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This file contains Tables S1-S3. Table S1 shows number of injected mice and tumor incidence. Table S2 shows genes and fold changes of commonly up and down regulated genes in mouse Sox5/6/21fl/fl tumors and human GBM. Table S3 shows Sox21 ChIPseq peaks association to nearest gene.

This file contains Figures S1-S6. Figure S1 shows proliferation of neural stem cells after in utero electroporation of Sox5, Sox6 or Sox21, and the successful activation of viral vector expression by CRE enzyme. Figure S2 shows reduction of SOX5/6/21 levels after intracranial ARC injection. H

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult. Cancer Res; 77(18); 4985–97. ©2017 AACR.

This file contains additional description of western blot analysis, immunohistochemistry, antibodies, Sox21 targeting in mouse, bioinformatics, in utero electroporation, proliferation, senescence and cell death assays, NPC cultures and assays, and qRT-PCR.

Glioblastoma is believed to originate from nervous system cells; however, a putative origin from vessel-associated progenitor cells has not been considered. We deeply single-cell RNA-sequenced glioblastoma progenitor cells of 18 patients and integrated 710 bulk tumors and 73,495 glioma single cells of 100 patients to determine the relation of glioblastoma cells to normal brain cell types. A novel neural network-based projection of the developmental trajectory of normal brain cells uncovered two principal cell-lineage features of glioblastoma, neural crest perivascular and radial glia, carrying defining methylation patterns and survival differences. Consistently, introducing tumorigenic alterations in naïve human brain perivascular cells resulted in brain tumors. Thus, our results suggest that glioblastoma can arise from the brains' vasculature, and patients with such glioblastoma have a significantly poorer outcome.

Glial tumors grow diffusely in the brain. Survival is correlated to the extent of tumor removal, but tumor borders are often invisible. Resection beyond the borders as defined by conventional methods may further improve prognosis. In this proof-of-concept study, we evaluate diffuse reflectance spectroscopy (DRS) for discrimination between glial tumors and normal brain ex vivo. DRS spectra and histology were acquired from 22 tumor samples and nine brain tissue samples retrieved from 30 patients. The content of biological chromophores and scattering features were estimated by fitting a model derived from diffusion theory to the DRS spectra. DRS parameters differed significantly between tumor and normal brain tissue. Classification using random forest yielded a sensitivity and specificity for the detection of low-grade gliomas of 82.0% and 82.7%, respectively, and the area under curve (AUC) was 0.91. Applied in a hand-held probe or biopsy needle, DRS has the potential to provide intra-operative tissue analysis.

Study design Observational study. Objective The aim of this study was to evaluate the accuracy of a new frameless reference marker system for patient tracking by analyzing the effect of vertebral position within the surgical field. Summary of background data Most modern navigation systems for spine surgery rely on a dynamic reference frame attached to a vertebra for tracking the patient. This solution has the drawback of being bulky and obstructing the surgical field, while requiring that the dynamic reference frame is moved between vertebras to maintain accuracy. Methods An augmented reality surgical navigation (ARSN) system with intraoperative cone beam computed tomography (CBCT) capability was installed in a hybrid operating room. The ARSN system used input from four video cameras for tracking adhesive skin markers placed around the surgical field. The frameless reference marker system was evaluated first in four human cadavers, and then in 20 patients undergoing navigated spine surgery. In each CBCT, the impact of vertebral position in the surgical field on technical accuracy was analyzed. The technical accuracy of the inserted pedicle devices was determined by measuring the distance between the planned position and the placed pedicle device, at the bone entry point. Results The overall mean technical accuracy was 1.65 ± 1.24 mm at the bone entry point (n = 366). There was no statistically significant difference in technical accuracy between levels within CBCTs (P ≥ 0.12 for all comparisons). Linear regressions showed that null- to negligible parts of the effect on technical accuracy could be explained by the number of absolute levels away from the index vertebrae (r ≤ 0.007 for all, β ≤ 0.071 for all). Conclusion The frameless reference marker system based on adhesive skin markers is unobtrusive and affords the ARSN system a high accuracy throughout the navigated surgical field, independent of vertebral position. Level of evidence 3.

BACKGROUND Anterior cervical corpectomy and fusion (ACCF) is a treatment option for several cervical pathologies. Various graft materials such as autografts, titanium mesh cages (TMC), or poly-ether-ether-ketone (PEEK) cages are used. Additional posterior fixation (PF) to provide extra support and improve stability is sometimes performed initially, or later as supplementary treatment. OBJECTIVE To describe our retrospective study of 119 consecutive cases of ACCF with synthetic grafts, in 3 cohorts of cervical spondylotic myelopathy (CSM), infectious and neoplastic processes, and trauma, with special focus on need for supplementary PF. METHODS A total of 135 adult patients treated with ACCF between January 2005 and January 2018 were identified. Patients lost to follow-up were excluded, and 119 remaining patients were included for retrospective clinical and radiological assessment. RESULTS Synthetic grafts were used in 116 (97%) cases. Only 9 (8%) ACCF cases required later supplementary PF, where 7 (78%) cases were multilevel. There was a statistically significant difference in revision rate with PF for single-level compared to multilevel ACCFs (P = .001). Revision rates with PF were 2%, 29%, and 7% in CSM, infectious and neoplastic processes, and trauma cohorts, respectively. CONCLUSION The results indicate that ACCF is a safe and effective treatment for degenerative and traumatic cervical spine disorders, with low complication and revision rates. Single-level ACCF can be performed without additional PF. Multilevel ACCF (n > 2) and pathologies affecting bone quality seem to be risk factors for material subsidence and instability. In these cases, additional PF should be considered., Graphical Abstract Graphical Abstract

BackgroundThe first line of treatment for most cervical intradural tumors is surgical resection through laminotomy or laminectomy. This may cause a loss of posterior pulling force leading to kyphosis, which is associated with decreased functional outcome. However, the incidence and predictors of kyphosis in these patients are poorly understood.ObjectTo assess the incidence of posterior fixation (PF), as well as predictors of radiological kyphosis, following resection of cervical intradural tumors in adults.MethodsA population-based cohort study was conducted on adult patients who underwent intradural tumor resection via cervical laminectomy with or without laminoplasty between 2005 and 2017. Primary outcome was kyphosis requiring PF. Secondary outcome was radiological kyphotic increase, measured by the change in the C2–C7 Cobb angle between pre- and postoperative magnetic resonance images.ResultsEighty-four patients were included. Twenty-four percent of the tumors were intramedullary, and the most common diagnosis was meningioma. The mean laminectomy range was 2.4 levels, and laminoplasty was performed in 40% of cases. No prophylactic PF was performed. During a mean follow-up of 4.4 years, two patients (2.4%) required delayed PF. The mean radiological kyphotic increase after surgery was 3.0°, which was significantly associated with laminectomy of C2 and C3. Of these, C3 laminectomy demonstrated independent risk association.ConclusionsThere was a low incidence of delayed PF following cervical intradural tumor resection, supporting the practice of not performing prophylactic PF. Kyphotic increase was associated with C2 and C3 laminectomy, which could help identify at-risk patients were targeted follow-up is indicated.

Study design Prospective observational study. Objective To assess staff and patient radiation exposure during augmented reality surgical navigation in spine surgery. Summary of background data Surgical navigation in combination with intraoperative three-dimensional imaging has been shown to significantly increase the clinical accuracy of pedicle screw placement. Although this technique may increase the total radiation exposure compared with fluoroscopy, the occupational exposure can be minimized, as navigation is radiation free and staff can be positioned behind protective shielding during three-dimensional imaging. The patient radiation exposure during treatment and verification of pedicle screw positions can also be reduced. Methods Twenty patients undergoing spine surgery with pedicle screw placement were included in the study. The staff radiation exposure was measured using real-time active personnel dosimeters and was further compared with measurements using a reference dosimeter attached to the C-arm (i.e., a worst-case staff exposure situation). The patient radiation exposures were recorded, and effective doses (ED) were determined. Results The average staff exposure per procedure was 0.21 ± 0.06 μSv. The average staff-to-reference dose ratio per procedure was 0.05% and decreased to less than 0.01% after a few procedures had been performed. The average patient ED was 15.8 ± 1.8 mSv which mainly correlated with the number of vertebrae treated and the number of cone-beam computed tomography acquisitions performed. A low-dose protocol used for the final 10 procedures yielded a 32% ED reduction per spinal level treated. Conclusion This study demonstrated significantly lower occupational doses compared with values reported in the literature. Real-time active personnel dosimeters contributed to a fast optimization and adoption of protective measures throughout the study. Even though our data include both cone-beam computed tomography for navigation planning and intraoperative screw placement verification, we find low patient radiation exposure levels compared with published data. Level of evidence 3.

To report our experience and investigate frequencies of adverse events and functional status from the first 5 years of performing awake surgery for gliomas in a single-center population-based setting.We conducted a review of all patients with a glioma treated with awake surgery during the first 5 years following introduction of awake surgery at our center (February 2015 to February 2020). We assessed functional and radiological outcome, with adverse events classified according to the Landriel-Ibanez classification for neurosurgical complications, while neurological deficits were further subdivided into transient vs permanent. We sought to analyze our initial results and learning curve, as well as compare our results with literature.Forty-two patients were included. The median age was 38 years (range 18-66) and 13 (31%) were female. The indication for awake surgery was a presumed glioma in or near an eloquent area. The overall 30-day complication rate was 25 (59%), with 19 (45%) grade I complications, 3 (7%) grade II complications, and 3 (7%) grade III complications. Fifteen patients (36%) experienced transient neurological deficits, and 11 (26%) permanent neurological deficits. At 3-month follow-up, the Karnofsky Performance Score was 80 or higher for the entire cohort. The median extent of resection was 87%, with GTR achieved in 11 (26%). In search of potential learning curve difficulties, patients were divided into the 21 patients treated first (Early Group) versus the remaining 21 patients treated later (Late Group); no statistically significant difference in operating time, amount of tumor removed, or incidence of long-term postoperative neurological deficit was identified between groups. No awake surgery was aborted due to seizures. Comparison to the literature was limited by the diverse and unsystematic way in which previous studies have reported adverse events after awake craniotomy for gliomas.We provide a standardized report of adverse events and functional status following awake surgery for glioma during a single-center 5-year learning period, with similar rates of severe adverse events and functional outcome compared to literature without concerns of substantial learning curve difficulties. However, this comparison was flawed by non-standardized reporting of complications, highlighting a demand for more standardized reporting of adverse events after awake craniotomies.

Emerging research suggests that failure to target glioma stem cells (GSCs) rather than the inability to remove tumors through surgery, radiation, or chemotherapy, explains the poor survival of GBM patients. In this study, a luminescent conjugated oligothiophene (LCO), named GlioStem (p-HTMI), is used for non-invasive and non-amplified real-time detection of GSCs in live human GBM-tissue. More than 90 patient samples were stained, quantified, and analyzed by fluorescent microscopy for the presence of Gliostem-positive (GS+) cells. Approximately 30 of the samples were FACS-sorted for GS+ and GS- cells where quantification by FACS could verify microscopy results. In addition, GS+ cells were shown to express significantly higher levels of stem cell markers (CD271, CD133, PDGFRa, CD44) in FACS-experiments. Bulk RNA sequencing of 7 GBM patient samples with paired GS+ and GS- sorted cells revealed that GS+ patient samples clustered together, whereas the GS- populations did not cluster together neither with each other nor with the GS+ populations. These data suggest a distinct heterogeneity in the GS- samples and a certain level of homogeneity regarding the GS+ populations, independent of intra-patient or patient-to-patient heterogeneity. Moreover, the GS+ samples were found to express significantly higher levels of stem cell markers including SOX10, OLIG1/2, and ASCL1, compared to the GS- samples. More specifically, the GS+ samples exhibited significantly higher expression of 35 genes associated with stemness compared to the GS- samples, with most markers being associated with pre-oligodendrocyte precursor cells (pre-OPCs) and pro-neural subtypes. Our results suggest that GlioStem is a versatile tool for near-instant and selective detection of GSCs in live tumor tissue. Detecting and eliminating these cells during tumor resection may therefore be an important aim in efficiently preventing tumor regrowth and would mean a crucial step towards increased patient survival.

Simple Summary Spinal meningiomas are the most common adult primary intradural spinal tumors. While mostly benign, they may give rise to spinal cord compression with acute or chronic neurologic dysfunction. The primary treatment is surgical resection. Previous studies, limited by small sample sizes and short follow-up times, report that histopathological grade, tumor localization and size affect outcomes following surgery. In this population-based cohort study, we retrospectively reviewed 129 cases of surgically treated spinal meningiomas to assess postoperative complications, long-term clinical and radiological outcomes, predictors of neurological improvement and potential differences between elderly and non-elderly patients. Our median follow-up time was 8.2 years. We found that surgery was associated with significant neurological improvement. There was no significant difference in postoperative complications, tumor control or neurological improvement between elderly and non-elderly. Shorter time from diagnosis to surgery, larger tumor size and spinal cord compression predicted postoperative outcomes. Abstract Spinal meningiomas are the most common adult primary spinal tumor, constituting 24–45% of spinal intradural tumors and 2% of all meningiomas. The aim of this study was to assess postoperative complications, long-term outcomes, predictors of functional improvement and differences between elderly (≥70 years) and non-elderly (18–69 years) patients surgically treated for spinal meningiomas. Variables were retrospectively collected from patient charts and magnetic resonance images. Baseline comparisons, paired testing and regression analyses were used. In conclusion, 129 patients were included, with a median follow-up time of 8.2 years. Motor deficit was the most common presenting symptom (66%). The median time between diagnosis and surgery was 1.3 months. A postoperative complication occurred in 10 (7.8%) and tumor growth or recurrence in 6 (4.7%) patients. Surgery was associated with significant improvement of motor and sensory deficit, gait disturbance, bladder dysfunction and pain. Time to surgery, tumor area and the degree of spinal cord compression significantly predicted postoperative improvement in a modified McCormick scale (mMCs) in the univariable regression analysis, and spinal cord compression showed independent risk association in multivariable analysis. There was no difference in improvement, complications or tumor control between elderly and non-elderly patients. We concluded that surgery of spinal meningiomas was associated with significant long-term neurological improvement, which could be predicted by time to surgery, tumor size and spinal cord compression.

Study design Cadaveric animal laboratory study. Objective To evaluate the feasibility and accuracy of pedicle cannulation using an augmented reality surgical navigation (ARSN) system with automatic instrument tracking, yielding feedback of instrument position in relation to deep anatomy. Summary of background data Minimally invasive spine surgery (MISS) has the possibility of reducing surgical exposure resulting in shorter hospital stays, lower blood loss and infection rates compared with open surgery but the drawback of limiting visual feedback to the surgeon regarding deep anatomy. MISS is mainly performed using image-guided 2D fluoroscopy, thus exposing the staff to ionizing radiation. Methods A hybrid operating room (OR) equipped with a robotic C-arm with integrated optical cameras for augmented reality instrument navigation was used. In two pig cadavers, cone beam computed tomography (CBCT) scans were performed, a 3D model generated, and pedicle screw insertions were planned. Seventy-eight insertions were performed. Technical accuracy was assessed on post-insertion CBCTs by measuring the distance between the navigated device and the corresponding pre-planned path as well as the angular deviations. Drilling and hammering into the pedicle were also compared. Navigation time was measured. An independent reviewer assessed a simulated clinical accuracy according to Gertzbein. Results The technical accuracy was 1.7 ± 1.0 mm at the bone entry point and 2.0 ± 1.3 mm at the device tip. The angular deviation was 1.7 ± 1.7° in the axial and 1.6 ± 1.2° in the sagittal plane. Navigation time per insertion was 195 ± 93 seconds. There was no difference in accuracy between hammering and drilling into the pedicle. The clinical accuracy was 97.4% to 100% depending on the screw size considered for placement. No ionizing radiation was used during navigation. Conclusion ARSN with instrument tracking for MISS is feasible, accurate, and radiation-free during navigation. Level of evidence 3.

BackgroundConventional spinal navigation solutions have been criticized for having a negative impact on time in the operating room and workflow. AR navigation could potentially alleviate some of these concerns while retaining the benefits of navigated spine surgery. The objective of this study is to summarize the current evidence for using augmented reality (AR) navigation in spine surgery.MethodsWe performed a systematic review to explore the current evidence for using AR navigation in spine surgery. PubMed and Web of Science were searched from database inception to November 27, 2020, for data on the AR navigation solutions; the reported efficacy of the systems; and their impact on workflow, radiation, and cost-benefit relationships.ResultsIn this systematic review, 28 studies were included in the final analysis. The main findings were superior workflow and non-inferior accuracy when comparing AR to free-hand (FH) or conventional surgical navigation techniques. A limited number of studies indicated decreased use of radiation. There were no studies reporting mortality, morbidity, or cost-benefit relationships.ConclusionsAR provides a meaningful addition to FH surgery and traditional navigation methods for spine surgery. However, the current evidence base is limited and prospective studies on clinical outcomes and cost-benefit relationships are needed.

OBJECTIVE The aim of this study was to evaluate the accuracy (deviation from the target or intended path) and efficacy (insertion time) of an augmented reality surgical navigation (ARSN) system for insertion of biopsy needles and external ventricular drains (EVDs), two common neurosurgical procedures that require high precision. METHODS The hybrid operating room–based ARSN system, comprising a robotic C-arm with intraoperative cone-beam CT (CBCT) and integrated video tracking of the patient and instruments using nonobtrusive adhesive optical markers, was used. A 3D-printed skull phantom with a realistic gelatinous brain model containing air-filled ventricles and 2-mm spherical biopsy targets was obtained. After initial CBCT acquisition for target registration and planning, ARSN was used for 30 cranial biopsies and 10 EVD insertions. Needle positions were verified by CBCT. RESULTS The mean accuracy of the biopsy needle insertions (n = 30) was 0.8 mm ± 0.43 mm. The median path length was 39 mm (range 16–104 mm) and did not correlate to accuracy (p = 0.15). The median device insertion time was 149 seconds (range 87–233 seconds). The mean accuracy for the EVD insertions (n = 10) was 2.9 mm ± 0.8 mm at the tip with a 0.7° ± 0.5° angular deviation compared with the planned path, and the median insertion time was 188 seconds (range 135–400 seconds). CONCLUSIONS This study demonstrated that ARSN can be used for navigation of percutaneous cranial biopsies and EVDs with high accuracy and efficacy.

The combination of navigation and robotics in spine surgery has the potential to accurately identify and maintain bone entry position and planned trajectory. The goal of this study was to examine the feasibility, accuracy and efficacy of a new robot-guided system for semi-automated, minimally invasive, pedicle screw placement. A custom robotic arm was integrated into a hybrid operating room (OR) equipped with an augmented reality surgical navigation system (ARSN). The robot was mounted on the OR-table and used to assist in placing Jamshidi needles in 113 pedicles in four cadavers. The ARSN system was used for planning screw paths and directing the robot. The robot arm autonomously aligned with the planned screw trajectory, and the surgeon inserted the Jamshidi needle into the pedicle. Accuracy measurements were performed on verification cone beam computed tomographies with the planned paths superimposed. To provide a clinical grading according to the Gertzbein scale, pedicle screw diameters were simulated on the placed Jamshidi needles. A technical accuracy at bone entry point of 0.48 ± 0.44 mm and 0.68 ± 0.58 mm was achieved in the axial and sagittal views, respectively. The corresponding angular errors were 0.94 ± 0.83° and 0.87 ± 0.82°. The accuracy was statistically superior (p

STUDY DESIGN Retrospective comparison between an interventional and a control cohort. OBJECTIVE The aim of this study was to investigate whether the use of an augmented reality surgical navigation (ARSN) system for pedicle screw (PS) placement in deformity cases could alter the total implant density and PS to hook ratio compared to free-hand (FH) technique. SUMMARY OF BACKGROUND DATA Surgical navigation in deformity surgery provides the possibility to place PS in small and deformed pedicles were hooks would otherwise have been placed, and thereby achieve a higher screw density in the constructs that may result in better long-term patient outcomes. METHODS Fifteen deformity cases treated with ARSN were compared to 29 cases treated by FH. All surgeries were performed by the same orthopedic spine surgeon. PS, hook, and combined implant density were primary outcomes. Procedure time, deformity correction, length of hospital stay, and blood loss were secondary outcomes. The surgeries in the ARSN group were performed in a hybrid operating room (OR) with a ceiling-mounted robotic C-arm with integrated video cameras for AR navigation. The FH group was operated with or without fluoroscopy as deemed necessary by the surgeon. RESULTS Both groups had an overall high-density construct (>80% total implant density). The ARSN group, had a significantly higher PS density, 86.3% ± 14.6% versus 74.7% ± 13.9% in the FH group (P

OBJECTIVE: Surgical navigation is a well-established tool in endoscopic skull base surgery. However, navigational and endoscopic views are usually displayed on separate monitors, forcing the surgeon to focus on one or the other. Aiming to provide real-time integration of endoscopic and diagnostic imaging information, we present a new navigation technique based on augmented reality with fusion of intraoperative cone beam computed tomography (CBCT) on the endoscopic view. The aim of this study was to evaluate the accuracy of the method. MATERIAL AND METHODS: An augmented reality surgical navigation system (ARSN) with 3D CBCT capability was used. The navigation system incorporates an optical tracking system (OTS) with four video cameras embedded in the flat detector of the motorized C-arm. Intra-operative CBCT images were fused with the view of the surgical field obtained by the endoscope's camera. Accuracy of CBCT image co-registration was tested using a custom-made grid with incorporated 3D spheres. RESULTS: Co-registration of the CBCT image on the endoscopic view was performed. Accuracy of the overlay, measured as mean target registration error (TRE), was 0.55 mm with a standard deviation of 0.24 mm and with a median value of 0.51mm and interquartile range of 0.39--0.68 mm. CONCLUSION: We present a novel augmented reality surgical navigation system, with fusion of intraoperative CBCT on the endoscopic view. The system shows sub-millimeter accuracy.

Objective— Coronary artery thrombosis can occur in the absence of plaque rupture because of superficial erosion. Erosion-prone atheromata associate with more neutrophil extracellular traps (NETs) than lesions with stable or rupture-prone characteristics. The effects of NETs on endothelial cell (EC) inflammatory and thrombogenic properties remain unknown. We hypothesized that NETs alter EC functions related to erosion-associated thrombosis. Approach and Results— Exposure of human ECs to NETs increased VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) mRNA and protein expression in a time- and concentration-dependent manner. THP-1 monocytoid cells and primary human monocytes bound more avidly to NET-treated human umbilical vein ECs than to unstimulated cells under flow. Treatment of human ECs with NETs augmented the expression of TF (tissue factor) mRNA, increased EC TF activity, and hastened clotting of recalcified plasma. Anti-TF-neutralizing antibody blocked NET-induced acceleration of clotting by ECs. NETs alone did not exhibit TF activity or acceleration of clotting in cell-free assays. Pretreatment of NETs with anti-interleukin (IL)-1α–neutralizing antibody or IL-1Ra (IL-1 receptor antagonist)—but not with anti-IL-1β–neutralizing antibody or control IgG—blocked NET-induced VCAM-1, ICAM-1, and TF expression. Inhibition of cathepsin G, a serine protease abundant in NETs, also limited the effect of NETs on EC activation. Cathepsin G potentiated the effect of IL-1α on ECs by cleaving the pro-IL-1α precursor and releasing the more potent mature IL-1α form. Conclusions— NETs promote EC activation and increased thrombogenicity through concerted action of IL-1α and cathepsin G. Thus, NETs may amplify and propagate EC dysfunction related to thrombosis because of superficial erosion.

The prognosis for patients with glioblastoma is grim. Ex vivo expanded tumor-associated antigen (TAA)-reactive T-cells from patients with glioma may represent a viable source for anticancer-directed cellular therapies. Immunohistochemistry was used to test the survivin (n = 40 samples) and NY-ESO-1 (n = 38 samples) protein expression in tumor specimens. T-cells from peripheral blood were stimulated with TAAs (synthetic peptides) in IL-2 and IL-7, or using a combination of IL-2, IL-15 and IL-21. CD4+ and CD8+ T-cells were tested for antigen-specific proliferation by flow cytometry, and IFN-γ production was tested by ELISA. Twenty-eight out of 38 cancer specimens exhibited NY-ESO-1 protein expression, 2/38 showed a strong universal (4+) NY-ESO-1 staining, and 9/40 cancer lesions exhibited a strong (4+) staining for survivin. We could detect antigen-specific IFN-γ responses in 25% blood samples for NY-ESO-1 and 30% for survivin. NY-ESO-1-expanded T-cells recognized naturally processed and presented epitopes. NY-ESO-1 or survivin expression in glioma represents viable targets for anticancer-directed T-cells for the biological therapy of patients with glioma. Electronic supplementary material The online version of this article (doi:10.1007/s00262-017-2066-z) contains supplementary material, which is available to authorized users.

BACKGROUND CONTEXT Spinal meningiomas are rare entities where the first line of treatment is surgical resection. However, data on functional outcome after long-term follow-up is scarce. PURPOSE The aim of this study was to describe the demographics, histopathological distribution, symptomatology, surgical treatment strategies, functional outcome and long-term follow-up results, for patients surgically treated for spinal meningiomas. STUDY DESIGN/SETTING Retrospective cohort study. PATIENT SAMPLE Patients undergoing surgery for spinal meningiomas. OUTCOME MEASURES Postoperative functional outcome according to modified McCormick scale. Reoperation due to tumor progression or recurrence. METHODS A population-based cohort-study was conducted of all adult patients who underwent surgery for spinal meningiomas between 2005 and 2017, where 131 patients were included in the study. RESULTS The mean age was 63 years and 82% were female. Tumor localization was 31% cervical and 69% thoracic and 98% were WHO grade I. The mean preoperative modified McCormick scale was 2.2 ± 0.9.The mean time from diagnosis to surgery was 3.8 months, and the mean treatment range was 2.6 spinal levels. Gross total resection was achieved in 111 cases (85 %), and mean Simpson grade was 2.4 ± 0.7 as there were no Simpson grade 1 cases. During a mean follow-up time of 4.3 ± 2.9 years, local tumor progression was observed in three (2.3 %) and local tumor recurrence in another three patients. Only two patients underwent renewed tumor resection. The mean postoperative modified McCormick scale was 1.7 ± 0.9. Compared to the preoperative status, surgery was associated with a significant decrease in modified McCormick scale (p CONCLUSIONS Surgery for spinal meningiomas was associated with significant clinical improvement and long-term tumor control could be achieved even without reaching Simpson grade 1 resection. Time from diagnosis to surgery was identified as the single most important independent predictor for favorable functional outcome. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Introduction. Calcific aortic valve stenosis (CAVS) is a common disease associated with aging. Oxidative stress participates in the valve calcification process in CAVS. Semicarbazide-sensitive amine oxidase (SSAO), also referred to as vascular adhesion protein 1 (VAP-1), transforms primary amines into aldehydes, generating hydrogen peroxide and ammonia. SSAO is expressed in calcified aortic valves, but its role in valve calcification has remained largely unexplored. The aims of this study were to characterize the expression and the activity of SSAO during aortic valve calcification and to establish the effects of SSAO inhibition on human valvular interstitial cell (VIC) calcification. Methods. Human aortic valves from n=80 patients were used for mRNA extraction and expression analysis, Western blot, SSAO activity determination, immunohistochemistry, and the isolation of primary VIC cultures. Results. SSAO mRNA, protein, and activity were increased with increasing calcification within human aortic valves and localized in the vicinity of the calcified zones. The valvular SSAO upregulation was consistent after stratification of the subjects according to cardiovascular and CAVS risk factors associated with increased oxidative stress: body mass index, diabetes, and smoking. SSAO mRNA levels were significantly associated with poly(ADP-ribose) polymerase 1 (PARP1) in calcified tissue. Calcification of VIC was inhibited in the presence of the specific SSAO inhibitor LJP1586. Conclusion. The association of SSAO expression and activity with valvular calcification and oxidative stress as well as the decreased VIC calcification by SSAO inhibition points to SSAO as a possible marker and therapeutic target to be further explored in CAVS.

Autophagy serves as a cell survival mechanism which becomes dysregulated under pathological conditions and aging. Aortic valve thickening and calcification causing left ventricular outflow obstruction is known as calcific aortic valve stenosis (CAVS). CAVS is a chronic and progressive disease which increases in incidence and severity with age. Currently, no medical treatment exists for CAVS, and the role of autophagy in the disease remains largely unexplored. To further understand the role of autophagy in the progression of CAVS, we analyzed expression of key autophagy genes in healthy, thickened, and calcified valve tissue from 55 patients, and compared them with nine patients without significant CAVS, undergoing surgery for aortic regurgitation (AR). This revealed a upregulation in autophagy exclusively in the calcified tissue of CAVS patients. This difference in autophagy between CAVS and AR was explored by LC3 lipidation in valvular interstitial cells (VICs), revealing an upregulation in autophagic flux in CAVS patients. Inhibition of autophagy by bafilomycin-A1 led to a decrease in VIC survival. Finally, treatment of VICs with high phosphate led to an increase in autophagic activity. In conclusion, our data suggests that autophagy is upregulated in the calcified tissue of CAVS, serving as a compensatory and pro-survival mechanism.

Pedicle screw placement accuracy during spinal fixation surgery varies greatly and severe misplacement has been reported in 1-6.5 % of screws. Diffuse reflectance (DR) spectroscopy has previously been shown to reliably discriminate between tissues in the human body. We postulate that it could be used to discriminate between cancellous and cortical bone. Therefore, the purpose of this study is to validate DR spectroscopy as a warning system to detect impending pedicle screw breach in a cadaveric surgical setting using typical clinical breach scenarios. DR spectroscopy was incorporated at the tip of an integrated pedicle screw and screw driver used for tissue probing during pedicle screw insertions on six cadavers. Measurements were collected in the wavelength range of 400-1600 nm and each insertion was planned to result in a breach. Measurements were labelled as cancellous, cortical or representing a pre-cortical zone (PCZ) in between, based on information from cone beam computed tomographies at corresponding positions. In addition, DR spectroscopy data was recorded after breach. Four typical pedicle breach types were performed, and a total of 45 pedicle breaches were recorded. For each breach direction, the technology was able to detect the transition of the screw tip from the cancellous bone to the PCZ (P < 0.001), to cortical bone (P < 0.001), and to a subsequent breach (P < 0.001). Using support vector machine (SVM) classification, breach could reliably be detected with a sensitivity of 98.3 % [94.3-100 %] and a specificity of 97.7 % [91.0-100 %]. We conclude that DR spectroscopy reliably identifies the area of transition from cancellous to cortical bone in typical breach scenarios and can warn the surgeon of impending pedicle breach, thereby resulting in safer spinal fixation surgeries.

[Context] Automatically generated trace links must be vetted by human analysts before use. The task of vetting trace links is considered boring due to its repetitive nature and tools that are not engaging to the analyst. Therefore, a lack of developer engagement can hamper the successful implementation of a traceability strategy in an organisation. [Objective] In this study, we examine whether two gamification features, levels and badges, have a positive effect on human analysts’ engagement and ultimately on the quality of vetted trace links. [Method] We have conducted a controlled experiment with 24 participants that vetted trace link candidates and recorded their speed, correctness, enjoyment, and perceived usability of the tool. [Results] The results indicate that there was no significant difference between the speed, correctness, and perceived usability of the control and the experiment group. However, gamification features significantly increased the users’ perceived enjoyment. Levels and badges were perceived positively by the majority of the participants while some pitfalls and improvements were pointed out. [Conclusion] Our study indicates the need for further research as the results raise several questions, in particular w.r.t. what analyst behaviour gamification incentivises, and the impact of gamification on long-term enjoyment.

OBJECTIVEThe goal of this study was to develop and validate a system for automatic segmentation of the spine, pedicle identification, and screw path suggestion for use with an intraoperative 3D surgical navigation system.METHODSCone-beam CT (CBCT) images of the spines of 21 cadavers were obtained. An automated model-based approach was used for segmentation. Using machine learning methodology, the algorithm was trained and validated on the image data sets. For measuring accuracy, surface area errors of the automatic segmentation were compared to the manually outlined reference surface on CBCT. To further test both technical and clinical accuracy, the algorithm was applied to a set of 20 clinical cases. The authors evaluated the system’s accuracy in pedicle identification by measuring the distance between the user-defined midpoint of each pedicle and the automatically segmented midpoint. Finally, 2 independent surgeons performed a qualitative evaluation of the segmentation to judge whether it was adequate to guide surgical navigation and whether it would have resulted in a clinically acceptable pedicle screw placement.RESULTSThe clinically relevant pedicle identification and automatic pedicle screw planning accuracy was 86.1%. By excluding patients with severe spinal deformities (i.e., Cobb angle > 75° and severe spinal degeneration) and previous surgeries, a success rate of 95.4% was achieved. The mean time (± SD) for automatic segmentation and screw planning in 5 vertebrae was 11 ± 4 seconds.CONCLUSIONSThe technology investigated has the potential to aid surgeons in navigational planning and improve surgical navigation workflow while maintaining patient safety.

Half-bridge is an ideal topology of choice for 100W to 500W isolated DC-DC power conversion in telecom, networking and industrial applications, among others. To limit the inrush current and achieve monotonic startup of the output voltage, soft start function is typically implemented. Synchronous rectifiers (SRs) are usually utilized on the secondary side of the isolation boundary to reduce the rectifier conduction loss. The monotonic startup becomes challenging if the output capacitor is pre-biased/pre-charged prior to startup. The reverse current could cause voltage dip at the output which may result in undesired restart of the load being powered or even damage the power converter. This paper presents a novel scheme to address the pre-biased startup challenge. The bench test results are provided to validate the effectiveness of the proposed scheme.