Anteroposterior Combined Surgery of a Rare Massive Epithelioid Hemangioendothelioma at the Cervicothoracic Junction.

Epithelioid hemangioendothelioma is a rare mesenchymal tumor of vascular endothelial origin. Non-soft tissue epithelioid hemangioendothelioma can also be seen in different organs. Although chemotherapy has been used in some patients, complete surgical removal of the tumor tissue has proven to be the most durable solution. A 15-year-old female patient was admitted to our institution with right arm and neck pain. The patient complained of numbness and weakness in the right hand. Computerized tomography indicated an expansile lesion exhibiting osteolytic features located predominantly on the right side of the corpus, pedicle, lamina, and lateral processes of the C7-T1 vertebra. The patient underwent a surgical procedure involving the application of a bilateral C4-5-6 lateral mass screw, left C7-T1 pedicle screw, and bilateral T2-3 pedicle screw and fusion. The complete residual neoplasm was surgically removed during the procedure. Due to the rarity of epithelioid hemangioendothelioma, the existing literature on this topic is confined to case reports, supplemented by a small number of retrospective descriptive case series that aimed to improve our understanding of the clinical, pathological, and molecular features of the condition, as well as to guide potential treatment strategies.

Early brain injury, an evolving frontier in subarachnoid hemorrhage research.

Subarachnoid hemorrhage (SAH), predominantly caused by a ruptured aneurysm, is a devastating neurological disease that has a morbidity and mortality rate higher than 50%. Most of the traditional in vivo research has focused on the pathophysiological or morphological changes of large-arteries after intracisternal blood injection. This was due to a widely held assumption that delayed vasospasm following SAH was the major cause of delayed cerebral ischemia and poor outcome. However, the results of the CONSCIOUS-1 trial implicated some other pathophysiological factors, independent of angiographic vasospasm, in contributing to the poor clinical outcome. The term early brain injury (EBI) has been coined and describes the immediate injury to the brain after SAH, before onset of delayed vasospasm. During the EBI period, a ruptured aneurysm brings on many physiological derangements such as increasing intracranial pressure (ICP), decreased cerebral blood flow (CBF), and global cerebral ischemia. These events initiate secondary injuries such as blood-brain barrier disruption, inflammation, and oxidative cascades that all ultimately lead to cell death. Given the fact that the reversal of vasospasm does not appear to improve patient outcome, it could be argued that the treatment of EBI may successfully attenuate some of the devastating secondary injuries and improve the outcome of patients with SAH. In this review, we provide an overview of the major advances in EBI after SAH research.

PHA-543613 preserves blood-brain barrier integrity after intracerebral hemorrhage in mice.

BACKGROUND AND PURPOSE: Blood-brain barrier disruption and consequent vasogenic edema formation codetermine the clinical course of intracerebral hemorrhage (ICH). This study examined the effect of PHA-543613, a novel α7 nicotinic acetylcholine receptor agonist, on blood-brain barrier preservation after ICH. METHODS: Male CD-1 mice, subjected to intrastriatal blood infusion, received PHA-543613 alone or in combination with α7 nicotinic acetylcholine receptor antagonist methyllycaconitine or phosphatidylinositol 3-kinase inhibitor wortmannin. RESULTS: PHA-543613 alone, but not in combination with methyllycaconitine or wortmannin, inhibited glycogen synthase kinase-3ß, thus, stabilizing ß-catenin and tight junction proteins, which was paralleled by improved blood-brain barrier stability and ameliorated neurofunctional deficits in ICH animals. CONCLUSIONS: PHA-543613 preserved blood-brain barrier integrity after ICH, possibly through phosphatidylinositol 3-kinase-Akt-induced inhibition of glycogen synthase kinase-3ß and ß-catenin stabilization.

Role of SCH79797 in maintaining vascular integrity in rat model of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Plasma thrombin concentration is increased after subarachnoid hemorrhage (SAH). However, the role of thrombin receptor (protease-activated receptor-1 [PAR-1]) in endothelial barrier disruption has not been studied. The aims of this study were to investigate the role of PAR-1 in orchestrating vascular permeability and to assess the potential therapeutics of a PAR-1 antagonist, SCH79797, through maintaining vascular integrity. METHODS: SCH79797 was injected intraperitoneally into male Sprauge-Dawley rats undergoing SAH by endovascular perforation. Assessment was conducted at 24 hours after SAH for brain water content, Evans blue content, and neurobehavioral testing. To explore the role of PAR-1 activation and the specific mechanism of SCH79797's effect after SAH, Western blot, immunoprecipitation, and immunofluorescence of hippocampus tissue were performed. A p21-activated kinase-1 (PAK1) inhibitor, IPA-3, was used to explore the underlying protective mechanism of SCH79797. RESULTS: At 24 hours after SAH, animals treated with SCH79797 demonstrated a reduction in brain water content, Evans blue content, and neurobehavioral deficits. SCH79797 also attenuated PAR-1 expression and maintained the level of vascular endothelial-cadherin, an important component of adherens junctions. Downstream to PAR-1, c-Src-dependent activation of p21-activated kinase-1 led to an increased serine/threonine phosphorylation of vascular endothelial-cadherin; immunoprecipitation results revealed an enhanced binding of phosphorylated vascular endothelial-cadherin with endocytosis orchestrator ß-arrestin-2. These pathological states were suppressed after SCH79797 treatment. CONCLUSIONS: PAR-1 activation after SAH increases microvascular permeability, at least, partly through a PAR-1-c-Src-p21-activated kinase-1-vascular endothelial-cadherin phosphorylation pathway. Through suppressing PAR-1 activity, SCH79797 plays a protective role in maintaining microvascular integrity after SAH.

Transition of research focus from vasospasm to early brain injury after subarachnoid hemorrhage.

Subarachnoid hemorrhage is a devastating disease that can be difficult to manage. Not only is the initial bleeding and rebleeding associated with high mortality, but a large fraction of patients also develop a delayed neurological deficit even when the aneurysm was successfully secured with clipping or coiling. Past research effort has traditionally been focused on vasospasm, which was conceived to be the sole factor for delayed neurological deficit. The failure of anti-vasospastic drugs to improve outcome in clinical trials has brought into focus the significance of early brain injury. The immediate events associated with subarachnoid hemorrhage, including increased intracranial pressure, decreased cerebral blood flow and global ischemia initiate a cascade of pathological changes that occur before the onset of delayed vasospasm. These pathological changes in the very early stage of the hemorrhage propagate and cause blood-brain barrier disruption, inflammation, oxidative stress and cell death. Focusing only on the treatment of vasospasm with complete disregard for early brain injury is insufficient for the management of subarachnoid hemorrhage. Instead, a therapeutic intervention has to aim at stopping the molecular cascades of early brain injury that may lead to long-term deficits in addition to vasospasm. We review the pathological mechanisms of early brain injury, which may reveal new therapeutic avenues that can be exploited to serve as combination therapy with anti-vasospasm medications in the future.

Isoflurane attenuates blood-brain barrier disruption in ipsilateral hemisphere after subarachnoid hemorrhage in mice.

BACKGROUND AND PURPOSE: We examined effects of isoflurane, volatile anesthetics, on blood-brain barrier disruption in the endovascular perforation model of subarachnoid hemorrhage (SAH) in mice. METHODS: Animals were assigned to sham-operated, SAH+vehicle-air, SAH+1%, or 2% isoflurane groups. Neurobehavioral function, brain water content, Evans blue dye extravasation, and Western blotting for sphingosine kinases, occludin, claudin-5, junctional adhesion molecule, and vascular endothelial cadherin were evaluated at 24 hours post-SAH. Effects of sphingosine kinase (N,N-dimethylsphingosine) or sphingosine-1-phosphate receptor-1/3 (S1P1/3) inhibitors (VPC23019) on isoflurane's action were also examined. RESULTS: SAH aggravated neurological scores, brain edema, and blood-brain barrier permeability, which were prevented by 2% but not 1% isoflurane posttreatment. Two percent isoflurane increased sphingosine kinase-1 expression and prevented a post-SAH decrease in expressions of the blood-brain barrier-related proteins. Both N,N-dimethylsphingosine and VPC23019 abolished the beneficial effects of isoflurane. CONCLUSIONS: Two percent isoflurane can suppress post-SAH blood-brain barrier disruption, which may be mediated by sphingosine kinase 1 expression and sphingosine-1-phosphate receptor-1/3 activation.

Intraperitoneal administration of CDP-choline or a combination of cytidine plus choline improves nerve regeneration and functional recovery in a rat model of sciatic nerve injury.

OBJECTIVE: Topical cytidine-5'-diphosphocholine (CDP-choline) improves functional recovery and promotes nerve regeneration in sciatic nerve injury in rats. The aims of this study were to test whether systemic treatment with CDP-choline was effective in improving the recovery of injured sciatic nerve, and to determine whether the cytidine and/or choline moieties of CDP-choline contribute to its beneficial actions. METHODS: Seventy Sprague-Dawley rats underwent a surgical procedure that involved transectioning and immediate surgical repairing of the right sciatic nerve. Rats were assigned to one of five groups and administered intraperitoneally 1 ml/kg of saline (control) or saline containing 600 µmol/kg of each of CDP-choline, cytidine, choline, or cytidine+choline. RESULTS: Recovery in sciatic function index score was greater in rats treated with CDP-choline, choline, or cytidine+choline at 8 and 12 weeks after the interventions. Peripheral nerve regeneration evaluated by electromyography at 12 weeks was also greater in rats receiving CDP-choline (228% of control), choline (168% of control), or cytidine+choline (221% of control). Axon counts and axon density increased significantly following CDP-choline, choline, or cytidine+choline, respectively. Treatment with equivalent dose of cytidine failed to affect sciatic function index, electromyography, and axon counts. Treatment with CDP-choline, but not its metabolites improved nerve adherence and separability score. CONCLUSION: These data show that intraperitoneal CDP-choline, as well as the combination of its metabolites, cytidine+choline, improves functional recovery and promotes regeneration of injured sciatic nerves in rats. CDP-choline also improves nerve adherence and separability.

Fibroblast growth factors preserve blood-brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice.

Fibroblast growth factors (FGFs) maintain and promote vascular integrity; however whether FGFs protect the blood-brain barrier (BBB) after intracerebral hemorrhage (ICH) remains unexplored. In this present study, we hypothesized that exogenous FGF administration attenuates brain injury after ICH, specifically by preserving endothelial adherens junctions, therefore reducing vasogenic brain edema and attenuating neurofunctional deficits in mice subjected to experimental ICH. Acid fibroblast growth factor (FGF1) or basic fibroblast growth factor (FGF2) was administered intracerebroventricularly (ICV) at 0.5 h after intrastriatal injection of bacterial collagenase (cICH) or autologous whole blood (bICH). Fibroblast growth factor receptor (FGFR) inhibitor PD173074 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were additionally administered with FGF2. The selective Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) inhibitor Y27632 was independently administered at 0.5 h after cICH. Brain water content and neurofunctional deficits were evaluated at 24 and 72h after ICH induction. Evans blue extravasation as well as Western blot analysis for the quantification of activated FGFR, Akt, Ras-related C3 botulinum toxin substrate 1 (Rac1), Ras homolog gene family member A (RhoA) and adherens junction proteins (p120-catenin, ß-catenin and VE-cadherin) were conducted at 72 h post-cICH. FGF treatment reduced perihematomal brain edema and improved neurofunctional deficits at 72 h after experimental ICH (p<0.05, compared to vehicle); however, FGFR and PI3K inhibition reversed these neuroprotective effects. Exogenous FGF2 increased activated FGFR, Akt, and Rac1 but reduced activated RhoA protein expression at 72 h after cICH (p<0.05, compared to vehicle), which was reversed by FGFR and PI3K inhibition. Y27632 treatment reduced brain injury at 72 h after cICH (p<0.05, compared to vehicle) and increased the expression of catenins (p120-catenin, ß-catenin). In conclusion, our findings suggest that exogenous FGF treatment reduced RhoA activity via FGFR-induced activation of the PI3K-Akt-Rac1 signaling pathway, thus preserving BBB integrity, and therefore attenuating secondary brain injury after experimental ICH in mice.

Comparison of prognostic scores and surgical approaches to treat spinal metastatic tumors: a review of 57 cases.

Surgical treatment of metastatic spinal cord compression with or without neural deficit is controversial. Karnofsky and Tokuhashi scores have been proposed for prognosis of spinal metastasis. Here, we conducted a retrospective analysis of Karnofsky and modified Tokuhashi scores in 57 consecutive patients undergoing surgery for secondary spinal metastases to evaluate the value of these scores in aiding decision making for surgery. Comparison of preoperative Karnofsky and modified Tokuhashi scores with the type of the surgical approach for each patient revealed that both scores not only reliably estimate life expectancy, but also objectively improved surgical decisions. When the general status of the patient is poor (i.e., Karnofsky score less than 40% or modified Tokuhashi score of 5 or greater), palliative treatments and radiotherapy, rather than surgery, should be considered.