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Background: Thrombospondin-1 (TSP) is a 430-kd glycoprotein that is an important component of the extracellular matrix and is known to be a potent inhibitor of angiogenesis (i.e., formation of new blood vessels) both in vitro and in vivo. Several reports suggest that TSP possesses tumor suppressor function, possibly through its ability to inhibit tumor neovascularization. It has recently been shown that TSP expression is enhanced by the product of the p53 gene (also known as TP53). Purpose: We examined the role of TSP expression in tumor recurrence and overall survival in patients with invasive bladder cancer. We also examined the relationship between alterations in p53 protein expression, TSP expression, and tumor angiogenesis. Methods: Tumors from 163 patients (with a median follow-up of 7.7 years) who underwent radical cystectomy for invasive transitional cell carcinoma of the bladder (63 patients with organ-confined disease and no lymph node involvement, 48 patients with extravesical extension of the disease and no lymph node involvement, and 52 patients with metastasis to regional lymph nodes) were examined for TSP expression by immunohistochemistry, utilizing monoclonal antibody MA-II, which recognizes an epitope in the amino-terminal region of TSP. For each tumor, microvessel density counts and p53 protein expression status (via immunohistochemistry) were also determined. TSP expression was graded as low, moderate, or high without knowledge of clinical outcome, p53 status, and microvessel density count; tumors with moderate and high TSP levels were considered as one group. Groups of patients were compared by Kaplan-Meier product limit estimates of overall survival, the complement of cumulative incidence curves for recurrence-free survival, and the stratified logrank test. Reported P values are two-sided. Results: TSP expression was significantly associated with disease recurrence (P = .009) and overall survival (P = .023). Patients with low TSP expression exhibited increased recurrence rates and decreased overall survival. TSP expression was an independent predictor of disease recurrence (P = .002) and overall survival (P = .01) after stratifying for tumor stage, lymph node status, and histologic grade, but it was not independent of p53 status. TSP expression was significantly associated with p53 expression status (P = .001) and microvessel density counts (P = .001). Tumors with p53 alterations were significantly more likely to demonstrate low TSP expression, and tumors with low TSP expression were significantly more likely to demonstrate high microvessel density counts. Results of an analysis of variance were compatible with the hypothesis that p53 affects tumor angiogenesis by regulating the level of TSP expression. Conclusions and Implications: These data support the concept that TSP may possess a tumor-inhibitory function. TSP may act, in part, through the regulation of tumor neovascularity. These results may also provide insight into one mechanism by which p53 exerts its tumor suppressor effects, i.e., through the control of tumor angiogenesis. [J Natl Cancer Inst 1997;89:219-27]

OBJECTIVE: Clinical and radiographic responses were evaluated in patients with psoriatic arthritis (PsA) treated for up to 2 years with etanercept. METHODS: Patients were previously randomized to receive placebo or etanercept in a double-blind study and chose to participate in the current open-label extension phase. All patients received etanercept 25 mg twice weekly. Radiographic progression was determined at baseline, 1 year, and 2 years using the Sharp method modified to include joints frequently affected in PsA. Arthritis and psoriasis responses were determined using American College of Rheumatology 20% (ACR20) improvement criteria, PsA response criteria (PsARC), and the psoriasis area severity index (PASI). RESULTS: Of 205 patients randomized, 169 entered open-label, and 141 [71 randomized to receive placebo (placebo/etanercept) and 70 randomized to receive etanercept (etanercept/etanercept)] had radiographic data available for analysis at 2 years. ACR20 criteria, PsARC, and PASI 50 criteria were met by 64%, 84%, and 62%, respectively, of etanercept/etanercept patients at the end of the 48-week open-label period. Placebo/etanercept patients achieved comparable results within 12 weeks that were sustained at 48 weeks (63%, 80%, and 73%). Radiographic progression was inhibited in the etanercept/ etanercept patients (mean adjusted change in total Sharp score of -0.38 from baseline to 2 yrs). In placebo/etanercept patients, disease progression was inhibited once patients began receiving etanercept (mean adjusted change of -0.22 from 1 year to 2 years). Adverse event rates were similar to those observed during randomized phase, with only one serious adverse event deemed possibly related to etanercept. CONCLUSION: These data demonstrate a sustained benefit of etanercept treatment, including inhibition of radiographic progression, in patients with PsA.

OBJECTIVES: We hypothesized that oral estrogen replacement therapy would be less common among elderly women meeting criteria for Alzheimer's disease (AD) than among nondemented elderly women. For women with AD, we hypothesized that estrogen users would perform better on a cognitive task than would nonusers. DESIGN: A case-control study of estrogen replacement therapy, in which hierarchical procedures were used to control for potentially confounding effects of age and education. When cognitive performances were compared between estrogen users and nonusers with AD, the duration of dementia symptoms was an additional control variable. SETTING: Alzheimer's Disease Research Center at the University of Southern California, Los Angeles. SUBJECTS: Subjects were a volunteer sample of consecutively enrolled elderly women, recruited primarily from the community, who met clinical criteria for probable AD (n=143) or met criteria for nondemented control status (n=92). Seventy case patients who have subsequently died met histopathologic criteria for AD; one other demented woman who did not meet the autopsy criteria for AD was excluded from all analyses. MAIN OUTCOME MEASURES: Current use of estrogen replacement at the time of enrollment as reported by control subjects or by the primary caregivers of AD case patients. Among cases, performances on a brief cognitive screening instrument were compared between estrogen users (n=10) and nonusers (n=128) for whom this information was available. RESULTS: Alzheimer's disease case patients were significantly less likely than control subjects to use estrogen replacement (7% vs 18%), but groups did not differ with regard to the total number of prescription medications or to the most frequently prescribed class of drug (thyroid medication). Demented case patients using estrogen did not differ significantly from those not using estrogen in terms of age, education, or symptom duration, but their mean performance on a cognitive screening instrument was significantly better (Mini-Mental State examination scores of 14.9 vs 6.5). CONCLUSIONS: Findings are consistent with contentions that postmenopausal estrogen replacement therapy may be associated with a decreased risk of AD and that estrogen replacement may improve cognitive performance of women with this illness.

• OBJECTIVE. —We evaluated scores on a brief psychometric screening instrument—the Mini-Mental State Examination (MMSE)—for possible effects of gender, hypothesizing that women with Alzheimer's disease (AD) would perform more poorly than men. A significant gender difference was to be explored with post hoc item analyses. DESIGN. —Case-study design. A hierarchical regression procedure controlled for the possible influence on MMSE performance of demographic variables (eg, age, duration of dementia symptoms, education, and family history of dementia) before the effect of gender was analyzed. SETTING. —Data were gathered by trained neuropsychological examiners from subjects enrolled in the Alzheimer's Disease Research Center at the University of Southern California, Los Angeles. SUBJECTS. —One hundred forty-two subjects who met strict criteria for probable AD and 121 nondemented elderly subjects were included in the study. All subjects underwent periodic neuropsychological testing. We extracted MMSE scores and demographic data to test the hypothesis that women would perform more poorly than men on the MMSE. CRITERION MEASURE. —The MMSE was chosen because of its wide use in clinical and research settings to screen for the presence or severity of dementia. RESULTS. —After controlling for the demographic variables for subjects with AD, we observed a significant difference in the predicted direction for total MMSE score, but there was no significant gender effect on the MMSE for the nondemented elderly sample. Among subjects with AD, gender-associated differences were limited to only a subset of MMSE items. CONCLUSIONS. —Results imply that MMSE performance may differ between men and women with AD and that differences might pertain only to discrete areas of cognitive functioning. Although gender effects were relatively small, findings indicate the relevance of gender to studies of AD.