Barbara Carl

Nugget-cut: a segmentation scheme for spherically- and elliptically-shaped 3D objects

In this paper, a segmentation method for spherically-and elliptically-shaped objects is presented. It utilizes a user-defined seed point to set up a directed 3D graph. The nodes of the 3D graph are obtained by sampling along rays that are sent through the surface points of a polyhedron. Additionally, several arcs and a parameter constrain the set of possible segmentations and enforce smoothness. After the graph has been constructed, the minimal cost closed set on the graph is computed via a polynomial time s-t cut, creating an optimal segmentation of the object. The presented method has been evaluated on 50 Magnetic Resonance Imaging (MRI) data sets with World Health Organization (WHO) grade IV gliomas (glioblastoma multiforme). The ground truth of the tumor boundaries were manually extracted by three clinical experts (neurological surgeons) with several years (> 6) of experience in resection of gliomas and afterwards compared with the automatic segmentation results of the proposed scheme yielding an average Dice Similarity Coefficient (DSC) of 80.37±8.93%. However, no segmentation method provides a perfect result, so additional editing on some slices was required, but these edits could be achieved quickly because the automatic segmentation provides a border that fits mostly to the desired contour. Furthermore, the manual segmentation by neurological surgeons took 2-32 minutes (mean: 8 minutes), in contrast to the automatic segmentation with our implementation that took less than 5 seconds.

Costs and cost-driving factors for acute treatment of adults with status epilepticus: A multicenter cohort study from Germany

To provide first data on inpatient costs and cost‐driving factors due to nonrefractory status epilepticus (NSE), refractory status epilepticus (RSE), and super‐refractory status epilepticus (SRSE).

Merits and Limits of Tractography Techniques for the Uninitiated

The implementation of fiber tracking or tractography modules in commercial navigation systems resulted in a broad availability of visualization possibilities for major white matter tracts in the neurosurgical community. Unfortunately the implemented algorithms and tracking approaches do not represent the state of the art of tractography strategies and may lead to false tracking results. The application of advanced tractography techniques for neurosurgical procedures poses even additional challenges that relate to effects of the individual anatomy that might be altered by edema and tumor, to stereotactic inaccuracies due to image distortion, as well as to registration inaccuracies and brain shift.

Metalloproteinases ADAM12 and MMP‐14 are associated with cavernous sinus invasion in pituitary adenomas

Invasion of tumor cells critically depends on cell‐cell or cell‐extracellular matrix interactions. Enzymes capable of modulating these interactions belong to the proteinase families of ADAM (a disintegrin and metalloprotease) and MMP (matrix metalloprotease) proteins. Our objective is to examine their expression levels and evaluate the relationship between expression levels and cavernous sinus invasion in pituitary adenomas. Tissue samples from 35 patients with pituitary adenomas were analyzed. Quantitative real‐time polymerase chain reaction (qPCR) was employed to assess mRNA expression levels for ADAM and MMP genes. Protein levels were examined using immunohistochemistry and Western Blot. Correlation analyses between expression levels and clinical parameters were performed. By silencing ADAM12 and MMP‐14 with siRNA in a mouse pituitary adenoma cell line (TtT/GF), their cellular effects were investigated. In our study, nine women and 26 men were included, with a mean age of 53.1 years (range 15–84 years) at the time of surgery. There were 19 cases with cavernous sinus invasion. The proteins ADAM12 and MMP‐14 were significantly up‐regulated in invasive adenomas compared to noninvasive adenomas. Both human isoforms of ADAM12 (ADAM12L and ADAM12s) were involved in tumor invasion; moreover, ADAM12L was found to correlate positively with Ki‐67 proliferation index in pituitary adenomas. In TtT/GF pituitary adenoma cells, silencing of ADAM12 and MMP‐14 significantly inhibited cell invasion and migration, respectively, whereas only silencing of ADAM12 suppressed cell proliferation. We conclude that ADAM12 and MMP‐14 are associated with cavernous sinus invasion in pituitary adenomas, which qualifies these proteins in diagnosis and therapy.

Preoperative volume determination for pituitary adenoma

The most common sellar lesion is the pituitary adenoma, and sellar tumors are approximately 10-15% of all intracranial neoplasms. Manual slice-by-slice segmentation takes quite some time that can be reduced by using the appropriate algorithms. In this contribution, we present a segmentation method for pituitary adenoma. The method is based on an algorithm that we have applied recently to segmenting glioblastoma multiforme. A modification of this scheme is used for adenoma segmentation that is much harder to perform, due to lack of contrast-enhanced boundaries. In our experimental evaluation, neurosurgeons performed manual slice-by-slice segmentation of ten magnetic resonance imaging (MRI) cases. The segmentations were compared to the segmentation results of the proposed method using the Dice Similarity Coefficient (DSC). The average DSC for all datasets was 75.92%±7.24%. A manual segmentation took about four minutes and our algorithm required about one second.

The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells.

BACKGROUND Despite multimodal treatment, glioblastoma (GBM) therapy with temozolomide (TMZ) remains inefficient due to chemoresistance. Matrix metalloproteinase (MMP) and a disintegrin and metalloprotease (ADAM), increased in GBM, could contribute to chemoresistance and TMZ-induced recurrence of glioblastoma. METHODS TMZ inducibility of metalloproteases was determined in GBM cell lines, primary GBM cells, and tissues from GBM and recurrent GBM. TMZ sensitivity and invasiveness of GBM cells were assessed in the presence of the metalloprotease inhibitors batimastat (BB-94) and marimastat (BB-2516). Metalloprotease-dependent effects of TMZ on mitochondria and pAkt/phosphatidylinositol-3 kinase (PI3K) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) pathways were analyzed by fluorescence activated cell sorting, morphometry, and immunoblotting. Invasiveness of GBM cells was determined by Matrigel invasion assays. Potential metalloprotease substrates were identified by proteomics and tested for invasion using blocking antibodies. RESULTS TMZ induces expression of MMP-1, -9, -14, and ADAM8 in GBM cells and in recurrent GBM tissues. BB-94, but not BB-2516 (ADAM8-sparing) increased TMZ sensitivity of TMZ-resistant and -nonresistant GBM cells with different O(6)-methylguanine-DNA methyltransferase states, suggesting that ADAM8 mediates chemoresistance, which was confirmed by ADAM8 knockdown, ADAM8 overexpression, or pharmacological inhibition of ADAM8. Levels of pAkt and pERK1/2 were increased in GBM cells and correlated with ADAM8 expression, cell survival, and invasiveness. Soluble hepatocyte growth factor (HGF) R/c-met and CD44 were identified as metalloprotease substrates in TMZ-treated GBM cells. Blocking of HGF R/c-met prevented TMZ-induced invasiveness. CONCLUSIONS ADAM8 causes TMZ resistance in GBM cells by enhancing pAkt/PI3K, pERK1/2, and cleavage of CD44 and HGF R/c-met. Specific ADAM8 inhibition can optimize TMZ chemotherapy of GBM in order to prevent formation of recurrent GBM in patients.

Historical, Current, and Future Intraoperative Imaging Modalities

Intraoperative imaging has become widely accepted in neurosurgery in recent years. The possibility to objectively determine the extent of tumor removal is highly advantageous. If the resection is incomplete, clinicians can attempt to remove the residual tumor that was missed during the same operation. Furthermore, the positioning of implants in spinal surgery, as well as in cranial surgery, can be controlled and modified during the procedure. Intraoperative imaging acts as immediate quality control and offers improved patient safety. This article gives a brief overview of the different intraoperative imaging modalities and their potential applications in modern neurosurgery.

ADAM8 expression in breast cancer derived brain metastases: Functional implications on MMP-9 expression and transendothelial migration in breast cancer cells

Metastatic breast cancer affects long‐term survival and is a major cause of cancer death for women worldwide. The Metalloprotease‐Disintegrin ADAM8 promotes breast cancer development and brain metastasis in a mouse breast cancer model. Here, abundant ADAM8 expression was detected in primary human breast tumors and associated brain metastases. To investigate the function of ADAM8 in metastasis, MB‐231 breast cancer cells with ADAM8 knockdown (MB‐231_shA8) and scramble control cells (MB‐231_shCtrl) were analyzed for their capability to develop metastases. In vitro, formation of metastatic complexes in hanging drops is dependent on ADAM8 and blocked by ADAM8 inhibition. MB‐231_shA8 in contrast to MB‐231_shCtrl cells were impaired in transmigration through an endothelial and a reconstituted blood‐brain barrier. Out of 23 MMP and 22 ADAM genes, only the MMP‐9 gene was affected by ADAM8 knockdown in MB‐231_shA8 cells. Following re‐expression of wild‐type ADAM8 in contrast to ADAM8 lacking the cytoplasmic domain in MB‐231_shA8 cells caused increased levels of activated pERK1/2 and pCREB (S133) that were associated with elevated MMP‐9 transcription. Application of ADAM8 and MMP‐9 antibodies reduced transmigration of MB‐231 cells suggesting that ADAM8 affects transmigration of breast cancer cells by MMP‐9 regulation. ADAM8‐dependent transmigration was confirmed in Hs578t cells overexpressing ADAM8. Moreover, transmigration of MB‐231 and Hs578t cells was significantly reduced for cells treated with an antibody directed against P‐selectin glycoprotein ligand (PSGL‐1), a substrate of ADAM8. From these data we conclude that ADAM8 promotes early metastatic processes such as transendothelial migration by upregulation of MMP‐9 and shedding of PSGL‐1 from breast cancer cells.

Microstructural white matter changes and their relation to neuropsychological deficits in patients with juvenile myoclonic epilepsy

OBJECTIVE Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsy syndrome. Neuropsychological, electrophysiological, and neuroimaging studies have led to the hypothesis that JME is related to dysfunction of frontal brain regions and mainly frontal thalamocortical networks. METHODS We investigated possible microstructural white matter abnormalities of 20 patients with JME as compared with 20 healthy control subjects using diffusion tensor imaging (DTI). We analyzed whole-head DTI scans without an a-priori hypothesis using Tract-Based Spatial Statistics (TBSS). To analyze associated gray matter changes, we applied voxel-based morphometry (VBM) to a 3D T1 magnetization prepared rapid gradient echo (MPRAGE) sequence. Neuropsychological testing and personality trait tests were performed to bridge the gap between structure and function. RESULTS In patients, DTI revealed microstructural white matter changes in anterior parts of the Corpus callosum, anterior parts of the cingulate gyrus, and widespread frontal white matter bilaterally as well as in anterior parts of the right thalamus, which were not accompanied by gray matter changes in VBM. Microstructural changes in the cingulum correlated with personality traits. Neuropsychological test results showed impaired attention and executive functions and reduced short-term memory in the patient group. Also, there was a tendency toward alexithymia and significantly higher scores on depression. SIGNIFICANCE The present study results showed neuropsychological deficits including frontal lobe cognitive performance and a tendency toward alexithymia as well as accompanying microstructural neuroimaging changes in patients with JME, which all point to alterations in frontal brain regions and frontal thalamocortical networks in these patients.

Chapter 7 – Intraoperative Imaging

Intraoperative imaging has attracted increasing interest in recent years. The ability to objectively determine the extent of tumor removal during surgery is highly advantageous. If the resection is incomplete, one can attempt to remove the tumor residues that were initially missed during the same operation. In contrast to the subjective estimation by the surgeon, intraoperative imaging allows for an objective evaluation, thus acting as quality control during surgery. By integrating multimodal navigation into the surgery, overly extensive resections which could lead to new neurological deficits may be avoided. Intraoperative imaging can compensate for the effects of brain shift, while the integrated navigation can visualize the tumor remnants depicted by intraoperative imaging in the surgical field so that these remnants can be localized without much guesswork.