Stratifying quality of life outcome in subthalamic stimulation for Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) improves quality of life (QoL), motor and non-motor symptoms (NMS). However, in previous studies, 43%-49% of patients did not experience clinically relevant postoperative QoL improvement. To inform individualised prediction of postoperative QoL improvement, we developed a stratification analysis of QoL outcomes based on preoperative non-motor total burden, severity of motor progression and motor response in levodopa challenge tests. METHODS: This was a prospective, open-label, multicentre, international study with a 6-month follow-up. A distribution-based threshold identified 'QoL responders' in the PDQuestionnaire-8 Summary Index (PDQ-8 SI). After baseline stratification based on the NMS Scale, Hoehn and Yahr Scale and levodopa response assessed with the Unified PD Rating Scale-III, we compared postoperative QoL response between these strata. To assess the clinical usefulness and statistical feasibility of stratifications, we compared cumulative distribution function curves, respectively PDQ-8 within-stratum variation. RESULTS: All main outcomes improved postoperatively. Based on the 8.1 points threshold for clinically meaningful PDQ-8 SI improvement, only 80/161 patients were classified as 'QoL responders'. The absolute risk reductions for QoL non-response among respective non-motor, motor progression and levodopa response strata were 23%, 8% and 3%, respectively. Only non-motor stratification reduced PDQ-8 within-stratum variation compared with the overall cohort. CONCLUSIONS: Non-motor stratification, but not motor progression or levodopa response stratification, is clinically useful and statistically feasible for personalised preoperative prediction of postoperative QoL outcome of STN-DBS for PD. Our findings highlight that non-motor assessments are necessary components of a case-based, holistic approach of DBS indication evaluations geared towards optimising postoperative QoL outcomes. TRIAL REGISTRATION NUMBER: GermanClinicalTrialsRegister: #6735.

The Feasibility and Accuracy of Holographic Navigation with Laser Crosshair Simulator Registration on a Mixed-Reality Display.

Addressing conventional neurosurgical navigation systems' high costs and complexity, this study explores the feasibility and accuracy of a simplified, cost-effective mixed reality navigation (MRN) system based on a laser crosshair simulator (LCS). A new automatic registration method was developed, featuring coplanar laser emitters and a recognizable target pattern. The workflow was integrated into Microsoft's HoloLens-2 for practical application. The study assessed the system's precision by utilizing life-sized 3D-printed head phantoms based on computed tomography (CT) or magnetic resonance imaging (MRI) data from 19 patients (female/male: 7/12, average age: 54.4 ± 18.5 years) with intracranial lesions. Six to seven CT/MRI-visible scalp markers were used as reference points per case. The LCS-MRN's accuracy was evaluated through landmark-based and lesion-based analyses, using metrics such as target registration error (TRE) and Dice similarity coefficient (DSC). The system demonstrated immersive capabilities for observing intracranial structures across all cases. Analysis of 124 landmarks showed a TRE of 3.0 ± 0.5 mm, consistent across various surgical positions. The DSC of 0.83 ± 0.12 correlated significantly with lesion volume (Spearman rho = 0.813, p < 0.001). Therefore, the LCS-MRN system is a viable tool for neurosurgical planning, highlighting its low user dependency, cost-efficiency, and accuracy, with prospects for future clinical application enhancements.

Single-Center Experience in Microsurgical Resection of Acoustic Neurinomas and the Benefit of Microscope-Based Augmented Reality.

Background and Objectives: Microsurgical resection with intraoperative neuromonitoring is the gold standard for acoustic neurinomas (ANs) which are classified as T3 or T4 tumors according to the Hannover Classification. Microscope-based augmented reality (AR) can be beneficial in cerebellopontine angle and lateral skull base surgery, since these are small areas packed with anatomical structures and the use of this technology enables automatic 3D building of a model without the need for a surgeon to mentally perform this task of transferring 2D images seen on the microscope into imaginary 3D images, which then reduces the possibility of error and provides better orientation in the operative field. Materials and Methods: All patients who underwent surgery for resection of ANs in our department were included in this study. Clinical outcomes in terms of postoperative neurological deficits and complications were evaluated, as well as neuroradiological outcomes for tumor remnants and recurrence. Results: A total of 43 consecutive patients (25 female, median age 60.5 ± 16 years) who underwent resection of ANs via retrosigmoid osteoclastic craniotomy with the use of intraoperative neuromonitoring (22 right-sided, 14 giant tumors, 10 cystic, 7 with hydrocephalus) by a single surgeon were included in this study, with a median follow up of 41.2 ± 32.2 months. A total of 18 patients underwent subtotal resection, 1 patient partial resection and 24 patients gross total resection. A total of 27 patients underwent resection in sitting position and the rest in semi-sitting position. Out of 37 patients who had no facial nerve deficit prior to surgery, 19 patients were intact following surgery, 7 patients had House Brackmann (HB) Grade II paresis, 3 patients HB III, 7 patients HB IV and 1 patient HB V. Wound healing deficit with cerebrospinal fluid (CSF) leak occurred in 8 patients (18.6%). Operative time was 317.3 ± 99 min. One patient which had recurrence and one further patient with partial resection underwent radiotherapy following surgery. A total of 16 patients (37.2%) underwent resection using fiducial-based navigation and microscope-based AR, all in sitting position. Segmented objects of interest in AR were the sigmoid and transverse sinus, tumor outline, cranial nerves (CN) VII, VIII and V, petrous vein, cochlea and semicircular canals and brain stem. Operative time and clinical outcome did not differ between the AR and the non-AR group. However, use of AR improved orientation in the operative field for craniotomy planning and microsurgical resection by identification of important neurovascular structures. Conclusions: The single-center experience of resection of ANs showed a high rate of gross total (GTR) and subtotal resection (STR) with low recurrence. Use of AR improves intraoperative orientation and facilitates craniotomy planning and AN resection through early improved identification of important anatomical relations to structures of the inner auditory canal, venous sinuses, petrous vein, brain stem and the course of cranial nerves.

Surgical Treatment of Calcified Thoracic Herniated Disc Disease via the Transthoracic Approach with the Use of Intraoperative Computed Tomography (iCT) and Microscope-Based Augmented Reality (AR).

Background and Objectives: The aim of this study is to present our experience in the surgical treatment of calcified thoracic herniated disc disease via a transthoracic approach in the lateral position with the use of intraoperative computed tomography (iCT) and augmented reality (AR). Materials and Methods: All patients who underwent surgery for calcified thoracic herniated disc via a transthoracic transpleural approach at our Department using iCT and microscope-based AR were included in the study. Results: Six consecutive patients (five female, median age 53.2 ± 6.4 years) with calcified herniated thoracic discs (two patients Th 10-11 level, two patients Th 7-8, one patient Th 9-10, one patient Th 11-12) were included in this case series. Indication for surgery included evidence of a calcified thoracic disc on magnet resonance imaging (MRI) and CT with spinal canal stenosis of >50% of diameter, intractable pain, and neurological deficits, as well as MRI-signs of myelopathy. Five patients had paraparesis and ataxia, and one patient had no deficit. All surgeries were performed in the lateral position via a transthoracic transpleural approach (Five from left side). CT for automatic registration was performed following the placement of the reference array, with a high registration accuracy. Microscope-based AR was used, with segmented structures of interest such as vertebral bodies, disc space, herniated disc, and dural sac. Mean operative time was 277.5 ± 156 min. The use of AR improved orientation in the operative field for identification, and tailored the resection of the herniated disc and the identification of the course of dural sac. A control-iCT scan confirmed the complete resection in five patients and incomplete resection of the herniated disc in one patient. In one patient, complications occurred, such as postoperative hematoma, and wound healing deficit occurred. Mean follow-up was 22.9 ± 16.5 months. Five patients improved following surgery, and one patient who had no deficits remained unchanged. Conclusions: Optimal surgical therapy in patients with calcified thoracic disc disease with compression of dural sac and myelopathy was resectioned via a transthoracic transpleural approach. The use of iCT-based registration and microscope-based AR significantly improved orientation in the operative field and facilitated safe resection of these lesions.

Changes in calpain-2 expression during glioblastoma progression predisposes tumor cells to temozolomide resistance by minimizing DNA damage and p53-dependent apoptosis.

BACKGROUND: Glioblastoma multiforme (GBM) is characterized by an unfavorable prognosis for patients affected. During standard-of-care chemotherapy using temozolomide (TMZ), tumors acquire resistance thereby causing tumor recurrence. Thus, deciphering essential molecular pathways causing TMZ resistance are of high therapeutic relevance. METHODS: Mass spectrometry based proteomics were used to study the GBM proteome. Immunohistochemistry staining of human GBM tissue for either calpain-1 or -2 was performed to locate expression of proteases. In vitro cell based assays were used to measure cell viability and survival of primary patient-derived GBM cells and established GBM cell lines after TMZ ± calpain inhibitor administration. shRNA expression knockdowns of either calpain-1 or calpain-2 were generated to study TMZ sensitivity of the specific subunits. The Comet assay and É£H2AX signal measurements were performed in order to assess the DNA damage amount and recognition. Finally, quantitative real-time PCR of target proteins was applied to differentiate between transcriptional and post-translational regulation. RESULTS: Calcium-dependent calpain proteases, in particular calpain-2, are more abundant in glioblastoma compared to normal brain and increased in patient-matched initial and recurrent glioblastomas. On the cellular level, pharmacological calpain inhibition increased the sensitivities of primary glioblastoma cells towards TMZ. A genetic knockdown of calpain-2 in U251 cells led to increased caspase-3 cleavage and sensitivity to neocarzinostatin, which rapidly induces DNA strand breakage. We hypothesize that calpain-2 causes desensitization of tumor cells against TMZ by preventing strong DNA damage and subsequent apoptosis via post-translational TP53 inhibition. Indeed, proteomic comparison of U251 control vs. U251 calpain-2 knockdown cells highlights perturbed levels of numerous proteins involved in DNA damage response and downstream pathways affecting TP53 and NF-κB signaling. TP53 showed increased protein abundance, but no transcriptional regulation. CONCLUSION: TMZ-induced cell death in the presence of calpain-2 expression appears to favor DNA repair and promote cell survival. We conclude from our experiments that calpain-2 expression represents a proteomic mode that is associated with higher resistance via "priming" GBM cells to TMZ chemotherapy. Thus, calpain-2 could serve as a prognostic factor for GBM outcome.

Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice.

The tumor microenvironment in glioblastoma (GB) is considered to be "cold", i.e., the fraction of cytotoxic T cells, for instance, is low. Instead, macrophages are the major immune cell population in GB, which stem either from tissue response (resident microglia) or recruitment of macrophages from the periphery, thereby undergoing tumor-dependent "imprinting" mechanisms by which macrophages can adapt a tumor-supportive phenotype. In this regard, it is important to describe the nature of macrophages associated with GB, in particular under therapy conditions using the gold standard chemotherapy drug temozolomide (TMZ). Here, we explored the suitability of combining information from in vivo magnetic resonance spectroscopic (MRS) approaches (metabolomics) with in vitro molecular analyses to assess therapy response and characterize macrophage populations in mouse GB using an isogenic GL261 model. For macrophage profiling, expression levels of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) were determined, since their gene products affect macrophage-tumor cell communication by extensive cleavage of immunomodulatory membrane proteins, such as PD-L1. In tumor mice with an overall therapy response, expression of genes encoding the proteases ADAM8, ADAM10, and ADAM17 was increased and might contribute to the immunosuppressive phenotype of GB and immune cells. In tumors responding to therapy, expression levels of ADAM8 were upregulated by TMZ, and higher levels of PD-L1 were correlated significantly. Using a CRISPR/Cas9 knockout of ADAM8 in GL261 cells, we demonstrated that soluble PD-L1 (sPD-L1) is only generated in the presence of ADAM8. Moreover, primary macrophages from WT and ADAM8-deficient mice showed ADAM8-dependent release of sPD-L1, independent of the macrophage polarization state. Since ADAM8 expression is induced in responding tumors and PD-L1 shedding is likely to decrease the anti-tumor activities of T-cells, we conclude that immunotherapy resistance is caused, at least in part, by the increased presence of proteases, such as ADAM8.

Augmented Reality to Compensate for Navigation Inaccuracies.

This study aims to report on the capability of microscope-based augmented reality (AR) to evaluate registration and navigation accuracy with extracranial and intracranial landmarks and to elaborate on its opportunities and obstacles in compensation for navigation inaccuracies. In a consecutive single surgeon series of 293 patients, automatic intraoperative computed tomography-based registration was performed delivering a high initial registration accuracy with a mean target registration error of 0.84 ± 0.36 mm. Navigation accuracy is evaluated by overlaying a maximum intensity projection or pre-segmented object outlines within the recent focal plane onto the in situ patient anatomy and compensated for by translational and/or rotational in-plane transformations. Using bony landmarks (85 cases), there was two cases where a mismatch was seen. Cortical vascular structures (242 cases) showed a mismatch in 43 cases and cortex representations (40 cases) revealed two inaccurate cases. In all cases, with detected misalignment, a successful spatial compensation was performed (mean correction: bone (6.27 ± 7.31 mm), vascular (3.00 ± 1.93 mm, 0.38° ± 1.06°), and cortex (5.31 ± 1.57 mm, 1.75° ± 2.47°)) increasing navigation accuracy. AR support allows for intermediate and straightforward monitoring of accuracy, enables compensation of spatial misalignments, and thereby provides additional safety by increasing overall accuracy.

ADAM8 affects glioblastoma progression by regulating osteopontin-mediated angiogenesis.

Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer with a median survival of only 15 months. To complement standard treatments including surgery, radiation and chemotherapy, it is essential to understand the contribution of the GBM tumor microenvironment. Brain macrophages and microglia particularly contribute to tumor angiogenesis, a major hallmark of GBM. ADAM8, a metalloprotease-disintegrin strongly expressed in tumor cells and associated immune cells of GBMs, is related to angiogenesis and correlates with poor clinical prognosis. However, the specific contribution of ADAM8 to GBM tumorigenesis remains elusive. Knockdown of ADAM8 in U87 glioma cells led to significantly decreased angiogenesis and tumor volumes of these cells after stereotactic injection into striate body of mice. We found that the angiogenic potential of ADAM8 in GBM cells and in primary macrophages is mediated by the regulation of osteopontin (OPN), an important inducer of tumor angiogenesis. By in vitro cell signaling analyses, we demonstrate that ADAM8 regulates OPN via JAK/STAT3 pathway in U87 cells and in primary macrophages. As ADAM8 is a dispensable protease for physiological homeostasis, we conclude that ADAM8 could be a tractable target to modulate angiogenesis in GBM with minor side-effects.

Predictors of short-term impulsive and compulsive behaviour after subthalamic stimulation in Parkinson disease.

BACKGROUND: The effects of subthalamic stimulation (subthalamic nucleus-deep brain stimulation, STN-DBS) on impulsive and compulsive behaviours (ICB) in Parkinson's disease (PD) are understudied. OBJECTIVE: To investigate clinical predictors of STN-DBS effects on ICB. METHODS: In this prospective, open-label, multicentre study in patients with PD undergoing bilateral STN-DBS, we assessed patients preoperatively and at 6-month follow-up postoperatively. Clinical scales included the Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS), PD Questionnaire-8, Non-Motor Symptom Scale (NMSS), Unified PD Rating Scale in addition to levodopa-equivalent daily dose total (LEDD-total) and dopamine agonists (LEDD-DA). Changes at follow-up were analysed with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We explored predictors of QUIP-RS changes using correlations and linear regressions. Finally, we dichotomised patients into 'QUIP-RS improvement or worsening' and analysed between-group differences. RESULTS: We included 55 patients aged 61.7 years±8.4 with 9.8 years±4.6 PD duration. QUIP-RS cut-offs and psychiatric assessments identified patients with preoperative ICB. In patients with ICB, QUIP-RS improved significantly. However, we observed considerable interindividual variability of clinically relevant QUIP-RS outcomes as 27.3% experienced worsening and 29.1% an improvement. In post hoc analyses, higher baseline QUIP-RS and lower baseline LEDD-DA were associated with greater QUIP-RS improvements. Additionally, the 'QUIP-RS worsening' group had more severe baseline impairment in the NMSS attention/memory domain. CONCLUSIONS: Our results show favourable ICB outcomes in patients with higher preoperative ICB severity and lower preoperative DA doses, and worse outcomes in patients with more severe baseline attention/memory deficits. These findings emphasise the need for comprehensive non-motor and motor symptoms assessments in patients undergoing STN-DBS. TRIAL REGISTRATION NUMBER: DRKS00006735.

Temporal encephaloceles in epilepsy patients and asymptomatic cases: Size may indicate epileptogenicity.

OBJECTIVE: This study was undertaken to identify temporal encephaloceles (TEs) and examine their characteristics in patients with temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE), as well as in asymptomatic cases. METHODS: Four hundred fifty-eight magnetic resonance imaging scans were examined retrospectively to identify TE in 157 patients with TLE, 150 patients with ETLE, and 151 healthy controls (HCs). RESULTS: At least one TE was identified in 9.6% of the TLE patients (n = 15, 95% confidence interval [CI] = 5.3%-15.3%), in 3.3% of patients with ETLE (n = 5, 95% CI = 1.1%-7.6%), and in 2.0% of the HCs (n = 3, 95% CI = .4%-5.7%), indicating a significantly higher frequency in patients with TLE compared to ETLE and HC subjects (p = .027, p = .005). Examining the characteristics of TEs in both asymptomatic and epilepsy patients, we found that TEs with a diameter of less than 6.25 mm were more likely to be asymptomatic, with a sensitivity of 91.7% and a specificity of 73.3% (area under the curve = .867, 95% CI = .723-1.00, p = .001). SIGNIFICANCE: Temporal encephaloceles may occur without presenting any clinical symptoms. Patients with TLE show a higher frequency of TEs compared to the ETLE and HC groups. According to our study, TE size could be used to suggest potential epileptogenicity.

Comparing Fiducial-Based and Intraoperative Computed Tomography-Based Registration for Frameless Stereotactic Brain Biopsy.

OBJECTIVE: The aim of this work was to compare fiducial-based and intraoperative computed tomography (iCT)-based registration for frameless stereotactic brain biopsy. METHODS: Of 50 frameless stereotactic biopsies with the VarioGuide, 30 cases were registered as iCT based and 20 as fiducial based. Statistical analysis of the target registration error (TRE), dose length product, effective radiation dose (ED), operation time, and diagnostic yield was performed. RESULTS: The mean TRE was significantly lower using iCT-based registration (mean ± SD: 0.70 ± 0.32 vs. 2.43 ± 0.73 mm, p < 0.0001). The ED was significantly lower when using iCT-based registration compared to standard navigational CT (mean ± SD: 0.10 ± 0.13 vs. 2.23 ± 0.34 mSv, p < 0.0001). Post-biopsy iCT was associated with a significant lower (p < 0.0001) ED compared to standard CT (mean ± SD: 1.04 ± 0.18 vs. 1.65 ± 0.26 mSv). The mean surgical time was shorter using iCT-based registration, although the mean total operating room (OR) time did not differ significantly. The diagnostic yield was 96.7% (iCT group) versus 95% (fiducial group). Post-biopsy imaging revealed severe bleeding in 3.3% (iCT group) versus 5% (fiducial group). CONCLUSION: iCT-based registration for frameless stereotactic biopsies increases the accuracy significantly without negative effects on the surgical time or the overall time in the OR. Appropriate scan protocols in iCT registration contribute to a significant reduction of the radiation exposure. The high accuracy of the iCT makes it the more favorable registration strategy when taking biopsies of small tumors or lesions near eloquent brain areas.

Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells.

About 95% of Glioblastoma (GBM) patients experience tumor relapse as a consequence of resistance to the first-line standard chemotherapy using temozolomide (TMZ). Recent studies reported consistently elevated expression levels of carbonic anhydrase CA2 in recurrent glioblastoma and temozolomide-resistant glioblastoma stem-like cells (GSCs). Here we show that CA2 is preferentially expressed in GSCs and upregulated by TMZ treatment. When expressed in GBM cell lines, CA2 exerts significant metabolic changes reflected by enhanced oxygen consumption and increased extracellular acidification causing higher rates of cell invasion. Notably, GBM cells expressing CA2 respond to combined treatment with TMZ and brinzolamide (BRZ), a non-toxic and potent CA2 inhibitor. Interestingly, brinzolamide was more effective than the pan-CA inhibitor Acetazolamide (ACZ) to sensitize naïve GSCs and TMZ-resistant GSCs to TMZ induced cell death. Mechanistically, we demonstrated that the combined treatment of GBM stem cells with TMZ and BRZ caused autophagy of GBM cell lines and GSCs, reflected by enhanced LC3 cleavage (LC3-II) and p62 reduction. Our findings illustrate the potential of CA2 as a chemo-sensitizing drug target in recurrent GBM and propose a combined treatment of TMZ with CA2 inhibitor to tackle GBM chemoresistance and recurrence.

Application of an Expandable Cage for Reconstruction of the Cervical Spine in a Consecutive Series of Eighty-Six Patients.

Background and objectives: Expandable cages are frequently used to reconstruct the anterior spinal column after a corpectomy. In this retrospective study, we evaluated the perioperative advantages and disadvantages of corpectomy reconstruction with an expandable cage. Materials and Methods: Eighty-six patients (45 male and 41 female patients, medium age of 61.3 years) were treated with an expandable titanium cage for a variety of indications from January 2012 to December 2019 and analyzed retrospectively. The mean follow-up was 30.7 months. Outcome was measured by clinical examination and visual analogue scale (VAS); myelopathy was classified according to the EMS (European Myelopathy Scale) and gait disturbances with the Nurick score. Radiographic analysis comprised measurement of fusion, subsidence and the C2-C7 angle. Results: Indications included spinal canal stenosis with myelopathy (46 or 53.5%), metastasis (24 or 27.9%), spondylodiscitis (12 or 14%), and fracture (4 or 4.6%). In 39 patients (45.3%), additional dorsal stabilization (360° fusion) was performed. In 13 patients, hardware failure occurred, and in 8 patients, adjacent segment disease occurred. Improvement of pain symptoms, myelopathy, and gait following surgery were statistically significant (p < 0.05), with a medium preoperative VAS of 8, a postoperative score of 3.2, and medium EMS scores of 11.3 preoperatively vs. 14.3 postoperatively. Radiographic analysis showed successful fusion in 74 patients (86%). As shown in previous studies, correction of the C2-C7 angle did not correlate with improvement of neurological symptoms. Conclusion: Our results show that expandable titanium cages are a safe and useful tool in anterior cervical corpectomies for providing adequate anterior column support and stability.

ADAM8 in invasive cancers: links to tumor progression, metastasis, and chemoresistance.

Ectodomain shedding of extracellular and membrane proteins is of fundamental importance for cell-cell communication in neoplasias. A Disintegrin And Metalloproteinase (ADAM) proteases constitute a family of multifunctional, membrane-bound proteins with traditional sheddase functions. Their protumorigenic potential has been attributed to both, essential (ADAM10 and ADAM17) and 'dispensable' ADAM proteases (ADAM8, 9, 12, 15, and 19). Of specific interest in this review is the ADAM proteinase ADAM8 that has been identified as a significant player in aggressive malignancies including breast, pancreatic, and brain cancer. High expression levels of ADAM8 are associated with invasiveness and predict a poor patient outcome, indicating a prognostic and diagnostic potential of ADAM8. Current knowledge of substrates and interaction partners gave rise to the hypothesis that ADAM8 dysregulation affects diverse processes in tumor biology, attributable to different functional cores of the multidomain enzyme. Proteolytic degradation of extracellular matrix (ECM) components, cleavage of cell surface proteins, and subsequent release of soluble ectodomains promote cancer progression via induction of angiogenesis and metastasis. Moreover, there is increasing evidence for significance of a non-proteolytic function of ADAM8. With the disintegrin (DIS) domain ADAM8 binds integrins such as ß1 integrin, thereby activating integrin signaling pathways. The cytoplasmic domain is critical for that activation and involves focal adhesion kinase (FAK), extracellular regulated kinase (ERK1/2), and protein kinase B (AKT/PKB) signaling, further contributing to cancer progression and mediating chemoresistance against first-line therapies. This review highlights the remarkable effects of ADAM8 in tumor biology, concluding that pharmacological inhibition of ADAM8 represents a promising therapeutic approach not only for monotherapy, but also for combinatorial therapies.

Implementation of augmented reality support in spine surgery.

PURPOSE: To implement a straightforward workflow that allows to establish augmented reality (AR) support in spine surgery. METHODS: Intraoperative computed tomography (iCT) applying a 32-slice movable scanner was used for navigation registration in a series of 10 patients who underwent surgery for extra- or intradural spinal lesions. Preoperative multimodal image data were integrated by nonlinear registration with the iCT images. Automatic segmentation was used to delineate the 3-dimensional (3-D) outline of the vertebra, and in addition, the tumor extent, as well as implants, was segmented and visualized. RESULTS: Automatic patient registration without user interaction resulted in high navigation accuracy with a mean registration error of only about 1 mm. Moreover, the workflow for establishing AR was straightforward and could be easily integrated in the normal surgical procedure. Low-dose iCT protocols resulted in a radiation exposure of 0.35-0.98 mSv for cervical, 2.16-6.92 mSv for thoracic, and 3.55-4.20 mSv for lumbar surgeries, which is a reduction in the effective radiation dose by 70%. The segmented structures were intuitively visualized in the surgical field using the heads-up display of the operating microscope. In parallel, the microscope video was superimposed with the segmented 3-D structures, which were visualized in a semitransparent manner along with various display modes of the image data. CONCLUSIONS: A microscope-based AR environment was successfully implemented for spinal surgery. The application of iCT for registration imaging ensures high navigational accuracy. AR greatly supports the surgeon in understanding the 3-D anatomy thereby facilitating surgery. These slides can be retrieved under Electronic Supplementary Material.

Reliable navigation registration in cranial and spine surgery based on intraoperative computed tomography.

OBJECTIVE: Low registration errors are an important prerequisite for reliable navigation, independent of its use in cranial or spinal surgery. Regardless of whether navigation is used for trajectory alignment in biopsy or implant procedures, or for sophisticated augmented reality applications, all depend on a correct registration of patient space and image space. In contrast to fiducial, landmark, or surface matching-based registration, the application of intraoperative imaging allows user-independent automatic patient registration, which is less error prone. The authors' aim in this paper was to give an overview of their experience using intraoperative CT (iCT) scanning for automatic registration with a focus on registration accuracy and radiation exposure. METHODS: A total of 645 patients underwent iCT scanning with a 32-slice movable CT scanner in combination with navigation for trajectory alignment in biopsy and implantation procedures (n = 222) and for augmented reality (n = 437) in cranial and spine procedures (347 craniotomies and 42 transsphenoidal, 56 frameless stereotactic, 59 frame-based stereotactic, and 141 spinal procedures). The target registration error was measured using skin fiducials that were not part of the registration procedure. The effective dose was calculated by multiplying the dose length product with conversion factors. RESULTS: Among all 1281 iCT scans obtained, 1172 were used for automatic patient registration (645 initial registration scans and 527 repeat iCT scans). The overall mean target registration error was 0.86 ± 0.38 mm (± SD) (craniotomy, 0.88 ± 0.39 mm; transsphenoidal, 0.92 ± 0.39 mm; frameless, 0.74 ± 0.39 mm; frame-based, 0.84 ± 0.34 mm; and spinal, 0.80 ± 0.28 mm). Compared with standard diagnostic scans, a distinct reduction of the effective dose could be achieved using low-dose protocols for the initial registration scan with mean effective doses of 0.06 ± 0.04 mSv for cranial, 0.50 ± 0.09 mSv for cervical, 4.12 ± 2.13 mSv for thoracic, and 3.37 ± 0.93 mSv for lumbar scans without impeding registration accuracy. CONCLUSIONS: Reliable automatic patient registration can be achieved using iCT scanning. Low-dose protocols ensured a low radiation exposure for the patient. Low-dose scanning had no negative effect on navigation accuracy.

Augmented reality in intradural spinal tumor surgery.

BACKGROUND: Microscope-based augmented reality (AR) is commonly used in cranial surgery; however, until recently, this technique was not implemented for spinal surgery. We prospectively investigated, how AR can be applied for intradural spinal tumor surgery. METHODS: For ten patients with intradural spinal tumors (ependymoma, glioma, hemangioblastoma, meningioma, and metastasis), AR was provided by head-up displays (HUDs) of operating microscopes. User-independent automatic AR registration was established by low-dose intraoperative computed tomography. The objects visualized by AR were segmented in preoperative imaging data; non-linear image registration was applied to consider spine flexibility. RESULTS: In all cases, AR supported surgery by visualizing the tumor outline and other relevant surrounding structures. The overall AR registration error was 0.72 ± 0.24 mm (mean ± standard deviation), a close matching of visible tumor outline and AR visualization was observed for all cases. Registration scanning resulted in a low effective dose of 0.22 ± 0.16 mSv for cervical and 1.68 ± 0.61 mSv for thoracic lesions. The mean HUD AR usage in relation to microscope time was 51.6 ± 36.7%. The HUD was switched off and turned on again in a range of 2 to 17 times (5.7 ± 4.4 times). Independent of the status of the HUD, the AR visualization was displayed on monitors throughout surgery. CONCLUSIONS: Microscope-based AR can be reliably applied to intradural spinal tumor surgery. Automatic AR registration ensures high precision and provides an intuitive visualization of the extent of the tumor and surrounding structures. Given this setting, all advanced multi-modality options of cranial AR can also be applied to spinal surgery.

Nucleolipids of the Nucleoside Antibiotics Formycins A and B: Synthesis and Biomedical Characterization Particularly Using Glioblastoma Cells.

Two lipophilic derivatives of formycin A (1) and formycin B (5) carrying an O-2',3'-(ethyl levulinate) ketal group have been prepared. These were base-alkylated at N(1) (for 1) and N(1) and N(6) (for 5) with both isopentenyl and all-trans-farnesyl residues. Upon the prenylation, side reactions were observed, resulting in the formation of nucleolipids with a novel tricyclic nucleobase (→4a, 4b). In the case of formycin B, O-2',3'-(ethyl levulinate) (6) farnesylation gave the double prenylated nucleolipid 7. All new compounds were characterized by 1 H-, 13 C-, UV/VIS and fluorescence spectroscopy, by ESI-MS spectrometry and/or by elemental analysis. Log P determinations between water and octanol as well as water and cyclohexane of a selection of compounds allowed qualitative conclusions concerning their potential blood-brain barrier passage efficiency. All compounds were investigated in vitro with respect to their cytotoxic activity toward rat malignant neuroectodermal BT4Ca as well as against a series of human glioblastoma cell lines (GOS 3, U-87 MG and GBM 2014/42). In order to differentiate between anticancer and side effects of the novel nucleolipids, we also studied their activity on PMA-differentiated human THP-1 macrophages. Here, we show that particularly the formycin A derivative 3b possesses promising antitumor properties in several cancer cell lines with profound cytotoxic effects partly on human glioblastoma cells, with a higher efficacy than the chemotherapeutic drug 5-fluorouridine.

Outcome after Interdisciplinary Treatment for Aneurysmal Subarachnoid Hemorrhage-A Single Center Experience.

Background and Objectives: To identify predictors of outcome after aneurysmal subarachnoid hemorrhage (aSAH) in our interdisciplinary setting. Materials and Methods: 176 patients who had been treated for aSAH by a team of neurosurgeons and neuroradiologists between 2009 and 2017 were analyzed retrospectively. Age, gender, clinical presentation according to the Hunt and Hess (H&H) grading on admission, overall clot burden, aneurysm localization, modality of aneurysm obliteration, early deterioration (ED), occurrence of vasospasm in transcranial Doppler ultrasonography, delayed cerebral ischemia (DCI), spasmolysis, decompressive craniectomy (DC), cerebrospinal fluid (CSF) shunt placement, deep vein thrombosis (DVT), pulmonary embolism (PE), severe cardiac events (SCE), mortality on Days 14, and 30 after admission, and outcome at one year after the hemorrhage according to the Glasgow Outcome Scale (GOS) were recorded. Chi square, Fisher's exact, Welch's t, and Wilcoxon rank sum served as statistical tests. Generalized linear models were fitted, and ordered logistic regression was performed. Results: SCE (p = 0.049) were a significant predictor of mortality at 14 days after aSAH, but not later during the first year after the hemorrhage. Clipping as opposed to coiling (p = 0.049) of ruptured aneurysms was a significant predictor of survival on Day 30 after aSAH, but not later during the first year after the hemorrhage, while coiling as opposed to clipping of ruptured aneurysms was significantly related to a lower frequency of DVT during hospitalization (p = 0.024). Aneurysms of the anterior circulation were significantly more often clipped, while aneurysms of the posterior circulation were significantly more often coiled (p < 0.001). Age over 70 years (p = 0.049), H&H grade on admission (p = 0.022), overall clot burden (p = 0.035), ED (p = 0.009), DCI (p = 0.013), DC (p = 0.0005), and CSF shunt placement (p = 0.038) proved to be predictive of long-term outcome after aSAH. Conclusion: Long-term results after clipping and coiling of ruptured aneurysms appear equal in an interdisciplinary setting that takes aneurysm localization, available staff, and equipment into account.

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.