Head and neck cancer recurrence and mortality in nonselective cyclooxygenase inhibitor users.

OBJECTIVE: To determine whether ongoing use of a cyclooxygenase (COX) inhibitor is associated with a reduction in mortality and disease recurrence after head and neck cancer treatment. DESIGN: Retrospective case-control study. Patients A total of 325 potential subjects with head and neck squamous cell carcinoma were identified using an electronic patient database. Main Outcome Measure The rate of COX inhibitor use among patients who had died or whose disease had recurred (cases) was compared with the rate of use among survivors or those without recurrence (controls). The comparison was controlled for tumor site, tumor stage, treatment received, age, sex, race, smoking, and alcohol use. RESULTS: The 325 patients were compared by logistic regressions, with recurrence rate and survival status as the dependent variables. There was no difference in COX inhibitor exposure between patients with recurrence and those with no recurrence (P = .42) or between survivors and those who died of disease (P = .66). The median survival of COX inhibitor users, however, was 96 months, compared with 47 months in nonusers. The only independent variable with a significant impact on recurrence and survival was tumor stage at the time of diagnosis. CONCLUSIONS: Although preliminary in vitro studies suggest an antitumor effect of COX inhibitors in head and neck cancer, this study found no difference in head and neck cancer recurrence or survival in nonselective COX inhibitor users vs nonusers. A randomized, double-blinded controlled trial is needed to determine if COX inhibitors are an effective chemopreventive therapy in patients with head and neck cancer.

Renal artery stenosis by three-dimensional magnetic resonance angiography in type 2 diabetics with uncontrolled hypertension and chronic renal insufficiency: prevalence and effect on renal function.

BACKGROUND: The variable course of renal disease in type 2 diabetes mellitus in part may reflect associated atherosclerotic nephropathy. METHODS: To determine the influence of subcritical (<65%) renal artery stenosis (RAS) on the progression of chronic kidney disease, 45 patients with type 2 diabetes with uncontrolled hypertension and serum creatinine levels of 1.8 mg/dL or greater (>/=159.1 micromol/L) were screened by three-dimensional magnetic resonance angiography (MRA). Mean monthly decrease in reciprocal serum creatinine x 100 and time to initiation of dialysis therapy, adjusting for baseline serum creatinine level, were compared in those with and without RAS. Follow-up was censored at the time of death or angioplasty. RESULTS: At baseline, RAS-negative (RAS(-); n = 27) and RAS-positive (RAS(+); n = 18) groups were similar in duration of diabetes and hypertension, hyperlipidemia, blood pressure, diabetic management, and renal function. RAS(+) subjects were older (P = 0.04) and more likely to have claudication (P = 0.006), smoke (P = 0.02), and have heart disease (P = 0.06). During a median follow-up of 9.4 months, 3 patients underwent stent placement, 2 patients died, and 12 patients progressed to dialysis therapy. The RAS(+) group had a more rapid monthly decline in reciprocal serum creatinine x 100 (mean, 1.63 +/- 0.9 versus 0.69 +/- 1.0 [SD]; P = 0.04). The relative risk for progression to end-stage renal disease was 2.4 in the RAS(+) versus RAS(-) group. Multivariate analysis showed that this effect was not independent of several established atherosclerotic risk factors. CONCLUSION: MRA-detected RAS is common (40%) in patients with type 2 diabetes with uncontrolled hypertension and renal insufficiency. Subcritical (<65%) RAS is a significant risk factor for progressive renal failure.

Altered patterns of cellular gene expression in dermal microvascular endothelial cells infected with Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV; also called human herpesvirus 8) is believed to be the etiologic agent of Kaposi's sarcoma, multicentric Castleman's disease, and AIDS-associated primary effusion lymphoma. KSHV infection of human dermal microvascular endothelial cells (DMVEC) in culture results in the conversion of cobblestone-shaped cells to spindle-shaped cells, a characteristic morphological feature of cells in KS lesions. All spindle-shaped cells in KSHV-infected DMVEC cultures express the latency-associated nuclear protein LANA1, and a subfraction of these cells undergo spontaneous lytic cycle induction that can be enhanced by tetradecanoyl phorbol acetate (TPA) treatment. To study the cellular response to infection by KSHV, we used two different gene array screening systems to examine the expression profile of either 2,350 or 9,180 human genes in infected compared to uninfected DMVEC cultures in both the presence and absence of TPA. In both cases, between 1.4 and 2.5% of the genes tested were found to be significantly upregulated or downregulated. Further analysis by both standard and real-time reverse transcription-PCR procedures directly confirmed these results for 14 of the most highly upregulated and 13 of the most highly downregulated genes out of a total of 37 that were selected for testing. These included strong upregulation of interferon-responsive genes such as interferon response factor 7 (IRF7) and myxovirus resistance protein R1, plus upregulation of exodus 2 beta-chemokine, RDC1 alpha-chemokine receptor, and transforming growth factor beta3, together with strong downregulation of cell adhesion factors alpha(4)-integrin and fibronectin plus downregulation of bone morphogenesis protein 4, matrix metalloproteinase 2, endothelial plasminogen activator inhibitor 1, connective tissue growth factor, and interleukin-8. Significant dysregulation of several other cytokine-related genes or receptors, as well as endothelial cell and macrophage markers, and various other genes associated with angiogenesis or transformation was also detected. Western immunoblot and immunohistochemical analyses confirmed that the cellular IRF7 protein levels were strongly upregulated during the early lytic cycle both in KSHV-infected DMVEC and in the body cavity-based lymphoma BCBL1 PEL cell line.

Patterns of gene expression and a transactivation function exhibited by the vGCR (ORF74) chemokine receptor protein of Kaposi's sarcoma-associated herpesvirus.

The ORF74 or vGCR gene encoded by Kaposi's sarcoma-associated herpesvirus (KSHV; also called human herpesvirus 8) has properties of a ligand-independent membrane receptor signaling protein with angiogenic properties that is predicted to play a key role in the biology of the virus. We have examined the expression of vGCR mRNA and protein in primary effusion lymphoma (PEL) cell lines, PEL and multicentric Castleman's disease (MCD) tumors, Kaposi's sarcoma lesions and infected endothelial cell cultures. The vGCR gene proved to be expressed in PEL cell lines as a large spliced bicistronic mRNA of 3.2 kb that also encompasses the upstream vOX2 (K14) gene. This mRNA species was induced strongly by phorbol ester (TPA) and sodium butyrate treatment in the BCBL-1 cell line, but only weakly in the HBL6 cell line, and was classified as a relatively late and low-abundance delayed early class lytic cycle gene product. A complex bipartite upstream lytic cycle promoter for this mRNA was nestled within the intron of the 5'-overlapping but oppositely oriented latent-state transcription unit for LANA1/vCYC-D/vFLIP and responded strongly to both TPA induction and cotransfection with the KSHV RNA transactivator protein (RTA or ORF50) in transient reporter gene assays. A vGCR protein product of 45 kDa that readily dimerized was detected by Western blotting and in vitro translation and was localized in a cytoplasmic and membrane pattern in DNA-transfected Vero and 293T cells or adenovirus vGCR-transduced dermal microvascular endothelial cells (DMVEC) as detected by indirect immunofluorescence assay (IFA) and immunohistochemistry with a specific rabbit anti-vGCR antibody. Similarly, a subfraction of KSHV-positive cultured PEL cells and of KSHV (JSC-1) persistently infected DMVEC cells displayed cytoplasmic vGCR protein expression, but only after TPA or spontaneous lytic cycle induction, respectively. The vGCR protein was also detectable by immunohistochemical staining in a small fraction (0.5 to 3%) of the cells in PEL and MCD tumor and nodular Kaposi's sarcoma lesion specimens that were apparently undergoing lytic cycle expression. These properties are difficult to reconcile with the vGCR protein's playing a direct role in spindle cell proliferation, transformation, or latency, but could be compatible with proposed contributions to angiogenesis via downstream paracrine effects. The ability of vGCR to transactivate expression of both several KSHV promoter-driven luciferase (LUC) reporter genes and an NFkappaB motif containing the chloramphenicol acetyltransferase (CAT) reporter gene may also suggest an unexpected regulatory role in viral gene expression.