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BackgroundStroke is a major global health problem and was the second leading cause of death worldwide in 2020. However, the lack of public stroke awareness especially in low- and middle-income countries (LMICs) such as Nepal severely hinders the effective provision of stroke care. Efficient and cost-effective strategies to raise stroke awareness in LMICs are still lacking. This study aims to (a) explore the feasibility of a social media-based stroke awareness campaign in Nepal using a cost-benefit analysis and (b) identify best practices for social media health education campaigns.MethodsWe performed a stroke awareness campaign over a period of 6 months as part of a Stroke Project in Nepal on four social media platforms (Facebook, Instagram, Twitter, TikTok) with organic traffic and paid advertisements. Adapted material based on the World Stroke Day Campaign and specifically created videos for TikTok were used. Performance of the campaign was analyzed with established quantitative social media metrics (impressions, reach, engagement, costs).ResultsCampaign posts were displayed 7.5 million times to users in Nepal. 2.5 million individual social media users in Nepal were exposed to the campaign on average three times, which equals 8.6% of Nepal's total population. Of those, 250,000 users actively engaged with the posts. Paid advertisement on Facebook and Instagram proved to be more effective in terms of reach and cost than organic traffic. The total campaign cost was low with a "Cost to reach 1,000 users" of 0.24 EUR and a "Cost Per Click" of 0.01 EUR.DiscussionSocial media-based campaigns using paid advertisement provide a feasible and, compared to classical mass medias, a very cost-effective approach to inform large parts of the population about stroke awareness in LMICs. Future research needs to further analyze the impact of social media campaigns on stroke knowledge.

To correlate histopathologic findings from biopsy specimens with their corresponding location within enhancing areas, non-enhancing areas and necrotic areas on contrast enhanced T1-weighted MRI scans (cT1).In 37 patients with newly diagnosed glioblastoma who underwent stereotactic biopsy, we obtained a correlation of 561 1mm3 biopsy specimens with their corresponding position on the intraoperative cT1 image at 1.5 Tesla. Biopsy points were categorized as enhancing (CE), non-enhancing (NE) or necrotic (NEC) on cT1 and tissue samples were categorized as "viable tumor cells", "blood" or "necrotic tissue (with or without cellular component)". Cell counting was done semi-automatically.NE had the highest content of tissue categorized as viable tumor cells (89% vs. 60% in CE and 30% NEC, respectively). Besides, the average cell density for NE (3764 ± 2893 cells/mm2) was comparable to CE (3506 ± 3116 cells/mm2), while NEC had a lower cell density with 2713 ± 3239 cells/mm2. If necrotic parts and bleeds were excluded, cell density in biopsies categorized as "viable tumor tissue" decreased from the center of the tumor (NEC, 5804 ± 3480 cells/mm2) to CE (4495 ± 3209 cells/mm2) and NE (4130 ± 2817 cells/mm2).The appearance of a glioblastoma on a cT1 image (circular enhancement, central necrosis, peritumoral edema) does not correspond to its diffuse histopathological composition. Cell density is elevated in both CE and NE parts. Hence, our study suggests that NE contains considerable amounts of infiltrative tumor with a high cellularity which might be considered in resection planning.

The purpose of this study was to investigate whether a voxel-wise analysis of apparent diffusion coefficient (ADC) values may differentiate between progressive disease (PD) and pseudoprogression (PsP) in patients with high-grade glioma using the parametric response map, a newly introduced postprocessing tool.Twenty-eight patients with proven PD and seven patients with PsP were identified in this retrospective feasibility study. For all patients ADC baseline and follow-up maps on four subsequent MRIs were available. ADC maps were coregistered on contrast enhanced T1-weighted follow-up images. Subsequently, enhancement in the follow-up contrast enhanced T1-weighted image was manually delineated and a reference region of interest (ROI) was drawn in the contralateral white matter. Both ROIs were transferred to the ADC images. Relative ADC (rADC) (baseline)/reference ROI values and rADC (follow up)/reference ROI values were calculated for each voxel within the ROI. The corresponding voxels of rADC (follow up) and rADC (baseline) were subtracted and the percentage of all voxels within the ROI that exceeded the threshold of 0.25 was quantified.rADC voxels showed a decrease of 59.2% (1st quartile (Q1) 36.7; 3rd quartile (Q3) 78.6) above 0.25 in patients with PD and 18.6% (Q1 3.04; Q3 26.5) in patients with PsP (p = 0.005). Receiver operating characteristic curve analysis showed the optimal decreasing rADC cut-off value for identifying PD of > 27.05% (area under the curve 0.844±0.065, sensitivity 0.86, specificity 0.86, p = 0.014).This feasibility study shows that the assessment of rADC using parametric response maps might be a promising approach to contribute to the differentiation between PD and PsP. Further research in larger patient cohorts is necessary to finally determine its clinical utility.

BACKGROUND AND PURPOSE:Perfusion weighted imaging (PWI) is inherently unreliable in patients with severe perfusion abnormalities. We compared the diagnostic accuracy of a novel index of microvascular flow-patterns, so-called capillary transit time heterogeneity (CTH) to that of the commonly used delay parameter Tmax in patients with bilateral high grade internal carotid artery stenosis (ICAS). METHODS:Consecutive patients with bilateral ICAS ≥ 70%NASCET who underwent PWI were retrospectively examined. Maps of CTH and Tmax were analyzed with a volumetric approach using several thresholds. Predictors of favorable outcome (modified Rankin scale at discharge 0-2) were identified using univariate and receiver operating characteristic (ROC) curve analysis. RESULTS:Eighteen patients were included. CTH ≥ 30s differentiated best between patients with favorable and unfavorable outcome when both hemispheres were taken into account (sensitivity 83%, specificity 73%, area under the curve [AUC] 0.833 [confidence interval (CI) 0.635; 1.000]; p = 0.027). The best discrimination using Tmax was achieved with a threshold of ≥ 4s (sensitivity 83%, specificity 64%, AUC 0.803 [CI 0.585;1.000]; p = 0.044). The highest AUC was found for left sided volume with CTH ≥ 15s (sensitivity 83%, specificity 91%, AUC 0.924 [CI 0.791;1.000]; p = 0.005). CONCLUSION:The study suggests that CTH is superior to Tmax in discriminating ICAS patients with favorable from non-favorable outcome. This finding may reflect the simultaneous involvement of large vessels and microvessels in ICAS and underscore the need to diagnose and manage both aspects of the disease.

Several studies have analyzed a correlation between the apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI and the tumor cellularity of corresponding histopathological specimens in brain tumors with inconclusive findings. Here, we compared a large dataset of ADC and cellularity values of stereotactic biopsies of glioblastoma patients using a new postprocessing approach including trajectory analysis and automatic nuclei counting.Thirty-seven patients with newly diagnosed glioblastomas were enrolled in this study. ADC maps were acquired preoperatively at 3T and coregistered to the intraoperative MRI that contained the coordinates of the biopsy trajectory. 561 biopsy specimens were obtained; corresponding cellularity was calculated by semi-automatic nuclei counting and correlated to the respective preoperative ADC values along the stereotactic biopsy trajectory which included areas of T1-contrast-enhancement and necrosis.There was a weak to moderate inverse correlation between ADC and cellularity in glioblastomas that varied depending on the approach towards statistical analysis: for mean values per patient, Spearman's ρ = -0.48 (p = 0.002), for all trajectory values in one joint analysis Spearman's ρ = -0.32 (p < 0.001). The inverse correlation was additionally verified by a linear mixed model.Our data confirms a previously reported inverse correlation between ADC and tumor cellularity. However, the correlation in the current article is weaker than the pooled correlation of comparable previous studies. Hence, besides cell density, other factors, such as necrosis and edema might influence ADC values in glioblastomas.

To explore the correlation between Nuclear Overhauser Enhancement (NOE)-mediated signals and tumor cellularity in glioblastoma utilizing the apparent diffusion coefficient (ADC) and cell density from histologic specimens. NOE is one type of chemical exchange saturation transfer (CEST) that originates from mobile macromolecules such as proteins and might be associated with tumor cellularity via altered protein synthesis in proliferating cells.For 15 patients with newly diagnosed glioblastoma, NOE-mediated CEST-contrast was acquired at 7 Tesla (asymmetric magnetization transfer ratio (MTRasym) at 3.3ppm, B1 = 0.7 μT). Contrast enhanced T1 (CE-T1), T2 and diffusion-weighted MRI (DWI) were acquired at 3 Tesla and coregistered. The T2 edema and the CE-T1 tumor were segmented. ADC and MTRasym values within both regions of interest were correlated voxelwise yielding the correlation coefficient rSpearman (rSp). In three patients who underwent stereotactic biopsy, cell density of 12 specimens per patient was correlated with corresponding MTRasym and ADC values of the biopsy site.Eight of 15 patients showed a weak or moderate positive correlation of MTRasym and ADC within the T2 edema (0.16≤rSp≤0.53, p0.05, n = 4) or yielded rSp≈0 (p0.05, n = 6). The biopsy-analysis within CE-T1 tumor revealed a strong positive correlation between tumor cellularity and MTRasym values in two of the three patients (rSppatient3 = 0.69 and rSppatient15 = 0.87, p

PurposeTo analyze if tumor vessels can be visualized, segmented and quantified in glioblastoma patients with time of flight (ToF) angiography at 7 Tesla and multiscale vessel enhancement filtering.Materials and methodsTwelve patients with newly diagnosed glioblastoma were examined with ToF angiography (TR = 15 ms, TE = 4.8 ms, flip angle = 15°, FOV = 160 × 210 mm(2), voxel size: 0.31 × 0.31 × 0.40 mm(3)) on a whole-body 7 T MR system. A volume of interest (VOI) was placed within the border of the contrast enhancing part on T1-weighted images of the glioblastoma and a reference VOI was placed in the non-affected contralateral white matter. Automated segmentation and quantification of vessels within the two VOIs was achieved using multiscale vessel enhancement filtering in ImageJ.ResultsTumor vessels were clearly visible in all patients. When comparing tumor and the reference VOI, total vessel surface (45.3 ± 13.9 mm(2) vs. 29.0 ± 21.0 mm(2) (pDiscussionToF angiography at 7-Tesla MRI enables characterization and quantification of the internal vascular morphology of glioblastoma and may be used for the evaluation of therapy response within future studies.

Background and purposeNuclear Overhauser Enhancement (NOE) mediated chemical exchange saturation transfer (CEST) is a novel magnetic resonance imaging (MRI) technique on the basis of saturation transfer between exchanging protons of tissue proteins and bulk water. The purpose of this study was to evaluate and compare the information provided by three dimensional NOE mediated CEST at 7 Tesla (7T) and standard MRI in glioblastoma patients.Patients and methodsTwelve patients with newly diagnosed histologically proven glioblastoma were enrolled in this prospective ethics committee-approved study. NOE mediated CEST contrast was acquired with a modified three-dimensional gradient-echo sequence and asymmetry analysis was conducted at 3.3 ppm (B1 = 0.7 µT) to calculate the magnetization transfer ratio asymmetry (MTR(asym)). Contrast enhanced T1 (CE-T1) and T2-weighted images were acquired at 3T and used for data co-registration and comparison.ResultsMean NOE mediated CEST signal based on MTR(asym) values over all patients was significantly increased (pConclusionNOE mediated CEST Imaging at 7 T provides additional information on the structure of peritumoral hyperintensities in glioblastoma and displays isolated high intensity regions within the CE-T1 tumor that cannot be acquired on CE-T1 or T2-weighted images. Further research is needed to determine the origin of NOE mediated CEST and possible clinical applications such as therapy assessment or biopsy planning.

ObjectivesThe application of susceptibility weighted imaging (SWI) in brain tumor imaging is mainly used to assess tumor-related "susceptibility based signals" (SBS). The origin of SBS in glioblastoma is still unknown, potentially representing calcifications or blood depositions. Reliable differentiation between both entities may be important to evaluate treatment response and to identify glioblastoma with oligodendroglial components that are supposed to present calcifications. Since calcifications and blood deposits are difficult to differentiate using conventional MRI, we investigated whether a new post-processing approach, quantitative susceptibility mapping (QSM), is able to distinguish between both entities reliably.Materials and methodsSWI, FLAIR, and T1-w images were acquired from 46 patients with glioblastoma (14 newly diagnosed, 24 treated with radiochemotherapy, 8 treated with radiochemotherapy and additional anti-angiogenic medication). Susceptibility maps were calculated from SWI data. All glioblastoma were evaluated for the appearance of hypointense or hyperintense correlates of SBS on the susceptibility maps.Results43 of 46 glioblastoma presented only hyperintense intratumoral SBS on susceptibility maps, indicating blood deposits. Additional hypointense correlates of tumor-related SBS on susceptibility maps, indicating calcification, were identified in 2 patients being treated with radiochemotherapy and in one patient being treated with additional anti-angiogenic medication. Histopathologic reports revealed an oligodendroglial component in one patient that presented calcifications on susceptibility maps.ConclusionsQSM provides a quantitative, local MRI contrast, which reliably differentiates between blood deposits and calcifications. Thus, quantitative susceptibility mapping appears promising to identify rare variants of glioblastoma with oligodendroglial components non-invasively and may allow monitoring the role of calcification in the context of different therapy regimes.

Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O(6)-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide. Hence, the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma. Since various different techniques are available for MGMT promoter methylation analysis, a generally accepted consensus as to the most suitable diagnostic method remains an unmet need. Here, we assessed methylation-specific polymerase chain reaction (MSP) as a qualitative and semi-quantitative method, pyrosequencing (PSQ) as a quantitative method, and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a semi-quantitative method in a series of 35 formalin-fixed, paraffin-embedded glioblastoma tissues derived from patients treated in a prospective clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide (UKT-05). Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival (PFS). The MGMT promoter methylation status was assessable by each method in almost all cases (n = 33/35 for MSP; n = 35/35 for PSQ; n = 34/35 for MS-MLPA). We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ (range, 11.5 to 44.9%) and at one CpG site assessed by MS-MLPA (3.6%) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible. Our results show that, unlike MS-MLPA, MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone (likelihood ratio tests: p

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that epigenetically silences gene transcription through histone H3 lysine trimethylation (H3K27me3). EZH2 has been implicated in stem cell maintenance and is overexpressed in hematological and solid malignancie`s including malignant glioma. EZH2 is thought to promote tumor progression by silencing tumor suppressor genes. Hence pharmacological disruption of the PRC2 is an attractive therapeutic strategy for cancer treatment. Here we show that EZH2 is expressed in human glioma and correlates with malignancy. Silencing of EZH2 reduced glioma cell proliferation and invasiveness. While we did not observe induction of cell cycle-associated tumor suppressor genes by silencing or pharmacological inhibition of EZH2, microarray analyses demonstrated a strong transcriptional reduction of the AXL receptor kinase. Neither histone nor DNA methylation appeared to be involved in the positive regulation of AXL by EZH2. Silencing AXL mimicked the antiinvasive effects of EZH2 knockdown. Finally, AXL expression is found in human gliomas with high EZH2 expression. Collectively these data suggest that EZH2 drives glioma invasiveness via transcriptional control of AXL independent of histone or DNA methylation.

1-methyl-D-tryptophan (1-D-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors with the aim of inhibiting indoleamine-2,3-dioxygenase (IDO)-mediated tumor immune escape. IDO is expressed in tumors and tumor-draining lymph nodes and degrades tryptophan (trp) to create an immunsuppressive micromilieu both by depleting trp and by accumulating immunosuppressive metabolites of the kynurenine (kyn) pathway. Here we show that proliferation of alloreactive T-cells cocultured with IDO1-positive human cancer cells paradoxically was inhibited by 1-D-MT. Surprisingly incubation with 1-D-MT increased kyn production of human cancer cells. Cell-free assays revealed that 1-D-MT did not alter IDO1 enzymatic activity. Instead, 1-D-MT induced IDO1 mRNA and protein expression through pathways involving p38 MAPK and JNK signalling. Treatment of cancer patients with 1-D-MT has transcriptional effects that may promote rather than suppress anti-tumor immune escape by increasing IDO1 in the cancer cells. These off-target effects should be carefully analyzed in the ongoing clinical trials with 1-D-MT.