Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T-cell responses. CD4(+), CD8(+), and regulatory T-cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very-low-carbohydrate diet as a clinical tool to improve human T-cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.

Background. Systemic infiltration of the brain by tumor cells is a hallmark of glioma pathogenesis which may cause disturbances in functional connectivity. We hypothesized that aggressive high-grade tumors cause more damage to functional connectivity than low-grade tumors. Methods. We designed an imaging tool based on resting-state functional (f)MRI to individually quantify abnormality of functional connectivity and tested it in a prospective cohort of patients with newly diagnosed glioma. Results. Thirty-four patients were analyzed (World Health Organization [WHO] grade II, n = 13; grade III, n = 6; grade IV, n = 15; mean age, 48.7 y). Connectivity abnormality could be observed not only in the lesioned brain area but also in the contralateral hemisphere with a close correlation between connectivity abnormality and aggressiveness of the tumor as indicated by WHO grade. Isocitrate dehydrogenase 1 (IDH1) mutation status was also associated with abnormal connectivity, with more alterations in IDH1 wildtype tumors independent of tumor size. Finally, deficits in neuropsychological performance were correlated with connectivity abnormality. Conclusion. Here, we suggested an individually applicable resting-state fMRI marker in glioma patients. Analysis of the functional connectome using this marker revealed that abnormalities of functional connectivity could be detected not only adjacent to the visible lesion but also in distant brain tissue, even in the contralesional hemisphere. These changes were associated with tumor biology and cognitive function.The ability of our novel method to capture tumor effects in nonlesional brain suggests a potential clinical value for both individualizing and monitoring glioma therapy.

Abstract BACKGROUND Current treatment guidelines for oligodendrogliomas (OD) recommend watch-and-wait strategies after gross total resection and radiation with subsequent chemotherapy (procarbazine, CCNU and vincristine (PCV)) after incomplete resection. The value of chemotherapy alone as an option to delay the risk of late cognitive deficits is not well defined yet. Here, we retrospectively investigated long-term outcome in OD WHO II with respect to initial therapy and tumor volume in magnetic resonance imaging (MRI). METHODS A total of 142 patients with OD WHO (World Health Organization) II according to WHO 2016 were retrospectively included. Patients either had watch and wait (W&W) after histological sampling through stereotactic biopsy (n=59) or tumor resection (n=27) or else stereotactic biopsy with subsequent temozolomide (TMZ) (n=26) or PCV (n=30). Pre- and post-therapeutic T2 tumor volumes were obtained. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of secondary malignization after 10 years (MR-10yrs) were correlated with clinical and volumetric data. RESULTS PFS was significantly longer in the PCV cohort compared to TMZ (9.1 vs. 3.6 years, p = 0.04), even after matching patients according to age and initial tumor volume (9.1 vs 4.7 yrs, p = 0.03). PFS in the W&W cohort was 5.1 years and 4.4 years in those receiving tumor resection only. MR-10yrs was 4% in PCV cohort, 18% in the W&W cohort and 52% in the resection only cohort (p = 0.01). In the W&W cohort, patients treated with PCV at first relapse had a longer PR-PFS than those treated with TMZ (in years, 7.2 vs 4.0, p = 0.04). Multivariate analysis confirmed initial PCV therapy (p = 0.01) and initial T2 tumor volume (p = 0.02) to be prognostic. CONCLUSION In oligodendrogliomas WHO II PCV chemotherapy alone is superior in terms of PFS and rate of secondary malignization compared to TMZ chemotherapy alone or tumor resection only.

Background. Inflammation is an important driver of malignant glioma disease. Inflammatory mediators are not only produced by immune cells in the tumor microenvironment, but also by glioblastoma (GBM) cells themselves creating a mutually reinforcing loop. We here aimed at identifying an "anti-inflammatory switch" that allows to dampen inflammation in GBM. Methods. We used human GBM specimens, primary cultures, and cell lines. The response of GBM cells toward inflammatory stimuli was tested by incubation with supernatant of stimulated human immune cells. Expression levels were measured by whole transcriptome microarrays and qRT-PCR, and protein was quantified by LUMINEX and SDS-PAGE. MicroRNA binding to 3'UTRs was analyzed by luciferase assays. Proliferation rates were determined by flow cytometry, and invasion and angiogenesis were studied using migration and endothelial tube formation assays. Results. We demonstrated GBM cells to secrete high amounts of proinflammatory mediators in an inflammatory microenvironment. We found miR-93 as a potential "anti-inflammatory tumor suppressor" dramatically downregulated in GBM. Concordantly, cytokine secretion dropped after miR-93 re-expression. Transfection of miR-93 in GBM cells led to down-regulation of hubs of the inflammatory networks, namely, HIF-1 alpha and MAP3K2 as well as IL-6, G-CSF, IL-8, LIF, IL-1 ss, COX2, and CXCL5. We showed only COX2 and CXCL5 to be indirectly regulated by miR-93 while all other genes are true targets. Phenotypically, re-expression of miR-93 in GBM cells substantially suppressed proliferation, migration, and angiogenesis. Conclusions. Alleviating GBM-derived inflammation by re-expression of miR-93 may be a powerful tool to mitigate these tumors' aggressiveness and holds promise for new clinical approaches.

Background: The recombinant IL-1 receptor antagonist anakinra—currently approved for the treatment of autoinflammatory diseases—blocks IL-1β-mediated inflammatory signaling. As inflammation is a major driver of cancer, we hypothesized that anakinra might be able to mitigate glioblastoma (GBM) aggressiveness. Methods: Primary GBM or T98G cells were incubated alone or with peripheral blood mononuclear cells (PBMCs) and were subsequently treated with IL-1β and/or anakinra. T cells were obtained by magnetic bead isolation. Protein and mRNA expression were quantified by SDS-PAGE, qRT-PCR, and ELISA, respectively. Cell proliferation and apoptosis were analyzed via flow cytometry. Chemotaxis was studied via time-lapse microscopy. Results: Upon IL-1β stimulation, anakinra attenuated proinflammatory gene expression in both GBM cells and PBMCs, and mitigated tumor migration and proliferation. In a more lifelike model replacing IL-1β stimulation by GBM–PBMC co-culture, sole presence of PBMCs proved sufficient to induce a proinflammatory phenotype in GBM cells with enhanced proliferation and migration rates and attenuated apoptosis. Anakinra antagonized these pro-tumorigenic effects and, moreover, reduced inflammatory signaling in T cells without compromising anti-tumor effector molecules. Conclusion: By dampening the inflammatory crosstalk between GBM and immune cells, anakinra mitigated GBM aggressiveness. Hence, counteracting IL-1β-mediated inflammation might be a promising strategy to pursue.

Objective To evaluate the diagnostic accuracy and safety of extended stereotactic brain biopsy (ESBB) in a single center cohort with suspected primary angiitis of the central nervous system (PACNS). Methods A standardized stereotactic biopsy targeting MRI-positive lesions and collecting samples from the meninges and the cortex as well as from the white matter was performed in 23 patients with clinically suspected PACNS between 2010 and 2017. The relationship between biopsy yield and clinical characteristics, cerebrospinal fluid parameters, MR-imaging, time point of biopsy and exact localization of biopsy as well as number of tissue samples were examined. Results PACNS was confirmed in 7 of 23 patients (30.4%). Alternative diagnoses were identified in 7 patients (30%). A shorter time period between the onset or worsening of symptoms (p = 0.018) and ESBB significantly increased the diagnostic yield. We observed only minor and transient postoperative complications in 3 patients (13.0%). ESBB led to a direct change of the therapeutic regime in 13 of 23 patients (56.5%). Careful neuropathological analysis furthermore revealed that cortical samples were crucial in obtaining a diagnosis. Conclusion ESBB is a safe approach with good feasibility, even in critically ill patients, and high diagnostic accuracy in patients with suspected PACNS changing future therapies in 13 of 23 patients (56.5%). Early biopsy after symptom onset/worsening is crucial and (sub)acute MRI-lesions should be targeted with a particular need for biopsy samples from the cortical layer.

According to the updated WHO classification of gliomas with its emphasis on molecular parameters, tumours with an IDH-wildtype status have a dismal prognosis. To ensure timely adjustment of treatment, demand for non-invasive prediction methods is high. 18F-FET PET has been shown to be an important diagnostic tool for glioma management. The aim of this study was to assess the value of dynamic 18F-FET PET for the non-invasive prediction of the IDH-mutation status. Newly diagnosed WHO grade II–IV glioma patients with MRI and dynamic 18F-FET PET were included. The 18F-FET PET parameters mean and maximal tumour-to-background ratio (TBRmean, TBRmax) and minimal time-to-peak (TTPmin) were evaluated. The diagnostic power for the prediction of the IDH genotype (positive/negative predictive value) was tested in the overall study group and in the subgroup of non-contrast enhancing gliomas. Three hundred forty-one patients were evaluated. Molecular analyses revealed 178 IDH-mutant and 163 IDH-wildtype tumours. Overall, 270/341 gliomas were classified as 18F-FET-positive (TBRmax > 1.6), 90.2% of the IDH-wildtype and 69.1% of IDH-mutant gliomas. Median TBRmax was significantly higher in IDH-wildtype compared with IDH-mutant gliomas (2.9 vs. 2.3, p < 0.001); however, ROC-analyses revealed no reliable cutoff due to a high overlap (range 1.0–7.1 vs. 1.1–7.9). Dynamic analysis revealed a significantly shorter TTPmin in IDH-wildtype gliomas; using TTPmin ≤ 12.5 min as indicator for IDH-wildtype gliomas, a positive predictive value of 87% was reached (negative predictive value 72%, AUC = 0.796, p ≤ 0.001). A total of 161/341 gliomas did not show contrast enhancement on MRI; even within this subgroup, TTPmin ≤ 12.5 min remained a good predictor of IDH-wildtype glioma (positive predictive value 83%, negative predictive value 90%; AUC = 0.868, p < 0.001). A short TTPmin in dynamic 18F-FET PET serves as good predictor of highly aggressive IDH-wildtype status in gliomas. In particular, a high diagnostic power was observed in the subgroup of non-contrast enhancing gliomas, which helps to identify patients with worse prognosis.

Short duration (<25 days) treatment schedules with a higher radiation dose were associated with higher EoRT lymphocyte counts, an observation consistent with published models indicating less radiation dose of circulating blood by an approach of radiotherapy using fewer fractions.Radiation to multiple sites and concomitant chemotherapy conversely independently lowered EoRT lymphocyte count.Radiation-induced lymphopenia was associated with increased risk of acquiring a subsequent infection and mortality.

Objectives Intraoperative CT (iCT) angiography of the brain with stereotactic frames is an integral part of navigated neurosurgery. Validated data regarding radiation dose and image quality in these special examinations are not available. We therefore investigated two iCT protocols in this IRB-approved study . Methods Retrospective analysis of patients, who received a cerebral stereotactic iCT angiography on a 128 slice CT scanner between February 2016 and December 2017. In group A, automated tube current modulation (ATCM; reference value 410 mAs) and automated tube voltage selection (reference value 120 kV) were enabled, and only examinations with a selected voltage of 120 kV were included. In group B, fixed parameters were applied (300 mAs, 120 kV). Radiation dose was measured by assessing the volumetric CT dose index (CTDI vol ), dose length product (DLP) and effective dose (ED). Signal-to-noise ratio (SNR) and image noise were assessed for objective image quality, visibility of arteries and grey-white differentiation for subjective image quality. Results Two hundred patients ( n = 100 in each group) were included. In group A, median selected tube current was 643 mAs (group B, 300 mAs; p < 0.001). Median values of CTDI vol , DLP and ED were 91.54 mGy, 1561 mGy cm and 2.97 mSv in group A, and 43.15 mGy, 769 mGy cm and 1.46 mSv in group B ( p < 0.001). Image quality did not significantly differ between groups ( p > 0.05). Conclusions ATCM yielded disproportionally high radiation dose due to substantial tube current increase at the frame level, while image quality did not improve. Thus, ATCM should preferentially be disabled. Key Points • Automated tube current modulation (ATCM) yields disproportionally high radiation dose in intraoperative CT angiography of the brain with stereotactic head frames. • ATCM does not improve overall image quality in these special examinations. • ATCM is not yet optimised for CT angiography of the brain with major extracorporeal foreign materials within the scan range.

The recombinant IL-1 receptor antagonist anakinra prevents binding of IL-1 to its receptor and blocks IL-1β-mediated proinflammatory signaling. It is currently used in the treatment of autoinflammatory diseases. As inflammation is a major driver of malignancy, we hypothesized that anakinra – by ameliorating the inflammatory tumor environment – might be capable to mitigate glioblastoma (GBM) progression. T98G GBM cells were cultivated with PBMC, separated by cell culture inserts with or without anakinra and incubated 48h in 5% O2 mimicking the GBM microenvironment. T-cells were obtained by magnetic bead isolation. mRNA expression levels were measured by quantitative Real-Time-PCR (qRT-PCR). Cytokine production was assessed by ELISA. Cell proliferation was analyzed by flow cytometric quantification of Ki-67 protein expression. Anakinra has been provided by Swedish Orphan Biovitrum AB (Sweden). Results are presented as mean±SEM, p-Values were calculated using Student’s t-test. After administration of anakinra, mRNA expression levels of the inflammatory and proangiogenic genes IL-1β, COX-2, CCL2 and IL-8 were reduced in T98G (-64%±19.1%, -56.2%±21.3%, -87.1%±28.8%, -91.7%±27.2%, n=7, p< 0.05). Surprisingly, no changes of these targets were detectable in PBMC. However, in T-cells, anakinra induced mRNA expression of Th2 transcription factor GATA3 and the antiinflammatory cytokines IL-4 and IL-10 (+6,7%±4,6%, +36,1%±22,9%, +69,1%32,8%, n=10, p< 0.05). The expression of the protumorigenic genes IL-22, IL-17 as well as IFNγ was dramatically repressed (-63.2%±21.9%, -88.1%±21.7%, -85.6%±45.2%, n=10, p< 0.05), protein secretion of IL-22 and IFNγ was strongly blocked (-36.3%±9.1%, -13.9%±0.5%, n=6, p< 0.05). Importantly, treatment with anakinra markedly attenuated GBM cell proliferation (-20.1%±5%, n=4, p< 0.05). Anakinra indeed puts the brake on proinflammatory signaling pathways in GBM cells and simultaneously promotes a shift towards an anti-inflammatory T-cell phenotype. As a result, GBM proliferation is diminished. Hence, administration of anakinra might be an interesting and novel therapeutic approach to reduce Glioblastoma aggressiveness.

Background. We aimed to elucidate the place of dynamic O-(2-[F-18]-fluoroethyl)-L-tyrosine (F-18-FET) PET in prognostic models of gadolinium (Gd)-negative gliomas. Methods. In 98 patients with Gd-negative gliomas undergoing F-18-FET PET guided biopsy, time activity curves (TACs) of each tumor were qualitatively categorized as either increasing or decreasing. Additionally, post-hoc quantitative analyses were done using minimal time-to-peak (TTPmin) measurements. Prognostic factors were obtained from multivariate hazards models.The fit of the biospecimen- and imaging-derived models was compared. Results. A homogeneous increasing, mixed, and homogeneous decreasing TAC pattern was seen in 51, 19, and 28 tumors, respectively. Mixed TAC tumors exhibited both increasing and decreasing TACs. Corresponding adjusted 5-year survival was 85%, 47%, and 19%, respectively (P < 0.001). Qualitative and quantitative TAC measurements were highly intercorrelated (P< 0.0001).TTPmin was longest (shortest) in the homogeneous increasing (decreasing) TAC group and in between in the mixed TAC group. TTPmin was longer in isocitrate dehydrogenase (/DH)-mutant tumors (P< 0.001). Outcome was similarly precisely predicted by biospecimen- and imaging-derived models. In the biospecimen model, World Health Organization (WHO) grade (P< 0.0001) and IDH status (P< 0.001) were predictors for survival. Outcome of homogeneous increasing (homogeneous decreasing) TAC tumors was nearly identical, with bothTTP(min) > 25 min (TTPmin <= 12.5 min) tumors and /DH-mutant grade II (/DH-wildtype) gliomas. Outcome of mixed TAC tumors matched that of both intermediate TTPmin (>12.5 min and <= 25 min) and /DH-mutant, grade III gliomas. Each of the 3 prognostic clusters differed significantly from the other ones of the respective models (P< 0.001). Conclusion. TAC measurements constitute a powerful biomarker independent from tumor grade and IDH status.

Purpose: The role of bevacizumab (BEV) in the setting of reirradiation (reRT) of malignant glioma recurrences is poorly defined. At our institution, reRT plus BEV was routinely used until its disapproval for glioma treatment by the European Medical Agency. Accordingly, reRT was applied without the addition of BEV since 2017. Here we present for the first time outcome and toxicity profiles of reRT plus BEV and reRT alone for malignant glioma recurrences. Patients and methods: All adult patients consecutively undergoing reRT of a recurrent malignant glioma (37 anaplastic astrocytoma, WHO III; 124 glioblastoma, WHO IV) between 2007 and 2017 were included. In one group of patients, BEV (10 mg/kg bodyweight) was applied concomitantly on days 1 and 15 of reRT. Radiation toxicity referred to clinically significant toxicities of proven symptomatic radionecrosis (RN) and symptomatic oedema (SE) requiring steroid treatment for more than six weeks after reRT. Post-recurrence survival (PRS) and freedom from RN/SE were estimated with the Kaplan-Meier method. Prognostic factors were obtained from proportional hazards models. Results: BEV plus reRT was applied in 124 and reRT alone in 37 patients. Both groups were comparable in terms of their patient-, tumour-, and RT/reRT-related variables. PRS was independent from the applied reRT protocols. RN/SE was less frequently seen after reRT plus BEV absolutely (27/124 (21.8%) vs. 14/37 (37.8%) patients; p = 0.025) and over time (1-year RN/SE rate: 23.9% vs. 54.1%; p = 0.013). The unadjusted and adjusted hazard ratio for RN/SE was doubled in case of reRT alone. Absence of BEV remained the only risk factor for RN/SE in multivariate models (p = 0.026). Conclusion: Concomitant BEV effectively reduces treatment toxicity of reRT and should be reconsidered in future reRT protocols. (C) 2019 Elsevier B.V. All rights reserved.

Over the last decade, advances in molecular and imaging-based biomarkers have induced a more versatile diagnostic classification and prognostic evaluation of glioma patients. This, in combination with a growing therapeutic armamentarium, enables increasingly individualized, risk-benefit-optimized treatment strategies. This path to precision medicine in glioma patients requires surgical procedures to be reassessed within multidimensional management considerations. This article attempts to integrate the surgical intervention into a dynamic network of versatile diagnostic characterization, prognostic assessment, and multimodal treatment options in the light of the latest 2016 World Health Organization (WHO) classification of diffuse brain tumors, WHO grade II, III, and IV. Special focus is set on surgical aspects such as resectability, extent of resection, and targeted surgical strategies including minimal invasive stereotactic biopsy procedures, convection enhanced delivery, and photodynamic therapy. Moreover, the influence of recent advances in radiomics/radiogenimics on the process of surgical decision-making will be touched.

Refined localization of the epileptogenic zone (EZ) in patients with pharmacoresistant focal epilepsy proceeding to resective surgery might improve postoperative outcome. We here report seizure outcome after stereo EEG (sEEG) evaluation with individually planned stereotactically implanted depth electrodes and subsequent tailored resection.