Aneurysmal subarachnoid hemorrhage (aSAH) is a debilitating condition with significant morbidity and mortality rates. Despite advancements in treatment, understanding the underlying pathophysiology, particularly the inflammatory response, remains crucial for improving patient outcomes. In this study, we investigated the presence of transmembrane protein 119 (TMEM119) of microglial cells in cerebrospinal fluid (CSF) as a potential marker for neuroinflammation following aSAH. CSF samples were collected from aSAH patients, pathological and healthy controls, processed, and analyzed using immunocytochemistry. TMEM119-positive microglial cells were consistently identified in the CSF of aSAH patients, exhibiting amoeboid morphology and intense staining. Importantly, microglial cells were detected as early as the first day post-bleeding, persisting throughout the acute phase in some cases. Analysis of consecutive samples revealed varying trends in microglial cell numbers, with a peak during the initial phase followed by a gradual decline. Our findings suggest that microglia may migrate into the CSF following aSAH, potentially serving as an early predictor of inflammatory-related CNS damage. This study underscores the importance of understanding neuroinflammatory processes in aSAH and opens avenues for further research on the role of microglia in CNS disorders by liquid biopsy.

Background Mobile 3-dimensional fluoroscopes are an integral part of modern neurosurgical operating theatres and can also be used in combination with free available image post processing to depict cerebral vessels. In preparation of stereotactic surgery, preoperative Computed Tomography (CT) may be required for image fusion. Contrast CT may be of further advantage for image fusion as it regards the vessel anatomy in trajectory planning. Time-consuming in-hospital transports are necessary for this purpose. Mobile 3D-fluoroscopes may be used to generate a CT equal preoperative data set without an in-hospital transport. This study was performed to determine the feasibility and image quality of intraoperative 3-dimensional fluoroscopy with intravenous contrast administration in combination with stereotactical procedures. Methods 6 patients were included in this feasibility study. After fixation in a radiolucent Mayfield clamp a rotational fluoroscopy scan was performed with 50 mL iodine contrast agent. The image data sets were merged with the existing MRI images at a planning station and visually evaluated by two observer. The operation times were compared between the frame-based and frameless systems (“skin-to-skin” and “OR entry to exit”). Results The procedure proves to be safe. The entire procedure from fluoroscope positioning to the transfer to the planning station took 5–6 min with an image acquisition time of 24 s. In 5 of 6 cases, the fused imaging was able to reproduce the vascular anatomy accurately and in good quality. Both time end-points were significantly shorter compared to frame-based interventions. Conclusion The images could easily be transferred to the planning and navigation system and were successfully merged with the MRI data set. The procedure can be completely integrated into the surgical workflow. Preoperative CT imaging or transport under anaesthesia may even be replaced by this technique in the future. Furthermore, hemorrhages can be successfully visualized intraoperatively and might prevent time delays in emergencies.

Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. We recently reported its use for imaging cerebral vascular malformations and aneurysms. This study was conducted to evaluate various radiation settings for the imaging of cerebral aneurysms before and after surgical occlusion. Eighteen patients with cerebral aneurysms with the indication for surgical clipping were included in this prospective analysis. Before surgery the patients were randomized into one of three different scan protocols according (default settings of the 3D fluoroscope): Group 1: 110 kV, 80 mA (enhanced cranial mode), group 2: 120 kV, 64 mA (lumbar spine mode), group 3: 120 kV, 25 mA (head/neck settings). Prior to surgery, a rotational fluoroscopy scan (duration 24 s) was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® MD 10.0 software. The procedure was repeated after clip placement. The image quality regarding preoperative aneurysm configuration and postoperative assessment of aneurysm occlusion and vessel patency was analyzed by 2 independent reviewers using a 6-grade scale. This technique quickly supplies images of adequate quality to depict intracranial aneurysms and distal vessel patency after aneurysm clipping. Regarding these features, a further optimization to our previous protocol seems possible lowering the voltage and increasing tube current. For quick intraoperative assessment, image subtraction seems not necessary. Thus, a native scan without a contrast agent is not necessary. Further optimization may be possible using a different contrast injection protocol.

Glioblastoma multiforme (GBM) treatment consists of surgery, radiotherapy and chemotherapy with Temozolomide (TMZ). After subtotal resection (STR), residual tumors rarely undergo spontaneous regression. Overall survival (OS) and progression-free survival (PFS) are reduced when compared with gross total resection. There is evidence that adding Tumor Treating Fields (TTFields) to standard management may lead to a significant increase in PFS and OS. In 2015 and 2016, STR was performed in 27 patients with GBM. Of these, four subsequently received TTFields therapy in addition to chemotherapy. The present study presents a series of three patients with GBM (44-54 years; isocitrate dehydrogenase wild-type, methylated 06-methylguanine-DNA methyltransferase promoter) that were treated with radiochemotherapy and TTFields after STR. Therapy with TTFields started concomitantly to TMZ following radiotherapy and was maintained for 14, 24 and 37 months. TTFields were used as monotherapy in one case, as TMZ treatment had to be stopped due to toxicity for 1 month. In all patients, TTFields therapy was well tolerated at high compliance levels, resulting in complete response (CR) after 4, 5 and 7 months, respectively. Two patients remain tumor-free at 16 and 40 months after STR. One patient exhibited multifocal recurrence 11 months after the beginning of TTFields treatment but remains alive, presenting a mild neurological decline 24 months after starting TTFields. All three presented patients gave written informed consent for their data to be published. In conclusion, the current report detailed three patients with GBM who underwent STR and were subsequently treated with TMZ and TTFields. TTFields treatment was tolerated well and was applied accurately and with high compliance by these patients, which may have contributed to the complete response. Four of the 27 patients treated with STR received additional TTFields treatment. Three of these 4 showed a CR, while a CR was observed only 2 of the remaining 23 patients without TTFields. The current series supports the effects in clinical practice, as demonstrated in recent clinical trials. The results also demonstrated that adjuvant TTFields therapy can structurally affect residual tumors after STR.

Background Glioblastoma multiforme (GBM) is the most frequent malignant neoplasm in the adult brain. In contrast, arteriovenous malformations (AVMs) are presumably congenital lesions, usually presenting with hemorrhage. Hypervascular low-grade gliomas associated with AVMs were previously called “angioglioma.” An association of AVMs and GBM was also described. Study Aims We discuss the data of the largest series of locally coincident GBM with AVM in a single institution so far. All analyses were explorative only. Patients We report a series of four patients presenting at our department from 2006 to 2014. All patients underwent surgery. The cases were analyzed regarding initial presentation, clinical findings, tumor localization, and histopathologic results. Conclusions A local coincidence of cerebral AVM and GBM is rare. Only a few reports can be found in the literature. The radiologic as well as the clinical presentations are individual. Proangiogenic factors are discussed as involved in the appearance of both entities in the same location. However, the presence of pathologic vessels within malignant gliomas is well known to all neurosurgeons and proangiogenic activity has been proven. Therefore, it seems possible that tumor activity itself contributes to the pathogenesis of a vascular malformation.

Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacks reliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associated in colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinical outcome and therapy response in glioblastomas. MACC1 transcripts were significantly higher in patients compared to controls. Low MACC1 levels clustered together with other prognostically favorable markers. It was associated with patients' prognosis in conjunction with the isocitrate dehydrogenase (IDH) mutation status: IDH1 R132H mutation and low MACC1 was most favorable (median overall survival (OS) not yet reached), IDH1 wildtype and high MACC1 was worst (median OS 8.1 months), while IDH1 wildtype and low MACC1 was intermediate (median OS 9.1 months). No patients displayed IDH1 R132H mutation and high MACC1. Patients with low MACC1 levels receiving standard therapy survived longer (median OS 22.6 months) than patients with high MACC1 levels (median OS 8.1 months). Patients not receiving the standard regimen showed the worst prognosis, independent of MACC1 levels (low: 6.8 months, high: 4.4 months). Addition of circulating MACC1 transcript levels to the existing prognostic workup may improve the accuracy of outcome prediction and help define more precise risk categories of glioblastoma patients.

Objective: Therapy with Tumor Treating Fields (TTFields) in combination with adjuvant temozolomide following surgical resection and radiochemotherapy significantly increased survival rates in patients with newly diagnosed glioblastoma (ndGBM) in the phase III trial EF-14. The importance of a high compliance/usage rate was supported by a recently published subgroup analysis, revealing a strong correlation of adherence to TTFields therapy with prolonged overall survival (OS). A compliance rate of 75% and more was demonstrated to be a beneficial independent prognostic factor for OS. Here, TTFields therapy adherence of 36 high-grade glioma (HGG) patients is reported. Methods: 36 patients diagnosed with HGG received TTFields therapy, amongst them 28 patients diagnosed with GBM and 8 patients with astrocytoma WHO°III. Patients were introduced to the therapy during neurooncologic consultation hours. For assessment of adherence to TTFields therapy, the compliance/usage reports generated at the monthly technical check of the device were analyzed. Results: At initiation of therapy, the median age of HGG patients was 53.5 years (range 29-67 years). 21 of the 28 GBM patients were diagnosed with ndGBM and the remaining ones had recurrences (rGBM). In these patients, the gender distribution female to male was 1:1.15, which represents a higher ratio of female patients compared to the typical GBM population with 1:1.64. At the time point of data cut-off, ndGBM patients were on TTFields therapy for a median of 6.9 months with a median compliance/usage rate of 84.2%. Regarding therapy adherence, no significant differences were observed between female (84.3%) and male (81.1%) patients. Moreover, comparison between patients with ndGBM and recurrent GBM (rGBM) showed no significant difference in therapy adherence with a median compliance of 71.1% in rGBM patients. For patients diagnosed with astrocytoma WHO°III a compliance rate of 84.5% was reported. Conclusion: In the reported patients receiving TTFields therapy a high median compliance to TTFields therapy was observed, irrespective of sex and diagnosis. No significant differences regarding the compliance/usage rate was detected between the different groups. TTFields therapy was well accepted by all HGG patients, in particular by female GBM patients. Across all groups, the median compliance/usage rate was substantially above the independent prognostic threshold of 75%. In conclusion, TTFields therapy can be recommended to all eligible patients with HGG. Citation Format: Carsten Hagemann, Judith Weiland, Nadine Lilla, Thomas Linsenmann, Ralf-Ingo Ernestus, Mario Löhr, Almuth F. Kessler. Adherence to tumor treating fields (TTFields) in high-grade glioma patients - a single center experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-155.

The use of [18F]fluoroethyl)-l-tyrosine ([18F]FET) positron emission tomography/computed tomography (PET/CT) has proven valuable in brain tumor management. This study aimed to investigate the prognostic value of radiotracer uptake in newly diagnosed grade II or III gliomas according to the current 2016 World Health Organization (WHO) classification. A total of 35 treatment-naive patients (mean age, 48 ± 17 years) with histologically proven WHO grade II or III gliomas as defined by the current 2016 WHO classification were included. Static PET/CT imaging was performed 20 min after intravenous [18F]FET injection. Images were assessed visually and semi-quantitatively using regions of interest for both tumor (SUVmax, SUVmean) and background (BKGmean) to calculate tumor-to-background (TBR) ratios. The association among histological results, molecular markers (including isocitrate dehydrogenase enzyme and methylguanine-DNA methyltransferase status), clinical features (age), and PET findings was tested and compared with outcome (progression-free [PFS] and overall survival [OS]). Fourteen patients presented with grade II (diffuse astrocytoma n = 10, oligodendroglioma n = 4) and 21 patients with grade III glioma (anaplastic astrocytoma n = 15, anaplastic oligodendroglioma n = 6). Twenty-seven out of the 35 patients were PET-positive (grade II n = 8/14, grade III n = 19/21), with grade III tumors exhibiting significantly higher amino acid uptake (TBRmean and TBRmax; p = 0.03 and p = 0.02, respectively). PET-negative lesions demonstrated significantly prolonged PFS (p = 0.003) as compared to PET-positive gliomas. PET-positive disease had a complementary value in prognostication in addition to patient age, glioma grade, and molecular markers. Amino acid uptake as assessed by [18F]FET-PET/CT imaging is useful as non-invasive read-out for tumor biology and prognosis in newly diagnosed, treatment-naive gliomas according to the 2016 WHO classification.

PURPOSE:PET/CT using O-(2-[F]fluoroethyl)-L-tyrosine (F-FET) has proven valuable in differentiating tumor recurrence and progression from therapy-induced changes. This study aimed to investigate the diagnostic performance of several analytic approaches in the setting of suspected late pseudoprogression (PsP) in glioblastoma multiforme (GBM). METHODS:Retrospective analysis of tumor recurrence was performed in 36 patients with histopathologically confirmed GBM and suspicion of recurrence/disease progression more than 12 weeks from cessation of irradiation based on MRI and Response Assessment in Neuro-Oncology working group criteria. For differentiation of late PsP from true tumor recurrence, images were analyzed semiquantitatively employing tumor-to-brain ratios using 5 different approaches for tumor and normal brain reference region definition, respectively. Histopathology and/or clinical and imaging follow-up served as reference. Respective areas under the receiver operating characteristic curve were compared. RESULTS:F-FET PET was able to reliably differentiate PsP from true tumor progression with areas under the receiver operating characteristic curve ranging from 0.80 to 0.88 (all P < 0.01). Irrespective of the approach chosen, the classification differences between the applied methods were not significant (all P > 0.05), albeit approaches focusing on voxels with the highest uptake tended to perform superior. CONCLUSIONS:Irrespective of the analytical approach, F-FET PET is a robust tool for detection of late PsP with only minor differences between different analytical approaches. However, methodological standardization and harmonization are needed to ensure comparability between different centers.

Pseudoprogression (PsP) in glioblastoma presents a significant obstacle in distinguishing genuine tumour recurrence from treatment-induced contrast enhancement on MRI. Only retrospectively identifiable, PsP is believed to be at least partly a result of radiochemotherapy-based alterations in the blood–brain barrier (BBB). Radiation-induced hypoxia has been suggested to upregulate vascular endothelial growth factor, which then mediates blood vessel permeability and fosters BBB dysregulation.Typically understood to occur within the first 12 weeks following radiotherapy, PsP has recently been demonstrated to also appear significantly later (‘late pseudoprogression’).1Given its ability to mimic true tumour development, late PsP can lead to interference with treatment course or unwarranted surgical intervention. Thus, its prompt and definitive detection serves a critical role in glioblastoma management.Positron emission tomography (PET) using radiolabelled amino acids such as O-(2-(18F)fluoroethyl)-L-tyrosine ((18F)FET) has proven a useful tool in the differentiation of true tumour progression from treatment-induced changes, as tracer uptake reflects amino acid transport rather than inflammatory processes. The purpose of this study was to further substantiate the available data on the suitability of (18F)FET-PET in suspected late PsP.### SubjectsThis retrospective study included 36 consecutive patients (22 males and 14 females, ages ranging from 24 to 75 years, with a mean of 54±14) with histopathologically confirmed glioblastoma. Between April 2010 and August 2016, patients were referred to (18F)FET-PET/CT due to suspicion of recurrence/disease progression as determined by the Response Assessment in Neuro-Oncology (RANO) working group criteria.2 The interval between cessation of radiotherapy and …

Regulation of the host immune response serves a pivotal role in the persistence and progression of malignant glioma. To date, cytotoxic cluster of differentiation (CD)-8+ T and natural killer cells are considered the main cellular components of host tumor control. The influence of macrophages in an orthotropic C6 tumor implantation model was investigated and the aim of the present study was to characterize the effects of systemic macrophage-activation on glioma growth by using the granulocyte macrophage colony stimulating factor (rhGM-CSF). A total of 20 male Sprague-Dawley rats were orthotopically implanted with C6 glioma spheroids and treated subcutaneously with 10 µg/kg rhGM-CSF every other day; 9 animals served as controls. Serial magnetic resonance imaging was performed on days 7, 14, 21, 28, 32 and 42 post-implantation to monitor tumor volume. Histological work-up included hematoxylin and eosin, CD68/ED-1 macrophage, CD8 T-cell and Ki-67 MIB1 proliferation staining in gliomas and spleen. Experimental C6-gliomas developed in 15/20 (75%) animals. In rhGM-CSF treated rats, tumors developed significantly later and reached a smaller size (median, 134 mm3) compared with the controls (median, 262 mm3). On day 14, solid tumors presented in 11/17 (65%) rhGM-CSF-treated animals; in control animals tumor growth was detected in 3/9 animals on day 7 and in all animals on day 14. The mean survival time was 35 days in the rhGM-CSF group and significantly longer when compared with the control group (24 days). Immunohistochemistry exhibited significantly more macrophages in tumors, particularly in the perivascular zone of the rhGM-CSF group when compared with untreated animals; intratumoral CD8+ counts were equal in both groups. A systemic stimulation of macrophages by rhGM-CSF resulted in significantly reduced and delayed tumor growth in the rodent C6 glioma model. The present data suggested a significant role of macrophages in host control of experimental gliomas on the innate immune response. Until now, the role of macrophages may have been underestimated in host glioma control.