Urinary estrogen metabolites and prostate cancer: a case-control study in the United States

Objective: To analyze the association of prostate cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone (2-OHE1) to 16-hydroxyestrone (16-OHE1), in a case–control study conducted in Buffalo, NY, between 1998 and 2001. Methods: One hundred and thirteen men, aged 45–85 years, with incident, primary pathologically confirmed prostate cancer were enrolled in the study; 317 residence-matched controls were also enrolled. Cases were enrolled and the specimens collected before starting any therapy. To exclude latent prostate carcinomas, the present study included only patients with clinically apparent disease (stage B and higher). Prostate cancer cases and control subjects were excluded if on hormonal treatment, or affected with metabolic or endocrine diseases. Control subjects with a prostate-specific antigen (PSA) value higher than 4ng/ml were excluded from the control group. Urine was used for the determinations of 2-OHE1 and 16-OHE1. Age, race, body weight, waist-to-hip ratio, and smoking were analyzed as possible confounders. Results: Although the results were not statistically significant, elevated 2-OHE1 urinary levels suggested a reduced prostate cancer risk: men in the highest tertile had an adjusted odds ratio (OR) for prostate cancer of 0.83 (95% confidence interval (CI) 0.43–1.44). Conversely, elevated 16-OHE1 urinary levels were associated with an increased risk of prostate cancer: the highest tertile had an adjusted OR for prostate cancer of 1.69 (95% CI 0.93–3.06, p for linear trend = 0.02). Finally, the 2-OHE1 to 16-OHE1 ratio was associated with a reduced risk of prostate cancer with an OR of 0.61 (95% CI 0.33–1.15, p for linear trend = 0.04). Conclusion: Results of this case–control study suggest that the estrogen metabolic pathway favoring 2-hydroxylation over 16-hydroxylation may reduce risk of clinically evident prostate cancer.     

Expression of hypoxia-inducible factor-1alpha in cervical carcinomas: correlation with tumor oxygenation

PURPOSE: To investigate the relations between hypoxia-inducible factor-1 (HIF-1), tumor oxygenation, and clinical correlates in patients with locally advanced carcinoma of the uterine cervix. METHODS AND MATERIALS: Biopsies from 42 patients with invasive cervical carcinoma and previous polarographic O2 measurements were assessed for the expression of HIF-1alpha using digitized microscopic imaging and analysis. RESULTS: The HIF-1alpha expression levels ranged from <0.1% to 10.7% of the total tumor area; the positive staining was localized exclusively to the nuclei. Three distinct arrangement patterns of HIF-1alpha-positive cells in relation to blood vessels were identified using spatial image mapping: (1) most HIF-1alpha-positive cells were located within the typical oxygen diffusion distance in tissue (< or =150 microm to the nearest blood vessel); (2) most HIF-1alpha-positive cells were located in the vicinity (< or =60 microm) of the blood vessels; and (3) no apparent spatial relationship was found between HIF-1alpha-positive cells and blood vessels. A statistically significant association was found between HIF-1alpha expression and tumor oxygenation (Spearman correlation coefficient = 0.4, p <0.01), as determined with the Eppendorf pO2 histograph. No correlation was found between the level of HIF-1alpha expression and patient outcome, using disease-free survival as the end point. CONCLUSION: Our results suggest that HIF-1alpha expression may represent a useful biologic marker for hypoxia in uterine cervical cancer.     

Pretreatment with troglitazone decreases lethality during endotoxemia in mice

Troglitazone is an oral antidiabetic drug that is a ligand for peroxisome proliferator activated receptor gamma (PPARgamma). Based on other studies that have implicated an immunosuppressive role for PPARgamma during inflammatory responses, we hypothesized that troglitazone treatment would improve survival in a murine model of endotoxemia and that the protective effect would be mediated by decreased expression of inflammatory mediators. C57Bl/6N x Sv/129 (wild-type [WT]) or PPARalpha null mice treated for 2 weeks with dietary troglitazone (0.1%) had significantly fewer deaths and a higher LD(50) value compared to control-fed mice when challenged with lipopolysaccharide (LPS). PPARalpha null mice were more sensitive to the lethal effects of LPS as evidenced by a 2-fold lower LD(50) (6.6 mg/kg) compared to WT mice (14.6 mg/kg). Troglitazone treatment had no significant effect on LPS-induced plasma TNF, glucose, or nitric oxide levels in WT or PPARalpha null mice at any of the time points examined. However, troglitazone treatment significantly reduced LPS-induced plasma IL-6 levels in both WT and PPARalpha null mice. The results of these studies suggest that troglitazone treatment protects mice against a lethal challenge of LPS, but whether or not this effect is mediated through decreased expression of inflammatory mediators remains unclear.     

Comparison of pre- and postcontrast 3D time-of-flight MR angiography for the evaluation of distal intracranial branch occlusions in acute ischemic stroke

BACKGROUND AND PURPOSE: Three-dimensional time-of-flight (TOF) MR angiography is used routinely in stroke workup to detect arterial occlusions, but a major drawback is its inadequate depiction of vessels with slow or in-plane flow. We hypothesized that the use of contrast-enhanced MR angiography improves delineation of vessels with diminished or absent flow on precontrast MR angiograms. METHODS: Pre- and postcontrast 3D TOF MR angiograms were acquired in 55 consecutive patients with acute stroke. Patency of 480 intracranial vessels was assessed on both the pre- and postcontrast angiograms. Diffusion-weighted (DW) and perfusion-weighted (PW) imaging data were also obtained and results correlated with those of pre- and postcontrast MR angiography. RESULTS: For 50 abnormal vessel segments seen on precontrast MR angiograms, postcontrast MR angiograms resulted in change in the vascular signal intensity in 70% (35 vessel segments); 94% of these changes showed a greater extent of vessel patency. Venous and soft-tissue contrast enhancement had no effect on assessment in 95% of all 480 vessels examined. Interobserver reliability was moderate, with postcontrast interpretation (kappa = 0.48) showing a slight improvement over precontrast interpretation (kappa = 0.41). Good agreement was found between the TOF results and the pooled DW and PW imaging results. CONCLUSIONS: Compared with precontrast 3D TOF MR angiograms, postcontrast 3D TOF angiograms improve assessment of intracranial vessel patency in acutely ischemic vascular territories. In some patients, an improved understanding of acute ischemic stroke was obtained by viewing the pre- and postcontrast images. Postcontrast MR angiography should be included in the MR evaluation of acute stroke.