Objectives
Magnetic resonance imaging (MRI) is the method of choice for imaging meningiomas. Volumetric assessment of meningiomas is highly relevant for therapy planning and monitoring. We used a ...multiparametric deep-learning model (DLM) on routine MRI data including images from diverse referring institutions to investigate DLM performance in automated detection and segmentation of meningiomas in comparison to manual segmentations.
Methods
We included 56 of 136 consecutive preoperative MRI datasets T1/T2-weighted, T1-weighted contrast-enhanced (T1CE), FLAIR of meningiomas that were treated surgically at the University Hospital Cologne and graded histologically as tumour grade I (
n
= 38) or grade II (
n
= 18). The DLM was trained on an independent dataset of 249 glioma cases and segmented different tumour classes as defined in the brain tumour image segmentation benchmark (BRATS benchmark). The DLM was based on the DeepMedic architecture. Results were compared to manual segmentations by two radiologists in a consensus reading in FLAIR and T1CE.
Results
The DLM detected meningiomas in 55 of 56 cases. Further, automated segmentations correlated strongly with manual segmentations: average Dice coefficients were 0.81 ± 0.10 (range, 0.46-0.93) for the total tumour volume (union of tumour volume in FLAIR and T1CE) and 0.78 ± 0.19 (range, 0.27-0.95) for contrast-enhancing tumour volume in T1CE.
Conclusions
The DLM yielded accurate automated detection and segmentation of meningioma tissue despite diverse scanner data and thereby may improve and facilitate therapy planning as well as monitoring of this highly frequent tumour entity.
Key Points
• Deep learning allows for accurate meningioma detection and segmentation
• Deep learning helps clinicians to assess patients with meningiomas
• Meningioma monitoring and treatment planning can be improved
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign ...meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.
Meningioma grading is relevant to therapy decisions in complete or partial resection, observation, and radiotherapy because higher grades are associated with tumor growth and recurrence. The ...differentiation of low and intermediate grades is particularly challenging. This study attempts to apply radiomics-based shape and texture analysis on routine multiparametric magnetic resonance imaging (MRI) from different scanners and institutions for grading.
We used MRI data (T1-weighted/T2-weighted, T1-weighted-contrast-enhanced T1CE, fluid-attenuated inversion recovery FLAIR, diffusion-weighted imaging DWI, apparent diffusion coefficient ADC) of grade I (n = 46) and grade II (n = 25) nontreated meningiomas with histologic workup. Two experienced radiologists performed manual tumor segmentations on FLAIR, T1CE, and ADC images in consensus. The MRI data were preprocessed through T1CE and T1-subtraction, coregistration, resampling, and normalization. A PyRadiomics package was used to generate 990 shape/texture features. Stepwise dimension reduction and robust radiomics feature selection were performed. Biopsy results were used as standard of reference.
Four statistically independent radiomics features were identified as showing the strongest predictive values for higher tumor grades: roundness-of-FLAIR-shape (area under curve AUC, 0.80), cluster-shades-of-FLAIR/T1CE-gray-level (AUC, 0.80), DWI/ADC-gray-level-variability (AUC, 0.72), and FLAIR/T1CE-gray-level-energy (AUC, 0.76). In a multivariate logistic regression model, the combination of the features led to an AUC of 0.91 for the differentiation of grade I and grade II meningiomas.
Our results indicate that radiomics-based feature analysis applied on routine MRI is viable for meningioma grading, and a multivariate logistic regression model yielded strong classification performances. More advanced tumor stages are identifiable through certain shape parameters of the lesion, textural patterns in morphologic MRI sequences, and DWI/ADC variability.
Thioredoxin (Trx) overexpression is known to be a cause of chemotherapy resistance in various tumor entities. However, Trx effects on resistance are complex and depend strictly on tissue type. In the ...present study, we analyzed the impact of the Trx system on intrinsic chemoresistance of human glioblastoma multiforme (GBM) cells to cytostatic drugs. Resistance of GBM cell lines and primary cells to drugs and signaling inhibitors was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Impact of Trx inhibition on apoptosis was investigated by proteome profiling of a subset of proteins and annexin V apoptosis assays. Trx-interacting protein (TXNIP) was overexpressed by transfection and protein expression was determined by immunoblotting. Pharmacological inhibition of Trx by 1-methyl-2-imidazolyl-disulfide (PX-12) reduced viability of three GBM cell lines, induced expression of active caspase-3, and reduced phosphorylation of AKT-kinase and expression of β-catenin. Sensitivity to cisplatin could be restored by both PX-12 and recombinant expression of the upstream Trx inhibitor TXNIP, respectively. In addition, PX-12 also sensitized primary human GBM cells to temozolomide. Combined inhibition of Trx and the phosphatidylinositide 3-kinase (PI3K) pathway resulted in massive cell death. We conclude that the Trx system and the PI3K pathway act as a sequential cascade and could potentially present a new drug target.
The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has changed the clinical day-to-day practice. The aim of this study was to evaluate the impact of the pandemic on patients with ...high-grade glioma (HGG) as well as to derive best practice recommendations. We compared a multi-institutional cohort with HGG (n = 251) from 03/2020 to 05/2020 (n = 119) to a historical cohort from 03/2019 to 05/2019 (n = 132). The endpoints were outcome (progression-free survival (PFS) and overall survival (OS)) as well as patterns of care and time intervals between treatment steps. The median OS for WHO grade 4 gliomas was 12 months in 2019 (95% Confidence Interval 9.7-14.3 months), and not reached in 2020 (p = .026). There were no other significant differences in the Kaplan-Meier estimates for OS and PFS between cohorts of 2019 and 2020, neither did stratification by WHO grade reveal any significant differences for OS, PFS or for patterns of care. The time interval between cranial magnetic resonance imaging (cMRI) and biopsy was significantly longer in 2020 cohort (11 versus 21 days, p = .031). Median follow-up was 10 months (range 0-30 months). Despite necessary disease containment policies, it is crucial to ensure that patients with HGG are treated in line with the recent guidelines and standard of care (SOC) algorithms. Therefore, we strongly suggest pursuing no changes to SOC treatment, a timely diagnosis and treatment with short time intervals between first symptoms, initial diagnosis, and treatment, as well as a guideline-based cMRI follow-up.
Stent-assisted coiling (SAC) for ruptured intracranial aneurysms (RIAs) remains controversial due to an inherent risk of potential thromboembolic and hemorrhagic complications. We compared SAC and ...coiling alone for the management of RIAs using propensity score-adjustment. Sixty-four patients treated by SAC and 220 by stand-alone coiling were retrospectively reviewed and compared using inverse probability of treatment weighting (IPTW) with propensity scores. Functional outcome, procedure-related and overall complications and angiographic results were analyzed. Aneurysms treated by SAC had a larger diameter, a wider neck and were more frequently located at the posterior circulation. SAC had a higher risk for thromboembolic complications (17.2% vs. 7.7%, p = 0.025), however, this difference did not persist in the IPTW analysis (OR 1.2, 95% CI 0.7-2.3, adjusted p = 0.458). In the adjusted analysis, rates of procedural cerebral infarction (p = 0.188), ventriculostomy-related hemorrhage (p = 0.584), in-hospital mortality (p = 0.786) and 6-month favorable functional outcome (p = 0.471) were not significantly different between the two groups. SAC yielded a higher complete occlusion (80.0% vs. 67.2%, OR 3.2, 95% CI 1.9-5.4, p < 0.001) and a lower recanalization rate (17.5% vs. 26.1%, OR 0.3, 95% CI 0.2-0.6, p < 0.001) than stand-alone coiling at 6-month follow-up. In conclusion, SAC of large and wide-necked RIAs provided higher aneurysm occlusion and similar clinical outcome, when compared to stand-alone coiling.
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune ...cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
Synopsis
While recurrent glioblastoma is treated by inhibiting angiogenesis, resistance limits therapeutic efficacy. Angiopoietin‐2 (Ang‐2), a potent endothelium‐derived angiogenesis factor and regulator of myeloid cell infiltration, is a therapeutic target for treating naive and bevacizumab‐resistant glioblastoma.
The therapeutic benefit of co‐targeting Ang‐2 and VEGF signaling (using AMG386 and aflibercept/VEGF‐trap) is shown in mouse models of GBM.
Ang‐2 and VEGF combination therapy decreased GBM angiogenesis and permeability, improved vascular maturation, and limited the number of tumor‐associated macrophages.
Numbers of CD206+ (M2‐like) macrophages remained high upon therapy, suggestive of subsequent targeting of M2‐like macrophages in bevacizumab‐resistant GBM.
Inhibition of Ang‐2, either alone or in combination with VEGF inhibition is of potential use to overcome resistance in GBM patients that have failed bevacizumab therapy.
While recurrent glioblastoma is treated by inhibiting angiogenesis, resistance limits therapeutic efficacy. Angiopoietin‐2 (Ang‐2), a potent endothelium‐derived angiogenesis factor and regulator of myeloid cell infiltration, is a therapeutic target for treating naive and bevacizumab‐resistant glioblastoma.
To evaluate the effect of timing of radiotherapy (RT) on survival in patients with newly diagnosed primary glioblastoma (GBM) treated with the same therapeutical protocol.
Patients with newly ...diagnosed primary GBM treated with the same therapeutical scheme between 2010 and 2015 in our institution were retrospectively reviewed. The population was trichotomized based on the time interval from surgery till initiation of RT (< 28 days, 28-33 days, > 33 days). Kaplan-Meier and Cox regression analyses were used to compare progression free survival (PFS) and overall survival (OS) between the groups. The influence of various extensively studied prognostic factors on survival was assessed by multivariate analysis.
One-hundred-fifty-one patients met the inclusion criteria. Between the three groups no significant difference in PFS (p = 0.516) or OS (p = 0.902) could be demonstrated. Residual tumor volume (RTV) and midline structures involvement were identified as independent prognostic factors of PFS while age, O-6-Methylguanine Methyltransferase (MGMT) status, Ki67 index, RTV and midline structures involvement represented independent predictors of OS. Patients starting RT after a prolonged delay (> 48 days) exhibited a significantly shorter OS (p = 0.034).
Initiation of RT within a timeframe of 48 days is not associated with worsened survival. A prolonged delay (> 48 days) may be associated with worse OS. RT should neither be delayed, nor forced, but should rather start timely, as soon as the patient has recovered from surgery.
Chronic subdural hematoma (CSDH), a common condition in elderly patients, presents a therapeutic challenge with recurrence rates of 33%. We aimed to identify specific prognostic factors for ...recurrence using quantitative analysis of hematoma volume and density.
We retrospectively reviewed radiographic and clinical data of 227 CSDHs in 195 consecutive patients who underwent evacuation of the hematoma through a single burr hole, 2 burr holes, or a mini-craniotomy. To examine the relationship between hematoma recurrence and various clinical, radiologic, and surgical factors, we used quantitative image-based analysis to measure the hematoma and trapped air volumes and the hematoma densities.
Recurrence of CSDH occurred in 35 patients (17.9%). Multivariate logistic regression analysis revealed that the percentage of hematoma drained and postoperative CSDH density were independent risk factors for recurrence. All 3 evacuation methods were equally effective in draining the hematoma (71.7% vs. 73.7% vs. 71.9%) without observable differences in postoperative air volume captured in the subdural space.
Quantitative image analysis provided evidence that percentage of hematoma drained and postoperative CSDH density are independent prognostic factors for subdural hematoma recurrence.
The intrinsic autofluorescence of biological tissues interferes with the detection of fluorophores administered for fluorescence guidance, an emerging auxiliary technique in oncological surgery. Yet, ...autofluorescence of the human brain and its neoplasia is sparsely examined. This study aims to assess autofluorescence of the brain and its neoplasia on a microscopic level by stimulated Raman histology (SRH) combined with two-photon fluorescence.
With this experimentally established label-free microscopy technique unprocessed tissue can be imaged and analyzed within minutes and the process is easily incorporated in the surgical workflow. In a prospective observational study, we analyzed 397 SRH and corresponding autofluorescence images of 162 samples from 81 consecutive patients that underwent brain tumor surgery. Small tissue samples were squashed on a slide for imaging. SRH and fluorescence images were acquired with a dual wavelength laser (790 nm and 1020 nm) for excitation. In these images tumor and non-tumor regions were identified by a convolutional neural network that reliably differentiates between tumor, healthy brain tissue and low quality SRH images. The identified areas were used to define regions.of- interests (ROIs) and the mean fluorescence intensity was measured.
In healthy brain tissue, we found an increased mean autofluorescence signal in the gray (11.86,
2.61,
=29) compared to the white matter (5.99,
5.14,
=11,
<0.01) and in the cerebrum (11.83,
3.29,
=33) versus the cerebellum (2.82,
0.93,
=7,
<0.001), respectively. The signal of carcinoma metastases, meningiomas, gliomas and pituitary adenomas was significantly lower (each
<0.05) compared to the autofluorescence in the cerebrum and dura, and significantly higher (each
<0.05) compared to the cerebellum. Melanoma metastases were found to have a higher fluorescent signal (
<0.01) compared to cerebrum and cerebellum.
In conclusion we found that autofluorescence in the brain varies depending on the tissue type and localization and differs significantly among various brain tumors. This needs to be considered for interpreting photon signal during fluorescence-guided brain tumor surgery.
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