Purpose: Glioblastoma (GBM) is the most common primary brain tumor. The identification of blood biomarkers reflecting the tumor status represents a major unmet need for optimal clinical management of patients with GBM. Their high number in body fluids, their stability, and the presence of many tumor-associated proteins and RNAs make extracellular vesicles potentially optimal biomarkers. Here, we investigated the potential role of plasma extracellular vesicles from patients with GBM for diagnosis and follow-up after treatment and as a prognostic tool. Experimental Design: Plasma from healthy controls (n ¼ 33), patients with GBM (n ¼ 43), and patients with different central nervous system malignancies (n ¼ 25) were collected. Extracellular vesicles were isolated by ultracentrifugation and characterized in terms of morphology by transmission electron microscopy, concentration, and size by nanoparticle tracking analysis, and protein composition by mass spectrometry. An orthotopic mouse model of human GBM confirmed human plasma extracellular vesicle quantifications. Associations between plasma extracellular vesicle concentration and clinicopathologic features of patients with GBM were analyzed. All statistical tests were two-sided. Results: GBM releases heterogeneous extracellular vesicles detectable in plasma. Plasma extracellular vesicle concentration was higher in GBM compared with healthy controls (P < 0.001), brain metastases (P < 0.001), and extra-axial brain tumors (P < 0.001). After surgery, a significant drop in plasma extracellular vesicle concentration was measured (P < 0.001). Plasma extracellular vesicle concentration was also increased in GBM-bearing mice (P < 0.001). Proteomic profiling revealed a GBM-distinctive signature. Conclusions: Higher extracellular vesicle plasma levels may assist in GBM clinical diagnosis: their reduction after GBM resection, their rise at recurrence, and their protein cargo might provide indications about tumor, therapy response, and monitoring.

Background: Sacroiliac joint pain is increasingly recognized as a cause of low back pain. We compared the safety and effectiveness of minimally invasive sacroiliac joint arthrodesis using triangular titanium implants and conservative management in patients with chronic sacroiliac joint pain. Methods: This study was a prospective, multicenter randomized controlled trial of adults with chronic sacroiliac joint pain assigned to either conservative management or sacroiliac joint arthrodesis with triangular titanium implants. The study end points included self-rated low back pain (visual analog scale [VAS]), back dysfunction (Oswestry Disability Index [ODI]), and quality of life. Ninety percent of subjects in both groups completed the study. Results: Between June 6, 2013, and May 15, 2015, 103 subjects were randomly assigned to conservative management (n = 51) or sacroiliac joint arthrodesis (n = 52). At 2 years, the mean low back pain improved by 45 points (95% confidence interval [CI], 37 to 54 points) after sacroiliac joint arthrodesis and 11 points (95% CI, 2 to 20 points) after conservative management, with a mean difference between groups of 34 points (p < 0.0001). The mean ODI improved by 26 points (95% CI, 21 to 32 points) after sacroiliac joint arthrodesis and 8 points (95% CI, 2 to 14 points) after conservative management, with a mean difference between groups of 18 points (p < 0.0001). Parallel improvements were seen in quality of life. In the sacroiliac joint arthrodesis group, the prevalence of opioid use decreased from 56% at baseline to 33% at 2 years (p = 0.009), and no significant change was observed in the conservative management group (47.1% at baseline and 45.7% at 2 years). Subjects in the conservative management group, after crossover to the surgical procedure, showed improvements in all measures similar to those originally assigned to sacroiliac joint arthrodesis. In the first 6 months, the frequency of adverse events did not differ between groups (p = 0.664). By month 24, we observed 39 severe adverse events after sacroiliac joint arthrodesis, including 2 cases of sacroiliac joint pain, 1 case of a postoperative gluteal hematoma, and 1 case of postoperative nerve impingement. The analysis of computed tomographic (CT) imaging at 12 months after sacroiliac joint arthrodesis showed radiolucencies adjacent to 8 implants (4.0% of all implants). Conclusions: For patients with chronic sacroiliac joint pain due to joint degeneration or disruption, minimally invasive sacroiliac joint arthrodesis with triangular titanium implants was safe and more effective throughout 2 years in improving pain, disability, and quality of life compared with conservative management. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

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The results of this study show an imbalance of the antioxidant enzymatic activities in the human brain after SAH. which is linked to the severity of the initial bleeding and possibly modified by the development of arterial vasospasm.

We studied the ex vivo production of prostaglandin D 2 , prostaglandin E^, 6-ketoprostaglandin F la , and leukotriene C 4 in the brain tissue of rats subjected to experimental subarachnoid hemorrhage. The ex vivo method allows the study of arachidonic acid metabolites released from brain slices at different times after subarachnoid hemorrhage induction and reflects the residual capacity for arachidonic acid metabolism after the pathologic event The rats were sacrificed 30 minutes, 1 and 6 hours, and 2 days after subarachnoid hemorrhage was induced by the injection of 0 JO ml autologous arterial blood into the cisterna magna. Concentration of prostaglandin D 2 and 6-ketoprostaglandin F, a was increased significantly relative to control 2 days after induction. The concentration of prostaglandin E 2 was increased significantly 6 hours after induction, while ex vivo production of leukotriene C 4 was increased significantly at 1 and 6 hours and 2 days. The correlation between these results and the occurrence of vasospasm after subarachnoid hemorrhage is discussed. The results obtained from the ex vivo incubation of brain tissue slices after experimental subarachnoid hemorrhage suggest that after the hemorrhage there is a significant modification of brain eicosanoid metabolism, which could be of great importance in interpreting the pathogenesis of subarachnoid hemorrhage-related neuronal impairment (Stroke 1990;21:328-332)

Recent studies have suggested that metalloproteinases (MMP) might be involved in the pathogenesis of cerebral aneurysm formation and rupture and that elevated serum levels of MMP may effectively be considered as possible markers of cerebrovascular malformations. The present study was planned in order to verify if serum levels of MMPs may be the mirror of the MMP activity in the wall of intracranial aneurysms, reflecting the predisposition to aneurysm development and/or rupture. A series of 84 patients operated for intracranial cerebrovascular lesions (63 aneurysms and 21 arterovenous malformations (AVM)) and 20 controls entered the study. Among the 63 cases of intracranial aneurysms, nine were discovered before rupture, while 54 patients were included after subarachnoid hemorrhage (SAH). Using radioimmunoassay, plasma elastase levels were measured in all cases, while in 25 cases, when aneurysmectomy was possible, the activity of elastase and collagenase were measured in aneurysm samples. Mean plasma elastase level in patients bearing both an intracranial aneurysm or an intracranial AVM was significantly higher than in controls, while there was no significant difference between plasmatic level of elastase in patients with aneurysms when compared with patients bearing an intracranial AVM; there was no significant difference between mean elastase level in patients who suffered SAH and patients bearing an intracranial unruptured aneurysm. The activity of elastase and collagenase measured in the aneurysm wall were significantly higher in cases of ruptured than in unruptured aneurysms. The present results show that plasmatic level of elastase does not reflect the activity of MMP as measured in the aneurysm wall and that the patterns of MMP activities measured in the aneurysm wall differ considerably at different stages of SAH. This suggests that local rather than systemic changes in metalloproteases activity might be involved in cerebral aneurysm formation and rupture.

Endothelin (ET) is considered one of the most potent vasoconstrictor polypeptides; several experimental studies have suggested its possible role in the pathogenesis of arterial vasospasm after subarachnoid haemorrhage (SAH). Previously reported data on plasma and CSF levels of endothelin in patients with a diagnosis of SAH have been controversial. Cisternal endothelin CSF levels and the possibility that they could be related to vasospasm and other clinical patterns of SAH were investigated. CSF samples were obtained from 55 patients admitted after angiographic diagnosis of intracranial aneurysm. Levels of ET-1 and ET-3 were measured through radioimmunoassay technique.

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