Citations

Historically, the management of carotid artery disease has primarily focused on the degree of stenosis as the main indicator for assessing stroke etiology, risk, and need for intervention. However, accumulating evidence suggests that structural and biological features within the arterial wall, such as intraplaque hemorrhage, may have superior diagnostic, prognostic, and therapeutic values. Under current guidelines, unless an atheroma results in ≥50% stenosis, it is not considered the cause of a cerebrovascular event. This results in extensive and often unproductive diagnostic workup, prescription of ineffective medical therapy, and preclusion of patients from receiving revascularization procedures that have been shown to prevent recurrent cerebrovascular events in cases of ≥50% stenosis. A subset of embolic strokes of undetermined source, which account for up to 25% of all ischemic cerebrovascular events, are thought to be due to thromboembolic phenomena from undiagnosed plaque disruptions in nonstenotic arteries (<50% stenosis). Recently, it has been proposed to reclassify this subgroup of patients as symptomatic nonstenotic carotid if the carotid plaque ipsilateral to the cerebrovascular event presents with high-risk features including intraplaque hemorrhage, lipid-rich necrotic core, thinning/rupture of the fibrous cap, and ulceration. In this review, we first provide a historical overview of the chain of events and circumstances that resulted in the present management of carotid artery disease. Second, we embed the contemporary biomarkers of plaque vulnerability in a modern mechanistic paradigm of carotid plaque disruption and thromboembolization. Third, we review the clinically available imaging tools to detect these biomarkers, and how their use has started to shed light on the prevalence and natural history of this underdiagnosed condition. Fourth, we review recent clinical studies employing a contemporary definition of symptomatic nonstenotic carotid and discuss targeted treatments for this condition. Finally, we make a case to generate the much-needed high-level evidence to align the clinical management of patients with symptomatic nonstenotic carotid with a contemporary understanding of plaque disruption and thromboembolization.

ARISE (Aneurysm/AVM/cSDH Roundtable Discussion With Industry and Stroke Experts) organized a one-and-a-half day meeting and workshop and brought together representatives from academia, industry, and government to discuss the most promising approaches to improve outcomes for patients with chronic subdural hematoma (cSDH). The emerging role of middle meningeal artery embolization in clinical practice and the design of current and potential future trials were the primary focuses of discussion. Existing evidence for imaging, indications, agents, and techniques was reviewed, and areas of priority for study and key questions surrounding the development of new and existing treatments for cSDH were identified. Multiple randomized, controlled trials have met their primary efficacy end points, providing high-level evidence that middle meningeal artery embolization is a potent adjunctive therapy to the standard (surgical and nonsurgical) management of neurologically stable cSDH patients in terms of reducing rates of disease recurrence. Pooled data analyses following the formal conclusion and publication of these trials will form a robust foundation upon which guidelines can be strengthened for cSDH treatment modalities and optimal patient selection, as well as delineate future lines of investigation.

Abstract Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. Clin Cancer Res; 24(13); 3186–96. ©2018 AACR.