Faculty Bibliography

BACKGROUND: Studies in animals have suggested that calcium may reduce the risk of colorectal cancer. However, results from epidemiologic studies of intake of calcium or dairy foods and colorectal cancer risk have been inconclusive. METHODS: We pooled the primary data from 10 cohort studies in five countries that assessed usual dietary intake by using a validated food frequency questionnaire at baseline. For most studies, follow-up was extended beyond that in the original publication. The studies included 534 536 individuals, among whom 4992 incident cases of colorectal cancer were diagnosed between 6 and 16 years of follow-up. Pooled multivariable relative risks for categories of milk intake and quintiles of calcium intake and 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided. RESULTS: Milk intake was related to a reduced risk of colorectal cancer. Compared with the lowest category of intake (<70 g/day), relative risks of colorectal cancer for increasing categories (70-174, 175-249, and > or =250 g/day) of milk intake were 0.94 (95% CI = 0.86 to 1.02), 0.88 (95% CI = 0.81 to 0.96), and 0.85 (95% CI = 0.78 to 0.94), respectively (P(trend)<.001). Calcium intake was also inversely related to the risk of colorectal cancer. The relative risk for the highest versus the lowest quintile of intake was 0.86 (95% CI = 0.78 to 0.95; P(trend) =.02) for dietary calcium and 0.78 (95% CI = 0.69 to 0.88; P(trend)<.001) for total calcium (combining dietary and supplemental sources). These results were consistent across studies and sex. The inverse association for milk was limited to cancers of the distal colon (P(trend)<.001) and rectum (P(trend) =.02). CONCLUSION: Higher consumption of milk and calcium is associated with a lower risk of colorectal cancer

PURPOSE: Neutral endopeptidase (NEP) is a cell-surface peptidase that inactivates neuropeptide growth factors implicated in prostate cancer progression. The clinical significance of decreased NEP expression observed in prostate cancer is unclear. We investigated whether decreased NEP expression in localized prostate cancers is associated with prostate-specific antigen (PSA) relapse after radical prostatectomy. EXPERIMENTAL DESIGN: NEP expression patterns were examined by immunohistochemistry in 223 men, who underwent radical prostatectomy between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) with available representative tissues and adequate follow up. We also examined whether hypermethylation of the NEP promoter contributes to down-regulation of NEP protein expression in a subset of patients that showed decreased NEP expression (n = 22). RESULTS: Three patterns of NEP expression were observed: (a) membranous expression similar to benign prostate epithelium (n = 82; 37%); (b) complete loss of NEP expression in prostate cancer compared with adjacent benign prostate glands (n = 105; 47%); and (c) heterogeneous NEP expression (n = 36; 16%). In a multivariate analysis, complete loss of NEP expression was associated with PSA relapse after controlling for grade, stage, pretreatment PSA, and race simultaneously (hazard ratio, 1.99; 95% confidence interval, 1.13-3.52; two-sided chi(2) P = 0.017). In addition, DNA hypermethylation of the NEP promoter was frequently (73%) identified in a subset of 22 of cases that showed decreased NEP expression. CONCLUSION: Our data suggest that decreased NEP expression might contribute to progression of localized prostate cancer after surgery. Data also suggest that methylation is an important mechanism of NEP protein silencing. Larger prospective studies are required for confirmation

Experimental and epidemiological evidence supports a role for sex steroid hormones in the pathogenesis of ovarian cancer. We investigated the association between ovarian cancer risk and pre-diagnostic blood concentrations of testosterone, androstenedione, DHEAS, estrone and SHBG. A case-control study nested within 3 cohorts, in New York (USA), Umea (Sweden) and Milan (Italy), included 132 subjects with primary invasive epithelial ovarian cancer. For each case subject, 2 controls were selected who matched a case on cohort, menopausal status, age and date of recruitment and, if premenopausal, day of the menstrual cycle at blood donation. Only women who did not use exogenous hormones at blood donation were included in the study. Conditional logistic regression was used to relate cancer risk to sex steroid hormone concentrations with adjustment for potential confounders. No clear association was observed between ovarian cancer risk and any of the 5 hormones under study. In the premenopausal group, the risk appeared to increase with increasing blood concentrations of androstenedione (upper vs. lower tertile OR = 2.35; 95% CI = 0.81-6.82.), but the small number of subjects in the sub-group precluded reaching unambiguous conclusions about such association. Our study does not support previous observations relating elevations in blood levels of the major sex steroid hormones to an increased risk of ovarian cancer, but offers some evidence that elevated circulating androstenedione before menopause may be associated with increased ovarian cancer risk

BACKGROUND: Follicle-stimulating hormone (FSH), a member of gonadotropin family, is critical for follicular maturation and ovarian steroidogenesis. Serum FSH levels are known to fluctuate during different phases of menstrual cycle in premenopausal women, and increase considerably after the menopause as a result of ovarian function cessation. There is little existing evidence to guide researchers in estimating the reliability of serum FSH measurements. The objective of this study was to assess the reliability of FSH measurement using stored sera from an ongoing prospective cohort - the NYU Women's Health Study. METHODS: Sixty healthy women (16 premenopausal, 44 postmenopausal), who donated at least two blood samples at approximately 1-year intervals were studied. An immunoradiometric assay using a sandwich monoclonal antibodies technique was used to measure FSH levels in serum. RESULTS: The reliability of a single log-transformed FSH measurement, as determined by the intraclass correlation coefficient, was 0.70 for postmenopausal women (95% confidence interval (CI), 0.55-0.82) and 0.09 for premenopausal women (95% CI, 0-0.54). CONCLUSIONS: These results suggest that a single measurement is sufficient to characterize the serum FSH level in postmenopausal women and could be a useful tool in epidemiological research. For premenopausal women, however, the reliability coefficient was low, suggesting that a single determination is insufficient to reliably estimate a woman's true average serum FSH level and repeated measurements are desirable

Reliability of serum levels of iron, ferritin and nitrite (NO(2)(-)) over a 2-year period were evaluated in 40 healthy women (20 pre-menopausal and 20 post-menopausal), ages 39-65 years, from the New York University Women's Health Study (NYUWHS). Three blood samples per woman collected at yearly intervals were analyzed. Reliability coefficients (RCs) of serum iron, ferritin, and nitrite were 0.03 (95% confidence interval (CI), 0-0.33), 0.90 (95% CI, 0.79-0.95), and 0.72 (95% CI, 0.50-0.86), respectively, for pre-menopausal women, and 0.26 (95% CI, 0-0.56), 0.77 (95% CI, 0.59-0.89), and 0.55 (95% CI, 0.30-0.77), respectively, for post-menopausal women. In a case-control study nested within NYUWHS cohort, serum levels of nitrite, ferritin, and iron were measured in women apparently healthy at the time of blood donation but diagnosed with renal cancer 1.8-12.2 years later (n=24) and in individually matched controls (two per case). The results suggest that high serum levels of ferritin and nitrite may be associated with a decreased risk of renal cancer (odds ratio (OR), 0.55, 95% CI, 0.15-2.01 for ferritin, and OR, 0.52, 95% CI, 0.17-1.60 for nitrite in women with above median level as compared to women with below median level). The possible role of ferritin and nitrite in renal cancer is discussed

PURPOSE: Melanoma cells can be found in the circulation of patients with melanoma. The following study was conducted to examine whether changes in their presence could provide an early marker of response to therapy. EXPERIMENTAL DESIGN: We measured the presence of several markers of melanoma cells in the peripheral blood of 118 patients with resected stage IIb, III, or IV melanoma before and after immunotherapy with a polyvalent, shed antigen, melanoma vaccine using reverse transcription-PCR assays for tyrosinase, gp100, MART-1, and MAGE-3. Assays were conducted at baseline and after 3, 5, and 11 months of therapy. RESULTS: Overall, 47% of patients were positive for at least one marker during the study. Before vaccine treatment, circulating melanoma cell markers were present in 23% of patients. After 5 and 7 months of vaccine therapy, the proportion of patients with circulating markers decreased by 27% and 55%, respectively (P for trend = 0.02). The recurrence-free survival of patients whose melanoma cell markers disappeared during vaccine treatment was significantly longer than that of patients in whom they increased, i.e., the percentage of patients who were recurrence free at 1 year was 80% versus 58% (P = 0.03). CONCLUSIONS: Therapy with a polyvalent melanoma vaccine was associated with clearance of melanoma cell markers from the circulation, and the clearance was associated with an improved prognosis. These findings suggest that the sequential assay of tumor cells in the circulation by reverse transcription-PCR may provide an early indication of the effectiveness of cancer therapy

PURPOSE: Vaccine-induced antitumor CD8+ T-cell responses are believed to play an important role in increasing resistance to melanoma. The following study was conducted to examine whether these responses are associated with improved clinical outcome in melanoma vaccine-treated patients. EXPERIMENTAL DESIGN: We measured CD8+ T-cell responses to gp100, MART-1, MAGE-3, and tyrosinase by enzyme-linked immunospot assay in peripheral blood of 131 HLA-A*01- or HLA-A*02-positive melanoma patients before and after immunization to a polyvalent, shed antigen, melanoma vaccine, and correlated the results with clinical outcome. RESULTS: Fifty-six percent of patients had a vaccine-induced CD8+ T-cell response to at least one of the four antigens. Recurrences were significantly reduced in patients with vaccine-induced responses to MAGE-3 (hazard ratio, 0.42; 95% confidence interval, 0.18-0.99; P = 0.03) by the Cox proportional hazard model but were unrelated to responses to the other three antigens. Patients with a preexisting response to any of the four antigens were significantly more likely to have a further vaccine-boosted response to that same antigen (P < 0.0001-0.036). CONCLUSIONS: There was a correlation between vaccine-induced CD8+ T-cell responses to melanoma-associated antigens and improved clinical outcome, but the correlation depended on the antigen against which the response is directed. The only significant correlation was with responses to MAGE-3

PURPOSE: The purpose is to investigate the clinical relevance of altered patterns of p27 and Skp2 expression in African-American patients with localized prostate cancer. The abundance of p27, an inhibitor of cell proliferation, is controlled by Skp2-dependent proteolysis. EXPERIMENTAL DESIGN: A well-characterized cohort of 162 African-Americans who underwent radical prostatectomy at the Veterans Affairs Medical Center of New York between 1990 and 2000 was studied. We analyzed p27 and Skp2 expression by immunohistochemistry. Altered expression of p27 (defined as <40% tumor cells expressing the protein) and Skp2 (defined as > or ==' BORDER='0'>20% tumor cells expressing the protein) were correlated with clinicopathological parameters and time to prostate-specific antigen (PSA) recurrence. RESULTS: Altered expression of p27 and Skp2 was observed in 112 of 162 (69.1%) and 93 of 162 (57.4%) cases, respectively. Inverse patterns of Skp2 and p27 protein expression were seen in 87 of 162 (53.7%) cases. A marginally significant association was found between Skp2 overexpression and extracapsular extension (P = 0.065). Moreover, patients with Skp2 overexpression had a 2.77 years decreased median time to PSA recurrence compared with patients with low Skp2 expression; however, the difference was not statistically significant. In multivariate analysis, only tumor grade and stage independently predicted PSA recurrence in this cohort. CONCLUSIONS: Our data suggest a role for Skp2 overexpression in prostate cancer pathogenesis that might not be exclusively related to p27 degradation. More studies are needed to determine the mechanistic role of Skp2 in prostate cancer