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.

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.

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.