CT-defined sarcopenia predicts treatment response in primary central nervous system lymphomas.

OBJECTIVE: Body composition assessment derived from cross-sectional imaging has shown promising results as a prognostic biomarker in several tumor entities. Our aim was to analyze the role of low skeletal muscle mass (LSMM) and fat areas for prognosis of dose-limiting toxicity (DLT) and treatment response in patients with primary central nervous system lymphoma (PCNSL). METHODS: Overall, 61 patients (29 female patients, 47.5%) with a mean age of 63.8 ± 12.2 years, range 23-81 years, were identified in the data base between 2012 and 2020 with sufficient clinical and imaging data. Body composition assessment, comprising LSMM and visceral and subcutaneous fat areas, was performed on one axial slice on L3-height derived from staging computed tomography (CT) images. DLT was assessed during chemotherapy in clinical routine. Objective response rate (ORR) was measured on following magnetic resonance images of the head accordingly to the Cheson criteria. RESULTS: Twenty-eight patients had DLT (45.9%). Regression analysis revealed that LSMM was associated with objective response, OR = 5.19 (95% CI 1.35-19.94, p = 0.02) (univariable regression), and OR = 4.23 (95% CI 1.03- 17.38, p = 0.046) (multivariable regression). None of the body composition parameters could predict DLT. Patients with normal visceral to subcutaneous ratio (VSR) could be treated with more chemotherapy cycles compared to patients with high VSR (mean, 4.25 vs 2.94, p = 0.03). Patients with ORR had higher muscle density values compared to patients with stable and/or progressive disease (34.46 ± vs 28.18 ± HU, p = 0.02). CONCLUSIONS: LSMM is strongly associated with objective response in patients with PCNSL. Body composition parameters cannot predict DLT. CLINICAL RELEVANCE STATEMENT: Low skeletal muscle mass on computed tomography (CT) is an independent prognostic factor of poor treatment response in central nervous system lymphoma. Analysis of the skeletal musculature on staging CT should be implemented into the clinical routine in this tumor entity. KEY POINTS: • Low skeletal muscle mass is strongly associated with the objective response rate. • No body composition parameters could predict dose-limiting toxicity.

Unveiling rupture risk and clinical outcomes in midline aneurysms: A matched cohort analysis investigating the impact of localization within the anterior or posterior circulation.

Intracranial aneurysms (IAs) located in the anterior and posterior circulations of the Circle of Willis present differential rupture risks. This study aimed to compare the rupture risk and clinical outcomes of anterior communicating artery aneurysms (AcomA) and basilar tip aneurysms (BAs); two IA types located along the midline within the Circle of Willis. We retrospectively collected data from 1026 patients presenting with saccular IAs. Only AcomA and BAs with a 3D angiography were included. Out of 186 included IAs, a cohort of 32 BAs was matched with AcomA based on the patients' pre-existing conditions and morphological parameters of IAs. Clinical outcomes, including rupture risk, hydrocephalus development, vasospasm incidence, and patients' outcome, were compared. The analysis revealed no significant difference in rupture risk, development of hydrocephalus, need for ventricular drainage, or vasospasm incidence between the matched AcomA and BA cohorts. Furthermore, the clinical outcomes post-rupture did not significantly differ between the two groups, except for a higher Fisher Grade associated with BAs. Once accounting for morphological and patient factors, the rupture risk between AcomA and BAs is comparable. These findings underscore the importance of tailored management strategies for specific IA types and suggest that further investigations should focus on the role of individual patient and aneurysm characteristics in IA rupture risk and clinical outcomes.

Multimodal validation of focal enhancement in intracranial aneurysms as a surrogate marker for aneurysm instability.

PURPOSE: Circumferential enhancement on MR vessel wall imaging has been proposed as a biomarker of a higher risk of rupture in intracranial aneurysms. Focal enhancement is frequently encountered in unruptured aneurysms, but its implication for risk stratification and patient management remains unclear. This study investigates the association of focal wall enhancement with hemodynamic and morphological risk factors and histologic markers of wall inflammation and degeneration. METHODS: Patients with an unruptured middle cerebral artery aneurysm who underwent 3D rotational angiography and 3T MR vessel wall imaging showing focal wall enhancement were included. Hemodynamic parameters were calculated based on flow simulations and compared between enhanced regions and the entire aneurysm surface. Morphological parameters were semiautomatically extracted and quantitatively associated with wall enhancement. Histological analysis included detection of vasa vasorum, CD34, and myeloperoxidase staining in a subset of patients. RESULTS: Twenty-two aneurysms were analyzed. Enhanced regions were significantly associated with lower AWSS, lower maxOSI, and increased LSA. In multivariate analysis, higher ellipticity index was an independent predictor of wall enhancement. Histologic signs of inflammation and degeneration and higher PHASES score were significantly associated with focal enhancement. CONCLUSION: Focal wall enhancement is colocalized with hemodynamic factors that have been related to a higher rupture risk. It is correlated with morphological factors linked to rupture risk, higher PHASES score, and histologic markers of wall destabilization. The results support the hypothesis that focal enhancement could serve as a surrogate marker for aneurysm instability.

Suitability of intravascular imaging for assessment of cerebrovascular diseases.

PURPOSE: Arteriosclerosis of the vascular system is associated with many accompanying diseases. Especially cerebral arteriosclerosis is a main risk factor for ischemic strokes. We want to verify the practicability of intravascular imaging like intravascular ultrasound and optical coherence tomography for the assessment of cerebral vessel walls and plaques. METHODS: We examined 18 Circuli arteriosi willisii postmortem. The data contained 48 plaques from 48 different vessel parts. The samples underwent intravascular and histological imaging to conduct a quantitative assessment of vessel wall parameters (healthy vessel wall, thinnest vessel wall, plaque thickness and vessel diameter) as well as to qualitatively evaluate the healthy vessel wall, fibrotic plaques, calcifications and cholesterol deposits in diseased vessels. RESULTS: The comparison showed statistically significant smaller measurements for thinnest vessel walls, normal vessel walls and vessel diameters in histology than in imaging. No statistically significant difference was reached for plaque diameters. Fibrotic plaques were characterized as hyper-intense with dorsal attenuation and calcifications as hypo-intense with dorsal attenuation in optical coherence tomography. In intravascular ultrasound, fibrotic plaques showed a homogeneous echogenicity without distal attenuation and calcifications were depicted as hyperechoic with dorsal sound shadows. Cholesterol deposits were hyper-intense in optical coherence tomography with strongly attenuated signals and in intravascular ultrasound; the deposits were hyper-intense with almost no attenuation. CONCLUSION: Both intravascular methods allow for plaque characterization and quantification of plaque diameter in cerebral vessel walls. When compared with histology, a statistically significant bias was obtained for the ex vivo measurements of the normal vessel wall diameters.

Multiple Aneurysms AnaTomy CHallenge 2018 (MATCH): uncertainty quantification of geometric rupture risk parameters.

BACKGROUND: Geometric parameters have been proposed for prediction of cerebral aneurysm rupture risk. Predicting the rupture risk for incidentally detected unruptured aneurysms could help clinicians in their treatment decision. However, assessment of geometric parameters depends on several factors, including the spatial resolution of the imaging modality used and the chosen reconstruction procedure. The aim of this study was to investigate the uncertainty of a variety of previously proposed geometric parameters for rupture risk assessment, caused by variability of reconstruction procedures. MATERIALS: 26 research groups provided segmentations and surface reconstructions of five cerebral aneurysms as part of the Multiple Aneurysms AnaTomy CHallenge (MATCH) 2018. 40 dimensional and non-dimensional geometric parameters, describing aneurysm size, neck size, and irregularity of aneurysm shape, were computed. The medians as well as the absolute and relative uncertainties of the parameters were calculated. Additionally, linear regression analysis was performed on the absolute uncertainties and the median parameter values. RESULTS: A large variability of relative uncertainties in the range between 3.9 and 179.8% was found. Linear regression analysis indicates that some parameters capture similar geometric aspects. The lowest uncertainties < 6% were found for the non-dimensional parameters isoperimetric ratio, convexity ratio, and ellipticity index. Uncertainty of 2D and 3D size parameters was significantly higher than uncertainty of 1D parameters. The most extreme uncertainties > 80% were found for some curvature parameters. CONCLUSIONS: Uncertainty analysis is essential on the road to clinical translation and use of rupture risk prediction models. Uncertainty quantification of geometric rupture risk parameters provided by this study may help support development of future rupture risk prediction models.

A review on the reliability of hemodynamic modeling in intracranial aneurysms: why computational fluid dynamics alone cannot solve the equation.

Computational blood flow modeling in intracranial aneurysms (IAs) has enormous potential for the assessment of highly resolved hemodynamics and derived wall stresses. This results in an improved knowledge in important research fields, such as rupture risk assessment and treatment optimization. However, due to the requirement of assumptions and simplifications, its applicability in a clinical context remains limited.This review article focuses on the main aspects along the interdisciplinary modeling chain and highlights the circumstance that computational fluid dynamics (CFD) simulations are embedded in a multiprocess workflow. These aspects include imaging-related steps, the setup of realistic hemodynamic simulations, and the analysis of multidimensional computational results. To condense the broad knowledge, specific recommendations are provided at the end of each subsection.Overall, various individual substudies exist in the literature that have evaluated relevant technical aspects. In this regard, the importance of precise vessel segmentations for the simulation outcome is emphasized. Furthermore, the accuracy of the computational model strongly depends on the specific research question. Additionally, standardization in the context of flow analysis is required to enable an objective comparison of research findings and to avoid confusion within the medical community. Finally, uncertainty quantification and validation studies should always accompany numerical investigations.In conclusion, this review aims for an improved awareness among physicians regarding potential sources of error in hemodynamic modeling for IAs. Although CFD is a powerful methodology, it cannot provide reliable information, if pre- and postsimulation steps are inaccurately carried out. From this, future studies can be critically evaluated and real benefits can be differentiated from results that have been acquired based on technically inaccurate procedures.

Transformers for colorectal cancer segmentation in CT imaging.

PURPOSE: Most recently transformer models became the state of the art in various medical image segmentation tasks and challenges, outperforming most of the conventional deep learning approaches. Picking up on that trend, this study aims at applying various transformer models to the highly challenging task of colorectal cancer (CRC) segmentation in CT imaging and assessing how they hold up to the current state-of-the-art convolutional neural network (CNN), the nnUnet. Furthermore, we wanted to investigate the impact of the network size on the resulting accuracies, since transformer models tend to be significantly larger than conventional network architectures. METHODS: For this purpose, six different transformer models, with specific architectural advancements and network sizes were implemented alongside the aforementioned nnUnet and were applied to the CRC segmentation task of the medical segmentation decathlon. RESULTS: The best results were achieved with the Swin-UNETR, D-Former, and VT-Unet, each transformer models, with a Dice similarity coefficient (DSC) of 0.60, 0.59 and 0.59, respectively. Therefore, the current state-of-the-art CNN, the nnUnet could be outperformed by transformer architectures regarding this task. Furthermore, a comparison with the inter-observer variability (IOV) of approx. 0.64 DSC indicates almost expert-level accuracy. The comparatively low IOV emphasizes the complexity and challenge of CRC segmentation, as well as indicating limitations regarding the achievable segmentation accuracy. CONCLUSION: As a result of this study, transformer models underline their current upward trend in producing state-of-the-art results also for the challenging task of CRC segmentation. However, with ever smaller advances in total accuracies, as demonstrated in this study by the on par performances of multiple network variants, other advantages like efficiency, low computation demands, or ease of adaption to new tasks become more and more relevant.

Assessment of intracranial aneurysm neck deformation after contour deployment.

PURPOSE: The contour neurovascular system (CNS) is a novel device to treat intracranial wide-necked bifurcation aneurysms, with few studies assessing its long-term effects. Particularly its impact on aneurysm morphology has not been explored yet. We present a preliminary study to explore this impact for the first time, focusing on the neck curve and ostium of the aneurysm. METHODS: We investigated seven aneurysms treated with the CNS to assess ostium deformation after CNS deployment by comparing models extracted from in vivo medical pre-treatment and follow-up scans via morphological analysis. Time between pre- and follow-up scans was ten months on average. Size and shape indices like area, neck diameter, ellipticity index, undulation index, and more were assessed. RESULTS: Ostium size was reduced after treatment. On average, ostium area was reduced at a rate of - 0.58 (± 4.88) mm2 per year, from 15.52 (± 3.51) mm2 to 13.30 (± 2.27) mm2, and ostium width from 5.01 (± 0.54) mm to 4.49 (± 0.45) mm, with an average reduction of - 0.59 (± 0.87) mm. This shrinking positively correlated with time passing. Shape deformation was low, though notably mean ellipticity index was reduced by 0.06 (± 0.15) on average, indicating ostia were less elongated after treatment. CONCLUSION: We interpret the shrinking of the ostium as part of the healing process. Shape changes were found to be small enough to conclude no shape deformation of the ostium from CNS deployment, but the analysis of more cases with more parameters and information is necessary.

Image-based hemodynamic simulations for intracranial aneurysms: the impact of complex vasculature.

PURPOSE: Hemodynamics play an important role in the assessment of intracranial aneurysm (IA) development and rupture risk. The purpose of this study was to examine the impact of complex vasculatures onto the intra-vessel and intra-aneurysmal blood flow. METHODS: Complex segmentation of a subject-specific, 60-outlet and 3-inlet circle of Willis model captured with 7T magnetic resonance imaging was performed. This model was trimmed to a 10-outlet model version. Two patient-specific IAs were added onto both models yielding two pathological versions, and image-based blood flow simulations of the four resulting cases were carried out. To capture the differences between complex and trimmed model, time-averaged and centerline velocities were compared. The assessment of intra-saccular blood flow within the IAs involved the evaluation of wall shear stresses (WSS) at the IA wall and neck inflow rates (NIR). RESULTS: Lower flow values are observed in the majority of the complex model. However, at specific locations (left middle cerebral artery 0.5 m/s, left posterior cerebral artery 0.25 m/s), higher flow rates were visible when compared to the trimmed counterpart. Furthermore, at the centerlines the total velocity values reveal differences up to 0.15 m/s. In the IAs, the reduction in the neck inflow rate and WSS in the complex model was observed for the first IA (IA-A δNIRmean = - 0.07ml/s, PCA.l δWSSmean = - 0.05 Pa). The second IA featured an increase in the neck inflow rate and WSS (IA-B δNIRmean = 0.04 ml/s, PCA.l δWSSmean = 0.07 Pa). CONCLUSION: Both the magnitude and shape of the flow distribution vary depending on the model's complexity. The magnitude is primarily influenced by the global vessel model, while the shape is determined by the local structure. Furthermore, intra-aneurysmal flow strongly depends on the location in the vessel tree, emphasizing the need for complex model geometries for realistic hemodynamic assessment and rupture risk analysis.

Deep learning in computed tomography super resolution using multi-modality data training.

BACKGROUND: One of the limitations in leveraging the potential of artificial intelligence in X-ray imaging is the limited availability of annotated training data. As X-ray and CT shares similar imaging physics, one could achieve cross-domain data sharing, so to generate labeled synthetic X-ray images from annotated CT volumes as digitally reconstructed radiographs (DRRs). To account for the lower resolution of CT and the CT-generated DRRs as compared to the real X-ray images, we propose the use of super-resolution (SR) techniques to enhance the CT resolution before DRR generation. PURPOSE: As spatial resolution can be defined by the modulation transfer function kernel in CT physics, we propose to train a SR network using paired low-resolution (LR) and high-resolution (HR) images by varying the kernel's shape and cutoff frequency. This is different to previous deep learning-based SR techniques on RGB and medical images which focused on refining the sampling grid. Instead of generating LR images by bicubic interpolation, we aim to create realistic multi-detector CT (MDCT) like LR images from HR cone-beam CT (CBCT) scans. METHODS: We propose and evaluate the use of a SR U-Net for the mapping between LR and HR CBCT image slices. We reconstructed paired LR and HR training volumes from the same CT scans with small in-plane sampling grid size of 0.20 × 0.20 mm 2 $0.20 \times 0.20 \, {\rm mm}^2$ . We used the residual U-Net architecture to train two models. SRUN R e s K $^K_{Res}$ : trained with kernel-based LR images, and SRUN R e s I $^I_{Res}$ : trained with bicubic downsampled data as baseline. Both models are trained on one CBCT dataset (n = 13 391). The performance of both models was then evaluated on unseen kernel-based and interpolation-based LR CBCT images (n = 10 950), and also on MDCT images (n = 1392). RESULTS: Five-fold cross validation and ablation study were performed to find the optimal hyperparameters. Both SRUN R e s K $^K_{Res}$ and SRUN R e s I $^I_{Res}$ models show significant improvements (p-value < $<$ 0.05) in mean absolute error (MAE), peak signal-to-noise ratio (PSNR) and structural similarity index measures (SSIMs) on unseen CBCT images. Also, the improvement percentages in MAE, PSNR, and SSIM by SRUN R e s K $^K_{Res}$ is larger than SRUN R e s I $^I_{Res}$ . For SRUN R e s K $^K_{Res}$ , MAE is reduced by 14%, and PSNR and SSIMs increased by 6 and 8%, respectively. To conclude, SRUN R e s K $^K_{Res}$ outperforms SRUN R e s I $^I_{Res}$ , which the former generates sharper images when tested with kernel-based LR CBCT images as well as cross-modality LR MDCT data. CONCLUSIONS: Our proposed method showed better performance than the baseline interpolation approach on unseen LR CBCT. We showed that the frequency behavior of the used data is important for learning the SR features. Additionally, we showed cross-modality resolution improvements to LR MDCT images. Our approach is, therefore, a first and essential step in enabling realistic high spatial resolution CT-generated DRRs for deep learning training.

Fusiform versus Saccular Intracranial Aneurysms-Hemodynamic Evaluation of the Pre-Aneurysmal, Pathological, and Post-Interventional State.

Minimally-invasive therapies are well-established treatment methods for saccular intracranial aneurysms (SIAs). Knowledge concerning fusiform IAs (FIAs) is low, due to their wide and alternating lumen and their infrequent occurrence. However, FIAs carry risks like ischemia and thus require further in-depth investigation. Six patient-specific IAs, comprising three position-identical FIAs and SIAs, with the FIAs showing a non-typical FIA shape, were compared, respectively. For each model, a healthy counterpart and a treated version with a flow diverting stent were created. Eighteen time-dependent simulations were performed to analyze morphological and hemodynamic parameters focusing on the treatment effect (TE). The stent expansion is higher for FIAs than SIAs. For FIAs, the reduction in vorticity is higher (Δ35-75% case 2/3) and the reduction in the oscillatory velocity index is lower (Δ15-68% case 2/3). Velocity is reduced equally for FIAs and SIAs with a TE of 37-60% in FIAs and of 41-72% in SIAs. Time-averaged wall shear stress (TAWSS) is less reduced within FIAs than SIAs (Δ30-105%). Within this study, the positive TE of FDS deployed in FIAs is shown and a similarity in parameters found due to the non-typical FIA shape. Despite the higher stent expansion, velocity and vorticity are equally reduced compared to identically located SIAs.

Are hemodynamics responsible for inflammatory changes in venous vessel walls? A quantitative study of wall-enhancing intracranial arteriovenous malformation draining veins.

OBJECTIVE: Signal enhancement of vascular walls on vessel wall MRI might be a biomarker for inflammation. It has been theorized that contrast enhancement on vessel wall imaging (VWI) in draining veins of intracranial arteriovenous malformations (AVMs) may be associated with disease progression and development of venous stenosis. The aim of this study was to investigate the relationship between vessel wall enhancement and hemodynamic stressors along AVM draining veins. METHODS: Eight AVM patients with 15 draining veins visualized on VWI were included. Based on MR venography data, patient-specific 3D surface models of the venous anatomy distal to the nidus were segmented. The enhanced vascular wall regions were manually extracted and mapped onto the venous surface models after registration of image data. Using image-based blood flow simulations applying patient-specific boundary conditions based on phase-contrast quantitative MR angiography, hemodynamics were investigated in the enhanced vasculature. For the shear-related parameters, time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT) were calculated. Velocity, oscillatory velocity index (OVI), and vorticity were extracted for the intraluminal flow-related hemodynamics. RESULTS: Visual observations demonstrated overlap of enhancement with local lower shear stresses resulting from decreased velocities. Thus, higher RRT values were measured in the enhanced areas. Furthermore, nonenhancing draining veins showed on average slightly higher flow velocities and TAWSS. Significant decreases of 55% (p = 0.03) for TAWSS and of 24% (p = 0.03) for vorticity were identified in enhanced areas compared with near distal and proximal domains. Velocity magnitude in the enhanced region showed a nonsignificant decrease of 14% (p = 0.06). Furthermore, increases were present in the OSI (32%, p = 0.3), RRT (25%, p = 0.15), and OVI (26%, p = 0.3) in enhanced vessel sections, although the differences were not significant. CONCLUSIONS: This novel multimodal investigation of hemodynamics in AVM draining veins allows for precise prediction of occurring shear- and flow-related phenomena in enhanced vessel walls. These findings may suggest low shear to be a local predisposing factor for venous stenosis in AVMs.

Virtual Reality vs Phantom Model: Benefits and Drawbacks of Simulation Training in Neurosurgery.

BACKGROUND AND OBJECTIVES: Traditional neurosurgical education has relied heavily on the Halstedian "see one, do one, teach one" approach which is increasingly perceived as inefficient in contemporary settings marked by a steady decline in surgical caseload. In recent years, simulation training has emerged as an effective and accessible training alternative. To date, however, there is no standardized criterion pertaining to the quality and implementation of simulators in neurosurgical education and training. This research aims to compare the efficacy of virtual reality (VR) and Phantom-based simulation training in the context of neurosurgical skill acquisition, with a focus on middle cerebral artery aneurysm clipping. METHODS: An immersive VR clipping tool and a haptic clipping simulator incorporating 3-dimensional printing, additive manufacturing, and rheological analyses were developed. Twenty-two participants, comprising 12 medical students, 6 neurosurgical residents, and 4 experienced neurosurgeons, tested and evaluated both simulators for face and content validity. Construct and predictive validity of the simulators were assessed using an objective structured assessment scale for aneurysm clipping, measuring participants' performances and progress. RESULTS: Both modalities were deemed highly advantageous for educational purposes. Objective evaluations, however, revealed measurable differences in usability, efficacy, and transferability of the learned skills with VR excelling in procedural planning and visualization while Phantom simulation being noticeably superior in conveying surgical skills. CONCLUSION: Simulation training can accelerate the neurosurgical learning curve. The results of this study highlight the importance of establishing standardized criteria for the implementation and assessment of simulation modalities, ensuring consistent quality and efficacy in neurosurgical education.

Deformable 3D/3D CT-to-digital-tomosynthesis image registration in image-guided bronchoscopy interventions.

Traditional navigational bronchoscopy procedures rely on preprocedural computed tomography (CT) and intraoperative chest radiography and cone-beam CT (CBCT) to biopsy peripheral lung lesions. This navigational approach is challenging due to the projective nature of radiography, and the high radiation dose, long imaging time, and large footprints of CBCT. Digital tomosynthesis (DTS) is considered an attractive alternative combining the advantages of radiography and CBCT. Only the depth resolution cannot match a full CBCT image due to the limited angle acquisition. To address this issue, preoperative CT is a good auxiliary in guiding bronchoscopy interventions. Nevertheless, CT-to-body divergence caused by anatomic changes and respiratory motion, hinders the effective use of CT imaging. To mitigate CT-to-body divergence, we propose a novel deformable 3D/3D CT-to-DTS registration algorithm employing a multistage, multiresolution approach and using affine and elastic B-spline transformation models with bone and lung mask images. A multiresolution strategy with a Gaussian image pyramid and a multigrid strategy within the B-spline model are applied. The normalized correlation coefficient is included in the cost function for the affine model and a multimetric weighted cost function is used for the B-spline model, with weights determined heuristically. Tested on simulated and real patient bronchoscopy data, the algorithm yields promising results. Assessed qualitatively by visual inspection and quantitatively by computing the Dice coefficient (DC) and the average symmetric surface distance (ASSD), the algorithm achieves mean DC of 0.82±0.05 and 0.74±0.05, and mean ASSD of 0.65±0.29mm and 0.93±0.43mm for simulated and real data, respectively. This algorithm lays the groundwork for CT-aided intraoperative DTS imaging in image-guided bronchoscopy interventions with future studies focusing on automated metric weight setting.

Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4.

There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies.

Deep learning-based semantic vessel graph extraction for intracranial aneurysm rupture risk management.

PURPOSE: Intracranial aneurysms are vascular deformations in the brain which are complicated to treat. In clinical routines, the risk assessment of intracranial aneurysm rupture is simplified and might be unreliable, especially for patients with multiple aneurysms. Clinical research proposed more advanced analysis of intracranial aneurysm, but requires many complex preprocessing steps. Advanced tools for automatic aneurysm analysis are needed to transfer current research into clinical routine. METHODS: We propose a pipeline for intracranial aneurysm analysis using deep learning-based mesh segmentation, automatic centerline and outlet detection and automatic generation of a semantic vessel graph. We use the semantic vessel graph for morphological analysis and an automatic rupture state classification. RESULTS: The deep learning-based mesh segmentation can be successfully applied to aneurysm surface meshes. With the subsequent semantic graph extraction, additional morphological parameters can be extracted that take the whole vascular domain into account. The vessels near ruptured aneurysms had a slightly higher average torsion and curvature compared to vessels near unruptured aneurysms. The 3D surface models can be further employed for rupture state classification which achieves an accuracy of 83.3%. CONCLUSION: The presented pipeline addresses several aspects of current research and can be used for aneurysm analysis with minimal user effort. The semantic graph representation with automatic separation of the aneurysm from the parent vessel is advantageous for morphological and hemodynamical parameter extraction and has great potential for deep learning-based rupture state classification.

A hybrid hierarchical strategy for registration of 7T TOF-MRI to 7T PC-MRI intracranial vessel data.

PURPOSE: 7T time-of-flight (TOF) MRI provides high resolution for the evaluation of cerebrovascular vessels and pathologies. In combination with 4D flow fields acquired with phase-contrast (PC) MRI, hemodynamic information can be extracted to enhance the analysis by providing direct measurements in the larger arteries or patient-specific boundary conditions. Hence, a registration between both modalities is required. METHODS: To combine TOF and PC-MRI data, we developed a hybrid registration approach. Vessels and their centerlines are segmented from the TOF data. The centerline is fit to the intensity ridges of the lower resolved PC-MRI data, which provides temporal information. We used a metric that utilizes a scaled sum of weighted intensities and gradients on the normal plane. The registration is then guided by decoupled local affine transformations. It is applied hierarchically following the branching order of the vessel tree. RESULTS: A landmark validation over Monte Carlo simulations yielded an average mean squared error of 184.73 mm and an average Hausdorff distance of 15.20 mm. The hierarchical traversal that transforms child vessels with their parents registers even small vessels not detectable in the PC-MRI. CONCLUSION: The presented work combines high-resolution tomographic information from 7T TOF-MRI and measured flow data from 4D 7T PC-MRI scan for the arteries of the brain. This enables usage of patient-specific flow parameters for realistic simulations, thus supporting research in areas such as cerebral small vessel disease. Automatization and free deformations can help address the limiting error measures in the future.

Multimodal exploration of the intracranial aneurysm wall.

PURPOSE: Intracranial aneurysms (IAs) are pathological changes of the intracranial vessel wall, although clinical image data can only show the vessel lumen. Histology can provide wall information but is typically restricted to ex vivo 2D slices where the shape of the tissue is altered. METHODS: We developed a visual exploration pipeline for a comprehensive view of an IA. We extract multimodal information (like stain classification and segmentation of histologic images) and combine them via 2D to 3D mapping and virtual inflation of deformed tissue. Histological data, including four stains, micro-CT data and segmented calcifications as well as hemodynamic information like wall shear stress (WSS), are combined with the 3D model of the resected aneurysm. RESULTS: Calcifications were mostly present in the tissue part with increased WSS. In the 3D model, an area of increased wall thickness was identified and correlated to histology, where the Oil red O (ORO) stained images showed a lipid accumulation and the alpha-smooth muscle actin (aSMA) stained images showed a slight loss of muscle cells. CONCLUSION: Our visual exploration pipeline combines multimodal information about the aneurysm wall to improve the understanding of wall changes and IA development. The user can identify regions and correlate how hemodynamic forces, e.g. WSS, are reflected by histological structures of the vessel wall, wall thickness and calcifications.

Assessment of the flow-diverter efficacy for intracranial aneurysm treatment considering pre- and post-interventional hemodynamics.

Endovascular treatment of intracranial aneurysms with flow diverters (FD) has become one of the most promising interventions. Due to its woven high-density structure they are particularly applicable for challenging lesions. Although several studies have already conducted realistic hemodynamic quantification of the FD efficacy, a comparison with morphologic post-interventional data is still missing. This study analyses the hemodynamics of ten intracranial aneurysm patients treated with a novel FD device. Based on pre- and post-interventional 3D digital subtraction angiography image data, patient-specific 3D models of both treatment states are generated applying open source threshold-based segmentation methods. Using a fast virtual stenting approach, the real stent positions available in the post-interventional data are virtually replicated and both treatment scenarios were characterized using image-based blood flow simulations. The results show FD-induced flow reductions at the ostium by a decrease in mean neck flow rate (51%), inflow concentration index (56%) and mean inflow velocity (53%). Intraluminal reductions in flow activity for time-averaged wall shear stress (47%) and kinetic energy (71%) are present as well. However, an intra-aneurysmal increase in flow pulsatility (16%) for the post-interventional cases can be observed. Patient-specific FD simulations demonstrate the desired flow redirection and activity reduction inside the aneurysm beneficial for thrombosis formation. Differences in the magnitude of hemodynamic reduction exist over the cardiac cycle which may be addressed in a clinical setting by anti-hypertensive treatment in selected cases.

Is Accurate Lumen Segmentation More Important than Outlet Boundary Condition in Image-Based Blood Flow Simulations for Intracranial Aneurysms?

PURPOSE: Image-based blood flow simulations are increasingly used to investigate the hemodynamics in intracranial aneurysms (IAs). However, a strong variability in segmentation approaches as well as the absence of individualized boundary conditions (BCs) influence the quality of these simulation results leading to imprecision and decreased reliability. This study aims to analyze these influences on relevant hemodynamic parameters within IAs. METHODS: As a follow-up study of an international multiple aneurysms challenge, the segmentation results of five IAs differing in size and location were investigated. Specifically, five possible outlet BCs were considered in each of the IAs. These are comprised of the zero-pressure condition (BC1), a flow distribution based on Murray's law with the exponents n = 2 (BC2) and n = 3 (BC3) as well as two advanced flow-splitting models considering the real vessels by including circular cross sections (BC4) or anatomical cross sections (BC5), respectively. In total, 120 time-dependent blood flow simulations were analyzed qualitatively and quantitatively, focusing on five representative intra-aneurysmal flow and five shear parameters such as vorticity and wall shear stress. RESULTS: The outlet BC variation revealed substantial differences. Higher shear stresses (up to Δ9.69 Pa), intrasaccular velocities (up to Δ0.15 m/s) and vorticities (up to Δ629.22 1/s) were detected when advanced flow-splitting was applied compared to the widely used zero-pressure BC. The tendency of outlets BCs to over- or underestimate hemodynamic parameters is consistent across different segmentations of a single aneurysm model. Segmentation-induced variability reaches Δ19.58 Pa, Δ0.42 m/s and Δ957.27 1/s, respectively. Excluding low fidelity segmentations, however, (a) reduces the deviation drastically (>43%) and (b) leads to a lower impact of the outlet BC on hemodynamic predictions. CONCLUSION: With a more realistic lumen segmentation, the influence of the BC on the resulting hemodynamics is decreased. A realistic lumen segmentation can be ensured, e.g., by using high-resolved 2D images. Furthermore, the selection of an advanced outflow-splitting model is advised and the use of a zero-pressure BC and BC based on Murray's law with exponent n = 3 should be avoided.