Role of Delta-Notch signaling in cerebral cavernous malformations.

Cerebral cavernous malformations (CCM) commonly known as cavernous hemangioma are associated with abnormally enlarged thin-walled blood vessels. As a result, these dilated capillaries are prone to leakage and result in hemorrhages. Clinically, such hemorrhages lead to severe headaches, focal neurological deficits, and epileptic seizures. CCM is caused by loss of function mutations in one of the three well-known CCM genes: Krev interaction trapped 1 (KRIT1), OSM, and programmed cell death 10 (PDCD10). Loss of CCM genes have been shown to be synergistically related to decreased Notch signaling and excessive angiogenesis. Despite recent evidences indicating that Notch signaling plays a pivotal role in regulating angiogenesis, the role of Notch in CCM development and progression is still not clear. Here, we provide an update literature review on the current knowledge of the structure of Notch receptor and its ligands, its relevance to angiogenesis and more precisely to CCM pathogenesis. In addition to reviewing the current literatures, this review will also focus on the cross talk between Delta-Notch and vascular endothelial growth factor (VEGF) signaling in angiogenesis and in CCM pathogenesis. Understanding the role of Notch signaling in CCM development and progression might help provide a better insight for novel anti-angiogenic therapies.

Superselective arterial spin labeling applied for flow territory mapping in various cerebrovascular diseases.

In three example patients suffering from internal carotid artery occlusion, intracranial steno-occlusive disease, and symptomatic arteriovenous malformation (AVM), a new method named superselective pseudo-continuous arterial spin labeling (pCASL) was used in addition to clinical routine measurements. The capabilities of this method are demonstrated to gain important information in diagnosis, risk analysis, and treatment monitoring that are neither accessible by digital subtraction angiography nor by existing selective arterial spin labeling methods and thus to propose future applications in clinical routine. In all cases superselective pCASL enabled the assessment of tissue viability and of territorial brain perfusion at different levels starting from major brain feeding vessels to collateral circulation at the level of the Circle of Willis to even distal branching arteries. This made it possible to estimate the contribution of an extracranial-intracranial bypass to the brain perfusion; to depict individual arteries to important functional brain areas; to identify en-passant feeding vessels of an AVM and to track possible changes in their perfusion territories after intervention.

SlicerCBM: automatic framework for biomechanical analysis of the brain.

PURPOSE: Brain shift that occurs during neurosurgery disturbs the brain's anatomy. Prediction of the brain shift is essential for accurate localisation of the surgical target. Biomechanical models have been envisaged as a possible tool for such predictions. In this study, we created a framework to automate the workflow for predicting intra-operative brain deformations. METHODS: We created our framework by uniquely combining our meshless total Lagrangian explicit dynamics (MTLED) algorithm for computing soft tissue deformations, open-source software libraries and built-in functions within 3D Slicer, an open-source software package widely used for medical research. Our framework generates the biomechanical brain model from the pre-operative MRI, computes brain deformation using MTLED and outputs results in the form of predicted warped intra-operative MRI. RESULTS: Our framework is used to solve three different neurosurgical brain shift scenarios: craniotomy, tumour resection and electrode placement. We evaluated our framework using nine patients. The average time to construct a patient-specific brain biomechanical model was 3 min, and that to compute deformations ranged from 13 to 23 min. We performed a qualitative evaluation by comparing our predicted intra-operative MRI with the actual intra-operative MRI. For quantitative evaluation, we computed Hausdorff distances between predicted and actual intra-operative ventricle surfaces. For patients with craniotomy and tumour resection, approximately 95% of the nodes on the ventricle surfaces are within two times the original in-plane resolution of the actual surface determined from the intra-operative MRI. CONCLUSION: Our framework provides a broader application of existing solution methods not only in research but also in clinics. We successfully demonstrated the application of our framework by predicting intra-operative deformations in nine patients undergoing neurosurgical procedures.

Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families.

Pathogenic germline variants in the DNA polymerase genes POLE and POLD1 cause polymerase proofreading-associated polyposis, a dominantly inherited disorder with increased risk of colorectal carcinomas and other tumors. POLE/POLD1 variants may result in high somatic mutation and neoantigen loads that confer susceptibility to immune checkpoint inhibitors (ICIs). To explore the role of POLE/POLD1 germline variants in glioma predisposition, whole-exome sequencing was applied to leukocyte DNA of glioma patients from 61 tumor families with at least one glioma case each. Rare heterozygous POLE/POLD1 missense variants predicted to be deleterious were identified in glioma patients from 10 (16%) families, co-segregating with the tumor phenotype in families with available DNA from several tumor patients. Glioblastoma patients carrying rare POLE variants had a mean overall survival of 21 months. Additionally, germline variants in POLD1, located at 19q13.33, were detected in 2/34 (6%) patients with 1p/19q-codeleted oligodendrogliomas, while POLE variants were identified in 2/4 (50%) glioblastoma patients with a spinal metastasis. In 13/15 (87%) gliomas from patients carrying POLE/POLD1 variants, features of defective polymerase proofreading, e.g. hypermutation, POLE/POLD1-associated mutational signatures, multinucleated cells, and increased intratumoral T cell response, were observed. In a CRISPR/Cas9-derived POLE-deficient LN-229 glioblastoma cell clone, a mutator phenotype and delayed S phase progression were detected compared to wildtype POLE cells. Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy.

Computer simulation of tumour resection-induced brain deformation by a meshless approach.

Tumour resection requires precise planning and navigation to maximise tumour removal while simultaneously protecting nearby healthy tissues. Neurosurgeons need to know the location of the remaining tumour after partial tumour removal before continuing with the resection. Our approach to the problem uses biomechanical modelling and computer simulation to compute the brain deformations after the tumour is resected. In this study, we use meshless Total Lagrangian explicit dynamics as the solver. The problem geometry is extracted from the patient-specific magnetic resonance imaging (MRI) data and includes the parenchyma, tumour, cerebrospinal fluid and skull. The appropriate non-linear material formulation is used. Loading is performed by imposing intra-operative conditions of gravity and reaction forces between the tumour and surrounding healthy parenchyma tissues. A finite frictionless sliding contact is enforced between the skull (rigid) and parenchyma. The meshless simulation results are compared to intra-operative MRI sections. We also calculate Hausdorff distances between the computed deformed surfaces (ventricles and tumour cavities) and surfaces observed intra-operatively. Over 80% of points on the ventricle surface and 95% of points on the tumour cavity surface were successfully registered (results within the limits of two times the original in-plane resolution of the intra-operative image). Computed results demonstrate the potential for our method in estimating the tissue deformation and tumour boundary during the resection.

Automatic framework for patient-specific modelling of tumour resection-induced brain shift.

Our motivation is to enable non-biomechanical engineering specialists to use sophisticated biomechanical models in the clinic to predict tumour resection-induced brain shift, and subsequently know the location of the residual tumour and its boundary. To achieve this goal, we developed a framework for automatically generating and solving patient-specific biomechanical models of the brain. This framework automatically determines patient-specific brain geometry from MRI data, generates patient-specific computational grid, assigns material properties, defines boundary conditions, applies external loads to the anatomical structures, and solves differential equations of nonlinear elasticity using Meshless Total Lagrangian Explicit Dynamics (MTLED) algorithm. We demonstrated the effectiveness and appropriateness of our framework on real clinical cases of tumour resection-induced brain shift.

Eloquent Lower Grade Gliomas, a Highly Vulnerable Cohort: Assessment of Patients' Functional Outcome After Surgery Based on the LoG-Glio Registry.

Majority of lower grade glioma (LGG) are located eloquently rendering surgical resection challenging. Aim of our study was to assess rate of permanent deficits and its predisposing risk factors. We retrieved 83 patients harboring an eloquently located LGGs from the prospective LoG-Glio Database. Patients without surgery or incomplete postoperative data were excluded. Sign rank test, explorative correlations by Spearman ρ and multivariable regression for new postoperative deficits were calculated. Eloquent region involved predominantly motor (45%) and language (40%). At first follow up after 3 months permanent neuro-logical deficits (NDs) were noted in 39%. Mild deficits remained in 29% and severe deficits in 10%. Complete tumor removal (CTR) was successfully in 62% of intended cases. Postoperative and 3-month follow up National Institute of Health Stroke Score (NIHSS) showed significantly lower values than preoperatively (p<0.001). 38% cases showed a decreased NIHSS at 3-month, while occurrence was only 14% at 9-12-month follow up. 6/7 patients with mild aphasia recovered after 9-12 months, while motor deficits present at 3-month follow up were persistent in majority of patients. Eastern oncology group functional status (ECOG) significantly decreased by surgery (p < 0.001) in 31% of cases. Between 3-month and 9-12-months follow up no significant improvement was seen. In the multivariable model CTR (p=0.019, OR 31.9), and ECOG>0 (p=0.021, OR 8.5) were independent predictors for permanent postoperative deficit according to NIHSS at 3-month according to multivariable regression model. Patients harboring eloquently located LGG are highly vulnerable for permanent deficits. Almost one third of patients have a permanent reduction of their functional status based on ECOG. Risk of an extended resection has to be balanced with the respective oncological benefit. Especially, patients with impaired pre-operative status are at risk for new permanent deficits. There is a relevant improvement of neurological symptoms in the first year after surgery, especially for patients with slight aphasia.

High-field iMRI in glioblastoma surgery: improvement of resection radicality and survival for the patient?

Since the first patients underwent intracranial tumor removal with the radicality control of intraoperative MRI (ioMRI) in September 2005 in our department, the majority of operations performed in the ioMRI room have been indicated for high grade gliomas. In order to elucidate the role of ioMRI scanning in patients harboring high-grade gliomas (HGG) on their survival, one hundred ninety three patients with gliomas WHO grades III and IV were operated either in a standard microsurgical neuronavigated fashion or using additionally ioMRI and were included in a follow-up study. The series started with surgeries from September 2005 until October 2007. Patient attribution to the two groups was based on the logistical availability of the ioMRI on a scheduled surgery day, and on the assumed "difficulty" of the surgery based on the location of the glioma in or near to an eloquent area. Surgery was intended to be as radical as possible without reduction of quality of life. First surgery was performed in 103 patients (75 WHO IV and 28 WHO III) and will be the main topic of this paper. In 60 patients, ioMRI was used, while in 43 patients standard microsurgical neuronavigated resection techniques were applied. Patients were followed in regular intervals mostly until death. Statistical analysis showed a median survival time for patients in whom ioMRI had been used of 20, 37 months compared to 10, 3 months in the cohort who had undergone conventional microsurgical removal. Major influencing concomitants were WHO grades and age which were balanced in both groups.

Intraoperative dynamic susceptibility contrast MRI (iDSC-MRI) is as reliable as preoperatively acquired perfusion mapping.

DSC-MRI was applied intraoperatively during human brain tumor removal. Immediately after complete tumor resection was presumed, MRI including a dynamic susceptibility contrast T2-weighted EPI sequence was performed in 30 patients while the skull was still open using a flexible two-channel coil system at an intraoperative 1.5-Tesla MR scanner. Maps of relative regional blood flow (rCBF), blood volume (rCBV), and mean transit time (MTT) were calculated, and ratios of these maps were compared to preoperatively acquired DSC-MRI data. The extent of the resection was compared with the postoperative MRI performed 24 h after the operation. In 8 of these patients residual tumor tissue was depicted at the time of intraoperative MRI. In corresponding regions ratios for rCBV and rCBF did not differ significantly between pre- and intraoperatively acquired data (two-tailed t-test). Furthermore, we found a high correlation between ratios created from pre- and intraoperatively measured data for both rCBV and rCBF, respectively (Pearson correlation; r(2)(rCBV)=0.86, p

Rapid recovery of motor and cognitive functions after resection of a right frontal lobe meningioma in a child.

PURPOSE: The purpose of this study is to provide longitudinal data on neurological and neuropsychological restitution following resection of an extra-axial space-occupying lesion. CASE REPORT: A comprehensive neuropsychological test battery was utilised preoperatively and 1, 4, 11, and 24 months, respectively, after removal of a parasagittal meningioma compressing the right frontal lobe in a right-handed 6-year-old boy with average intelligence. RESULTS: Symptoms related to brain compression (left-sided hemiparesis, diplopia) resolved shortly after surgery. Recovery of specific cognitive functions (short- and long-term memory, attention, and dichotic listening performance) was more protracted. CONCLUSION: Here, we illustrate the potential of a structured follow-up analysis, based on neuropsychological testing. We were able to distinguish separate time-courses for neurological functions but even more distinct within complex neuropsychological processes. This time-dependent recovery should be considered when designing longitudinal follow-up studies.

Intraoperative dynamic susceptibility contrast weighted magnetic resonance imaging (iDSC-MRI) - Technical considerations and feasibility.

DSC-MRI was applied intraoperatively during brain tumor removal. Immediately after presumed complete tumor resection an MRI including a dynamic susceptibility contrast T2-weighted EPI sequence was performed in 6 patients while the skull was still open using a flexible two-channel coil system at an intraoperative 1.5-Tesla MR scanner. After an initial baseline period of this iDSC-MRI sequence a bolus of contrast agent was administered intravenously. Maps of relative regional blood flow (rCBF), blood volume (rCBV) and the mean transit time (MTT) were calculated. These maps were compared to preoperatively acquired DSC-MRI data. The extent of the resection was compared with the postoperative MRI performed 24 h after the operation. In five patients complete tumor removal was already achieved at the time of iDSC-MRI and no areas of elevated perfusion values adjacent to the resection cavity were found. Complete removal was again documented on the postoperatively performed MRI. In one case there was residual tumor that showed both contrast enhancement and identical perfusion ratios as in the preoperatively acquired data. Removal of the remaining tumor was performed. iDSC-MRI is technically feasible as there are no significant susceptibility artifacts. DSC-MRI has been used to distinguish different tumor entities preoperatively and recurrent disease from radiation necrosis. Despite brain shift and thus invalidated preoperative image data or contrast leakage caused by intraoperative manipulation, iDCS-MRI furthermore reliably detects residual tumor intraoperatively at a timepoint where further resection is still possible and thus enables the neurosurgeon to complete the resection during the same procedure.

Severe hyponatraemia in the setting of hypopituitarism associated with empty sella and herniation of the optic chiasm and gyrus rectus.

We present a patient with progressive weakness over months caused by untreated hyponatraemia. When hyponatraemia became severe, the patient could not move without help, was lethargic and had endocrinological dysfunction. Symptomatic therapy brought no improvement. MRI of the brain showed empty sella with gross herniation of the optic chiasma, gyrus rectus and third ventricle. After fluid and salt supplementation was combined with hydrocortisone, the patient regained his strength and could leave the hospital. Panhypopituitarism caused by empty sella should always be considered when hyponatraemia is not responsive to salt and fluid substitution alone. Additional hydrocortisone supplementation can be life saving.

Computer-assisted planning for a concentric tube robotic system in neurosurgery.

PURPOSE: Laser-induced thermotherapy in the brain is a minimally invasive procedure to denature tumor tissue. However, irregularly shaped brain tumors cannot be treated using existing commercial systems. Thus, we present a new concept for laser-induced thermotherapy using a concentric tube robotic system. The planning procedure is complex and consists of the optimal distribution of thermal laser ablations within a volume as well as design and configuration parameter optimization of the concentric tube robot. METHODS: We propose a novel computer-assisted planning procedure that decomposes the problem into task- and robot-specific planning and uses a multi-objective particle swarm optimization algorithm with variable length. RESULTS: The algorithm determines a Pareto-front of optimal ablation distributions for three patient datasets. It considers multiple objectives and determines optimal robot parameters for multiple trajectories to access the tumor volume. CONCLUSIONS: We prove the effectiveness of our planning procedure to enable the treatment of irregularly shaped brain tumors. Multiple trajectories further increase the applicability of the procedure.

Magnetic Resonance Imaging-Apparent Diffusion Coefficient Assessment of Vestibular Schwannomas: Systematic Approach, Methodology, and Pitfalls.

OBJECTIVE: To investigate the validity of various approaches to extract quantitative measurements of diffusion imaging (i.e., apparent diffusion coefficient [ADC]) to investigate tumors of the central nervous system. In current studies, the region of interest (ROI) for the quantitative measurements are placed arbitrarily according to morphology. Our aim is to investigate how placement patterns influence the ADC estimation in intracranial tumors. METHODS: Twenty consecutive patients affected by vestibular schwannoma were studied using diffusion imaging. ADC values were obtained using different ROI placement methods: segmentation ADC values of the entire volume (vADC), random ADC values were obtained in 10 different ROI points, and a single ROI in the ADC of the internal auditory canal portion of the tumor. RESULTS: ADC of the internal auditory canal portion of the tumor and vADC differed significantly (P < 0.01). vADC was different between cystic and microcystic schwannomas (P = 0.009) and between cystic and solid schwannomas (P = 0.006). CONCLUSIONS: The positioning of ROI in these measurements is pivotal. Although "whole tumor volume" measurements represent the largest amount of information, multiple seed points can be used as well. However, there must be multiple seeds and their placement must be reported. ADC can be used as a versatile tool for tumor assessment but must be used judiciously and structured to yield comparable results.

Non-invasive qualitative and semiquantitative presurgical investigation of the feeding vasculature to intracranial meningiomas using superselective arterial spin labeling.

BACKGROUND: Intracranial meningiomas may be amenable to presurgical embolization to reduce bleeding complications. Detailed information usually obtained by digital subtraction angiography (DSA) on the contribution of blood supply from internal and external carotid artery branches is required to prevent non-target embolization and is helpful for pre-surgical planning. PURPOSE: To investigate the contribution of the feeding vasculature to intracranial meningiomas with superselective arterial spin labelling (sASL) as an alternative to DSA. MATERIAL AND METHODS: Consecutive patients presenting for meningioma resection were prospectively included. sASL perfusion images acquired on a clinical 3T MRI scanner were independently rated by two readers. Contribution of the external carotid artery (ECA), internal carotid artery (ICA) and vertebral/basilar artery (VA/BA) was rated as none, <50% or >50%. Correlation of sASL was performed in two patients undergoing DSA. RESULTS: 32 patients (61 ± 13 years) harboring 42 meningiomas could be included. sASL was technically successful in all patients. 19 meningiomas had ICA dominant supply, 19 had ECA dominant supply. One meningioma had mixed supply and in three meningiomas a perfusion signal could not be detected. While exclusive unilateral ECA supply was common (n = 14) and exclusive unilateral ICA was rare (n = 4), mixed supply from multiple vessels (n = 20) was a frequent finding. Interrater agreement was substantial (κ = 0.73). Agreement with DSA was perfect within our predefined categories. CONCLUSION: sASL is able to identify the presence and extent of the feeding vasculature in intracranial meningiomas.

Registration of vascular structures using a hybrid mixture model.

PURPOSE: Morphological changes to anatomy resulting from invasive surgical procedures or pathology, typically alter the surrounding vasculature. This makes it useful as a descriptor for feature-driven image registration in various clinical applications. However, registration of vasculature remains challenging, as vessels often differ in size and shape, and may even miss branches, due to surgical interventions or pathological changes. Furthermore, existing vessel registration methods are typically designed for a specific application. To address this limitation, we propose a generic vessel registration approach useful for a variety of clinical applications, involving different anatomical regions. METHODS: A probabilistic registration framework based on a hybrid mixture model, with a refinement mechanism to identify missing branches (denoted as HdMM+) during vasculature matching, is introduced. Vascular structures are represented as 6-dimensional hybrid point sets comprising spatial positions and centerline orientations, using Student's t-distributions to model the former and Watson distributions for the latter. RESULTS: The proposed framework is evaluated for intraoperative brain shift compensation, and monitoring changes in pulmonary vasculature resulting from chronic lung disease. Registration accuracy is validated using both synthetic and patient data. Our results demonstrate, HdMM+ is able to reduce more than [Formula: see text] of the initial error for both applications, and outperforms the state-of-the-art point-based registration methods such as coherent point drift and Student's t-distribution mixture model, in terms of mean surface distance, modified Hausdorff distance, Dice and Jaccard scores. CONCLUSION: The proposed registration framework models complex vascular structures using a hybrid representation of vessel centerlines, and accommodates intricate variations in vascular morphology. Furthermore, it is generic and flexible in its design, enabling its use in a variety of clinical applications.

Fast and accurate automatic registration for MR-guided procedures using active microcoils.

A fast, robust, accurate, and automatic registration technique based on magnetic resonance (MR) active microcoils (active markers) for registration of tracked medical devices to preprocedural MR-images is presented. This allows for a straight-forward integration of position measurement systems into clinical procedures. The presented method is useful for guidance purposes in clinical applications with high demands on accuracy and ease-of-use (e.g., neurosurgical or orthopedic applications). The determination of the positions of the active markers is integrated into the preparation phase of the actual MR imaging scan. The technique features a generic interface using DICOM standards for communication with navigation workstations linked to an MR system. The position of the active markers is fixed with respect to a reference system of an optical positioning measurement system (OPMS) and thus the coregistration of the MR system and the OPMS is established. In a phantom study, a mean overall targeting accuracy of 0.9+/-0.1 mm was achieved and compared favorably to results obtained from manual registration tests (1.8+/-0.3 mm) carried out in parallel. For a test person trained for both registration methods, workflow improvements of 3-6 min per registration step were found. The need for manual interaction is entirely eliminated thus avoiding user-bias, which is advantageous for the usage in clinical routine. The method improves the ease-of-use of tracking equipment during stereotactic guidance. The method is finally demonstrated in a volunteer study using a model of a Mayfield skull clamp with integrated active and optical reference markers.

De novo development of intraosseous cavernous hemangioma.

Intraosseous cavernous hemangiomas are rare and not often multifocal. De novo development of a skull cavernous hemangioma has not been described previously. We present a 20-year-old man who was operated upon for a skull cavernoma in the right frontal area and developed a new lesion 3 years later in the right occipital region. The first lesion was removed completely and the postoperative course was uneventful. Histology showed an intraosseous cavernous hemangioma. MRI follow-up revealed a new lesion in the right occipital region. At the time of the first operation this lesion was not seen on CT or MRI scan. Surgical removal was performed and histology again showed a cavernous hemangioma. The patient seems to be unique and it is important to keep young patients with the diagnosis of cavernous hemangioma under close follow-up. This supports the experience from parenchymatous cavernous hemangiomas that this malformation may become a dynamic disease.

A Survey of auditory display in image-guided interventions.

PURPOSE: This article investigates the current state of the art of the use of auditory display in image-guided medical interventions. Auditory display is a means of conveying information using sound, and we review the use of this approach to support navigated interventions. We discuss the benefits and drawbacks of published systems and outline directions for future investigation. METHODS: We undertook a review of scientific articles on the topic of auditory rendering in image-guided intervention. This includes methods for avoidance of risk structures and instrument placement and manipulation. The review did not include auditory display for status monitoring, for instance in anesthesia. RESULTS: We identified 15 publications in the course of the search. Most of the literature (60%) investigates the use of auditory display to convey distance of a tracked instrument to an object using proximity or safety margins. The remainder discuss continuous guidance for navigated instrument placement. Four of the articles present clinical evaluations, 11 present laboratory evaluations, and 3 present informal evaluation (2 present both laboratory and clinical evaluations). CONCLUSION: Auditory display is a growing field that has been largely neglected in research in image-guided intervention. Despite benefits of auditory displays reported in both the reviewed literature and non-medical fields, adoption in medicine has been slow. Future challenges include increasing interdisciplinary cooperation with auditory display investigators to develop more meaningful auditory display designs and comprehensive evaluations which target the benefits and drawbacks of auditory display in image guidance.