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Neoplasms can compromise spinal cord function, resulting in devastating neurological deficits with significant limitations in daily functioning, including immobilizing pain and neurological dysfunction. Among all causes of myelopathies in cancer patients, epidural spinal cord compression (ESCC) is by far the most common, but its incidence varies widely based on cancer type. An estimated 5% of cancer patients develop epidural metastatic invasion, and 2.5% of all cancer patients have at least one hospitalization for epidural spinal metastases. In a cancer patient reporting back pain, incontinence, weakness, or sensory changes, it is essential that epidural disease be considered. Knowledge of pathophysiology, clinical features, diagnostic approaches, and treatment options of ESCC is essential in decreasing the potential morbidities associated with this entity in cancer patients.

Objective—The purpose of this study was to distinguish the contributions of CD44 expressed on bone marrow–derived and non–bone marrow–derived cells to atherosclerosis.Methods and Results—Using bone marrow chimeras, we compared the contributions of CD44 expressed on bone marrow–derived cells versus non–bone marrow–derived cells to the vascular inflammation underlying atherosclerosis. We show that CD44 in both bone marrow–derived and non–bone marrow–derived compartments promotes atherosclerosis in apoE−/−mice and mediates macrophage and T cell recruitment to lesions in vivo. We also demonstrate that CD44 on endothelial cells (ECs) as well as on macrophages and T cells enhances leukocyte-endothelial cell adhesion and transendothelial migration in vitro. Furthermore, CD44 on vascular smooth muscle cells (VSMCs) regulates their hyaluronan (HA)-dependent migration. Interestingly, in mice lacking CD44 in both compartments, where we observed the least inflammation, we also observed enhanced fibrous cap formation.Conclusions—CD44 expressed on bone marrow–derived and non–bone marrow–derived cells both promote atherosclerosis in apoE-deficient mice. Furthermore, CD44 plays a pivotal role in determining the balance between inflammation and fibrosis in atherosclerotic lesions which can impact clinical outcome in humans.

Objective—To identify early changes in vascular gene expression mediated by CD44 that promote atherosclerotic disease in apolipoprotein E (apoE)–deficient (apoE−/−) mice.Methods and Results—We demonstrate that CD44 is upregulated and functionally activated in aortic arch in the atherogenic environment of apoE−/− mice relative to wild-type (C57BL/6) controls. Moreover, CD44 activation even in apoE−/− mice is selective to lesion-prone regions because neither the thoracic aorta from apoE−/− mice nor the aortic arch of C57BL/6 mice exhibited upregulation of CD44 compared with thoracic aorta of CD57BL/6 mice. Consistent with these observations, gene expression profiling using cDNA microarrays and quantitative polymerase chain reaction revealed that ≈155 of 19 200 genes analyzed were differentially regulated in the aortic arch, but not in the thoracic aorta, in apoE−/− CD44−/− mice compared with apoE−/− CD44+/+ mice. However, these genes were not regulated by CD44 in the context of a C57BL/6 background, illustrating the selective impact of CD44 on gene expression in a proatherogenic environment. The patterns of differential gene expression implicate CD44 in focal adhesion formation, extracellular matrix deposition, and angiogenesis, processes critical to atherosclerosis.Conclusions—CD44 is an early mediator of atherogenesis by virtue of its ability to regulate vascular gene expression in response to a proatherogenic environment.

Background— Antagonism or deletion of the receptor (the TP) for the cyclooxygenase (COX) product thromboxane (Tx)A 2 , retards atherogenesis in apolipoprotein E knockout (ApoE KO) mice. Although inhibition or deletion of COX-1 retards atherogenesis in ApoE and LDL receptor (LDLR) KOs, the role of COX-2 in atherogenesis remains controversial. Other products of COX-2, such as prostaglandin (PG) I 2 and PGE 2 , may both promote inflammation and restrain the effects of TxA 2 . Thus, combination with a TP antagonist might reveal an antiinflammatory effect of a COX-2 inhibitor in this disease. We addressed this issue and the role of TxA 2 in the promotion and regression of diffuse, established atherosclerosis in Apobec-1/LDLR double KOs (DKOs). Methods and Results— TP antagonism with S18886, but not combined inhibition of COX-1 and COX-2 with indomethacin or selective inhibition of COX-2 with Merck Frosst (MF) tricyclic, retards significantly atherogenesis in DKOs. Although indomethacin depressed urinary excretion of major metabolites of both TxA 2 , 2,3-dinor TxB 2 (Tx-M), and PGI 2 , 2,3-dinor 6-keto PGF 1α (PGI-M), only PGI-M was depressed by the COX-2 inhibitor. None of the treatments modified significantly the increase in lipid peroxidation during atherogenesis, reflected by urinary 8,12-iso-iPF 2α -VI. Combination with the COX-2 inhibitor failed to augment the impact of TP antagonism alone on lesion area. Rather, analysis of plaque morphology reflected changes consistent with destabilization of the lesion coincident with augmented formation of TxA 2 . Despite a marked effect on disease progression, TP antagonism failed to induce regression of established atherosclerotic disease in this model. Conclusions— TP antagonism is more effective than combined inhibition of COX-1 and COX-2 in retarding atherogenesis in Apobec-1/LDLR DKO mice, which perhaps reflects activation of the receptor by multiple ligands during disease initiation and early progression. Despite early intervention, selective inhibition of COX-2, alone or in combination with a TP antagonist, failed to modify disease progression but may undermine plaque stability when combined with the antagonist. TP antagonism failed to induce regression of established atherosclerotic disease. TP ligands, including COX-1 (but not COX-2)–derived TxA 2 , promote initiation and early progression of atherogenesis in Apobec-1/LDLR DKOs but appear unimportant in the maintenance of established disease.

Prostaglandin (PG) E 2 is formed from PGH 2 by a series of PGE synthase (PGES) enzymes. Microsomal PGES-1 −/− (mPGES-1 −/− ) mice were crossed into low-density lipoprotein receptor knockout (LDLR −/− ) mice to generate mPGES-1 −/− LDLR −/− s. Urinary 11α-hydroxy-9, 15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M) was depressed by mPGES-1 deletion. Vascular mPGES-1 was augmented during atherogenesis in LDLR −/− s. Deletion of mPGES-1 reduced plaque burden in fat-fed LDLR −/− s but did not alter blood pressure. mPGES-1 −/− LDLR −/− plaques were enriched with fibrillar collagens relative to LDLR −/− , which also contained small and intermediate-sized collagens. Macrophage foam cells were depleted in mPGES-1 −/− LDLR −/− lesions, whereas the total areas rich in vascular smooth muscle cell (VSMC) and matrix were unaltered. mPGES-1 deletion augmented expression of both prostacyclin (PGI 2 ) and thromboxane (Tx) synthases in endothelial cells, and VSMCs expressing PGI synthase were enriched in mPGES-1 −/− LDLR −/− lesions. Stimulation of mPGES-1 −/− VSMC and macrophages with bacterial LPS increased PGI 2 and thromboxane A 2 to varied extents. Urinary PGE-M was depressed, whereas urinary 2,3-dinor 6-keto PGF 1α , but not 2,3-dinor-TxB 2 , was increased in mPGES-1 −/− LDLR −/− s. mPGES-1-derived PGE 2 accelerates atherogenesis in LDLR −/− mice. Disruption of this enzyme retards atherogenesis, without an attendant impact on blood pressure. This may reflect, in part, rediversion of accumulated PGH 2 to augment formation of PGI 2 . Inhibitors of mPGES-1 may be less likely than those selective for cyclooxygenase 2 to result in cardiovascular complications because of a divergent impact on the biosynthesis of PGI 2 .