Bauman, Megan M. J.

Abstract Background Glioblastoma (GBM) is the most common malignant brain tumor and has a poor prognosis. Imaging findings at diagnosis and in response to treatment are nonspecific. Developing noninvasive assays to augment imaging would be helpful. Plasma extracellular vesicles (EVs) are a promising biomarker source for this. Here, we develop spectral flow cytometry techniques that demonstrate differences in bulk plasma EV phenotype between GBM patients and normal donors that could serve as the basis of a liquid biopsy. Methods Plasma EVs were stained for EV-associated tetraspanins (CD9/CD63/CD81), markers indicating cell of origin (CD11b/CD31/CD41a/CD45), and actin/phalloidin (to exclude cell debris). EVs were analyzed using spectral flow cytometry. Multiparametric analysis using t-distributed stochastic neighbor embedding (t-SNE) and self-organizing maps on flow cytometry data (FlowSOM) was performed comparing GBM and normal donor (ND) plasma EVs. Results Size exclusion chromatography plus spectral-based flow cytometer threshold settings enriched plasma EVs while minimizing background noise. GBM patients had increased CD9+, CD63+, CD81+, and myeloid-derived (CD11b+) EVs. Multiparametric analysis demonstrated distinct surface marker expression profiles in GBM plasma EVs compared to ND EVs. Fifteen plasma EV sub-populations differing in size and surface marker expression were identified, six enriched in GBM patients and two in normal donors. Conclusions Multiparametric analysis demonstrates that GBM patients have a distinct nonneoplastic plasma EV phenotype compared to ND. This simple rapid analysis can be performed without purifying tumor EVs and may serve as the basis of a liquid biopsy.

OBJECTIVE Tectal plate gliomas are rare, slow-growing tumors of the midbrain that are discovered predominantly in the pediatric population. Because of their indolent nature, treatment mainly consists of observation and management of hydrocephalus. Unfortunately, a subset of tectal gliomas may exhibit tumor enlargement and disease progression. Currently, there are no established guidelines for predicting future progression of tectal gliomas or the need for tumor-directed treatment. In this paper, the authors present a large case series of tectal plate gliomas with the aim of determining early indicators of tumor progression and the need for tumor-directed treatment in a pediatric population, along with providing their experience in treating progressive tumors. METHODS A retrospective chart review of 170 patients diagnosed with tectal plate glioma from a single institution, of whom 67 were pediatric patients (≤ 18 years of age), was performed. Univariate analysis was used to determine statistically significant predictors of symptomatic disease progression requiring eventual tumor-directed therapy. RESULTS The median patient age of the full cohort was 24 years (range 0–73 years). Compared with the pediatric population, the adult population had more instances of incidental lesions (p < 0.001) and lower rates of hydrocephalus (50% vs 84%, p < 0.001). Of the pediatric patients who had ≥ 5 years of follow-up (n = 51), 12 (24%) experienced radiological progression and 13 (25%) required treatment for their tumor. The 1-year, 5-year, and 10-year radiographic progression-free survival (PFS) rates were 98%, 90%, and 86%, respectively. In univariate analysis, lesion involvement of the pons, moderate T1 hypointensity, and moderate contrast enhancement on baseline radiology were significantly associated with worse radiographic PFS. Alternatively, significant predictors of requiring tumor-directed treatment included extraocular eye movement abnormalities at presentation, involvement of the lesion beyond the tectum on baseline radiology, moderate T1 hypointensity, moderate contrast enhancement, and an increase in total lesion size during progression. At the most recent follow-up, 94% of the patients had stable/nonprogressive disease, 2% had progressive disease, and 4% died of tumor progression. CONCLUSIONS Patients who demonstrate radiographic progression may not necessarily experience clinical/symptomatic progression or require tumor-directed treatment. Certain patient presentation characteristics and baseline radiographic features may be predictive of worse radiographic PFS or the need for future tumor-directed treatment in the pediatric population. Typically, the natural history of these lesions lends to excellent long-term survival, even in patients who experience clinical progression, should appropriate treatment be initiated.

OBJECTIVE Bone morphogenetic proteins (BMPs) are part of the transforming growth factor–beta superfamily and are involved in bone formation and repair. In spine surgery, recombinant human BMP (rhBMP) is used as an alternative to autografts for spinal fusions. This study aimed to evaluate bibliometric parameters and citations of the literature on BMPs to provide an overview of how the field has evolved. METHODS A comprehensive search of the literature was conducted using Elsevier’s Scopus database to capture all the published and indexed studies relevant to BMPs from 1955 to the present. A discrete set of validated bibliometric parameters was extracted and analyzed. All statistical analyses were performed using R 4.1.1. RESULTS The 100 most cited articles were published between 1994 and 2018 by 472 unique authors in 40 sources (e.g., journals and books). On average, there were 279 citations per publication and 17.69 citations per publication per year. The United States had the publications with the most citations (n = 23,761), followed by Hong Kong (n = 580) and the United Kingdom (n = 490). The three institutions in the United States with the greatest number of publications in the field were Emory University (n = 14), Hughston Clinic (n = 9), Hospital for Special Surgery (n = 6), and University of California (n = 6). CONCLUSIONS The authors evaluated and characterized the 100 most cited articles about BMP. Most of the publications were clinical in nature and focused on BMP’s application in spine surgery. While early scientific efforts focused on basic science research to advance the understanding of BMP’s mechanism of action in promoting bone formation, the majority of the more recent publications are clinically focused. It will be beneficial to conduct more controlled clinical trials to compare the outcomes of BMP use with other methods.

Introduction There have been several studies of Moyamoya disease (MMD) with concurrent autoimmune (AI) disease. It has been proposed that there may be a causal or synergistic effect of autoimmune and inflammatory conditions in patients with MMD. As such, in the present study we seek to characterizethe surgical outcomes of adults and children with MMD and coexisting AI conditions. Methods A systematic review was performed of published studies reporting patient level data of Moyamoya disease and concomitant autoimmune disease. Relevant studies were identified using Preferred reporting Items for Systematic Reviews and Meta‐Analysis criteria. Results A total of 149 studies were included, encompassing 257 patients. Of the 257 patients with concurrent AI and MMD, 107 (88 females, 19 males) underwent surgery. The average age was 31.3 years (Range 5–65; SD 12.5). Five cases presented with hemorrhagic symptoms, 87 ischemic, and 15 were unspecified. The most commonly associated AI conditions were Graves’ disease (71 cases, 66.4%), Lupus (17 cases, 15.9%), and T1DM (6 cases, 5.6%).Follow‐up was reported in 25 cases and was an average of 17.8 months. Surgical outcomes were reported in 82 cases; 63 (76.8%) improved, 7 (8.5%) were stable, 9 (10.9%) developed a new deficit, and 3 (3.7%) died at most recent follow up. Eight patients (7.5%) had disease progression. 63 (58.8%) patients were treated with additional autoimmune therapy although this therapy did not lead to any difference in outcomes. Twenty patients (18.7%) required additional supportive medical therapy (eg: aspirin, statins). Conclusions Moyamoya disease may be multifactorial. Patients with concomitant AI and Moyamoya disease may be at increased risk and warrant additional surveillance or intervention. The ideal therapy for these patients remains to be understood. These findings warrant further study into optimal diagnostic and therapeutic techniques for concomitant MMD and AI conditions.

Introduction Moyamoya disease was first described in the 1950’s. After over six decades, however, the underlying etiology of Moyamoya still remains unknown. It has been postulated that underlying inflammatory or autoimmune (AI) processes may play a role in the development of this condition. In order to further investigate this hypothesis, we studied the clinical and epidemiological attributes of patients with concurrent Moyamoya disease and AI condition(s). Methods A systematic review was performed including studies reporting patient level data of Moyamoya disease and concomitant autoimmune disease. Relevant studies were identified using Preferred reporting Items for Systematic Reviews and Meta‐Analysis criteria. Results There were 739 results of which 149 were included in this study. The first reports of concurrent Moyamoya and AI occurred in 1991 and involved 2 cases of Moyamoya and associated Graves’ disease. These patients were treated with antithyroid medication alone and showed improvement. Altogether, our search yielded a total of 257 patients (192 females, 48 males, 17 unspecified). A total of 158 cases were reported as “Moyamoya Disease” and 99 were reported as “Moyamoya Syndrome/Vasculopathy.” Most cases were ischemic (175 ischemic, 15 hemorrhagic) in nature. Bilaterality of the disease was reported in 130 cases, unilaterality in 34 cases. The most commonly reported ethnicity was Chinese (26 cases), followed by Japanese (17 cases), and Korean (17 cases). The most common co‐presenting AI conditions were Graves’ disease (150 cases, 58.4%), Lupus (26 cases, 10.1%), antiphospholipid syndrome (19 cases, 7.4%), Type 1 Diabetes (19 cases, 7.4%), and Multiple Sclerosis (7 cases, 2.7%). Conclusions There are numerous reports describing patients diagnosed with Moyamoya in addition to coexisting AI conditions. Our study shows that the demographic characteristics of co‐presentation align with the common autoimmune (female predominance) and Moyamoya (high east Asian prevalence) attributes. These results warrant further investigation into a possible causal or synergistic relationship between Moyamoya and AI disease.

Extracellular vesicles (EVs) are membrane-bound particles released by all cells. Previous research has found that these microscopic vesicles contribute to intercellular signaling and communication. EVs carry a variety of cargo, including nucleic acids, proteins, metabolites, and lipids. The composition of EVs varies based on cell of origin. Therefore, EVs can serve as an important biomarker in the diagnosis and treatment of various cancers. EVs derived from glioblastoma (GBM) cells carry biomarkers, which could serve as the basis for a potential diagnostic strategy known as liquid biopsy. Multiple EV isolation techniques exist, including ultrafiltration, size exclusion chromatography, flow field-flow fractionation, sequential filtration, differential ultracentrifugation, and density-gradient ultracentrifugation. Recent and ongoing work aims to identify cellular markers to distinguish GBM-derived EVs from those released by noncancerous cells. Strategies include proteomic analysis of GBM EVs, identification of GBM-specific metabolites, and use of Food and Drug Administration-approved 5-aminolevulinic acid—an oral agent that causes fluorescence of GBM cells—to recognize GBM EVs in a patient's blood. In addition, accurately and precisely monitoring changes in EV cargo concentrations could help differentiate between pseudoprogression and GBM recurrence, thus preventing unnecessary surgical interventions.