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Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

In silico quantification of cell proportions from mixed-cell transcriptomics data (deconvolution) requires a reference expression matrix, called basis matrix. We hypothesize that matrices created using only healthy samples from a single microarray platform would introduce biological and technical biases in deconvolution. We show presence of such biases in two existing matrices, IRIS and LM22, irrespective of deconvolution method. Here, we present immunoStates, a basis matrix built using 6160 samples with different disease states across 42 microarray platforms. We find that immunoStates significantly reduces biological and technical biases. Importantly, we find that different methods have virtually no or minimal effect once the basis matrix is chosen. We further show that cellular proportion estimates using immunoStates are consistently more correlated with measured proportions than IRIS and LM22, across all methods. Our results demonstrate the need and importance of incorporating biological and technical heterogeneity in a basis matrix for achieving consistently high accuracy. Cell type deconvolution from bulk expression data rely on a reference expression matrix. Here, the authors introduce a basis matrix built using data from both healthy and diseased samples profiled on 42 platforms, reducing biases introduced by single-platform matrices built using healthy samples.

Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are typically low, particularly in patients with localized disease, requiring highly sophisticated methods for detection and quantification. Multiple liquid biopsy methods have been developed for ctDNA analysis in solid tumor malignancies and are now enabling detection and assessment of earlier stages of disease, post-treatment molecular residual disease (MRD), resistance to targeted systemic therapy, and tumor mutational burden. Understanding ctDNA biology, mechanisms of release, and clearance and size characteristics, in conjunction with the application of molecular barcoding and targeted error correction, have increased the sensitivity and specificity of ctDNA detection techniques. Combinatorial approaches including integration of ctDNA data with circulating protein biomarkers may further improve assay sensitivity and broaden the scope of ctDNA applications. Circulating viral DNA may be utilized to monitor disease in some virally induced malignancies. In spite of increasingly accurate methods of ctDNA detection, results need to be interpreted with caution given that somatic mosaicisms such as clonal hematopoiesis of indeterminate potential (CHIP) may give rise to genetic variants in the bloodstream unrelated to solid tumors, and the limited concordance observed between different commercial platforms. Overall, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumor malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance, and treatment personalization based on real-time assessment of the tumor genomic landscape.

Grade III spinal ependymomas are rare central nervous system tumors with poor prognoses and limited treatment guidance. This study aimed to identify predictors of long-term mortality using a national dataset. The National Cancer Database was queried for patients diagnosed with grade III spinal ependymomas from 2004 to 2017. Demographic, clinical, and treatment variables were analyzed with traditional statistics and machine learning models. Model performance was evaluated with C-index and Integrated Brier Score (IBS), and SHAP analysis was used for feature interpretation. A total of 2,011 patients were included. Surgical resection was performed in 83% of cases, with gross total resection in 96% of those. Radiation was given to 33% (mean 41.4 Gy), and chemotherapy to 18%. Ten-year survival was 75%. Long-term survivors were younger (42 vs. 52 years, P  < 0.001), had fewer comorbidities ( P  < 0.001), and were more often privately insured. Mortality was higher among those receiving radiation (56% vs. 24%, P  < 0.001) or chemotherapy (37% vs. 12%, P  < 0.001). Random Survival Forest was the best-performing model (C-index 0.724; IBS 0.176), identifying tumor size, radiation, chemotherapy, and surgery as key correlates of mortality. Kaplan-Meier analysis showed reduced survival with radiation and chemotherapy, but improved survival with surgery. Stratified analyses revealed diminished surgical benefit in pediatric patients and small tumors. Tumor size emerged as the strongest correlate of mortality. Surgery improves survival, though benefit varies by age and tumor features. Chemotherapy and radiation correlated with higher mortality, underscoring the need for individualized treatment planning and prospective validation.

Purpose Augmented reality (AR) technology integrates intraoperative imaging into the surgical field through AR headsets, enabling real-time, heads-up surgical navigation. While previous work has demonstrated that AR navigation achieves excellent radiographic accuracy for instrumentation placement, no studies have reported long-term patient-reported outcomes (PROs) following AR-guided spine surgery. Methods In this retrospective study with prospective follow-up, patient electronic medical records were reviewed for demographic, clinical, and outcome data. Pre- and postoperative PROs were collected, including Oswestry Disability Index (ODI) and 36-Item Short Form Survey (SF-36). Mental (MCS) and physical (PCS) component scores were derived from SF-36 responses. Univariate statistics and paired Wilcoxon tests were used to analyze patient characteristics and PROs. Multivariate linear regression was used to assess predictors of postoperative improvement in outcomes of interest. Results We identified 59 patients who underwent AR-guided spine surgery with ≥ 10 months follow-up (34% male, median age: 61 years, median follow-up: 25 months). Nine patients (15.3%) underwent reoperation at a median of 19 months—three for adjacent segment disease, four for pseudarthrosis, and two for other indications. Preoperatively, median ODI was 44 (severe disability), and MCS and PCS were 41.3 and 27.0. Postoperatively, ODI was 24 (moderate disability), and MCS and PCS were 54.1 and 37.7—representing significant improvements that exceed the minimal clinically important differences reported in the literature (approximately 10 points for ODI and 4 points for PCS and MCS;  p  < 0.001,  p  = 0.03, and  p  = 0.001, respectively). Conclusion This study represents one of the first efforts to evaluate the clinical impact of augmented reality–assisted spinal surgery beyond intraoperative usage. While AR technology has been shown to enhance pedicle screw placement accuracy, our findings extend this knowledge by demonstrating sustained long-term improvements in physical functioning, mental health, and disability among patients undergoing AR-guided pedicle screw placement that are reasonably similar to those reported following other means of pedicle screw placement.

BACKGROUNDRapid diagnosis to facilitate urgent intervention is critical for treatment of acute spinal cord injury (SCI). We hypothesized that a multi-analyte blood biomarker would support point-of-care SCI diagnosis, correlate with injury severity, and predict long-term neurologic outcomes.METHODSDroplet digital PCR (ddPCR) assays were designed to amplify differentially hypomethylated genomic loci in spinal cord tissue. An optimized ddPCR assay was applied to cell-free DNA (cfDNA) from plasma samples collected from prospectively enrolled acute SCI patients. Targeted proteomic profiling was also performed. Spinal cord-derived cfDNA and plasma proteins were tested for their association with SCI and ability to predict conversion in American Spinal Injury Association (ASIA) score at 6 months.RESULTSA bespoke ddPCR assay detected spinal cord-derived cfDNA in plasma of 50 patients with acute SCI (AUC: 0.89, 95% CI 0.83-0.95, P < 0.0001). Levels of cfDNA were highest in patients with the most severe injury, i.e., ASIA A, compared with those with ASIA B (P = 0.04), ASIA C (P = 0.009), and ASIA D injuries (P < 0.001). Dimensionality reduction identified 4 candidate proteins (FABP3, REST, IL-6, NF-H) that were integrated with spinal cord-derived cfDNA to derive the Spinal Cord Injury Index (SCII), which has high sensitivity and specificity for SCI diagnosis (AUC: 0.91, 95% CI 0.82-0.99, P < 0.0001), correlates with injury severity (P < 0.0001), and predicts 6-month neurologic improvement (AUC: 0.77, 95% CI 0.61-0.93, P = 0.006).CONCLUSIONThe detection of spinal cord-derived cfDNA and plasma protein alterations as part of a multi-analyte blood test can inform SCI diagnosis and prognosis.FUNDINGNorth American Spine Society Young Investigator Award; Morton Cure Paralysis Fund.

Abstract BACKGROUND Traditional moyamoya disease (MMD) classification relies on morphological digital subtraction angiography (DSA) assessment, which do not reflect hemodynamic status, clinical symptoms, or surgical treatment outcome. OBJECTIVE To (1) validate the new Berlin MMD preoperative symptomatology grading system and (2) determine the clinical application of the grading system in predicting radiological and clinical outcomes after surgical revascularization. METHODS Ninety-six MMD patients (192 hemispheres) with all 3 investigations (DSA, magnetic resonance imaging [MRI], Xenon-CT) performed preoperatively at our institution (2007-2013) were included. Two clinicians independently graded the imaging findings according to the proposed criteria. Patients’ modified Rankin Score (mRS) scores (preoperative, postoperative, last follow-up), postoperative infarct (radiological, clinical) were collected and statistical correlations performed. RESULTS One hundred fifty-seven direct superficial temporal artery-middle cerebral artery bypasses were performed on 96 patients (66 female, mean age 41 yr, mean follow-up 4.3 yr). DSA, MRI, and cerebrovascular reserve capacity were independent factors associated hemispheric symptomatology (when analyzed individually or in the combined grading system). Mild (grade I), moderate (grade II), severe (grade III) were graded in 45, 71, and 76 hemispheres respectively; of which, clinical symptoms were found in 33% of grade I, 92% of grade II, 100% of grade III hemispheres (P < .0001). Two percent of grade I, 11% of grade II, 20% of grade III hemispheres showed postoperative radiological diffusion weighted image-positive ischemic changes or hemorrhage on MRI (P = .018). Clinical postoperative stroke was observed in 1.4% of grade II, 6.6% of grade III hemispheres (P = .077). The grading system also correlated well to dichotomized mRS postoperative outcome. CONCLUSION The Berlin MMD grading system is able to stratify preoperative hemispheric symptomatology. Furthermore, it correlated with postoperative new ischemic changes on MRI, and showed a strong trend in predicting clinical postoperative stroke.

Abstract BACKGROUND Intramedullary spinal cord cavernous malformations (CMs) account for 5% of all CMs in the central nervous system and 5% to 12% of all spinal cord vascular lesions, yet their optimal management is controversial. OBJECTIVE To identify factors associated with the clinical progression of spinal cord CMs and quantify the range of surgical outcomes. METHODS Retrospective observational cohort study of 32 patients who underwent open surgical resection for spinal CMs, the majority of which presented to a dorsal or lateral pial surface, from 1996 to 2017 at a single institution. We evaluated outcomes as clinically improved, worsened, or unchanged against preoperative baseline; Frankel and Aminoff–Logue disability grades were also calculated. RESULTS Mean age at presentation was 44.2 (range, 0.5-77 yr). Symptoms included sensory deficits (n = 26, 81%), loss of strength/coordination (n = 16, 50%), pain (n = 16, 50%), and bladder/bowel dysfunction (n = 6, 19%). Thoracic (n = 16, 50%) and cervical CMs (n = 16, 50%) were equally common, with overall mean size of 7.1 mm (range, 1-20 mm). Functional outcomes at last follow-up, compared to preoperative status for patients with >6 mo of follow-up, were improved in 6 (23%), unchanged in 19 (73%), and worsened in 1 (4%) patients. Preoperative Frankel grade and improved Frankel grade immediately following resection were strongly associated with improvement from baseline at long-term followup (P < .01). CONCLUSION Gross total resection of symptomatic spinal cord CMs can prevent further neurological decline. Our experience suggests excellent long-term outcomes and minimal surgical morbidity following resection.

Study Design: Narrative review. Objectives: Robotic systems in spinal surgery may offer potential benefits for both patients and surgeons. In this article, the authors explore the future prospects and current limitations of robotic systems in minimally invasive spine surgery. Methods: We describe recent developments in robotic spine surgery and minimally invasive spine surgery. Institutional review board approval was not needed. Results: Although robotic application in spine surgery has been gradual, the past decade has seen the arrival of several novel robotic systems for spinal procedures, suggesting the evolution of technology capable of augmenting surgical ability. Conclusion: Spine surgery is well positioned to benefit from robotic assistance and automation. Paired with enhanced navigation technologies, robotic systems have tremendous potential to supplement the skills of spine surgeons, improving patient safety and outcomes while limiting complications and costs.