Background

The supplementary grading system for brain arteriovenous malformations (AVMs) was introduced in 2010 as a tool for improving preoperative risk prediction and selecting surgical patients.

Objective

To demonstrate in this multicenter validation study that supplemented Spetzler-Martin (SM-Supp) grades have greater predictive accuracy than Spetzler-Martin (SM) grades alone.

Methods

Data collected from 1009 AVM patients who underwent AVM resection were used to compare the predictive powers of SM and SM-Supp grades. Patients included the original 300 University of California, San Francisco patients plus those treated thereafter (n = 117) and an additional 592 patients from 3 other centers.

Results

In the combined cohort, the SM-Supp system performed better than SM system alone: area under the receiver-operating characteristics curve (AUROC) = 0.75 (95% confidence interval, 0.71-0.78) for SM-Supp and AUROC = 0.69 (95% confidence interval, 0.65-0.73) for SM (P < .001). Stratified analysis fitting models within 3 different follow-up groupings (<6 months, 6 months-2 years, and >2 years) demonstrated that the SM-Supp system performed better than SM system for both medium (AUROC = 0.71 vs 0.62; P = .003) and long (AUROC = 0.69 vs 0.58; P = .001) follow-up. Patients with SM-Supp grades ≤6 had acceptably low surgical risks (0%-24%), with a significant increase in risk for grades >6 (39%-63%).

Conclusion

This study validates the predictive accuracy of the SM-Supp system in a multicenter cohort. An SM-Supp grade of 6 is a cutoff or boundary for AVM operability. Supplemented grading is currently the best method of estimating neurological outcomes after AVM surgery, and we recommend it as a starting point in the evaluation of AVM operability.

Objective

The objective of this study was to evaluate the existing Spetzler-Martin (SM), Spetzler-Ponce (SP), and Lawton-Young (LY) grading systems for cerebellar arteriovenous malformations (AVMs) and to propose a new grading system to estimate the risks associated with these lesions.

Methods

Data for patients with cerebellar AVMs treated microsurgically in two tertiary medical centers were retrospectively reviewed. Data from patients at institution 1 were collected from September 1999 to February 2013, and at institution 2 from October 2008 to October 2015. Patient outcomes were classified as favorable (modified Rankin Scale [mRS] score 0-2) or poor (mRS score 3-6) at the time of discharge. Using chi-square and logistic regression analysis, variables associated with poor outcomes were assigned risk points to design the proposed grading system. The proposed system included neurological status prior to treatment (poor, +2 points), emergency surgery (+1 point), age > 60 years (+1 point), and deep venous drainage (deep, +1 point). Risk point totals of 0-1 comprised grade 1, 2-3 grade 2, and 4-5 grade 3.

Results

A total of 125 cerebellar AVMs of 1328 brain AVMs were reviewed in 125 patients, 120 of which were treated microsurgically and included in the study. With our proposed grading system, we found poor outcomes differed significantly between each grade (p < 0.001), while with the SM, SP, and LY grading systems they did not (p = 0.22, p = 0.25, and p = 1, respectively). Logistic regression revealed grade 2 had 3.3 times the risk of experiencing a poor outcome (p = 0.008), while grade 3 had 9.9 times the risk (p < 0.001). The proposed grading system demonstrated a superior level of predictive accuracy (area under the receiver operating characteristic curve [AUROC] of 0.72) compared with the SM, SP, and LY grading systems (AUROC of 0.61, 0.57, and 0.51, respectively).

Conclusions

The authors propose a novel grading system for cerebellar AVMs based on emergency surgery, venous drainage, preoperative neurological status, and age that provides a superior prognostication power than the formerly proposed SM, SP, and LY grading systems. This grading system is clinically predictive of patient outcomes and can be used to better guide vascular neurosurgeons in clinical decision-making.

Background

Spetzler-Martin (SM) grade III arteriovenous malformations (AVMs) are at the boundary of safe operability, and preoperative embolization may reduce surgical risks.

Objective

To evaluate the benefits of preoperative AVM embolization by comparing neurological outcomes in patients with grade III AVMs treated with or without preoperative embolization.

Methods

All microsurgically treated grade III AVMs were identified from 2011 to 2018 at 2 medical centers. Neurological outcomes, measured as final modified Rankin Scale scores (mRS) and changes in mRS from preoperative baseline to last follow-up evaluation, were compared in patients with and without preoperative embolization.

Results

Of the 102 patients with grade III AVMs who were treated microsurgically, 57 (56%) underwent preoperative embolization. Significant differences were found between the patients with and without embolization in AVM eloquence (74% vs 93%, P = .02), size ≥ 3 cm (47% vs 73%, P = .01), diffuseness (7% vs 22%, P = .04), and mean final mRS (1.1 vs 2.0, P = .005). Poor outcomes were more frequent in patients without embolization (38%) than with embolization (7%) (final mRS > 2; P < .001). Propensity-adjusted analysis revealed AVM resection without embolization was a risk factor for poor outcome (mRS score > 2; odds ratio, 4.2; 95% CI, 1.1-16; P = .03).

Conclusion

Nonembolization of SM grade III AVMs is associated with an increased risk of poor neurological outcomes after microsurgical resection. Preoperative embolization of intermediate-grade AVMs selected because of large AVM size, surgical inaccessibility of feeding arteries, and high flow should be employed more often than anticipated, even in the context of increasing microsurgical experience with AVMs.

Introduction

Contrast-enhanced MRI (CE-MRI) represents the current mainstay for monitoring treatment response in glioblastoma multiforme (GBM), based on the premise that enlarging lesions reflect increasing tumor burden, treatment failure, and poor prognosis. Unfortunately, irradiating such tumors can induce changes in CE-MRI that mimic tumor recurrence, so called post treatment radiation effect (PTRE), and in fact, both PTRE and tumor re-growth can occur together. Because PTRE represents treatment success, the relative histologic fraction of tumor growth versus PTRE affects survival. Studies suggest that Perfusion MRI (pMRI)-based measures of relative cerebral blood volume (rCBV) can noninvasively estimate histologic tumor fraction to predict clinical outcome. There are several proposed pMRI-based analytic methods, although none have been correlated with overall survival (OS). This study compares how well histologic tumor fraction and OS correlate with several pMRI-based metrics.

Methods

We recruited previously treated patients with GBM undergoing surgical re-resection for suspected tumor recurrence and calculated preoperative pMRI-based metrics within CE-MRI enhancing lesions: rCBV mean, mode, maximum, width, and a new thresholding metric called pMRI-fractional tumor burden (pMRI-FTB). We correlated all pMRI-based metrics with histologic tumor fraction and OS.

Results

Among 25 recurrent patients with GBM, histologic tumor fraction correlated most strongly with pMRI-FTB (r = 0.82; P < .0001), which was the only imaging metric that correlated with OS (P<.02).

Conclusion

The pMRI-FTB metric reliably estimates histologic tumor fraction (i.e., tumor burden) and correlates with OS in the context of recurrent GBM. This technique may offer a promising biomarker of tumor progression and clinical outcome for future clinical trials.

Improved tools for providing specific intraoperative diagnoses could improve patient care. In neurosurgery, intraoperatively differentiating non-operative lesions such as CNS B-cell lymphoma from operative lesions can be challenging, often necessitating immunohistochemical (IHC) procedures which require up to 24-48 hours. Here, we evaluate the feasibility of generating rapid ex vivo specific labeling using a novel lymphoma-specific fluorescent switchable aptamer. Our B-cell lymphoma-specific switchable aptamer produced only low-level fluorescence in its unbound conformation and generated an 8-fold increase in fluorescence once bound to its target on CD20-positive lymphoma cells. The aptamer demonstrated strong binding to B-cell lymphoma cells within 15 minutes of incubation as observed by flow cytometry. We applied the switchable aptamer to ex vivo xenograft tissue harboring B-cell lymphoma and astrocytoma, and within one hour specific visual identification of lymphoma was routinely possible. In this proof-of-concept study in human cell culture and orthotopic xenografts, we conclude that a fluorescent switchable aptamer can provide rapid and specific labeling of B-cell lymphoma, and that developing aptamer-based labeling approaches could simplify tissue staining and drastically reduce time to histopathological diagnoses compared with IHC-based methods. We propose that switchable aptamers could enhance expeditious, accurate intraoperative decision-making.

Ten ongoing studies designed to test the possibility that extracellular RNAs may serve as biomarkers in human disease are described. These studies, funded by the NIH Common Fund Extracellular RNA Communication Program, examine diverse extracellular body fluids, including plasma, serum, urine and cerebrospinal fluid. The disorders studied include hepatic and gastric cancer, cardiovascular disease, chronic kidney disease, neurodegenerative disease, brain tumours, intracranial haemorrhage, multiple sclerosis and placental disorders. Progress to date and the plans for future studies are outlined.

Extracellular RNAs (exRNAs) have been identified in all tested biofluids and have been associated with a variety of extracellular vesicles, ribonucleoprotein complexes and lipoprotein complexes. Much of the interest in exRNAs lies in the fact that they may serve as signalling molecules between cells, their potential to serve as biomarkers for prediction and diagnosis of disease and the possibility that exRNAs or the extracellular particles that carry them might be used for therapeutic purposes. Among the most significant bottlenecks to progress in this field is the lack of robust and standardized methods for collection and processing of biofluids, separation of different types of exRNA-containing particles and isolation and analysis of exRNAs. The Sample and Assay Standards Working Group of the Extracellular RNA Communication Consortium is a group of laboratories funded by the U.S. National Institutes of Health to develop such methods. In our first joint endeavour, we held a series of conference calls and in-person meetings to survey the methods used among our members, placed them in the context of the current literature and used our findings to identify areas in which the identification of robust methodologies would promote rapid advancements in the exRNA field.

The Extracellular RNA Communication Consortium (ERCC) was launched to accelerate progress in the new field of extracellular RNA (exRNA) biology and to establish whether exRNAs and their carriers, including extracellular vesicles (EVs), can mediate intercellular communication and be utilized for clinical applications. Phase 1 of the ERCC focused on exRNA/EV biogenesis and function, discovery of exRNA biomarkers, development of exRNA/EV-based therapeutics, and construction of a robust set of reference exRNA profiles for a variety of biofluids. Here, we present progress by ERCC investigators in these areas, and we discuss collaborative projects directed at development of robust methods for EV/exRNA isolation and analysis and tools for sharing and computational analysis of exRNA profiling data.