Simple Summary MGMT-methylated glioblastomas have significantly lower ADC values, as compared to the glioblastomas with no MGMT methylation in peritumoral white matter. There were no differences in enhancing tumor areas. These findings could improve predictions of MGMT status in glioblastomas. Abstract Different results have been reported concerning the relationship of the apparent diffusion coefficient (ADC) values and the status of methylation as the promoter gene for the enzyme methylguanine-DNA methyltransferase (MGMT) in patients with glioblastomas (GBs). The aim of this study was to investigate if there were correlations between the ADC values of the enhancing tumor and peritumoral areas of GBs and the MGMT methylation status. In this retrospective study, we included 42 patients with newly diagnosed unilocular GB with one MRI study prior to any treatment and histopathological data. After co-registration of ADC maps with T1-weighted sequences after contrast administration and dynamic susceptibility contrast (DSC) perfusion, we manually selected one region-of-interest (ROI) in the enhancing and perfused tumor and one ROI in the peritumoral white matter. Both ROIs were mirrored in the healthy hemisphere for normalization. In the peritumoral white matter, absolute and normalized ADC values were significantly higher in patients with MGMT-unmethylated tumors, as compared to patients with MGMT-methylated tumors (absolute values p = 0.002, normalized p = 0.0007). There were no significant differences in the enhancing tumor parts. The ADC values in the peritumoral region correlated with MGMT methylation status, confirmed by normalized ADC values. In contrast to other studies, we could not find a correlation between the ADC values or the normalized ADC values and the MGMT methylation status in the enhancing tumor parts.

Simple Summary Radionecrosis is a common and rising problem in neuro-oncology. Image interpretation and management of these patients has to be conducted in an interdisciplinary setting in order to offer the best medical care to patients with gliomas or brain metastases. In this article, we provide a state-of-the-art institutional guideline for the current morphological, functional, metabolic and evolving imaging tools to distinguish radionecrosis from tumor recurrence. We also discuss the therapeutic possibilities and give an outlook on future developments to tackle this challenging topic. Abstract Radiation necrosis represents a potentially devastating complication after radiation therapy in brain tumors. The establishment of the diagnosis and especially the differentiation from progression and pseudoprogression with its therapeutic implications requires interdisciplinary consent and monitoring. Herein, we want to provide an overview of the diagnostic modalities, therapeutic possibilities and an outlook on future developments to tackle this challenging topic. The aim of this report is to provide an overview of the current morphological, functional, metabolic and evolving imaging tools described in the literature in order to (I) identify the best criteria to distinguish radionecrosis from tumor recurrence after the radio-oncological treatment of malignant gliomas and cerebral metastases, (II) analyze the therapeutic possibilities and (III) give an outlook on future developments to tackle this challenging topic. Additionally, we provide the experience of a tertiary tumor center with this important issue in neuro-oncology and provide an institutional pathway dealing with this problem.

Simple Summary Magnetic resonance spectroscopy (MRS) is a useful technique in diagnosis and follow-up of gliomas. In this review we provide an insight in the use of both proton and phosphorous MRS in clinical and scientific every day practice. Abstract Preoperative grade prediction is important in diagnostics of glioma. Even more important can be follow-up after chemotherapy and radiotherapy of high grade gliomas. In this review we provide an overview of MR-spectroscopy (MRS), technical aspects, and different clinical scenarios in the diagnostics and follow-up of gliomas in pediatric and adult populations. Furthermore, we provide a recap of the current research utility and possible future strategies regarding proton- and phosphorous-MRS in glioma research.

Simple Summary In order to compare responses to different therapies among clinical trials and to differentiate between therapy-induced changes and true tumor progression, reliable response parameters are crucial. With the advent of targeted and immunologic treatments, several assessment tools have been proposed. In this post hoc analysis we compared assessment criteria according to MacDonald, RANO, mRANO, iRANO as well as Vol-RANO and Vol-mRANO in patients with newly diagnosed glioblastoma treated with standard of care (SOC) ± tumor lysate-charged autologous dendritic cells (Audencel). We found that the best correlation between progression-free survival (PFS) and overall survival (OS) was seen for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel. Abstract Introduction: In this post hoc analysis we compared various response-assessment criteria in newly diagnosed glioblastoma (GB) patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression-free survival (PFS) and overall survival (OS). Methods: 76 patients enrolled in a multicenter phase II trial receiving standard of care (SOC, n = 40) or SOC + Audencel vaccine (n = 36) were included. MRI scans were evaluated using MacDonald, RANO, Vol-RANO, mRANO, Vol-mRANO and iRANO criteria. Tumor volumes (T1 contrast-enhancing as well as T2/FLAIR volumes) were calculated by semiautomatic segmentation. The Kruskal-Wallis-test was used to detect differences in PFS among the assessment criteria; for correlation analysis the Spearman test was used. Results: There was a significant difference in median PFS between mRANO (8.6 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.0 months), RANO (4.2 months) and Vol-RANO (5.4 months). For the vaccination arm, median PFS by iRANO was 6.2 months. There was no difference in PFS between SOC and SOC + Audencel. The best correlation between PFS/OS was detected for mRANO (r = 0.65) and Vol-mRANO (r = 0.69, each p < 0.001). A total of 16/76 patients developed a pure T2/FLAIR progressing disease, and 4/36 patients treated with Audencel developed pseudoprogression. Conclusion: When comparing different response-assessment criteria in GB patients treated with dendritic cell-based immunotherapy, the best correlation between PFS and OS was observed for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel.

Brain parenchyma infiltration with glioblastoma (GB) cannot be entirely visualized by conventional magnetic resonance imaging (MRI). The aim of this study was to investigate changes in the energy and membrane metabolism measured with phosphorous MR spectroscopy (31P-MRS) in the presumably “normal-appearing” brain following chemoradiation therapy (CRT) in GB patients in comparison to healthy controls. Twenty (seven female, thirteen male) GB patients underwent a 31P-MRS scan prior to surgery (baseline) and after three months of standard CRT (follow-up examination. The regions of interest “contrast-enhancing (CE) tumor” (if present), “adjacent to the (former) tumor”, “ipsilateral distant” hemisphere, and “contralateral” hemisphere were compared, differentiating between patients with stable (SD) and progressive disease (PD). Metabolite ratios PCr/ATP, Pi/ATP, PCr/Pi, PME/PDE, PME/PCr, and PDE/ATP were investigated. In PD, energy and membrane metabolism in CE tumor areas have a tendency to “normalize” under therapy. In different “normal-appearing” brain areas of GB patients, the energy and membrane metabolism either “normalized” or were “disturbed”, in comparison to baseline or controls. Differences were also detected between patients with SD and PD. 31P-MRS might contribute as an additional imaging biomarker for outcome measurement, which remains to be investigated in a larger cohort.

An auditory brainstem implant (ABI) represents an alternative for patients with profound hearing loss who are constrained from receiving a cochlear implant. The positioning of the ABI electrode influences the patient’s auditory capacity and, therefore, quality of life and is challenging even with available intraoperative electrophysiological monitoring. This work aims to provide and assess the feasibility of visual-spatial assistance for ABI positioning. The pose of the forceps instrument that grasps the electrode was electromagnetically navigated and interactively projected in the eyepieces of a surgical microscope with respect to a target point. Intraoperative navigation was established with an experimental technique for automated nasopharyngeal patient registration. Two ABI procedures were completed in a human specimen head. An intraoperative usability study demonstrated lower localization error when using the proposed visual display versus standard cross-sectional views. The postoperative evaluations of the preclinical study showed that the center of the electrode was misplaced to the planned position by 1.58 mm and 3.16 mm for the left and the right ear procedure, respectively. The results indicate the potential to enhance intraoperative feedback during ABI positioning with the presented system. Further improvements consider estimating the pose of the electrode itself to allow for better orientation during placement.

Response assessment in the treatment of glioblastoma (GB) based on MR-imaging is still challenging, in particular for immunotherapeutic strategies. Several assessment tools have been proposed. In this post-hoc analysis we compared response assessment criteria (MacDonald, RANO, mRANO, Vol.-mRANO, iRANO) in newly diagnosed GB patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression free survival (PFS) and overall survival (OS). 76 patients with newly diagnosed GB enrolled in a multicenter randomized phase II trial receiving standard of care (SOC, n= 40) or SOC + Audencel vaccine (n= 36) were included. Tumor volumes were calculated by semiautomatic segmentation. To detect differences in PFS among the assessment criteria Kruskal-Wallis-test, for correlation analysis Spearman test was used. There was a significant difference in median PFS based on the different assessments (mRANO 8.55 months [9.10-14.03], Vol.-mRANO 8.61 months [9.72-14.92] compared to MacDonald 4.04 months [5.21-8.75] and RANO 4.16 months [5.28-8.61]. For the vaccination arm only, median PFS by iRANO was 5.95 months [5.70-11.54]). There was no difference in PFS between SOC and SOC + Audencel using the different response criteria. The best correlation between PFS and OS was detected for mRANO (r= 0.65, p< 0.001) and Vol.-mRANO (r= 0.69, p< 0.001). At an 8-month landmark, the impact of progressive disease on median OS was best shown for mRANO (13.70 months [13.13-18.98], and Vol.-mRANO 12.03 months [12.51-17.94]) compared to MacDonald 17.97 months [15.45-20.92], RANO 17.97 months [15.92-20.95] and iRANO 17.34 months [14.99-22.73]. When comparing different response assessments in GB patients treated with dendritic cell-based immunotherapy the best correlation between PFS and OS was observed for mRANO and Vol.-mRANO. Overall, no difference in PFS and OS was seen between the two treatment arms. iRANO was not superior for predicting OS in patients treated with Audencel.

Simple Summary Gliobastoma is one of the deadliest tumors overall, yet the most common malignant brain tumor. The new World Health Organization Classification of Brain Tumors brought changes in how we look at this type of malignancy. Now we know that glioblastoma is rather a spectrum of similar tumors, but with some distinct characteristics that include molecular footprint, response to therapy and with that overall survival, among others. We hypothesised that by employing phosphorous magnetic resonance we will be able to show differences in cellular energy metabolism in these various subtypes of glioblastoma. For example, we found indices of faster cell reproduction and tumor growth in MGMT-methylated and EGFR-amplified tumors. These tumors also could have reduced energetic state or tissue oxygenation due to the increased necrosis. Tumors with EGFR-amplification could have increased apoptotic activity regardless of their MGMT status. Our study indicated various differences in energetic metabolism in tumors with different molecular characteristics, which could potentially be important in future therapeutic strategies. Abstract The World Health Organisation’s (WHO) classification of brain tumors requires consideration of both histological appearance and molecular characteristics. Possible differences in brain energy metabolism could be important in designing future therapeutic strategies. Forty-three patients with primary, isocitrate dehydrogenase 1 (IDH1) wild type glioblastomas (GBMs) were included in this study. Pre-operative standard MRI was obtained with additional phosphorous magnetic resonance spectroscopy (31-P-MRS) imaging. Following microsurgical resection of the tumors, biopsy specimens underwent neuropathological diagnostics including standard molecular diagnosis. The spectroscopy results were correlated with epidermal growth factor (EGFR) and O6-Methylguanine-DNA methyltransferase (MGMT) status. EGFR amplified tumors had significantly lower phosphocreatine (PCr) to adenosine triphosphate (ATP)-PCr/ATP and PCr to inorganic phosphate (Pi)-PCr/Pi ratios, and higher Pi/ATP and phosphomonoesters (PME) to phosphodiesters (PDE)-PME/PDE ratio than those without the amplification. Patients with MGMT-methylated tumors had significantly higher cerebral magnesium (Mg) values and PME/PDE ratio, while their PCr/ATP and PCr/Pi ratios were lower than in patients without the methylation. In survival analysis, not-EGFR-amplified, MGMT-methylated GBMs showed the longest survival. This group had lower PCr/Pi ratio when compared to MGMT-methylated, EGFR-amplified group. PCr/Pi ratio was lower also when compared to the MGMT-unmethylated, EGFR not-amplified group, while PCr/ATP ratio was lower than all other examined groups. Differences in energy metabolism in various molecular subtypes of wild-type-GBMs could be important information in future precision medicine approach.

Introduction: Various functional neuroimaging studies help to better understand the changes in brain activity during meditation. The purpose of this study was to investigate how brain energy metabolism changes during focused attention meditation (FAM) state, measured by phosphorous magnetic resonance spectroscopy (31P-MRS). Methods: 31P-MRS imaging was carried out in 27 participants after 7 weeks of FAM training. Metabolite ratios and the absolute values of metabolites were assessed after meditation training in two MRI measurements, by comparing effects in a FAM state with those in a distinct focused attention awake state during a backwards counting task. Results: The results showed decreased phosphocreatine/ATP (PCr/ATP), PCr/ inorganic phosphate (Pi), and intracellular pH values in the entire brain, but especially in basal ganglia, frontal lobes, and occipital lobes, and increased Pi/ATP ratio, cerebral Mg, and Pi absolute values were found in the same areas during FAM compared to the control focused attention awake state. Conclusions: Changes in the temporal areas and basal ganglia may be interpreted as a higher energetic state induced by meditation, whereas the frontal and occipital areas showed changes that may be related to a down-regulation in ATP turnover, energy state, and oxidative capacity.

Interactive image-guided surgery technologies enable accurate target localization while preserving critical nearby structures in many surgical interventions. Current state-of-the-art interfaces largely employ traditional anatomical cross-sectional views or augmented reality environments to present the actual spatial location of the surgical instrument in preoperatively acquired images. This work proposes an alternative, simple, minimalistic visual interface intended to assist during real-time surgical target localization. The estimated 3D pose of the interventional instruments and their positional uncertainty are intuitively presented in a visual interface with respect to the target point. A usability study with multidisciplinary participants evaluates the proposed interface projected in surgical microscope oculars against cross-sectional views. The latter was presented on a screen both stand-alone and combined with the proposed interface. The instruments were electromagnetically navigated in phantoms. The usability study demonstrated that the participants were able to detect invisible targets marked in phantom imagery with significant enhancements for localization accuracy and duration time. Clinically experienced users reached the targets with shorter trajectories. The stand-alone and multi-modal versions of the proposed interface outperformed cross-sectional views-only navigation in both quantitative and qualitative evaluations. The results and participants’ feedback indicate potential to accurately navigate users toward the target with less distraction and workload. An ongoing study evaluates the proposed system in a preclinical setting for auditory brainstem implantation.

Patient-to-image registration is currently mostly done in a semi-automated way. Fully automating this task can enhance surgical workflow and reduce human errors. Here, we present a novel solution with a nasal stent utilized to minimally invasively position spherical fiducials inside the nasopharynx and aimed for neurosurgery with electromagnetic navigation. The assembly was deployed into the pharyngeal region of a human specimen. The spherical fiducials are automatically detected in anatomy by integrated magnetic sensors while in preoperative imagery with a proposed u-net deep network. Temporal dislocation of the markers was measured interdaily after two brainstem procedures with CT imaging follow-ups. The u-net was trained to differentiate markers from other structures located in CT images. The ground-truth data was created from 22 CTs of phantoms, cadavers and swine. The dataset is split into 12, 5 and 5 for training, validation and testing, respectively. The dice coefficient was used as a similarity measure. The fiducial registration error resulted in 0.53±0.1 mm and 0.44±0.04 mm for the first and the second procedure, respectively. The fiducial positions deviated from the intraday baseline with the mean ± standard deviation 0.29±0.20 mm and 1.32±0.30 mm. The dice coefficient was 0.976, 0.878 and 0.764 during the training, validation and testing. The nasopharyngeal stent shows a potential for a stable marker fixation. The u-net can be adequately employed to segment titanium spherical fiducials.