values (p = 0.004). Vessel density was strongly reduced in Ki67 high BM (p < 0.001). These features differentiated between lung cancer BM entities (p ≤ 0.03 for all features) with SCLCs representing predominantly the Ki67 high group, while NSCLCs rather matching with Ki67 low features., Conclusion: Interpretable and easy to obtain MRI features may not be sufficient to predict directly the primary tumour entity of BM but seem to have the potential to aid differentiating high- and low-proliferative BMs, such as SCLC and NSCLC., (© 2022. The Author(s).)

Introduction: When evaluating MRIs for glioblastoma progression, previous scans are usually included into the review. Nowadays dynamic susceptibility contrast (DSC)-perfusion is an essential component in MR-diagnostics of gliomas, since the extent of hyperperfusion upon first diagnosis correlates with gene expression and survival. We aimed to investigate if this initial perfusion signature also characterizes the glioblastoma at time of progression. If so, DSC-perfusion data from the initial diagnosis could be of diagnostic benefit in follow-up assessments., Methods: We retrospectively identified 65 patients with isocitrate dehydrogenase wildtype glioblastoma who had received technically identical DSC-perfusion measurements at initial diagnosis and at time of first progression. We determined maximum relative cerebral blood volume values (rCBVmax) by standardized re-evaluation of the data including leakage correction. In addition, the corresponding tissue samples from 24 patients were examined histologically for the maximum vessel density within the tumor. Differences (paired t-test/ Wilcoxon matched pairs test) and correlations (Spearman) between the measurements at both timepoints were calculated., Results: The rCBVmax was consistently lower at time of progression compared to rCBVmax at time of first diagnosis (p < .001). There was no correlation between the rCBVmax values at both timepoints (r = .12). These findings were reflected in the histological examination, with a lower vessel density in progressive glioblastoma (p = .01) and no correlation between the two timepoints (r = -.07)., Conclusion: Our results suggest that the extent of hyperperfusion in glioblastoma at first diagnosis is not a sustaining tumor characteristic. Hence, the rCBVmax at initial diagnosis should be disregarded when reviewing MRIs for glioblastoma progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Steidl et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range: <.0001 to .08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44 and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population., Methods: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy., Results: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE., Conclusion: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures., Trial Registration: NCT01149109., (© 2023. The Author(s).)

Purpose: With increasing patient self-empowerment and participation in decision making, we hypothesized that patients with adult-type diffuse gliomas, CNS WHO grade 4 who change sites of treatment differ from patients being entirely treated in one neuro-oncological center., Methods: Prospectively collected data from all diffuse glioma grade 4 patients who underwent treatment in our neuro-oncological center between 2012 and 2018 were retrospectively examined for differences between patients having initially been diagnosed and/or treated elsewhere (External Group) and patients having entirely been treated in our neuro-oncological center (Internal Group). Additionally, a matched-pair analysis was performed to adjust for possible confounders., Results: A total of 616 patients was analyzed. Patients from the External Group (n = 78) were significantly younger, more frequently suffered from IDH-mutant astrocytoma grade 4, had a greater extent of tumor resection, more frequently underwent adjuvant therapy and experienced longer overall survival (all p < 0.001). However, after matching these patients to patients of the Internal Group considering IDH mutations, extent of resection, adjuvant therapy, age and gender, no difference in patients' overall survival was observed anymore., Conclusion: The present study demonstrates that mobile diffuse glioma grade 4 patients stand out from a comprehensive diffuse glioma grade 4 patient cohort due to their favorable prognostic characteristics. However, changing treatment sites did not result in survival benefit over similar patients being entirely taken care of within one neuro-oncological institution. These results underline the importance of treatment and molecular markers in glioma disease for patients' self-empowerment, including changing treatment sites according to patients' needs and wishes., (© 2022. The Author(s).)

Purpose: Seizures pose a significant burden in patients with primary and secondary brain tumors during the end-of-life period. A wide range of 6 to 56% of clinically observed epileptic seizures at the end of life has been reported. We aimed to analyse the incidence of epileptic seizures at the end of life in brain tumor patients more accurately using not only clinical but also electrophysiological findings., Methods: This retrospective, single center study included brain tumor patients who died during the stay on the ward or within 7 days after discharge between 01/2015 and 08/2020. Clinical observation of seizures derived from the original medical records and EEG findings (within 45 days prior to death) were analyzed to determine the incidence of seizures in that period., Results: Of the 68 eligible patients, 50 patients (73.5%) suffered from seizures within 45 days prior to death, of which n = 24 had a status epilepticus. The diagnosis of seizures/ status epilepticus was determined either by the presentation of clinical signs in 45 patients and if not, by the detection of a (possible) non-convulsive status epilepticus in the EEG of five patients., Conclusion: In the presence of neurologically trained staff and with the frequent use of routine EEG, we were able to identify seizures and to distinguish status epilepticus from encephalopathy/ hypoactive delirium. We detected a higher incidence of seizures and status epilepticus at the end of life in neurooncological patients than previously reported., (© 2022. The Author(s).)

Glioblastoma (GB) is the most common primary brain tumor, which is characterized by low immunogenicity of tumor cells and prevalent immunosuppression in the tumor microenvironment (TME). Targeted local combination immunotherapy is a promising strategy to overcome these obstacles. Here, we evaluated tumor-cell specific delivery of an anti-PD-1 immunoadhesin (aPD-1) via a targeted adeno-associated viral vector (AAV) as well as HER2-specific NK-92/5.28.z (anti-HER2.CAR/NK-92) cells as components for a combination immunotherapy. In co-culture experiments, target-activated anti-HER2.CAR/NK-92 cells modified surrounding tumor cells and bystander immune cells by triggering the release of inflammatory cytokines and upregulation of PD-L1. Tumor cell-specific delivery of aPD-1 was achieved by displaying a HER2-specific designed ankyrin repeat protein (DARPin) on the AAV surface. HER2-AAV mediated gene transfer into GB cells correlated with HER2 expression levels, without inducing anti-viral responses in transduced cells. Furthermore, AAV-transduction did not interfere with anti-HER2.CAR/NK-92 cell-mediated tumor cell lysis. After selective transduction of HER2 + cells, aPD-1 expression was detected at the mRNA and protein level. The aPD-1 immunoadhesin was secreted in a time-dependent manner, bound its target on PD-1-expressing cells and was able to re-activate T cells by efficiently disrupting the PD-1/PD-L1 axis. Moreover, high intratumoral and low systemic aPD-1 concentrations were achieved following local injection of HER2-AAV into orthotopic tumor grafts in vivo . aPD-1 was selectively produced in tumor tissue and could be detected up to 10 days after a single HER2-AAV injection. In subcutaneous GL261-HER2 and Tu2449-HER2 immunocompetent mouse models, administration of the combination therapy significantly prolonged survival, including complete tumor control in several animals in the GL261-HER2 model. In summary, local therapy with aPD-1 encoding HER2-AAVs in combination with anti-HER2.CAR/NK-92 cells may be a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce systemic side effects of immune-checkpoint inhibitors., Competing Interests: J.P.S has a consulting or advisory board membership with, or has received honoraria or travel or accommodation expenses from AbbVie, Medac, Novocure, Roche, and UCB. M.C.B has received honoraria for lectures or advisory board participation from Bristol-Myers Squibb and Gilead Sciences. All other authors report no conflict of interest., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Although malignant gliomas frequently show aberrant activation of the mammalian target of rapamycin (mTOR), mTOR inhibitors have performed poorly in clinical trials. Besides regulating cell growth and translation, mTOR controls the initiation of autophagy. By recycling cellular components, autophagy can mobilize energy resources, and has thus been attributed cancer-promoting effects. Here, we asked whether the activation of autophagy represents an escape mechanism to pharmacological mTOR inhibition in glioma cells, and explored co-treatment with mTOR and autophagy inhibitors as a therapeutic strategy. Mimicking conditions of the glioma microenvironment, glioma cells were exposed to nutrient starvation and hypoxia. We analyzed autophagic activity, cell growth, viability and oxygen consumption following (co-)treatment with the mTOR inhibitors torin2 or rapamycin, and autophagy inhibitors bafilomycin A1 or MRT68921. Changes in global proteome were quantified by mass spectrometry. In the context of hypoxia and starvation, autophagy was strongly induced in glioma cells and further increased by mTOR inhibition. While torin2 enhanced glioma cell survival, co-treatment with torin2 and bafilomycin A1 failed to promote cell death. Importantly, treatment with bafilomycin A1 alone also protected glioma cells from cell death. Mechanistically, both compounds significantly reduced cell growth and oxygen consumption. Quantitative proteomics analysis showed that bafilomycin A1 induced broad changes in the cellular proteome. More specifically, proteins downregulated by bafilomycin A1 were associated with the mitochondrial respiratory chain and ATP synthesis. Taken together, our results show that activation of autophagy does not account for the cytoprotective effects of mTOR inhibition in our in vitro model of the glioma microenvironment. Our proteomic findings suggest that the pharmacological inhibition of autophagy induces extensive changes in the cellular proteome that can support glioma cell survival under nutrient-deplete and hypoxic conditions. These findings provide a novel perspective on the complex role of autophagy in gliomas., (© 2022. The Author(s).)

Purpose: To investigate the potential of radiomics applied to static clinical PET data using the tracer O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) to differentiate treatment-related changes (TRC) from tumor progression (TP) in patients with gliomas., Patients and Methods: One hundred fifty-one (151) patients with histologically confirmed gliomas and post-therapeutic progressive MRI findings according to the response assessment in neuro-oncology criteria underwent a dynamic amino acid PET scan using the tracer O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET). Thereof, 124 patients were investigated on a stand-alone PET scanner (data used for model development and validation), and 27 patients on a hybrid PET/MRI scanner (data used for model testing). Mean and maximum tumor to brain ratios (TBR mean , TBR max ) were calculated using the PET data from 20 to 40 min after tracer injection. Logistic regression models were evaluated for the FET PET parameters TBR mean , TBR max , and for radiomics features of the tumor areas as well as combinations thereof to differentiate between TP and TRC. The best performing models in the validation dataset were finally applied to the test dataset. The diagnostic performance was assessed by receiver operating characteristic analysis., Results: Thirty-seven patients (25%) were diagnosed with TRC, and 114 (75%) with TP. The logistic regression model comprising the conventional FET PET parameters TBR mean and TBR max resulted in an AUC of 0.78 in both the validation (sensitivity, 64%; specificity, 80%) and the test dataset (sensitivity, 64%; specificity, 80%). The model combining the conventional FET PET parameters and two radiomics features yielded the best diagnostic performance in the validation dataset (AUC, 0.92; sensitivity, 91%; specificity, 80%) and demonstrated its generalizability in the independent test dataset (AUC, 0.85; sensitivity, 81%; specificity, 70%)., Conclusion: The developed radiomics classifier allows the differentiation between TRC and TP in pretreated gliomas based on routinely acquired static FET PET scans with a high diagnostic accuracy., (© 2022. The Author(s).)

Purpose: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy., Methods: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected., Results: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI., Conclusion: A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary., (© 2022. The Author(s).)

Introduction: The concurrent presence of both central nervous system (CNS) tumors and multiple sclerosis (MS) poses various diagnostic and therapeutic pitfalls and makes the clinical management of such patients challenging., Methods: In this retrospective, single-center cohort study, we searched our clinical databases (2006-2019) for patients with concurrent CNS tumors and MS and described their disease courses. Age at diagnosis of the respective disease and probabilities for MS disease activity events (DAEs) with vs. without prior tumor-specific therapy were tested pairwise using t-test for dependent samples and exact binomial test., Results: N = 16 patients with concurrent CNS tumors and MS were identified. MS diagnosis preceded the CNS oncological diagnosis by an average of 9 years (p = 0.004). More DAEs occurred in patients without prior chemotherapy (83.3%) than in patients with prior chemotherapy (16.7%; p = 0.008). This effect did not reach significance for patients with prior radiation therapy/radiosurgery (66.7% vs. 33.3%, p = 0.238). The average interval between DAEs and the last documented lymphopenia was 32.25 weeks., Conclusions: This study describes the clinical and demographic features of patients with concurrent CNS tumors and MS and suggests several practical approaches to their clinical management. Our findings suggest that adding a disease-modifying MS therapy to the regimen of patients treated with chemotherapy is necessary only if the patient suffers from a highly active, aggressive course of MS. In view of the lack of prospective trials, individual risk assessments should remain the foundation of the decision on MS treatment in concurrent CNS tumor diseases., (© 2022. The Author(s).)

Purpose: The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here, we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glioblastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy., Methods: The impact of obesity (BMI ≥ 30 kg/m 2 ) on overall survival (OS) and progression-free survival (PFS) was investigated with Kaplan-Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including known prognostic factors as covariables., Results: Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7-30.8) vs. 43.2 (32.5-54.4) months for obese and non-obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8-18.9) vs 17.6 (14.7-20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53-4.31), p < 0.001) adjusted for age, sex, extent of resection, baseline steroids, Karnofsky performance score, and treatment arm., Conclusion: Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblastoma patients., (© 2022. The Author(s).)

O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians' rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.

Introduction: Isocitrate dehydrogenase (IDH) mutations are disease-defining mutations in IDH-mutant astrocytomas and IDH-mutant and 1p/19q-codeleted oligodendrogliomas. In more than 80% of these tumors, point mutations in IDH type 1 (IDH1) lead to expression of the tumor-specific protein IDH1R132H. IDH1R132H harbors a major histocompatibility complex class II (MHCII)-restricted neoantigen that was safely and successfully targeted in a first-in human clinical phase 1 trial evaluating an IDH1R132H 20-mer peptide vaccine (IDH1-vac) in newly diagnosed astrocytomas concomitant to standard of care (SOC)., Methods: AMPLIFY-NEOVAC is a randomized, 3-arm, window-of-opportunity, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with avelumab (AVE), an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1 (PD-L1). The target population includes patients with resectable IDH1R132H-mutant recurrent astrocytoma or oligodendroglioma after SOC. Neoadjuvant and adjuvant immunotherapy will be administered to 48 evaluable patients. In arm 1, 12 patients will receive IDH1-vac; in arm 2, 12 patients will receive the combination of IDH1-vac and AVE, and in arm 3, 24 patients will receive AVE only. Until disease progression according to immunotherapy response assessment for neuro-oncology (iRANO) criteria, treatment will be administered over a period of maximum 43 weeks (primary treatment phase) followed by facultative maintenance treatment., Perspective: IDH1R132H 20-mer peptide is a shared clonal driver mutation-derived neoepitope in diffuse gliomas. IDH1-vac safely targets IDH1R132H in newly diagnosed astrocytomas. AMPLIFY-NEOVAC aims at (1) demonstrating safety of enhanced peripheral IDH1-vac-induced T cell responses by combined therapy with AVE compared to IDH1-vac only and (2) investigating intra-glioma abundance and phenotypes of IDH1-vac induced T cells in exploratory post-treatment tissue analyses. In an exploratory analysis, both will be correlated with clinical outcome., Trial Registration: NCT03893903., (© 2022. The Author(s).)

Background and Objective: To investigate the association of radiochemotherapy-induced cytopenia with sex and its potential effect on survival in patients with glioma., Methods: We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy in 492 patients with glioma. Histologic grading, molecular pathology, surgical procedures, adjuvant chemotherapy subsequent to the radiochemotherapy phase, and overall survival (OS) were recorded. The extent of cytopenia was correlated with sex and outcome., Results: Treatment-induced severe cytopenia (leukocytopenia, lymphocytopenia, neutropenia, and thrombocytopenia) was more frequent in women than men (44 vs 18%; p = 0.0002). In women with IDH -wt high-grade astrocytomas, there was a negative correlation of severe cytopenia in general and thrombocytopenia in particular during temozolomide radiochemotherapy with OS independent from other predictors (92 [77-111] vs 73 [21-127] weeks; p < 0.05). In men, there was also a trend for this unfavorable effect. In addition, severe cytopenia in all blood cell lineages correlated with reduced temozolomide dose exposure during radiochemotherapy (all p < 0.05 in the total cohort) and reduced dose exposure was independently associated with worse OS (hazard ratios for OS in complete vs reduced temozolomide dose in the total and female cohort 0.66 [0.47-0.92] and 0.4 [0.24-0.69], p < 0.05)., Discussion: Our analysis of treatment-induced cytopenia in a large cohort of patients with glioma confirms that women are at higher risk and demonstrates an association of cytopenia with shortened survival in women., Classification of Evidence: This study provides Class II evidence that women with glioma treated with temozolomide-based concomitant radiochemotherapy have more frequent treatment-induced severe cytopenia than men and that severe myelosuppression correlates with worse OS in women., (© 2022 American Academy of Neurology.)

Brain metastases are a common finding upon initial diagnosis of otherwise locally limited non-small cell lung cancer. We present a retrospective case series describing three cases of patients with symptomatic, synchronous brain metastases and resectable lung tumors. The patients received local ablative treatment of the brain metastases followed by neoadjuvant immunochemotherapy with pemetrexed, cisplatin, and pembrolizumab. Afterwards, resection of the pulmonary lesion with curative intent was performed. One patient showed progressive disease 12 months after initial diagnosis, and passed away 31 months after initial diagnosis. Two of the patients are still alive and maintain a good quality of life with a progression-free survival and overall survival of 28 and 35 months, respectively, illustrating the potential of novel combinatorial treatment approaches.