Anne Zeleniuch-Jacquotte, M.D.

Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer
Lukanova, Annekatrin; Surcel, Helja-Marja; Lundin, Eva; Kaasila, Marjo; Lakso, Hans-Ake; Schock, Helena; Husing, Anika; Kaaks, Rudolf; Koskela, Pentti; Grankvist, Kjell; Pukkala, Eero; Zeleniuch-Jacquotte, Anne; Lehtinen, Matti; Toniolo, Paolo
2012 Feb 15;130(4):910-920, International journal of cancer
Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (+/-6 months) and date of sampling (+/-3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed >/=age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40
— id: 149791, year: 2012, vol: 130, page: 910, stat: Journal Article,

Determinants of Maternal Sex Steroids During the First Half of Pregnancy (vol 118, pg 1029, 2011)
Toriola, A. T.; Vaarasmaki, M.; Lehtinen, M.; Zeleniuch-Jacquotte, A.; Lundin, E.; Rodgers, K-G; Lakso, H-A; Chen, T.; Schock, H.; Hallmans, G.; Pukkala, E.; Toniolo, P.; Grankvist, K.; Surcel, H-M; Lukanova, A.
2012 JAN ;119(1):186-187, Obstetrics & gynecology
— id: 150250, year: 2012, vol: 119, page: 186, stat: Journal Article,

Characterization of a genomic signature of pregnancy identified in the breast
Belitskaya-Levy, Ilana; Zeleniuch-Jacquotte, Anne; Russo, Jose; Russo, Irma H; Bordas, Pal; Ahman, Janet; Afanasyeva, Yelena; Johansson, Robert; Lenner, Per; Li, Xiaochun; de Cicco, Ricardo Lopez; Peri, Suraj; Ross, Eric; Russo, Patricia A; Santucci-Pereira, Julia; Sheriff, Fathima S; Slifker, Michael; Hallmans, Goran; Toniolo, Paolo; Arslan, Alan A
2011 Sep;4(9):1457-1464, Cancer prevention research (Philadelphia, Pa.)
The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer. Cancer Prev Res; 4(9); 1457-64. (c)2011 AACR
— id: 137065, year: 2011, vol: 4, page: 1457, stat: Journal Article,

Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer
Chen, Tianhui; Surcel, Helja-Marja; Lundin, Eva; Kaasila, Marjo; Lakso, Hans-Ake; Schock, Helena; Kaaks, Rudolf; Koskela, Pentti; Grankvist, Kjell; Hallmans, Goran; Pukkala, Eero; Zeleniuch-Jacquotte, Anne; Toniolo, Paolo; Lehtinen, Matti; Lukanova, Annekatrin
2011 Feb;20(2):324-336, Cancer epidemiology biomarkers & prevention
BACKGROUND: Sex steroid hormones have been proposed to play a role in the development of non-epithelial ovarian cancers (NEOC) but so far no direct epidemiologic data are available. METHODS: A case-control study was nested within the Finnish Maternity Cohort, the world's largest biorepository of serum specimens from pregnant women. Study subjects were selected among women who donated a blood sample during a singleton pregnancy that led to the birth of their last child preceding diagnosis of NEOC. Case subjects were 41 women with sex cord stromal tumors (SCST) and 21 with germ cell tumors (GCT). Three controls, matching the index case for age, parity at the index pregnancy, and date at blood donation were selected (n = 171). OR and 95% CI associated with concentrations of testosterone, androstenedione, 17-OH-progesterone, progesterone, estradiol, and sex hormone-binding globulin (SHBG) were estimated through conditional logistic regression. RESULTS: For SCST, doubling of testosterone, androstenedione, and 17-OH-progesterone concentrations were associated with about 2-fold higher risk of SCST [ORs and 95% CI of 2.16 (1.25-3.74), 2.16 (1.20-3.87), and 2.62 (1.27-5.38), respectively]. These associations remained largely unchanged after excluding women within 2-, 4-, or 6-year lag time between blood donation and cancer diagnosis. Sex steroid hormones concentrations were not related to maternal risk of GCT. CONCLUSIONS: This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST. IMPACT: Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC
— id: 134152, year: 2011, vol: 20, page: 324, stat: Journal Article,

Endogenous hormones and coronary heart disease in postmenopausal women
Chen, Yu; Zeleniuch-Jacquotte, Anne; Arslan, Alan A; Wojcik, Oktawia; Toniolo, Paolo; Shore, Roy E; Levitz, Mortimer; Koenig, Karen L
2011 Jun;216(2):414-419, Atherosclerosis
The association between serum levels of endogenous estrogens in postmenopausal women and the subsequent risk of coronary heart disease (CHD) was examined in a prospective case-control study nested within the New York University Women's Health Study (NYUWHS). The NYUWHS is a prospective cohort study of 14,274 healthy women enrolled between 1985 and 1991. A total of 99 women who were postmenopausal and free of cardiovascular disease at enrollment and who subsequently experienced CHD, defined as non-fatal myocardial infarction (MI), fatal CHD, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG), were matched 1:2 by baseline age, blood sampling date, and postmenopausal status to controls who remained free of CHD as of the date of diagnosis of the matching case. Biochemical analyses for total estradiol, estrone, percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), and SHBG were performed on pre-diagnostic stored serum samples. Participants had not used any hormone medications in the 6 months prior to blood collection. In the model adjusting only for matching factors, the risk of CHD in the top tertile of calculated bioavailable estradiol was elevated compared with the bottom tertile (OR=2.10; 95% CI=1.13-3.90, P for trend=0.03), and the risk in the top tertile of SHBG was reduced (OR=0.50, 95% CI=0.28-0.92, P for trend<0.01). However, these associations disappeared after adjusting for baseline hypertension status, body mass index, and serum cholesterol levels. These findings suggest that circulating estradiol and SHBG are not associated with CHD risk in postmenopausal women beyond what can be explained by the variation in hypertension status, BMI, and cholesterol
— id: 134306, year: 2011, vol: 216, page: 414, stat: Journal Article,

Circulating Inflammation Markers and Risk of Epithelial Ovarian Cancer
Clendenen TV; Lundin E; Zeleniuch-Jacquotte A; Koenig KL; Berrino F; Lukanova A; Lokshin AE; Idahl A; Ohlson N; Hallmans G; Krogh V; Sieri SA; Muti P; Marrangoni AM; Nolen B; Liu M; Shore RE; Arslan AA
2011 May;20(5):799-810, Cancer epidemiology biomarkers & prevention
BACKGROUND: Factors contributing to chronic inflammation appear to be associated with increased risk of ovarian cancer. The purpose of this study was to assess the association between circulating levels of inflammation mediators and subsequent risk of ovarian cancer.METHODS: We conducted a case-control study of 230 cases and 432 individually-matched controls nested within three prospective cohorts to evaluate the association of pre-diagnostic circulating levels of inflammation-related biomarkers (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFalpha, IL-1Ra, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1, and sTNF-R2) measured using Luminex xMap technology with risk of ovarian cancer. RESULTS: We observed a trend across quartiles for IL-2 (OR(Q4 vs. Q1): 1.57, 95% CI: 0.98, 2.52, p= 0.07), IL-4 (OR(Q4 vs. Q1): 1.50, 95% CI: 0.95, 2.38, p= 0.06), IL-6 (OR(Q4 vs. Q1): 1.63, 95% CI: 1.03, 2.58, p= 0.03), IL-12p40 (OR(Q4 vs. Q1): 1.60, 95% CI: 1.02, 2.51, p= 0.06), and IL-13 (OR(Q4 vs. Q1): 1.42, 95% CI: 0.90, 2.26, p= 0.11). Trends were also observed when cytokines were modeled on the continuous scale for IL-4 (p-trend=0.01), IL-6 (p-trend=0.01), IL-12p40 (p-trend=0.01), and IL-13 (p-trend=0.04). Odds ratios were not materially different after excluding cases diagnosed less than five years after blood donation or when limited to serous tumors.Conclusions and Impact: This study provides the first direct evidence that multiple inflammation markers, specifically IL-2, IL-4, IL-6, IL-12, and IL-13, may be associated with risk of epithelial ovarian cancer, and adds to the evidence that inflammation is involved in the development this disease
— id: 131785, year: 2011, vol: 20, page: 799, stat: Journal Article,

Factors associated with inflammation markers, a cross-sectional analysis
Clendenen, Tess V; Koenig, Karen L; Arslan, Alan A; Lukanova, Annekatrin; Berrino, Franco; Gu, Yian; Hallmans, Goran; Idahl, Annika; Krogh, Vittorio; Lokshin, Anna E; Lundin, Eva; Muti, Paola; Marrangoni, Adele; Nolen, Brian M; Ohlson, Nina; Shore, Roy E; Sieri, Sabina; Zeleniuch-Jacquotte, Anne
2011 Dec;56(3):769-778, Cytokine
Epidemiological studies have reported associations between circulating inflammation markers and risk of chronic diseases. It is of interest to examine whether risk factors for these diseases are associated with inflammation. We conducted a cross-sectional analysis to evaluate whether reproductive and lifestyle factors and circulating vitamin D were associated with inflammation markers, including C-reactive protein, cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFalpha), and cytokine modulators (IL-1RA, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1/R2), among 616 healthy women. We confirmed associations of several inflammation markers with age and BMI. We also observed significantly higher levels of certain inflammation markers in postmenopausal vs. premenopausal women (TNFalpha, sIL-1RII, sIL-2Ra), with increasing parity (IL-12p40), and with higher circulating 25(OH) vitamin D (IL-13) and lower levels among current users of non-steroidal anti-inflammatory drugs (NSAIDs) (IL-1beta, IL-2, IL-10, IL-12p70, and IL-12p40), current smokers (IL-4, IL-13, IL-12p40), and women with a family history of breast or ovarian cancer (IL-4, IL-10, IL-13). Our findings suggest that risk factors for chronic diseases (age, BMI, menopausal status, parity, NSAID use, family history of breast and ovarian cancer, and smoking) are associated with inflammation markers in healthy women
— id: 141702, year: 2011, vol: 56, page: 769, stat: Journal Article,

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies
Key, T J; Appleby, P N; Reeves, G K; Roddam, A W; Helzlsouer, K J; Alberg, A J; Rollison, D E; Dorgan, J F; Brinton, L A; Overvad, K; Kaaks, R; Trichopoulou, A; Clavel-Chapelon, F; Panico, S; Duell, E J; Peeters, P H M; Rinaldi, S; Fentiman, I S; Dowsett, M; Manjer, J; Lenner, P; Hallmans, G; Baglietto, L; English, D R; Giles, G G; Hopper, J L; Severi, G; Morris, H A; Hankinson, S E; Tworoger, S S; Koenig, K; Zeleniuch-Jacquotte, A; Arslan, A A; Toniolo, P; Shore, R E; Krogh, V; Micheli, A; Berrino, F; Barrett-Connor, E; Laughlin, G A; Kabuto, M; Akiba, S; Stevens, R G; Neriishi, K; Land, C E; Cauley, J A; Lui, Li Yung; Cummings, Steven R; Gunter, M J; Rohan, T E; Strickler, H D
2011 Aug 23;105(5):709-722, British journal of cancer
BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk
— id: 137962, year: 2011, vol: 105, page: 709, stat: Journal Article,

Loss of p27KIP1 Expression in Fully-staged Node-negative Breast Cancer: Association with Lack of Hormone Receptors in T1a/b, but not T1c Infiltrative Ductal Carcinoma
Mirchandani, Deepu; Roses, Daniel F; Inghirami, Giorgio; Zeleniuch-Jacquotte, Anne; Cangiarella, Joan; Guth, Amber; Safyan, Rachael Ann; Formenti, Silvia C; Pagano, Michele; Muggia, Franco
2011 Dec;31(12):4401-4405, Anticancer research
Nuclear expression of the cell cycle inhibitor p27(KIP1) is reduced in a variety of human malignancies, including breast cancer. Loss of nuclear p27(KIP1) during tumor progression, documented by immunohistochemistry (IHC), has been studied for its potential prognostic implication. We examined by IHC the association between nuclear p27(KIP1) expression and hormone receptor status in T1N0M0 breast cancer. PATIENTS AND METHODS: The correlation between nuclear p27(KIP1) expression and estrogen (ER) and progesterone (PR) hormone receptor status was analyzed in 122 human T1N0M0 (68 T1a/b, 54 T1c) breast cancer specimens. All patients were staged as N0 by axillary node dissection. RESULTS: A statistically significant reduction in p27(KIP1) expression was observed as tumor size increased from T1a/b (7%) to T1c (22%). The proportion of tumors with low nuclear p27(KIP1) expression was higher in the ER-negative/PR-negative group compared to the ER-positive/PR-positive group, but this difference was only statistically significant in the T1a/b subgroup (p=0.0007). CONCLUSION: Further investigations into causes of p27(KIP1) deregulation and their relationship to hormone receptor expression in T1N0M0 breast ductal carcinomas are warranted. Such studies may help identify prognostic, as well as predictive, markers of therapy resistance
— id: 149934, year: 2011, vol: 31, page: 4401, stat: Journal Article,

Determinants of maternal sex steroids during the first half of pregnancy
Toriola A.T.; Vaarasmaki M.; Lehtinen M.; Zeleniuch-Jacquotte A.; Lundin E.; Rodgers K.-G.; Lakso H.-A.; Chen T.; Schock H.; Hallmans G.; Pukkala E.; Toniolo P.; Grankvist K.; Surcel H.-M.; Lukanova A.
2011 ;118(5):1029-1036, Obstetrics & gynecology
Objective: To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and estradiol (E2). Methods: We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression. Results: Women older than age 30 years had lower androgen and E2 but higher progesterone concentrations than women younger than that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower E2 concentrations compared with nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared with nonsmoking women (all P<.05). E2 concentrations were 9% higher (P<.05) among women with a female fetus compared with those with a male fetus. Conclusion: Parity, smoking, and, to a lesser extent, maternal age and child sex are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation. 2011 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins
— id: 141088, year: 2011, vol: 118, page: 1029, stat: Journal Article,

Insulin-like growth factor-I and C-reactive protein during pregnancy and maternal risk of non-epithelial ovarian cancer: a nested case-control study
Toriola, Adetunji T.; Surcel, Helja-Marja; Lundin, Eva; Schock, Helena; Grankvist, Kjell; Pukkala, Eero; Chen, Tianhui; Toniolo, Paolo; Lehtinen, Matti; Zeleniuch-Jacquotte, Anne; Lukanova, Annekatrin
2011 NOV ;22(11):1607-1611, Cancer causes & control. ccc
Insulin-like growth factor-I (IGF-I) and C-reactive protein (CRP) may be positively associated with the risk of epithelial ovarian cancer (EOC) but no previous studies have investigated their associations with non-epithelial ovarian cancers (NEOC). A case-control study was nested within the Finnish Maternity Cohort. Case subjects were 58 women diagnosed with sex cord-stromal tumors (SCST) and 30 with germ cell tumors (GCT) after recruitment. Control subjects (144 for SCST and 74 for GCT) were matched for age, parity, and date of blood donation of the index case. Doubling of IGF-I concentration was not related to maternal risk of either SCST (OR 0.97, 95% CI 0.58-1.62) or GCT (OR 1.13, 95% CI 0.51-2.51). Similarly, doubling of CRP concentrations was not related to maternal risk of either SCST (OR 1.10, 95% CI 0.85-1.43) or GCT (OR 0.93, 95% CI 0.68-1.28). Pre-diagnostic IGF-I and CRP concentrations during the first trimester of pregnancy were not associated with increased risk of NEOC in the mother. Risk factors for NEOC may differ from those of EOC
— id: 140052, year: 2011, vol: 22, page: 1607, stat: Journal Article,

Circulating insulin-like growth factor-I in pregnancy and maternal risk of breast cancer
Toriola, Adetunji T; Lundin, Eva; Schock, Helena; Grankvist, Kjell; Pukkala, Eero; Chen, Tianhui; Zeleniuch-Jacquotte, Anne; Toniolo, Paolo; Lehtinen, Matti; Surcel, Helja-Marja; Lukanova, Annekatrin
2011 Aug;20(8):1798-1801, Cancer epidemiology biomarkers & prevention
BACKGROUND: Elevated serum concentrations of insulin-like growth factor (IGF)-I have been associated with increased risk of developing breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. This study was conducted to further characterize the association of IGF-I during pregnancy with maternal breast cancer risk. METHODS: A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women younger than 40 years, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched with each case on age and date at blood donation. Serum IGF-I concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate ORs and 95% CIs. RESULTS: No significant associations were observed between serum IGF-I concentrations and breast cancer risk in both the overall analysis (OR, 1.08; 95% CI, 0.80-1.47) and in analyses stratified by histologic subtype, lag time to cancer diagnosis, age at pregnancy, or age at diagnosis. CONCLUSION: There was no association between IGF-I and maternal breast cancer risk during early pregnancy in this large nested case-control study. IMPACT: Serum IGF-I concentrations during early pregnancy may not be related to maternal risk of developing breast cancer
— id: 137985, year: 2011, vol: 20, page: 1798, stat: Journal Article,

Postmenopausal circulating levels of 2- and 16alpha-hydroxyestrone and risk of endometrial cancer
Zeleniuch-Jacquotte, A; Shore, R E; Afanasyeva, Y; Lukanova, A; Sieri, S; Koenig, K L; Idahl, A; Krogh, V; Liu, M; Ohlson, N; Muti, P; Arslan, A A; Lenner, P; Berrino, F; Hallmans, G; Toniolo, P; Lundin, E
2011 Oct 25;105(9):1458-1464, British journal of cancer
Background:It has been suggested that the relative importance of oestrogen-metabolising pathways may affect the risk of oestrogen-dependent tumours including endometrial cancer. One hypothesis is that the 2-hydroxy pathway is protective, whereas the 16alpha-hydroxy pathway is harmful.Methods:We conducted a case-control study nested within three prospective cohorts to assess whether the circulating 2-hydroxyestrone : 16alpha-hydroxyestrone (2-OHE1 : 16alpha-OHE1) ratio is inversely associated with endometrial cancer risk in postmenopausal women. A total of 179 cases and 336 controls, matching cases on cohort, age and date of blood donation, were included. Levels of 2-OHE1 and 16alpha-OHE1 were measured using a monoclonal antibody-based enzyme assay.Results:Endometrial cancer risk increased with increasing levels of both metabolites, with odds ratios in the top tertiles of 2.4 (95% CI=1.3, 4.6; P(trend)=0.007) for 2-OHE1 and 1.9 (95% CI=1.1, 3.5; P(trend)=0.03) for 16alpha-OHE1 in analyses adjusting for endometrial cancer risk factors. These associations were attenuated and no longer statistically significant after further adjustment for oestrone or oestradiol levels. No significant association was observed for the 2-OHE1 : 16alpha-OHE1 ratio.Conclusion:Our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16alpha-OH pathway, protects against endometrial cancer
— id: 139737, year: 2011, vol: 105, page: 1458, stat: Journal Article,

Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan)
Arslan, Alan A; Helzlsouer, Kathy J; Kooperberg, Charles; Shu, Xiao-Ou; Steplowski, Emily; Bueno-de-Mesquita, H Bas; Fuchs, Charles S; Gross, Myron D; Jacobs, Eric J; Lacroix, Andrea Z; Petersen, Gloria M; Stolzenberg-Solomon, Rachael Z; Zheng, Wei; Albanes, Demetrius; Amundadottir, Laufey; Bamlet, William R; Barricarte, Aurelio; Bingham, Sheila A; Boeing, Heiner; Boutron-Ruault, Marie-Christine; Buring, Julie E; Chanock, Stephen J; Clipp, Sandra; Gaziano, J Michael; Giovannucci, Edward L; Hankinson, Susan E; Hartge, Patricia; Hoover, Robert N; Hunter, David J; Hutchinson, Amy; Jacobs, Kevin B; Kraft, Peter; Lynch, Shannon M; Manjer, Jonas; Manson, Joann E; McTiernan, Anne; McWilliams, Robert R; Mendelsohn, Julie B; Michaud, Dominique S; Palli, Domenico; Rohan, Thomas E; Slimani, Nadia; Thomas, Gilles; Tjonneland, Anne; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Virtamo, Jarmo; Wolpin, Brian M; Yu, Kai; Zeleniuch-Jacquotte, Anne; Patel, Alpa V
2010 May 10;170(9):791-802, Archives of internal medicine
BACKGROUND: Obesity has been proposed as a risk factor for pancreatic cancer. METHODS: Pooled data were analyzed from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) to study the association between prediagnostic anthropometric measures and risk of pancreatic cancer. PanScan applied a nested case-control study design and included 2170 cases and 2209 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight, height, waist circumference, and waist to hip ratio as well as conventional BMI categories (underweight, <18.5; normal weight, 18.5-24.9; overweight, 25.0-29.9; obese, 30.0-34.9; and severely obese, > or = 35.0). Models were adjusted for potential confounders. RESULTS: In all of the participants, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI quartile, 1.33; 95% CI, 1.12-1.58; P(trend) < .001). In men, the adjusted OR for pancreatic cancer for the highest vs lowest quartile of BMI was 1.33 (95% CI, 1.04-1.69; P(trend) < .03), and in women it was 1.34 (95% CI, 1.05-1.70; P(trend) = .01). Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1.87; 95% CI, 1.31-2.69; P(trend) = .003) but less so in men. CONCLUSIONS: These findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women
— id: 109679, year: 2010, vol: 170, page: 791, stat: Journal Article,

DNA methylation in pre-diagnostic serum samples of breast cancer cases: Results of a nested case-control study
Brooks, Jennifer D; Cairns, Paul; Shore, Roy E; Klein, Catherine B; Wirgin, Isaac; Afanasyeva, Yelena; Zeleniuch-Jacquotte, Anne
2010 Dec;34(6):717-723, Cancer Epidemiology
Background: Promoter methylation of tumor suppressor genes is a frequent and early event in breast carcinogenesis. Paired tumor tissue and serum samples from women with breast cancer show that promoter methylation is detectable in both sample types, with good concordance. This suggests the potential for these serum markers to be used for breast cancer detection. Methods: The current study was a case-control study nested within the prospective New York University Women's Health Study cohort aimed to assess the ability of promoter methylation in serum to detect pre-clinical disease. Cases were women with blood samples collected within the 6 months preceding breast cancer diagnosis (n=50). Each case was matched to 2 healthy cancer-free controls and 1 cancer-free control with a history of benign breast disease (BBD). Results: Promoter methylation analysis of four cancer-related genes: -RASSF1A, GSTP1, APC and RARbeta2, - was conducted using quantitative methylation-specific PCR. Results showed that the frequency of methylation was lower than expected among cases and higher than expected among controls. Methylation was detected in the promoter region of: RASSF1A in 22.0%, 22.9% and 17.2% of cases, BBD controls and healthy controls respectively; GSTP1 in 4%, 10.4% and 7.1% respectively; APC in 2.0%, 4.4% and 4.2% respectively and RARbeta2 in 6.7%, 2.3% and 1.1% respectively. Conclusion: Methylation status of the four genes included in this study was unable to distinguish between cases and either control group. This study highlights some methodological issues to be addressed in planning prospective studies to evaluate methylation markers as diagnostic biomarkers
— id: 114817, year: 2010, vol: 34, page: 717, stat: Journal Article,

IGF-I during primiparous pregnancy and maternal risk of breast cancer
Chen, Tianhui; Lukanova, Annekatrin; Grankvist, Kjell; Zeleniuch-Jacquotte, Anne; Wulff, Marianne; Johansson, Robert; Schock, Helena; Lenner, Per; Hallmans, Goran; Wadell, Goran; Toniolo, Paolo; Lundin, Eva
2010 May;121(1):169-175, Breast cancer research & treatment
Previously, we reported that insulin-like growth factor (IGF)-I during early pregnancy is positively associated with maternal risk of breast cancer. To further explore this association, we designed a new study limited to women who donated a blood sample during their first pregnancy ending with childbirth. A case-control study was nested within the Northern Sweden Maternity Cohort in which repository since 1975, serum specimens remaining after early pregnancy screening for infectious diseases had been preserved. Study subjects were selected among women who donated a blood sample during the full-term pregnancy that led to the birth of their first child. Two hundred and forty-four women with invasive breast cancer were eligible. Two controls, matching the index case for age and date at blood donation were selected (n = 453). IGF-I was measured in serum samples on an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. A significant positive association of breast cancer with IGF-I was observed, with OR of 1.73 (95% CI: 1.14-2.63) for the top tertile, P < 0.009. Subgroup analyses did not indicate statistical heterogeneity of the association by ages at sampling and diagnosis or by lag time to cancer diagnosis, although somewhat stronger associations with risk were observed in women < or = age 25 at index pregnancy and for cases diagnosed within 15 years of blood donation. The results of the study add further evidence for an adverse effect of elevated IGF-I concentrations during early reproductive life on risk of breast cancer
— id: 114698, year: 2010, vol: 121, page: 169, stat: Journal Article,

Maternal hormones during early pregnancy: a cross-sectional study
Chen, Tianhui; Lundin, Eva; Grankvist, Kjell; Zeleniuch-Jacquotte, Anne; Wulff, Marianne; Afanasyeva, Yelena; Schock, Helena; Johansson, Robert; Lenner, Per; Hallmans, Goran; Wadell, Goran; Toniolo, Paolo; Lukanova, Annekatrin
2010 May;21(5):719-727, Cancer causes & control. ccc
BACKGROUND: Little is known about correlates of first-trimester pregnancy hormones as in most studies maternal hormones have been measured later in gestation. We examined the associations of maternal characteristics and child sex with first-trimester maternal concentrations of four hormones implicated in breast cancer: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), insulin-like growth factor (IGF)-I, and IGF-II. METHODS: About 338 serum samples donated to the Northern Sweden Maternity Cohort (NSMC), 1975-2001, during the first trimester of uncomplicated pregnancies, were analyzed for the hormones of interest as a part of a case-control study. The associations of maternal characteristics and child sex with hormone concentrations were investigated by correlation, general linear regression, and multivariate regression models. RESULTS: In the first trimester, greater maternal age was inversely correlated with IGF-I and IGF-II. In comparison with women carrying their first child, already parous women had higher IGF-I but lower hCG. Greater maternal weight and smoking were inversely correlated with hCG. No differences in hormone levels by child sex were observed. CONCLUSIONS: Our analyses indicated that potentially modifiable maternal characteristics (maternal weight and smoking) influence first-trimester pregnancy maternal hormone concentrations
— id: 114693, year: 2010, vol: 21, page: 719, stat: Journal Article,

Temporal reliability of cytokines and growth factors in EDTA plasma
Clendenen, Tess V; Arslan, Alan A; Lokshin, Anna E; Idahl, Annika; Hallmans, Goran; Koenig, Karen L; Marrangoni, Adele M; Nolen, Brian M; Ohlson, Nina; Zeleniuch-Jacquotte, Anne; Lundin, Eva
2010 ;3:302-302, BMC research notes
ABSTRACT: BACKGROUND: Cytokines are involved in the development of chronic diseases, including cancer. It is important to evaluate the temporal reproducibility of cytokines in plasma prior to conducting epidemiologic studies utilizing these markers. FINDINGS: We assessed the temporal reliability of CRP, 22 cytokines and their soluble receptors (IL-1alpha, IL-1beta, IL-1RA, IL-2, sIL-2R, IL-4, IL-5, IL-6, sIL-6R, IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, TNFalpha, sTNF-R1, sTNF-R2, IFNalpha, IFNgamma) and eight growth factors (GM-CSF, EGF, bFGF, G-CSF, HGF, VEGF, EGFR, ErbB2) in repeated EDTA plasma samples collected an average of two years apart from 18 healthy women (age range: 42-62) enrolled in a prospective cohort study. We also estimated the correlation between serum and plasma biomarker levels using 18 paired clinical samples from postmenopausal women (age range: 75-86).Twenty-six assays were able to detect their analytes in at least 70% of samples. Of those 26 assays, we observed moderate to high intra-class correlation coefficients (ICCs)(ranging from 0.53-0.89) for 22 assays, and low ICCs (0-0.47) for four assays. Serum and plasma levels were highly correlated (r > 0.6) for most markers, except for seven assays (r < 0.5). CONCLUSIONS: For 22 of the 31 biomarkers, a single plasma measurement is a reliable estimate of a woman's average level over a two-year period
— id: 115276, year: 2010, vol: 3, page: 302, stat: Journal Article,

Body-Mass Index and Mortality among 1.46 Million White Adults
de Gonzalez, Amy Berrington; Hartge, Patricia; Cerhan, James R.; Flint, Alan J.; Hannan, Lindsay; MacInnis, Robert J.; Moore, Steven C.; Tobias, Geoffrey S.; Anton-Culver, Hoda; Freeman, Laura Beane; Beeson, W. Lawrence; Clipp, Sandra L.; English, Dallas R.; Folsom, Aaron R.; Freedman, D. Michal; Giles, Graham; Hakansson, Niclas; Henderson, Katherine D.; Hoffman-Bolton, Judith; Hoppin, Jane A.; Koenig, Karen L.; Lee, I-Min; Linet, Martha S.; Park, Yikyung; Pocobelli, Gaia; Schatzkin, Arthur; Sesso, Howard D.; Weiderpass, Elisabete; Willcox, Bradley J.; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Willett, Walter C.; Thun, Michael J.
2010 DEC 2 ;363(23):2211-2219, New England journal of medicine
Background: A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. Methods: We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). Results: The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. Conclusions: In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9. N Engl J Med 2010;363:2211-9
— id: 115284, year: 2010, vol: 363, page: 2211, stat: Journal Article,

Circulating 25-hydroxyvitamin D and the risk of rarer cancers: Design and methods of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Gallicchio, Lisa; Helzlsouer, Kathy J; Chow, Wong-Ho; Freedman, D Michal; Hankinson, Susan E; Hartge, Patricia; Hartmuller, Virginia; Harvey, Chinonye; Hayes, Richard B; Horst, Ronald L; Koenig, Karen L; Kolonel, Laurence N; Laden, Francine; McCullough, Marjorie L; Parisi, Dominick; Purdue, Mark P; Shu, Xiao-Ou; Snyder, Kirk; Stolzenberg-Solomon, Rachael Z; Tworoger, Shelley S; Varanasi, Arti; Virtamo, Jarmo; Wilkens, Lynne R; Xiang, Yong-Bing; Yu, Kai; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Abnet, Christian C; Albanes, Demetrius; Bertrand, Kimberly; Weinstein, Stephanie J
2010 Jul 1;172(1):10-20, American journal of epidemiology
The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP), a consortium of 10 prospective cohort studies from the United States, Finland, and China, was formed to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and the risk of rarer cancers. Cases (total n = 5,491) included incident primary endometrial (n = 830), kidney (n = 775), ovarian (n = 516), pancreatic (n = 952), and upper gastrointestinal tract (n = 1,065) cancers and non-Hodgkin lymphoma (n = 1,353) diagnosed in the participating cohorts. At least 1 control was matched to each case on age, date of blood collection (1974-2006), sex, and race/ethnicity (n = 6,714). Covariate data were obtained from each cohort in a standardized manner. The majority of the serum or plasma samples were assayed in a central laboratory using a direct, competitive chemiluminescence immunoassay on the DiaSorin LIAISON platform (DiaSorin, Inc., Stillwater, Minnesota). Masked quality control samples included serum standards from the US National Institute of Standards and Technology. Conditional logistic regression analyses were conducted using clinically defined cutpoints, with 50-<75 nmol/L as the reference category. Meta-analyses were also conducted using inverse-variance weights in random-effects models. This consortium approach permits estimation of the association between 25(OH)D and several rarer cancers with high accuracy and precision across a wide range of 25(OH)D concentrations
— id: 134375, year: 2010, vol: 172, page: 10, stat: Journal Article,

Circulating 25-hydroxyvitamin D and risk of kidney cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Gallicchio, Lisa; Moore, Lee E; Stevens, Victoria L; Ahn, Jiyoung; Albanes, Demetrius; Hartmuller, Virginia; Setiawan, V Wendy; Helzlsouer, Kathy J; Yang, Gong; Xiang, Yong-Bing; Shu, Xiao-Ou; Snyder, Kirk; Weinstein, Stephanie J; Yu, Kai; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Cai, Qiuyin; Campbell, David S; Chen, Yu; Chow, Wong-Ho; Horst, Ronald L; Kolonel, Laurence N; McCullough, Marjorie L; Purdue, Mark P; Koenig, Karen L
2010 Jul 1;172(1):47-57, American journal of epidemiology
Although the kidney is a major organ for vitamin D metabolism, activity, and calcium-related homeostasis, little is known about whether this nutrient plays a role in the development or the inhibition of kidney cancer. To address this gap in knowledge, the authors examined the association between circulating 25-hydroxyvitamin D (25(OH)D) and kidney cancer within a large, nested case-control study developed as part of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Concentrations of 25(OH)D were measured from 775 kidney cancer cases and 775 age-, sex-, race-, and season-matched controls from 8 prospective cohort studies. Overall, neither low nor high concentrations of circulating 25(OH)D were significantly associated with kidney cancer risk. Although the data showed a statistically significant decreased risk for females (odds ratio = 0.31, 95% confidence interval: 0.12, 0.85) with 25(OH)D concentrations of > or =75 nmol/L, the linear trend was not statistically significant and the number of cases in this category was small (n = 14). The findings from this consortium-based study do not support the hypothesis that vitamin D is inversely associated with the risk of kidney cancer overall or with renal cell carcinoma specifically
— id: 132233, year: 2010, vol: 172, page: 47, stat: Journal Article,

Circulating cytokines and risk of B-cell non-Hodgkin lymphoma: a prospective study
Gu, Yian; Shore, Roy E; Arslan, Alan A; Koenig, Karen L; Liu, Mengling; Ibrahim, Sherif; Lokshin, Anna E; Zeleniuch-Jacquotte, Anne
2010 Aug;21(8):1323-1333, Cancer causes & control. ccc
Cytokines play important roles in B-cell activation, proliferation, and apoptosis, thus may be etiologically related to risk of B-cell non-Hodgkin lymphoma (B-NHL). However, the association between circulating levels of cytokines and B-NHL risk has not been prospectively studied in non-HIV populations. The objective of this study was to assess this association by conducting a case-control study nested within a prospective cohort of non-HIV-infected, healthy women. Fifteen cytokines were measured in samples collected a median of 8.2 years prior to diagnosis in 92 cases and two matched controls per case. Only cytokines that showed adequate temporal reproducibility over a two-year period were included. The odds ratio (OR) for the highest tertile relative to the lowest was elevated for soluble IL-2 receptor (sIL-2R) (OR = 2.5, 95% CI = 1.4-4.7, p (trend) < 0.01) and decreased for IL-13 (OR = 0.5, 95% CI = 0.2-1.0, p (trend) = 0.05). Three other cytokines were marginally associated with risk of B-NHL: TNF-alpha (OR = 1.7, 95% CI = 0.9-3.3, p (trend) = 0.11), sTNF-R2 (OR = 1.9, 95% CI = 0.9-3.5, p (trend) = 0.06), and IL-5 (OR = 0.5, 95% CI = 0.3-1.0, p (trend) = 0.06). No association was observed between B-NHL risk and levels of the other cytokines measured (IL-1beta, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, IL-12p70, CRP and sTNF-R1). This study suggests that dysregulated cytokines may be involved in B-NHL development
— id: 138134, year: 2010, vol: 21, page: 1323, stat: Journal Article,

Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan)
Jacobs, Eric J; Chanock, Stephen J; Fuchs, Charles S; Lacroix, Andrea; McWilliams, Robert R; Steplowski, Emily; Stolzenberg-Solomon, Rachael Z; Arslan, Alan A; Bueno-de-Mesquita, H Bas; Gross, Myron; Helzlsouer, Kathy; Petersen, Gloria; Zheng, Wei; Agalliu, Ilir; Allen, Naomi E; Amundadottir, Laufey; Boutron-Ruault, Marie-Christine; Buring, Julie E; Canzian, Federico; Clipp, Sandra; Dorronsoro, Miren; Gaziano, J Michael; Giovannucci, Edward L; Hankinson, Susan E; Hartge, Patricia; Hoover, Robert N; Hunter, David J; Jacobs, Kevin B; Jenab, Mazda; Kraft, Peter; Kooperberg, Charles; Lynch, Shannon M; Sund, Malin; Mendelsohn, Julie B; Mouw, Tracy; Newton, Christina C; Overvad, Kim; Palli, Domenico; Peeters, Petra H M; Rajkovic, Aleksandar; Shu, Xiao-Ou; Thomas, Gilles; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Virtamo, Jarmo; Wactawski-Wende, Jean; Wolpin, Brian M; Yu, Kai; Zeleniuch-Jacquotte, Anne
2010 Sep 1;127(6):1421-1428, International journal of cancer
A family history of pancreatic cancer has consistently been associated with increased risk of pancreatic cancer. However, uncertainty remains about the strength of this association. Results from previous studies suggest a family history of select cancers (i.e., ovarian, breast and colorectal) could also be associated, although not as strongly, with increased risk of pancreatic cancer. We examined the association between a family history of 5 types of cancer (pancreas, prostate, ovarian, breast and colorectal) and risk of pancreatic cancer using data from a collaborative nested case-control study conducted by the Pancreatic Cancer Cohort Consortium. Cases and controls were from cohort studies from the United States, Europe and China, and a case-control study from the Mayo Clinic. Analyses of family history of pancreatic cancer included 1,183 cases and 1,205 controls. A family history of pancreatic cancer in a parent, sibling or child was associated with increased risk of pancreatic cancer [multivariate-adjusted odds ratios (ORs) = 1.76, 95% confidence interval (CI) = 1.19-2.61]. A family history of prostate cancer was also associated with increased risk (OR = 1.45, 95% CI = 1.12-1.89). There were no statistically significant associations with a family history of ovarian cancer (OR = 0.82, 95% CI = 0.52-1.31), breast cancer (OR = 1.21, 95% CI = 0.97-1.51) or colorectal cancer (OR = 1.17, 95% CI = 0.93-1.47). Our results confirm a moderate sized association between a family history of pancreatic cancer and risk of pancreatic cancer and also provide evidence for an association with a family history of prostate cancer worth further study
— id: 133778, year: 2010, vol: 127, page: 1421, stat: Journal Article,

Cox regression model with time-varying coefficients in nested case-control studies
Liu, Mengling; Lu, Wenbin; Shore, Roy E; Zeleniuch-Jacquotte, Anne
2010 Oct;11(4):693-706, Biostatistics (Oxford, England)
The nested case-control (NCC) design is a cost-effective sampling method to study the relationship between a disease and its risk factors in epidemiologic studies. NCC data are commonly analyzed using Thomas' partial likelihood approach under Cox's proportional hazards model with constant covariate effects. Here, we are interested in studying the potential time-varying effects of covariates in NCC studies and propose an estimation approach based on a kernel-weighted Thomas' partial likelihood. We establish asymptotic properties of the proposed estimator, propose a numerical approach to construct simultaneous confidence bands for time-varying coefficients, and develop a hypothesis testing procedure to detect time-varying coefficients. The proposed inference procedure is evaluated in simulations and applied to an NCC study of breast cancer in the New York University Women's Health Study
— id: 138187, year: 2010, vol: 11, page: 693, stat: Journal Article,

Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan)
Michaud, Dominique S; Vrieling, Alina; Jiao, Li; Mendelsohn, Julie B; Steplowski, Emily; Lynch, Shannon M; Wactawski-Wende, Jean; Arslan, Alan A; Bas Bueno-de-Mesquita, H; Fuchs, Charles S; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J; Lacroix, Andrea; Petersen, Gloria; Zheng, Wei; Allen, Naomi; Ammundadottir, Laufey; Bergmann, Manuela M; Boffetta, Paolo; Buring, Julie E; Canzian, Federico; Chanock, Stephen J; Clavel-Chapelon, Francoise; Clipp, Sandra; Freiberg, Matthew S; Michael Gaziano, J; Giovannucci, Edward L; Hankinson, Susan; Hartge, Patricia; Hoover, Robert N; Allan Hubbell, F; Hunter, David J; Hutchinson, Amy; Jacobs, Kevin; Kooperberg, Charles; Kraft, Peter; Manjer, Jonas; Navarro, Carmen; Peeters, Petra H M; Shu, Xiao-Ou; Stevens, Victoria; Thomas, Gilles; Tjonneland, Anne; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Tumino, Rosario; Vineis, Paolo; Virtamo, Jarmo; Wallace, Robert; Wolpin, Brian M; Yu, Kai; Zeleniuch-Jacquotte, Anne; Stolzenberg-Solomon, Rachael Z
2010 Aug;21(8):1213-1225, Cancer causes & control. ccc
The literature has consistently reported no association between low to moderate alcohol consumption and pancreatic cancer; however, a few studies have shown that high levels of intake may increase risk. Most single studies have limited power to detect associations even in the highest alcohol intake categories or to examine associations by alcohol type. We analyzed these associations using 1,530 pancreatic cancer cases and 1,530 controls from the Pancreatic Cancer Cohort Consortium (PanScan) nested case-control study. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression, adjusting for potential confounders. We observed no significant overall association between total alcohol (ethanol) intake and pancreatic cancer risk (OR = 1.38, 95% CI = 0.86-2.23, for 60 or more g/day vs. >0 to <5 g/day). A statistically significant increase in risk was observed among men consuming 45 or more grams of alcohol from liquor per day (OR = 2.23, 95% CI = 1.02-4.87, compared to 0 g/day of alcohol from liquor, P-trend = 0.12), but not among women (OR = 1.35, 95% CI = 0.63-2.87, for 30 or more g/day of alcohol from liquor, compared to none). No associations were noted for wine or beer intake. Overall, no significant increase in risk was observed, but a small effect among heavy drinkers cannot be ruled out
— id: 150008, year: 2010, vol: 21, page: 1213, stat: Journal Article,

A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33
Petersen, Gloria M; Amundadottir, Laufey; Fuchs, Charles S; Kraft, Peter; Stolzenberg-Solomon, Rachael Z; Jacobs, Kevin B; Arslan, Alan A; Bueno-de-Mesquita, H Bas; Gallinger, Steven; Gross, Myron; Helzlsouer, Kathy; Holly, Elizabeth A; Jacobs, Eric J; Klein, Alison P; LaCroix, Andrea; Li, Donghui; Mandelson, Margaret T; Olson, Sara H; Risch, Harvey A; Zheng, Wei; Albanes, Demetrius; Bamlet, William R; Berg, Christine D; Boutron-Ruault, Marie-Christine; Buring, Julie E; Bracci, Paige M; Canzian, Federico; Clipp, Sandra; Cotterchio, Michelle; de Andrade, Mariza; Duell, Eric J; Gaziano, J Michael; Giovannucci, Edward L; Goggins, Michael; Hallmans, Goran; Hankinson, Susan E; Hassan, Manal; Howard, Barbara; Hunter, David J; Hutchinson, Amy; Jenab, Mazda; Kaaks, Rudolf; Kooperberg, Charles; Krogh, Vittorio; Kurtz, Robert C; Lynch, Shannon M; McWilliams, Robert R; Mendelsohn, Julie B; Michaud, Dominique S; Parikh, Hemang; Patel, Alpa V; Peeters, Petra H M; Rajkovic, Aleksandar; Riboli, Elio; Rodriguez, Laudina; Seminara, Daniela; Shu, Xiao-Ou; Thomas, Gilles; Tjonneland, Anne; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Van Den Eeden, Stephen K; Virtamo, Jarmo; Wactawski-Wende, Jean; Wang, Zhaoming; Wolpin, Brian M; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Fraumeni, Joseph F Jr; Hoover, Robert N; Hartge, Patricia; Chanock, Stephen J
2010 Mar;42(3):224-228, Nature genetics
We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies
— id: 133482, year: 2010, vol: 42, page: 224, stat: Journal Article,

Circulating 25-hydroxyvitamin D and risk of non-hodgkin lymphoma: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Purdue, Mark P; Freedman, D Michal; Gapstur, Susan M; Helzlsouer, Kathy J; Laden, Francine; Lim, Unhee; Maskarinec, Gertraud; Rothman, Nathaniel; Shu, Xiao-Ou; Stevens, Victoria L; Zeleniuch-Jacquotte, Anne; Albanes, Demetrius; Bertrand, Kimberly; Weinstein, Stephanie J; Yu, Kai; Irish, Lonn; Horst, Ronald L; Hoffman-Bolton, Judith; Giovannucci, Edward L; Kolonel, Laurence N; Snyder, Kirk; Willett, Walter; Arslan, Alan A; Hayes, Richard B; Zheng, Wei; Xiang, Yong-Bing; Hartge, Patricia
2010 Jul 1;172(1):58-69, American journal of epidemiology
Case-control studies generally suggesting an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) have led to speculation that vitamin D may protect against lymphomagenesis. To examine this hypothesis, the authors conducted a pooled investigation of circulating 25-hydroxyvitamin D (25(OH)D) and subsequent NHL risk within 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. The authors analyzed measurements from 1,353 cases and 1,778 controls using conditional logistic regression and other methods to estimate the association of 25(OH)D with NHL. No clear evidence of association between categories of 25(OH)D concentration and NHL was observed overall (P(trend) = 0.68) or by sex (men, P(trend) = 0.50; women, P(trend) = 0.16). Findings for other measures (continuous log(25(OH)D), categories of 25(OH)D using sex-/cohort-/season-specific quartiles as cutpoints, categories of season-adjusted residuals of predicted 25(OH)D using quartiles as cutpoints) were generally null, although some measures of increasing 25(OH)D were suggestive of an increased risk for women. Results from stratified analyses and investigations of histologic subtypes of NHL were also null. These findings do not support the hypothesis that elevated circulating 25(OH)D concentration is associated with a reduced risk of NHL. Future research investigating the biologic basis for the sunlight-NHL association should consider alternative mechanisms, such as immunologic effects
— id: 134378, year: 2010, vol: 172, page: 58, stat: Journal Article,

Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Stolzenberg-Solomon, Rachael Z; Jacobs, Eric J; Arslan, Alan A; Qi, Dai; Patel, Alpa V; Helzlsouer, Kathy J; Weinstein, Stephanie J; McCullough, Marjorie L; Purdue, Mark P; Shu, Xiao-Ou; Snyder, Kirk; Virtamo, Jarmo; Wilkins, Lynn R; Yu, Kai; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Albanes, Demetrius; Cai, Qiuyin; Harvey, Chinonye; Hayes, Richard; Clipp, Sandra; Horst, Ronald L; Irish, Lonn; Koenig, Karen; Le Marchand, Loic; Kolonel, Laurence N
2010 Jul 1;172(1):81-93, American journal of epidemiology
Results from epidemiologic studies examining pancreatic cancer risk and vitamin D intake or 25-hydroxyvitamin D (25(OH)D) concentrations (the best indicator of vitamin D derived from diet and sun) have been inconsistent. Therefore, the authors conducted a pooled nested case-control study of participants from 8 cohorts within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) (1974-2006) to evaluate whether prediagnostic circulating 25(OH)D concentrations were associated with the development of pancreatic cancer. In total, 952 incident pancreatic adenocarcinoma cases occurred among participants (median follow-up, 6.5 years). Controls (n = 1,333) were matched to each case by cohort, age, sex, race/ethnicity, date of blood draw, and follow-up time. Conditional logistic regression analysis was used to calculate smoking-, body mass index-, and diabetes-adjusted odds ratios and 95% confidence intervals for pancreatic cancer. Clinically relevant 25(OH)D cutpoints were compared with a referent category of 50-<75 nmol/L. No significant associations were observed for participants with lower 25(OH)D status. However, a high 25(OH)D concentration (> or =100 nmol/L) was associated with a statistically significant 2-fold increase in pancreatic cancer risk overall (odds ratio = 2.12, 95% confidence interval: 1.23, 3.64). Given this result, recommendations to increase vitamin D concentrations in healthy persons for the prevention of cancer should be carefully considered
— id: 134377, year: 2010, vol: 172, page: 81, stat: Journal Article,

Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer
Toniolo, Paolo; Grankvist, Kjell; Wulff, Marianne; Chen, Tianhui; Johansson, Robert; Schock, Helena; Lenner, Per; Hallmans, Goran; Lehtinen, Matti; Kaaks, Rudolf; Wadell, Goran; Zeleniuch-Jacquotte, Anne; Lundin, Eva; Lukanova, Annekatrin
2010 Sep 1;70(17):6779-6786, Cancer research
Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86-21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy
— id: 136565, year: 2010, vol: 70, page: 6779, stat: Journal Article,

Temporal reproducibility of taurine measurements in frozen serum of healthy postmenopausal women
Wojcik, Oktawia P; Koenig, Karen L; Zeleniuch-Jacquotte, Anne; Costa, Max; Chen, Yu
2010 Sep;104(5):629-632, British journal of nutrition
Animal studies and small clinical trials have shown that taurine (2-aminoethanesulphonic acid), a sulphur-containing molecule mainly obtained from the diet in human subjects, has a variety of biological actions that are related to atherosclerosis and cardiovascular functions. However, epidemiological studies of taurine and CHD risk are lacking. We evaluated whether a single measurement of serum taurine could serve as an estimate for long-term serum levels. Serum taurine was measured using HPLC in three annual samples from thirty postmenopausal women selected from the New York University Women's Health Study. Overall, serum taurine values ranged from 62.8 to 245.3 nmol/ml, with a mean of 140 nmol/ml. The intraclass correlation coefficient of a single measurement of serum taurine was 0.48 (95 % CI 0.26, 0.68), which can be improved to 0.65 by using the mean of two annual measurements. The CV was 7 %. These results indicate that the mean of two or more annual measurements of serum taurine is a sufficiently reliable measure of long-term serum levels that can be used in epidemiological studies
— id: 132231, year: 2010, vol: 104, page: 629, stat: Journal Article,

The potential protective effects of taurine on coronary heart disease
Wojcik, Oktawia P; Koenig, Karen L; Zeleniuch-Jacquotte, Anne; Costa, Max; Chen, Yu
2010 Jan;208(1):19-25, Atherosclerosis
In humans, taurine (2-aminoethanesulfonic acid) is mainly obtained from diet. Despite the fact that the health effects of taurine are largely unknown, taurine has become a popular supplement and ingredient in energy drinks in recent years. Evidence from mechanistic and animal studies has shown that the main biological actions of taurine include its ability to conjugate bile acids, regulate blood pressure (BP), and act as a potent antioxidant and anti-inflammatory agent. These actions suggest that high levels of taurine may be protective against coronary heart disease (CHD). However, data from epidemiologic and intervention studies in humans are limited. We review what is known about taurine\'s metabolism, its transportation in the body, its food sources, and evidence of its effect on cardiovascular health from in vitro, animal, and epidemiologic studies. We also discuss shortcomings of the human studies that need to be addressed in the future. The identification of taurine as a preventive factor for CHD may be of great public health importance
— id: 101575, year: 2010, vol: 208, page: 19, stat: Journal Article,

Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium
Wolpin, Brian M; Kraft, Peter; Gross, Myron; Helzlsouer, Kathy; Bueno-de-Mesquita, H Bas; Steplowski, Emily; Stolzenberg-Solomon, Rachael Z; Arslan, Alan A; Jacobs, Eric J; Lacroix, Andrea; Petersen, Gloria; Zheng, Wei; Albanes, Demetrius; Allen, Naomi E; Amundadottir, Laufey; Anderson, Garnet; Boutron-Ruault, Marie-Christine; Buring, Julie E; Canzian, Federico; Chanock, Stephen J; Clipp, Sandra; Gaziano, John Michael; Giovannucci, Edward L; Hallmans, Goran; Hankinson, Susan E; Hoover, Robert N; Hunter, David J; Hutchinson, Amy; Jacobs, Kevin; Kooperberg, Charles; Lynch, Shannon M; Mendelsohn, Julie B; Michaud, Dominique S; Overvad, Kim; Patel, Alpa V; Rajkovic, Aleksandar; Sanchez, Maria-Jose; Shu, Xiao-Ou; Slimani, Nadia; Thomas, Gilles; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Vineis, Paolo; Virtamo, Jarmo; Wactawski-Wende, Jean; Yu, Kai; Zeleniuch-Jacquotte, Anne; Hartge, Patricia; Fuchs, Charles S
2010 Feb 1;70(3):1015-1023, Cancer research
A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18-1.62], 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk
— id: 133438, year: 2010, vol: 70, page: 1015, stat: Journal Article,

Variant ABO blood group alleles, secretor status, and risk of pancreatic cancer: results from the pancreatic cancer cohort consortium
Wolpin, Brian M; Kraft, Peter; Xu, Mousheng; Steplowski, Emily; Olsson, Martin L; Arslan, Alan A; Bueno-de-Mesquita, H Bas; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J; LaCroix, Andrea; Petersen, Gloria; Stolzenberg-Solomon, Rachael Z; Zheng, Wei; Albanes, Demetrius; Allen, Naomi E; Amundadottir, Laufey; Austin, Melissa A; Boutron-Ruault, Marie-Christine; Buring, Julie E; Canzian, Federico; Chanock, Stephen J; Gaziano, J Michael; Giovannucci, Edward L; Hallmans, Goran; Hankinson, Susan E; Hoover, Robert N; Hunter, David J; Hutchinson, Amy; Jacobs, Kevin B; Kooperberg, Charles; Mendelsohn, Julie B; Michaud, Dominique S; Overvad, Kim; Patel, Alpa V; Sanchez, Maria-Jose; Sansbury, Leah; Shu, Xiao-Ou; Slimani, Nadia; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Vineis, Paolo; Visvanathan, Kala; Virtamo, Jarmo; Wactawski-Wende, Jean; Watters, Joanne; Yu, Kai; Zeleniuch-Jacquotte, Anne; Hartge, Patricia; Fuchs, Charles S
2010 Dec;19(12):3140-3149, Cancer epidemiology biomarkers & prevention
BACKGROUND: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. METHODS: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. RESULTS: An increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). CONCLUSIONS: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. IMPACT: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34
— id: 133760, year: 2010, vol: 19, page: 3140, stat: Journal Article,

Circulating 25-hydroxyvitamin D and risk of endometrial cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Zeleniuch-Jacquotte, Anne; Gallicchio, Lisa; Hartmuller, Virginia; Helzlsouer, Kathy J; McCullough, Marjorie L; Setiawan, V Wendy; Shu, Xiao-Ou; Weinstein, Stephanie J; Weiss, Jocelyn M; Arslan, Alan A; De Vivo, Immaculata; Gao, Yu-Tang; Hayes, Richard B; Henderson, Brian E; Horst, Ronald L; Koenig, Karen L; Patel, Alpa V; Purdue, Mark P; Snyder, Kirk; Steplowski, Emily; Yu, Kai; Zheng, Wei; Hankinson, Susan E
2010 Jul 1;172(1):36-46, American journal of epidemiology
A nested case-control study, including 830 cases and 992 controls from 7 cohorts, was conducted to evaluate the association of circulating 25-hydroxyvitamin D (25(OH)D), the best indicator of vitamin D status, with risk of endometrial cancer. Matching factors included age at blood donation, date of blood donation, and race. Conditional logistic regression was used in the main analysis. The median concentration of 25(OH)D was slightly lower in cases (49.4 nmol/L) than in controls (50.8 nmol/L) (P = 0.08). However, there was no association between 25(OH)D concentration and disease risk, after adjustment for body mass index. Compared with the 50-<75 nmol/L 25(OH)D category, the body mass index-adjusted odds ratios and 95% confidence intervals were 1.08 (95% confidence interval: 0.73, 1.57) for the <25 nmol/L category and 0.90 (95% confidence interval: 0.51, 1.58) for the > or =100 nmol/L category (P(trend) = 0.99). Similarly null results were observed after further adjustment for other known risk factors and in stratified analyses. Although an effect of circulating 25(OH)D at high concentrations cannot be ruled out (the highest category of 25(OH)D was > or =100 nmol/L, and for stratified analyses, > or =75 nmol/L), these results do not support a protective role of vitamin D against endometrial cancer
— id: 110661, year: 2010, vol: 172, page: 36, stat: Journal Article,

Circulating 25-hydroxyvitamin D and risk of epithelial ovarian cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Zheng, Wei; Danforth, Kim N; Tworoger, Shelley S; Goodman, Marc T; Arslan, Alan A; Patel, Alpa V; McCullough, Marjorie L; Weinstein, Stephanie J; Kolonel, Laurence N; Purdue, Mark P; Shu, Xiao-Ou; Snyder, Kirk; Steplowski, Emily; Visvanathan, Kala; Yu, Kai; Zeleniuch-Jacquotte, Anne; Gao, Yu-Tang; Hankinson, Susan E; Harvey, Chinonye; Hayes, Richard B; Henderson, Brian E; Horst, Ronald L; Helzlsouer, Kathy J
2010 Jul 1;172(1):70-80, American journal of epidemiology
A role for vitamin D in ovarian cancer etiology is supported by ecologic studies of sunlight exposure, experimental mechanism studies, and some studies of dietary vitamin D intake and genetic polymorphisms in the vitamin D receptor. However, few studies have examined the association of circulating 25-hydroxyvitamin D (25(OH)D), an integrated measure of vitamin D status, with ovarian cancer risk. A nested case-control study was conducted among 7 prospective studies to evaluate the circulating 25(OH)D concentration in relation to epithelial ovarian cancer risk. Logistic regression models were used to estimate odds ratios and 95% confidence intervals among 516 cases and 770 matched controls. Compared with 25(OH)D concentrations of 50-<75 nmol/L, no statistically significant associations were observed for <37.5 (odds ratio (OR) = 1.21, 95% confidence interval (CI): 0.87, 1.70), 37.5-<50 (OR = 1.03, 95% CI: 0.75, 1.41), or > or =75 (OR = 1.11, 95% CI: 0.79, 1.55) nmol/L. Analyses stratified by tumor subtype, age, body mass index, and other variables were generally null but suggested an inverse association between 25(OH)D and ovarian cancer risk among women with a body mass index of > or =25 kg/m(2) (P(interaction) < 0.01). In conclusion, this large pooled analysis did not support an overall association between circulating 25(OH)D and ovarian cancer risk, except possibly among overweight women
— id: 134376, year: 2010, vol: 172, page: 70, stat: Journal Article,

Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer
Amundadottir, Laufey; Kraft, Peter; Stolzenberg-Solomon, Rachael Z; Fuchs, Charles S; Petersen, Gloria M; Arslan, Alan A; Bueno-de-Mesquita, H Bas; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J; LaCroix, Andrea; Zheng, Wei; Albanes, Demetrius; Bamlet, William; Berg, Christine D; Berrino, Franco; Bingham, Sheila; Buring, Julie E; Bracci, Paige M; Canzian, Federico; Clavel-Chapelon, Francoise; Clipp, Sandra; Cotterchio, Michelle; de Andrade, Mariza; Duell, Eric J; Fox, John W Jr; Gallinger, Steven; Gaziano, J Michael; Giovannucci, Edward L; Goggins, Michael; Gonzalez, Carlos A; Hallmans, Goran; Hankinson, Susan E; Hassan, Manal; Holly, Elizabeth A; Hunter, David J; Hutchinson, Amy; Jackson, Rebecca; Jacobs, Kevin B; Jenab, Mazda; Kaaks, Rudolf; Klein, Alison P; Kooperberg, Charles; Kurtz, Robert C; Li, Donghui; Lynch, Shannon M; Mandelson, Margaret; McWilliams, Robert R; Mendelsohn, Julie B; Michaud, Dominique S; Olson, Sara H; Overvad, Kim; Patel, Alpa V; Peeters, Petra H M; Rajkovic, Aleksandar; Riboli, Elio; Risch, Harvey A; Shu, Xiao-Ou; Thomas, Gilles; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Van Den Eeden, Stephen K; Virtamo, Jarmo; Wactawski-Wende, Jean; Wolpin, Brian M; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Chanock, Stephen J; Hartge, Patricia; Hoover, Robert N
2009 Sep;41(9):986-990, Nature genetics
We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B
— id: 143964, year: 2009, vol: 41, page: 986, stat: Journal Article,

Circulating vitamin d and risk of epithelial ovarian cancer
Arslan, Alan A; Clendenen, Tess V; Koenig, Karen L; Hultdin, Johan; Enquist, Kerstin; Agren, Asa; Lukanova, Annekatrin; Sjodin, Hubert; Zeleniuch-Jacquotte, Anne; Shore, Roy E; Hallmans, Goran; Toniolo, Paolo; Lundin, Eva
2009 ;2009:672492-672492, Journal of oncology
We conducted a nested case-control study within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Health and Disease Study, to examine the association between prediagnostic circulating levels of 25-hydroxy vitamin D (25(OH)D) and the risk of subsequent invasive epithelial ovarian cancer (EOC). The 25(OH)D levels were measured in serum or plasma from 170 incident cases of EOC and 373 matched controls. Overall, circulating 25(OH)D levels were not associated with the risk of EOC in combined cohort analysis: adjusted OR for the top tertile versus the reference tertile, 1.09 (95% CI, 0.59-2.01). In addition, there was no evidence of an interaction effect between VDR SNP genotype or haplotype and circulating 25(OH)D levels in relation to ovarian cancer risk, although more complex gene-environment interactions may exist
— id: 101966, year: 2009, vol: 2009, page: 672492, stat: Journal Article,

Circulating estrogen metabolites and risk for breast cancer in premenopausal women
Arslan, Alan A; Shore, Roy E; Afanasyeva, Yelena; Koenig, Karen L; Toniolo, Paolo; Zeleniuch-Jacquotte, Anne
2009 Aug;18(8):2273-2279, Cancer epidemiology biomarkers & prevention
BACKGROUND: It has been proposed that a shift toward 2-hydroxyestrone from 16alpha-hydroxyestrone metabolic pathway may be inversely associated with breast cancer risk because 2-hydroxyestrone is thought to be less genotoxic and estrogenic than 16alpha-hydroxyestrone. METHODS: We examined the associations of invasive breast cancer risk with circulating 2-hydroxyestrone, 16alpha-hydroxyestrone, and the 2-hydroxyestrone:16alpha-hydroxyestrone ratio in a case-control study on premenopausal women nested within a prospective cohort the New York University Women's Health Study. The serum levels of 2-hydroxyestrone and 16alpha-hydroxyestrone were measured in 377 incident premenopausal breast cancer cases and 377 premenopausal controls, who were matched on age at enrollment, number and dates of blood donations, and day and phase of menstrual cycle. RESULTS: Overall, no significant associations were observed between breast cancer risk and serum levels of 2-hydroxyestrone, 16alpha-hydroxyestrone, or their ratio. The 2-hydroxyestrone:16alpha-hydroxyestrone ratio was positively associated with risk for estrogen receptor-positive breast cancer in the analyses controlling for matching factors. However, the association was attenuated and not significant after adjustment for potential confounders (odds ratio for the highest versus the lowest quartile, 2.15; 95% CI, 0.88-5.27; P(trend) = 0.09). CONCLUSIONS: The results of the current study do not support the hypothesis that a metabolic shift from 16alpha-hydroxyestrone toward 2-hydroxyestrone in premenopausal women is associated with reduced risk for breast cancer. The association between the 2-hydroxy:16alpha-hydroxyestrone ratio and estrogen receptor-positive breast cancer needs to be explored in future studies
— id: 101449, year: 2009, vol: 18, page: 2273, stat: Journal Article,

Promoter methylation and the detection of breast cancer
Brooks, Jennifer; Cairns, Paul; Zeleniuch-Jacquotte, Anne
2009 Nov;20(9):1539-1550, Cancer causes & control. ccc
Mammographic screening has been shown to reduce breast cancer mortality in women over the age of 50 years, and to a lesser extent in younger women. The sensitivity of mammography, however, is reduced in some groups of women. There remains a need for a minimally invasive, cost-effective procedure that could be used along side mammography to improve screening sensitivity. Silencing of tumor suppressor genes through promoter hypermethylation is known to be a frequent and early event in carcinogenesis. Further, changes in methylation patterns observed in tumors are also detectable in the circulation of women with breast cancer. This makes these alterations candidate markers for early tumor detection. In this paper, we review the current literature on promoter hypermethylation changes and breast cancer and discuss issues that remain to be addressed in order for the potential of these markers to augment the sensitivity of screening mammography. In general, studies in well-defined populations, including appropriate controls and larger numbers are needed. Further, focus on the optimization of methods of methylation detection in small amounts of DNA is needed
— id: 104894, year: 2009, vol: 20, page: 1539, stat: Journal Article,

Postmenopausal levels of endogenous sex hormones and risk of colorectal cancer
Clendenen, Tess V; Koenig, Karen L; Shore, Roy E; Levitz, Mortimer; Arslan, Alan A; Zeleniuch-Jacquotte, Anne
2009 Jan;18(1):275-281, Cancer epidemiology biomarkers & prevention
Observational epidemiologic studies and randomized trials have reported a protective effect of oral hormonal replacement therapy on risk of colorectal cancer. Only one previous prospective study, the Women's Health Initiative Observational Study, has reported on the relationship between endogenous hormones and incident colorectal cancer. Contrary to expectation, the investigators found that women with higher circulating estradiol levels were at increased risk of developing colorectal cancer. We conducted a case-control study nested within the New York University Women's Health Study prospective cohort to evaluate the association between endogenous levels of estrone, estradiol, and sex hormone-binding globulin (SHBG) with risk of colorectal cancer. We measured hormones and SHBG in serum samples collected at enrollment from a total of 148 women who subsequently developed colorectal cancer and 293 matched controls. Circulating estrone levels were positively associated with risk of colorectal cancer: The odds ratio for the highest versus lowest quartile of estrone was 1.8 (95% confidence interval, 1.0-3.3). We found a nonsignificant inverse association between SHBG and colorectal cancer, which disappeared after adjusting for body mass index. We did not find an association between estradiol and colorectal cancer risk, but we cannot rule out a potential association because of substantial laboratory error in the measurement. Our results suggest that endogenous estrone is associated with increased risk of colorectal cancer in postmenopausal women
— id: 92142, year: 2009, vol: 18, page: 275, stat: Journal Article,

Reproducibility of serum cytokines and growth factors
Gu, Yian; Zeleniuch-Jacquotte, Anne; Linkov, Faina; Koenig, Karen L; Liu, Mengling; Velikokhatnaya, Lyudmila; Shore, Roy E; Marrangoni, Adele; Toniolo, Paolo; Lokshin, Anna E; Arslan, Alan A
2009 Jan;45(1):44-49, Cytokine
BACKGROUND: In most studies, circulating biomarkers are usually assessed from a single sample, assuming that this single measurement represents the long-term biomarker status of the individual. Such an assumption is rarely tested although it may not be valid for all biomarkers. The objective of this study was to investigate the temporal reproducibility of a panel of cytokines and growth factors. METHODS: Thirty-five postmenopausal women with two annual visits and 30 premenopausal women with three annual visits were randomly selected from the participants in an existing prospective cohort. A total of 23 serum cytokines, nine growth factors and C-reactive protein (CRP) were measured using the Luminex xMap technology. In addition, for eight biomarkers, regular and high sensitivity (hs) assays were compared. RESULTS: The biomarkers with adequate (>60%) detection rates and acceptable (> or =0.55) intra-class correlation coefficients (ICCs) were: hsIL-1beta, IL-1RA, hsIL-2, hsIL-4, hsIL-5, hsIL-6, hsIL-10, IL-12p40, hsIL-12p70, hsTNF-alpha, TNF-R1, TNF-R2, CRP, HGF, NGF, and EGFR. The remaining biomarkers either had low temporal reproducibility or were undetectable in more than 40% of samples. CONCLUSIONS: The results suggest that 16 of the 41 biomarkers measured with Luminex technology showed sufficient sensitivity and temporal reproducibility in sera
— id: 92177, year: 2009, vol: 45, page: 44, stat: Journal Article,

Reliability of tumor markers, chemokines, and metastasis-related molecules in serum
Linkov, Faina; Gu, Yian; Arslan, Alan A; Liu, Mengling; Shore, Roy E; Velikokhatnaya, Lyudmila; Koenig, Karen L; Toniolo, Paolo; Marrangoni, Adele; Yurkovetsky, Zoya; Zeleniuch-Jacquotte, Anne; Lokshin, Anna E
2009 Mar;20(1):21-26, European cytokine network
There is a growing interest in the role that cancer biomarkers, metastasis-related molecules, and chemokines may play in the development and progression of various cancers. However, few studies have addressed the reliability of such biomarkers in healthy individuals over time. The objective of this study was to investigate the temporal reliability of multiple proteins in serum samples from healthy women who donated blood over successive years. Thirty five, postmenopausal women with two, repeated annual visits, and thirty, premenopausal women with three, repeated annual visits were randomly selected among eligible subjects from an existing, prospective cohort. Multiplexing Luminex xMAPTM technology was used to measure the levels of 55 serum proteins representing cancer antigens, chemokines, angiogenic and anti-angiogenic factors, proteases, adipokines, apoptotic molecules, and other markers in these women. The biomarkers with high detection rates (> 60%) and acceptable reliability (intraclass correlation coefficient, ICCs > or = 0.55) using xMAPTM method were: cancer antigens: AFP, CA 15-3, CEA, CA-125, SCC, SAA; growth factors/related molecules: ErbB2, IGFBP-1; proteases and adhesion molecules: MMP-1, 8, 9, sE-selectin, human kallikreins (KLK) 8,10, ICAM-1, VCAM-1, chemokines: fractalkine, MCP-1,2, RANTES, MIP-1alpha, MIP-1beta, Eotaxin, GRO-alpha, IP-10; inhibitors of angiogenesis: angiostatin and endostatin; adipokines leptin and resistin; apoptotic factor: Fas, and other proteins mesothelin, myeloperoxidase (MPO), and PAI-1. The rest of the biomarkers under investigation either had ICCs less than 0.55 or had low levels of detection (< 60%). These included cancer antigens: CA 19-9, CA 72-4, MICA, S100, TTR, ULBP1, ULBP2, ULBP3; proteases: MMP 2, 3, 7, 12, 13; chemokines: MCP-3, MIF, MIG; adipokines: leptin and resistin; apoptotic factors: FasL, DR5, Cyfra 21-1; and inhibitors of angiogenesis and other markers: thrombospondin and heat shock protein (HSP) 27. In conclusion, 34 out of the 55 biomarkers investigated were present in detectable levels in > 60% of the samples, and with an ICC > or = 0.55, indicating that a single serum measurement can be used in prospective epidemiological studies using the xMAPTM method
— id: 126591, year: 2009, vol: 20, page: 21, stat: Journal Article,

C-reactive protein and ovarian cancer: a prospective study nested in three cohorts (Sweden, USA, Italy)
Lundin, Eva; Dossus, Laure; Clendenen, Tess; Krogh, Vittorio; Grankvist, Kjell; Wulff, Marianne; Sieri, Sabina; Arslan, Alan A; Lenner, Per; Berrino, Franco; Hallmans, Goran; Zeleniuch-Jacquotte, Anne; Toniolo, Paolo; Lukanova, Annekatrin
2009 Sep;20(7):1151-1159, Cancer causes & control. ccc
OBJECTIVES: Inflammatory processes may influence the risk of epithelial ovarian cancer, but available epidemiological evidence is limited and indirect. Circulating C-reactive protein (CRP), a sensitive marker of inflammation, may serve as a direct biological marker of an underlying association. METHODS: The association between ovarian cancer risk and pre-diagnostic circulating CRP was tested in a case-control study nested within three prospective cohorts from Sweden, USA, and Italy. The study included 237 cases and 427 individually matched controls. CRP was measured in stored blood samples by high-sensitivity immunoturbidimetric assay. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by conditional logistic regression. RESULTS: Overall, CRP was not related to risk of ovarian cancer. However, a marked increase in risk was observed for CRP concentrations >10 mg/l: OR (95% CI) 4.4 (1.8-10.9), which remained significant after limiting analyses to cases diagnosed more than two or five years after blood donation (OR 3.0 (1.2-8.0) and 3.6 (1.0-13.2), respectively). Risk of mucinous tumors increased with high CRP, but the number of cases in this analysis was small. CONCLUSION: Study results offer additional support to the concept that chronic inflammation plays a role in epithelial ovarian cancer
— id: 114702, year: 2009, vol: 20, page: 1151, stat: Journal Article,

Reproducibility of serum pituitary hormones in women
Arslan, Alan A; Gu, Yian; Zeleniuch-Jacquotte, Anne; Koenig, Karen L; Liu, Mengling; Velikokhatnaya, Lyudmila; Shore, Roy E; Toniolo, Paolo; Linkov, Faina; Lokshin, Anna E
2008 Aug;17(8):1880-1883, Cancer epidemiology biomarkers & prevention
Endogenous pituitary hormones are commonly used in clinical and epidemiologic studies and some of them are thought to influence the risk of several diseases in women. In most studies, endogenous levels of pituitary hormones are usually assessed at a single point in time, assuming that this single measurement represents the long-term biomarker status of the individual. Such an assumption is rarely tested and may not always be valid. This study examined the reproducibility of the following pituitary hormones: adrenocorticotropic hormone (ACTH), growth hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and prolactin, measured using the Luminex xMap method in sera of healthy premenopausal and postmenopausal women. The study included 30 premenopausal women with three yearly samples and 35 postmenopausal women with two repeated yearly samples randomly selected from an existing prospective cohort. Analysis of intraclass correlation coefficients suggested higher reproducibility in postmenopausal women compared with premenopausal women for the following hormones: FSH (0.72 and 0.37, respectively), LH (0.83 and 0.44, respectively), and growth hormone (0.60 and 0.35, respectively). The intraclass correlation coefficients were relatively high and similar between postmenopausal and premenopausal women for ACTH (0.95 and 0.94, respectively), TSH (0.85 and 0.85, respectively), and prolactin (0.72 and 0.69, respectively). This study found that serum concentrations of FSH, LH, and growth hormone are stable in postmenopausal women and that ACTH, TSH, and prolactin are stable in both premenopausal and postmenopausal women, suggesting that a single measurement may reliably categorize average levels over at least a 2-year period
— id: 91436, year: 2008, vol: 17, page: 1880, stat: Journal Article,

Polymorphisms in RAD51, XRCC2, and XRCC3 are not related to breast cancer risk
Brooks, Jennifer; Shore, Roy E; Zeleniuch-Jacquotte, Anne; Currie, Diane; Afanasyeva, Yelena; Koenig, Karen L; Arslan, Alan A; Toniolo, Paolo; Wirgin, Isaac
2008 Apr;17(4):1016-1019, Cancer epidemiology biomarkers & prevention
— id: 80287, year: 2008, vol: 17, page: 1016, stat: Journal Article,

Vitamin D receptor polymorphisms and risk of epithelial ovarian cancer
Clendenen, Tess V; Arslan, Alan A; Koenig, Karen L; Enquist, Kerstin; Wirgin, Isaac; Agren, Asa; Lukanova, Annekatrin; Sjodin, Hubert; Zeleniuch-Jacquotte, Anne; Shore, Roy E; Hallmans, Goran; Toniolo, Paolo; Lundin, Eva
2008 Feb 18;260(1-2):209-215, Cancer letters
The vitamin D receptor (VDR) is a critical mediator of the cellular effects of vitamin D. The associations between four common VDR polymorphisms (BSMI, APAI, TAQI, and FOKI) and risk of epithelial ovarian cancer (EOC) were assessed in a case-control study nested within two prospective cohorts. One hundred seventy incident cases of EOC and 323 individually matched controls were genotyped. Overall, no associations were observed in genotype analyses. Haplotypes combining three SNPs in high linkage disequilibrium (BSMI, APAI, and TAQI) were also not associated with risk. These observations do not support a role for BSMI, APAI, TAQI, and FOKI polymorphisms in epithelial ovarian cancer in a predominantly Caucasian population
— id: 76858, year: 2008, vol: 260, page: 209, stat: Journal Article,

Effect of long-term storage on hormone measurements in samples from pregnant women: the experience of the Finnish Maternity Cohort
Holl, Katsiaryna; Lundin, Eva; Kaasila, Marjo; Grankvist, Kjell; Afanasyeva, Yelena; Hallmans, Goran; Lehtinen, Matti; Pukkala, Eero; Surcel, Helja-Marja; Toniolo, Paolo; Zeleniuch-Jacquotte, Anne; Koskela, Pentti; Lukanova, Annekatrin
2008 ;47(3):406-412, Acta oncologica
Validity of biobank studies on hormone associated cancers depend on the extent the sample preservation is affecting the hormone measurements. We investigated the effect of long-term storage (up to 22 years) on immunoassay measurements of three groups of hormones and associated proteins: sex-steroids [estradiol, progesterone, testosterone, dihydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG)], pregnancy-specific hormones [human chorionic gonadotropin (hCG), placental growth hormone (pGH), alpha-fetoprotein (AFP)], and insulin-like growth factor (IGF) family hormones exploiting the world largest serum bank, the Finnish Maternity Cohort (FMC). Hormones of interest were analyzed in a random sample of 154 Finnish women in the median age (29.5 years, range 25 to 34 years) of their first pregnancy with serum samples drawn during the first trimester. All hormone measurements were performed using commercial enzyme-linked- or radio-immunoassays. Storage time did not correlate with serum levels of testosterone, DHEAS, hCG, pGH and total IGFBP-1. It had a weak or moderate negative correlation with serum levels of progesterone (Spearman's ranked correlation coefficient (r(s))=- 0.36), IGF-I (r(s)=-0.23) and IGF binding protein (BP)-3 (r(s)=-0.38), and weak positive correlation with estradiol (r(s)=0.23), SHBG (r(s)=0.16), AFP (r(s)=0.20) and non-phosphorylated IGF binding protein (BP)-1 (r(s)=0.27). The variation of all hormone levels studied followed the kinetics reported for early pregnancy. Bench-lag time (the time between sample collection and freezing for storage) did not materially affect the serum hormone levels. In conclusion, the stored FMC serum samples can be used to study hormone-disease associations, but close matching for storage time and gestational day are necessary design components of all related biobank studies
— id: 96693, year: 2008, vol: 47, page: 406, stat: Journal Article,

Serum prohepcidin is associated with soluble transferrin receptor-1 but not ferritin in healthy post-menopausal women
Huang, Xi; Fung, Eric T; Yip, Christine; Zeleniuch-Jacquotte, Anne
2008 Nov-Dec;41(3):265-269, Blood cells, molecules, & diseases
Hepcidin is a 25-amino-acid iron peptide hormone originated from its two precursors of prohepcidin (60-amino-acid) and preprohepcidin (84-amino-acid). Serum prohepcidin levels have been widely used to evaluate iron overload in clinical and preclinical studies. However, its usefulness is often questioned and its stepwise conversion mechanism remains largely unknown. Using New York University Women's Health Study subjects, we measured serum levels of prohepcidin with ELISA and hepcidin with mass spectrometry as well as ferritin and soluble transferrin receptor 1 (sTfR1) in 45 normal healthy post-menopausal women over a 1-year period with 2 samples per subject. We found that serum prohepcidin levels are correlated with the serum sTfR1 levels (r=0.45, p<0.01) but not to ferritin levels (r=0.08, p=0.60), suggesting that serum prohepcidin is not a biomarker of iron overload that was originally thought and designed for. Interestingly, serum hepcidin levels are associated with serum ferritin levels (r=0.64, p<0.0001) but not with sTfR1 levels (r=0.06, p=0.70), indicating that hepcidin is a measure of iron overload. Although hepcidin is a downstream product of prohepcidin, the amounts of hepcidin and prohepcidin are not related to each other (r=-0.007, p=0.90) under normal physiological conditions. The interrelationships between sTfR1 and prohepcidin or between ferritin and hepcidin suggest that ferritin- and sTfR1-sensed hepcidin conversion system exist in human body and maybe regulated at the post-translational level
— id: 93350, year: 2008, vol: 41, page: 265, stat: Journal Article,

Human chorionic gonadotropin and alpha-fetoprotein concentrations in pregnancy and maternal risk of breast cancer: a nested case-control study
Lukanova, Annekatrin; Andersson, Ritu; Wulff, Marianne; Zeleniuch-Jacquotte, Anne; Grankvist, Kjell; Dossus, Laure; Afanasyeva, Yelena; Johansson, Robert; Arslan, Alan A; Lenner, Per; Wadell, Goran; Hallmans, Goran; Toniolo, Paolo; Lundin, Eva
2008 Dec 1;168(11):1284-1291, American journal of epidemiology
Pregnancy hormones are believed to be involved in the protection against breast cancer conferred by pregnancy. The authors explored the association of maternal breast cancer with human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP). In 2001, a case-control study was nested within the Northern Sweden Maternity Cohort, an ongoing study in which blood samples have been collected from first-trimester pregnant women since 1975. Cases (n = 210) and controls (n = 357) were matched for age, parity, and date of blood donation. Concentrations of hCG and AFP were measured by immunoassay. No overall significant association of breast cancer with either hCG or AFP was observed. However, women with hCG levels in the top tertile tended to be at lower risk of breast cancer than women with hCG levels in the lowest tertile in the whole study population and in subgroups of age at sampling, parity, and age at cancer diagnosis. A borderline-significant decrease in risk with high hCG levels was observed in women who developed breast cancer after the median lag time to cancer diagnosis (> or =14 years; odds ratio = 0.53, 95% confidence interval: 0.27, 1.03; P = 0.06). These findings, though very preliminary, are consistent with a possible long-term protective association of breast cancer risk with elevated levels of circulating hCG in the early stages of pregnancy
— id: 93616, year: 2008, vol: 168, page: 1284, stat: Journal Article,

Polymorphisms in XPC and ERCC2 genes, smoking and breast cancer risk
Shore, Roy E; Zeleniuch-Jacquotte, Anne; Currie, Diane; Mohrenweiser, Harvey; Afanasyeva, Yelena; Koenig, Karen L; Arslan, Alan A; Toniolo, Paolo; Wirgin, Isaac
2008 May 1;122(9):2101-2105, International journal of cancer
To evaluate the associations of breast cancer risk with polymorphisms in the XPC and XPD/ERCC2 DNA nucleotide excision repair genes, a case-control study nested within a prospective cohort of 14,274 women was conducted. Genotypes were characterized for 612 incident, invasive breast cancer cases and their 1:1 matched controls. The homozygous variant of a poly(AT) insertion/deletion polymorphism in intron 9 of the XPC gene (XPC-PAT+/+), was associated with breast cancer risk [odds ratio (OR) = 1.45, 95% confidence interval: 1.07-1.97], after adjustment for other breast cancer risk factors. The breast cancer risk associated with XPC-PAT+/+ did not differ by age at diagnosis. There was an indication of an interaction (p = 0.08) between the XPC-PAT+/+ genotype and cigarette smoking. Ever smokers with the XPC-PAT+/+ genotype were at elevated risk of breast cancer (OR = 1.56, CI: 0.95-2.58), but no differences were observed among never smokers. Analyses of the ERCC2 Lys751Gln polymorphism did not show an association with breast cancer risk, either overall or at younger ages. The results suggest that breast cancer risk is related to the XPC haplotype tagged by the XPC-PAT+/+ insertion-deletion polymorphism in intron 9. Further study of the XPC haplotypes and their interactions with smoking in relation to breast cancer risk is needed
— id: 76390, year: 2008, vol: 122, page: 2101, stat: Journal Article,

Re: C-reactive protein and risk of breast cancer
Zeleniuch-Jacquotte, Anne; Gu, Yian; Bruning, Peter F; Bonfrer, Johannes M G; Koenig, Karen L; Arslan, Alan A; Toniolo, Paolo; Shore, Roy E
2008 Mar 19;100(6):443-444, Journal of the National Cancer Institute
— id: 93619, year: 2008, vol: 100, page: 443, stat: Journal Article,

Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies
Koushik, Anita; Hunter, David J; Spiegelman, Donna; Beeson, W Lawrence; van den Brandt, Piet A; Buring, Julie E; Calle, Eugenia E; Cho, Eunyoung; Fraser, Gary E; Freudenheim, Jo L; Fuchs, Charles S; Giovannucci, Edward L; Goldbohm, R Alexandra; Harnack, Lisa; Jacobs, David R Jr; Kato, Ikuko; Krogh, Vittorio; Larsson, Susanna C; Leitzmann, Michael F; Marshall, James R; McCullough, Marjorie L; Miller, Anthony B; Pietinen, Pirjo; Rohan, Thomas E; Schatzkin, Arthur; Sieri, Sabina; Virtanen, Mikko J; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zhang, Shumin M; Smith-Warner, Stephanie A
2007 Oct 3;99(19):1471-1483, Journal of the National Cancer Institute
BACKGROUND: Fruit and vegetable intakes have been associated with a reduced risk of colon cancer; however, in more recent studies associations have been less consistent. Statistical power to examine associations by colon site has been limited in previous studies. METHODS: Fruit and vegetable intakes in relation to colon cancer risk were examined in the Pooling Project of Prospective Studies of Diet and Cancer. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated separately in 14 studies using Cox proportional hazards model and then pooled using a random-effects model. Intakes of total fruits and vegetables, total fruits, and total vegetables were categorized according to quintiles and absolute cutpoints. Analyses were conducted for colon cancer overall and for proximal and distal colon cancer separately. All statistical tests were two-sided. RESULTS: Among 756,217 men and women followed for up to 6 to 20 years, depending on the study, 5838 were diagnosed with colon cancer. The pooled multivariable RRs (95% CIs) of colon cancer for the highest versus lowest quintiles of intake were 0.91 (0.82 to 1.01, P(trend) = .19) for total fruits and vegetables, 0.93 (0.85 to 1.02, P(trend) = .28) for total fruits, and 0.94 (0.86 to 1.02, P(trend) = .17) for total vegetables. Similar results were observed when intakes were categorized by identical absolute cut points across studies (pooled multivariable RR = 0.90, 95% CI = 0.77 to 1.05 for 800 or more versus <200 g/day of total fruits and vegetables, P(trend) = .06). The age-standardized incidence rates of colon cancer for these two intake categories were 54 and 61 per 100,000 person-years, respectively. When analyzed by colon site, the pooled multivariable RRs (95% CIs) comparing total fruit and vegetable intakes of 800 or more versus less than 200 g/day were 0.74 (0.57 to 0.95, P(trend) = .02) for distal colon cancers and 1.02 (0.82 to 1.27, P(trend) = .57) for proximal colon cancers. Similar site-specific associations were observed for total fruits and total vegetables. CONCLUSION: Fruit and vegetable intakes were not strongly associated with colon cancer risk overall but may be associated with a lower risk of distal colon cancer
— id: 95668, year: 2007, vol: 99, page: 1471, stat: Journal Article,

Reliability of serum assays of iron status in postmenopausal women
Zeleniuch-Jacquotte, Anne; Zhang, Qi; Dai, Jisen; Shore, Roy E; Arslan, Alan A; Koenig, Karen L; Karkoszka, Jerzy; Afanasyeva, Yelena; Frenkel, Krystyna; Toniolo, Paolo; Huang, Xi
2007 May;17(5):354-358, Annals of epidemiology
PURPOSE: The aim of the study is to determine the reliability during a 2-year period of several newly developed iron-related assays to assess their potential for use in prospective epidemiologic studies. METHODS: We assessed the temporal reliability of several iron-related assays by using three serum samples collected at yearly intervals from 50 postmenopausal participants in a large prospective study. RESULTS: We observed high reliability coefficients for ferritin (0.78; 95% confidence interval [CI], 0.67-0.86), soluble transferrin receptor (sTfR; 0.79; 95% CI, 0.69-0.87), sTfR/ferritin ratio (0.74; 95% CI, 0.62-0.83), and hepcidin (0.89; 95% CI, 0.84-0.94). In a subset of 30 women, lower reliability was observed for serum iron (0.50; 95% CI, 0.29-0.70), unsaturated iron-binding capacity (0.55; 95% CI, 0.34-0.73), total iron-binding capacity (0.60; 95% CI, 0.40-0.76), and serum transferrin saturation rate (0.44; 95% CI, 0.22-0.65). The reliability of anti-5-hydroxymethyl-2'-deoxyuridine autoantibody titers, a biomarker of oxidized DNA damage, one of the mechanisms by which iron is thought to impact disease risk, was very high (0.97, 95% CI, 0.5-0.99). CONCLUSIONS: Our results show that some newly developed iron-related assays could be useful tools to assess iron-disease associations in prospective cohorts that collect a single blood sample
— id: 73252, year: 2007, vol: 17, page: 354, stat: Journal Article,

Effects of parity on pregnancy hormonal profiles across ethnic groups with a diverse incidence of breast cancer
Arslan, Alan A; Zeleniuch-Jacquotte, Anne; Lukanova, Annekatrin; Afanasyeva, Yelena; Katz, Joseph; Levitz, Mortimer; Del Priore, Giuseppe; Toniolo, Paolo
2006 Nov;15(11):2123-2130, Cancer epidemiology biomarkers & prevention
Epidemiologic evidence suggests that a full-term pregnancy may affect maternal risk of breast cancer later in life. The objective of this cross-sectional study was to compare circulating levels of maternal hormones affecting breast differentiation (human chorionic gonadotropin and prolactin) and proliferation [alpha-fetoprotein, insulin-like growth factor I (IGF-I), and estradiol] between women at a low to moderate risk (Asians and Hispanics), as compared with women at a high risk for breast cancer (Caucasians and African-Americans). Between May 2002 and December 2004, a total of 586 pregnant women were approached during a routine prenatal visit. Among them, 450 women (206 Caucasian, 126 Asian, 88 Hispanic, and 30 African-American) met the inclusion criteria and signed the informed consent. Only singleton pregnancies were considered. Blood samples were drawn during the second trimester of pregnancy. Laboratory analyses were done using the IMMULITE 2000 immunoassay system. Gestational age standardized mean levels of estradiol, IGF-I, and prolactin were significantly higher in Hispanic women compared with Caucasian women. Mean concentration of IGF-I was significantly higher in African-American women compared with Caucasian and Asian women. No significant differences in pregnancy hormone levels were observed between Caucasian and Asian (predominantly second-generation Chinese) women in this study. Irrespective of ethnicity, women who had their first pregnancy had substantially higher mean levels of alpha-fetoprotein, human chorionic gonadotropin, estradiol, and prolactin compared with women who previously had at least one full-term pregnancy. These data suggest that circulating pregnancy hormone levels may explain some of the ethnic differences in breast cancer risk
— id: 72078, year: 2006, vol: 15, page: 2123, stat: Journal Article,

A pooled analysis of 12 cohort studies of dietary fat, cholesterol and egg intake and ovarian cancer
Genkinger, Jeanine M; Hunter, David J; Spiegelman, Donna; Anderson, Kristin E; Beeson, W Lawrence; Buring, Julie E; Colditz, Graham A; Fraser, Gary E; Freudenheim, Jo L; Goldbohm, R Alexandra; Hankinson, Susan E; Koenig, Karen L; Larsson, Susanna C; Leitzmann, Michael; McCullough, Marjorie L; Miller, Anthony B; Rodriguez, Carmen; Rohan, Thomas E; Ross, Julie A; Schatzkin, Arthur; Schouten, Leo J; Smit, Ellen; Willett, Walter C; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zhang, Shumin M; Smith-Warner, Stephanie A
2006 Apr;17(3):273-285, Cancer causes & control. ccc
Fat and cholesterol are theorized to promote ovarian carcinogenesis by increasing circulating estrogen levels. Although case-control studies have reported positive associations between total and saturated fat intake and ovarian cancer risk, two cohort studies have observed null associations. Dietary cholesterol and eggs have been positively associated with ovarian cancer risk. A pooled analysis was conducted on 12 cohort studies. Among 523,217 women, 2,132 incident epithelial ovarian cancer cases were identified. Study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Total fat intake was not associated with ovarian cancer risk (pooled multivariate RR = 1.08, 95% CI 0.86-1.34 comparing > or =45 to 30-<35% of calories). No association was observed for monounsaturated, polyunsaturated, trans-unsaturated, animal and vegetable fat, cholesterol and egg intakes with ovarian cancer risk. A weakly positive, but non-linear association, was observed for saturated fat intake (pooled multivariate RR = 1.29, 95% CI: 1.01-1.66 comparing highest versus lowest decile). Results for histologic subtypes were similar. Overall, fat, cholesterol and egg intakes were not associated with ovarian cancer risk. The positive association for saturated fat intake at very high intakes merits further investigation
— id: 72086, year: 2006, vol: 17, page: 273, stat: Journal Article,

Insulin-like growth factor I in pregnancy and maternal risk of breast cancer
Lukanova, Annekatrin; Toniolo, Paolo; Zeleniuch-Jacquotte, Anne; Grankvist, Kjell; Wulff, Marianne; Arslan, Alan A; Afanasyeva, Yelena; Johansson, Robert; Lenner, Per; Hallmans, Goran; Wadell, Goran; Lundin, Eva
2006 Dec;15(12):2489-2493, Cancer epidemiology biomarkers & prevention
BACKGROUND: The role of insulin-like growth factor (IGF)-I in breast cancer remains controversial, despite numerous reports on the association of the hormone with breast cancer or high-risk mammographic densities. We hypothesized that exposure to elevated IGF-I during early pregnancy, a period characterized by intense cell proliferation in the breasts and in the presence of high concentrations of sex steroids, will be associated with increased maternal risk to develop a breast malignancy. METHODS: The Northern Sweden Maternity Cohort is an ongoing prospective study, collecting blood samples from first-trimester-pregnant women since 1975 as part of screening for infectious diseases. A case-control study (212 cases and 369 controls) was nested among Northern Sweden Maternity Cohort members who delivered singleton babies. RIA was used to measure IGF-I and IGF-II levels. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Breast cancer risk increased with increasing IGF-I (top tertile OR, 1.7; 95% CI, 1.1-2.7). The association was stronger among the primiparous (OR, 2.2; 95% CI, 1.1-4.4) than in the nonprimiparous women (OR, 1.4; 95% CI, 0.7-2.8). Upper-tertile risks seemed to decrease within the <28-, 28 to 33, and >33-year groups of age at sampling, from 2.5 (0.9-7.6) to 2.1 (0.9-5.0) and 1.2 (0.5-2.5), respectively. There was no association of breast cancer with first-trimester-pregnancy IGF-II. CONCLUSIONS: The study offers further evidence that IGF-I is important in breast cancer. Our findings suggest that the adverse effect of IGF-I on the breast may be stronger before the remodeling of the gland induced by a first pregnancy
— id: 71414, year: 2006, vol: 15, page: 2489, stat: Journal Article,

Methods for pooling results of epidemiologic studies: the Pooling Project of Prospective Studies of Diet and Cancer
Smith-Warner, Stephanie A; Spiegelman, Donna; Ritz, John; Albanes, Demetrius; Beeson, W Lawrence; Bernstein, Leslie; Berrino, Franco; van den Brandt, Piet A; Buring, Julie E; Cho, Eunyoung; Colditz, Graham A; Folsom, Aaron R; Freudenheim, Jo L; Giovannucci, Edward; Goldbohm, R Alexandra; Graham, Saxon; Harnack, Lisa; Horn-Ross, Pamela L; Krogh, Vittorio; Leitzmann, Michael F; McCullough, Marjorie L; Miller, Anthony B; Rodriguez, Carmen; Rohan, Thomas E; Schatzkin, Arthur; Shore, Roy; Virtanen, Mikko; Willett, Walter C; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zhang, Shumin M; Hunter, David J
2006 Jun 1;163(11):1053-1064, American journal of epidemiology
With the growing number of epidemiologic publications on the relation between dietary factors and cancer risk, pooled analyses that summarize results from multiple studies are becoming more common. Here, the authors describe the methods being used to summarize data on diet-cancer associations within the ongoing Pooling Project of Prospective Studies of Diet and Cancer, begun in 1991. In the Pooling Project, the primary data from prospective cohort studies meeting prespecified inclusion criteria are analyzed using standardized criteria for modeling of exposure, confounding, and outcome variables. In addition to evaluating main exposure-disease associations, analyses are also conducted to evaluate whether exposure-disease associations are modified by other dietary and nondietary factors or vary among population subgroups or particular cancer subtypes. Study-specific relative risks are calculated using the Cox proportional hazards model and then pooled using a random- or mixed-effects model. The study-specific estimates are weighted by the inverse of their variances in forming summary estimates. Most of the methods used in the Pooling Project may be adapted for examining associations with dietary and nondietary factors in pooled analyses of case-control studies or case-control and cohort studies combined
— id: 72085, year: 2006, vol: 163, page: 1053, stat: Journal Article,

Association of low P27 with loss of hormone receptors in small (T1a/b) breast cancers
Wu, J; Mirchandani, D; Smith, JA; Inghirami, G; Roses, D; Zeleniuch-Jacquotte, A; Muggia, F
2006 JUN 20 ;24(18):33S-33S, Journal of clinical oncology
— id: 69294, year: 2006, vol: 24, page: 33S, stat: Journal Article,

Circulating enterolactone and risk of endometrial cancer
Zeleniuch-Jacquotte, Anne; Lundin, Eva; Micheli, Andrea; Koenig, Karen L; Lenner, Per; Muti, Paola; Shore, Roy E; Johansson, Ingegerd; Krogh, Vittorio; Lukanova, Annekatrin; Stattin, Par; Afanasyeva, Yelena; Rinaldi, Sabina; Arslan, Alan A; Kaaks, Rudolf; Berrino, Franco; Hallmans, Goran; Toniolo, Paolo; Adlercreutz, Herman
2006 Nov 15;119(10):2376-2381, International journal of cancer
It has been suggested that phytoestrogens protect against hormone-dependent cancers. Lignans are the main class of phytoestrogens in Western diets. We conducted a prospective study of endometrial cancer and circulating levels of the main human lignan, enterolactone. The design was a case-control study nested within 3 prospective cohort studies, in New York, Sweden and Italy. Serum or plasma samples had been collected at enrollment and stored at -80 degrees C. A total of 153 cases, diagnosed a median of 5.3 years after blood donation, and 271 matched controls were included. No difference in circulating enterolactone was observed between cases (median, 19.2 nmol/L) and controls (18.5 nmol/L). Adjusting for body mass index, the odds ratio for the top tertile of enterolactone, as compared to the lowest was 1.2 (95% CI, 0.7-2.0; p for trend = 0.53). Lack of association was observed in both pre- and postmenopausal women. No correlation was observed between enterolactone and circulating estrogens or SHBG in healthy postmenopausal women. These results do not support a protective role of circulating lignans, in the range of levels observed, against endometrial cancer
— id: 69245, year: 2006, vol: 119, page: 2376, stat: Journal Article,

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle
Hamilton, A L; Eder, J P; Pavlick, A C; Clark, J W; Liebes, L; Garcia-Carbonero, R; Chachoua, A; Ryan, D P; Soma, V; Farrell, K; Kinchla, N; Boyden, J; Yee, H; Zeleniuch-Jacquotte, A; Wright, J; Elliott, P; Adams, J; Muggia, F M
2005 Sep 1;23(25):6107-6116, Journal of clinical oncology
PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea
— id: 57888, year: 2005, vol: 23, page: 6107, stat: Journal Article,

Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies
Park, Yikyung; Hunter, David J; Spiegelman, Donna; Bergkvist, Leif; Berrino, Franco; van den Brandt, Piet A; Buring, Julie E; Colditz, Graham A; Freudenheim, Jo L; Fuchs, Charles S; Giovannucci, Edward; Goldbohm, R Alexandra; Graham, Saxon; Harnack, Lisa; Hartman, Anne M; Jacobs, David R Jr; Kato, Ikuko; Krogh, Vittorio; Leitzmann, Michael F; McCullough, Marjorie L; Miller, Anthony B; Pietinen, Pirjo; Rohan, Thomas E; Schatzkin, Arthur; Willett, Walter C; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zhang, Shumin M; Smith-Warner, Stephanie A
2005 Dec 14;294(22):2849-2857, JAMA
CONTEXT: Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer. OBJECTIVE: To evaluate the association between dietary fiber intake and risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725,628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model. MAIN OUTCOME MEASURE: Incident colorectal cancer. RESULTS: During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR = 0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR = 0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site = .07). CONCLUSIONS: In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer
— id: 72087, year: 2005, vol: 294, page: 2849, stat: Journal Article,

Insulin-like growth factor-I, IGF binding protein-3, and breast cancer in young women: a comparison of risk estimates using different peptide assays
Rinaldi, Sabina; Kaaks, Rudolf; Zeleniuch-Jacquotte, Anne; Arslan, Alan A; Shore, Roy E; Koenig, Karen L; Dossus, Laure; Riboli, Elio; Stattin, Par; Lukanova, Annekatrin; Toniolo, Paolo
2005 Jan;14(1):48-52, Cancer epidemiology biomarkers & prevention
Circulating insulin-like growth factor-I (IGF-I) and its major binding protein IGF binding protein-3 (IGFBP-3) have been associated with increased risk of premenopausal breast cancer, although risk estimates varied broadly. An extension of a case-control study (138 cases, 259 matched controls) on IGF-I and breast cancer in premenopausal women nested in the New York University Women's Health Study cohort offered the opportunity to address the hypothesis that such variability may have been the result of variations in the ability of different IGFBP-3 assays to specifically measure intact/functional forms of the protein. IGF-I and IGFBP-3 had originally been measured using in-house RIAs. These measurements were repeated using commercially available ELISAs [Diagnostic System Laboratories (DSL), Webster, Texas], and a third ELISA with greater specificity for active forms for IGFBP-3. Pearson's correlations between IGF-I concentrations in the original study and DSL ELISA were very high [r = 0.92; 95% CI, 0.90-0.94]. Correlations with DSL ELISA were much lower for IGFBP-3 (r = 0.58; 0.49-0.66) and even lower still with the assay for functional IGFBP-3 (r = 0.33; 0.20-0.44). IGF-I and IGFBP-3 measurements by the DSL ELISA methods showed statistically significant relationships with risk. The odds ratios (OR) for top versus bottom quartiles were 1.93 (1.00-3.72; P = 0.02) and 2.03 (1.09-3.76; P = 0.02), respectively, in agreement with the original observations. In contrast, measurements of functional IGFBP-3 tended to be unrelated to risk [ORs for the top versus bottom quartile, 0.97 (0.44-2.11)]. The association with IGF-I became substantially weaker and lost statistical significance after adjustment for IGFBP-3 using DSL ELISA, but became considerably stronger when adjusting for the functional IGFBP-3 measurements [OR = 2.43 (1.21-4.90); P = 0.005], or when considering the molar ratio of IGF-I to IGFBP-3 [OR = 2.37 (1.13-5.00); P = 0.02]. These results are consistent with an association of breast cancer risk in young women with elevated IGF-I and IGFBP-3, and show that for IGFBP-3, the strength of such an association could vary substantially depending on the assay used
— id: 72082, year: 2005, vol: 14, page: 48, stat: Journal Article,

IGF-I, IGFBP-3 and breast cancer in young women: a pooled re-analysis of three prospective studies
Rinaldi, Sabina; Toniolo, Paolo; Muti, Paola; Lundin, Eva; Zeleniuch-Jacquotte, Anne; Arslan, Alan; Micheli, Andrea; Lenner, Per; Dossus, Laure; Krogh, Vittorio; Shore, Roy E; Koenig, Karen L; Riboli, Elio; Stattin, Par; Berrino, Franco; Hallmans, Goran; Lukanova, Annekatrin; Kaaks, Rudolf
2005 Dec;14(6):493-496, European journal of cancer prevention
Prospective cohort studies on breast cancer risk among premenopausal women and insulin-like growth factor I (IGF-I) concentrations have so far included only few cases, and have shown inconsistent relative risk estimates. We pooled 220 cases of breast cancer diagnosed before age 50, and 434 control subjects, from three prospective studies in New York (USA), Umea (Northern Sweden) and Milan (Italy), and we measured IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) with common enzyme-linked immunosorbent assays. Overall, IGF-I and IGFBP-3 measurements obtained by the common method showed a positive but not significant relationship with breast cancer risk (odds ratios (ORs) 0.90 [95% confidence intervals (95% CI) 0.50-1.62], 1.63 [0.89-2.97], 1.46 [0.78-2.73] and 1.41 [0.75-2.63] for quintiles of IGF-I, and ORs 0.98 [0.54-1.75], 1.06 [0.59-1.91], 1.04 [0.58-1.87] and 1.77 [0.97-3.24] for quintiles of IGFBP-3). Our results give only moderate support for an association of blood IGF-I with breast cancer risk in young women
— id: 72088, year: 2005, vol: 14, page: 493, stat: Journal Article,

Postmenopausal levels of sex hormones and risk of breast carcinoma in situ: results of a prospective study
Zeleniuch-Jacquotte, Anne; Gu, Yian; Shore, Roy E; Koenig, Karen L; Arslan, Alan A; Kato, Ikuko; Rinaldi, Sabina; Kaaks, Rudolf; Toniolo, Paolo
2005 Mar 20;114(2):323-327, International journal of cancer
We report on a prospective study to assess the association of postmenopausal serum levels of sex hormones with subsequent risk of breast carcinoma in situ. We conducted a case-control study nested within the cohort of the New York University Women's Health Study, a large prospective study documenting a positive association of circulating levels of estrogens and androgens with invasive breast cancer. The study included 69 cases of incident in situ carcinoma and 134 individually matched controls. No statistically significant trend of increasing risk with increasing level of any of the hormones was observed. Odds ratios (95% CIs) for the highest tertile relative to the lowest were 1.10 (0.51-2.39) for estradiol, 0.95 (0.41-2.19) for estrone, 1.63 (0.69-3.88) for testosterone, 0.99 (0.44-2.24) for androstenedione, 0.99 (0.45-2.20) for dehydroepiandrosterone sulfate and 0.81 (0.38-1.74) for sex hormone-binding globulin. Adjusting for potential confounders did not materially affect the results, nor did limiting the analysis to the 59 cases of ductal carcinoma in situ, the lesion thought to be the direct precursor of most invasive breast cancers. Our results are at variance with the positive associations observed in this same cohort with risk of invasive breast cancer. Possible explanations for our results include lack of power, an effect of sex hormones limited to the progression from in situ to invasive tumors, overrepresentation of indolent tumors or an effect of sex hormones on the induction of only a subset of in situ tumors, those that would develop into invasive tumors
— id: 51094, year: 2005, vol: 114, page: 323, stat: Journal Article,

"A randomized, controlled 6-Mo intervention with soy protein isolate in men with biochemical recurrence after radical prostatectomy"
Bosland, MC; Zeleniuch-Jacquotte, A; Melamed, J; Lepor, H; Taneja, SS; Schmoll, J; Watanabe, H; Levinson, B; Randolph, C; Walden, PD
2004 MAY ;134(5):1259S-1259S, Journal of nutrition
— id: 46488, year: 2004, vol: 134, page: 1259S, stat: Journal Article,

Altered N-myc downstream-regulated gene 1 protein expression in African-American compared with caucasian prostate cancer patients
Caruso, Robert P; Levinson, Benjamin; Melamed, Jonathan; Wieczorek, Rosemary; Taneja, Samir; Polsky, David; Chang, Caroline; Zeleniuch-Jacquotte, Anne; Salnikow, Konstantin; Yee, Herman; Costa, Max; Osman, Iman
2004 Jan 1;10(1 Pt 1):222-227, Clinical cancer research
PURPOSE: The protein encoded by N-myc downstream-regulated gene 1 (NDRG1) is a recently discovered protein whose transcription is induced by androgens and hypoxia. We hypothesized that NDRG1 expression patterns might reveal a biological basis for the disparity of clinical outcome of prostate cancer patients with different ethnic backgrounds. EXPERIMENTAL DESIGN: Patients who underwent radical prostatectomy between 1990 and 2000 at Veterans Administration Medical Center of New York were examined. We studied 223 cases, including 157 African Americans and 66 Caucasians (T2, n = 144; >/=T3, n = 79; Gleason <7, n = 122; >/=7, n = 101). Three patterns of NDRG1 expression were identified in prostate cancer: (a) intense, predominately membranous staining similar to benign prostatic epithelium; (b) intense, nucleocytoplasmic localization; and (c) low or undetectable expression. We then examined the correlations between patients' clinicopathological parameters and different NDRG1 expression patterns. RESULTS: In this study of patients with equal access to care, African-American ethnic origin was an independent predictor of prostate-specific antigen recurrence (P < 0.05). We also observed a significant correlation between different patterns of NDRG1 expression and ethnic origin. Pattern 2 was less frequent in African Americans (21% versus 38%), whereas the reverse was observed for pattern 3 (60% in African Americans versus 44% in Caucasians; P = 0.03). This association remained significant after controlling for both grade and stage simultaneously (P = 0.02). CONCLUSIONS: Our data suggest that different NDRG1 expression patterns reflect differences in the response of prostatic epithelium to hypoxia and androgens in African-American compared with Caucasian patients. Further studies are needed to determine the contribution of NDRG1 to the disparity in clinical outcome observed between the two groups
— id: 44771, year: 2004, vol: 10, page: 222, stat: Journal Article,

Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies
Cho, Eunyoung; Smith-Warner, Stephanie A; Spiegelman, Donna; Beeson, W Lawrence; van den Brandt, Piet A; Colditz, Graham A; Folsom, Aaron R; Fraser, Gary E; Freudenheim, Jo L; Giovannucci, Edward; Goldbohm, R Alexandra; Graham, Saxon; Miller, Anthony B; Pietinen, Pirjo; Potter, John D; Rohan, Thomas E; Terry, Paul; Toniolo, Paolo; Virtanen, Mikko J; Willett, Walter C; Wolk, Alicja; Wu, Kana; Yaun, Shiaw-Shyuan; Zeleniuch-Jacquotte, Anne; Hunter, David J
2004 Jul 7;96(13):1015-1022, Journal of the National Cancer Institute
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
— id: 44778, year: 2004, vol: 96, page: 1015, stat: Journal Article,

Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women
Lukanova, A; Lundin, E; Zeleniuch-Jacquotte, A; Muti, P; Mure, A; Rinaldi, S; Dossus, L; Micheli, A; Arslan, A; Lenner, P; Shore, R E; Krogh, V; Koenig, K L; Riboli, E; Berrino, F; Hallmans, G; Stattin, P; Toniolo, P; Kaaks, R
2004 Feb;150(2):161-171, European journal of endocrinology
OBJECTIVE: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. CONCLUSIONS: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women
— id: 44748, year: 2004, vol: 150, page: 161, stat: Journal Article,

Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women
Lukanova, Annekatrin; Lundin, Eva; Micheli, Andrea; Arslan, Alan; Ferrari, Pietro; Rinaldi, Sabina; Krogh, Vittorio; Lenner, Per; Shore, Roy E; Biessy, Carine; Muti, Paola; Riboli, Elio; Koenig, Karen L; Levitz, Mortimer; Stattin, Par; Berrino, Franco; Hallmans, Goran; Kaaks, Rudolf; Toniolo, Paolo; Zeleniuch-Jacquotte, Anne
2004 Jan 20;108(3):425-432, International journal of cancer
Experimental and epidemiological data support a role for sex steroid hormones in the pathogenesis of endometrial cancer. The associations of pre-diagnostic blood concentrations of estradiol, estrone, testosterone, androstenedione, DHEAS and SHBG with endometrial cancer risk were investigated. A case-control study was nested within 3 cohorts in New York (USA), Umea (Sweden) and Milan (Italy). Cases were 124 postmenopausal women with invasive endometrial cancer. For each case, 2 controls were selected, matching the case on cohort, age and date of recruitment. Only postmenopausal women who did not use exogenous hormones at the time of blood donation were included. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated by conditional logistic regression. ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels, relative to the lowest were as follows: 4.13 (1.76-9.72), p(trend) = 0.0008 for estradiol, 3.67 (1.71-7.88), p(trend) = 0.0007 for estrone, 2.15 (1.05-4.40), p(trend) = 0.04 for androstenedione, 1.74 (0.88-3.46), p(trend) = 0.06 for testosterone, 2.90 (1.42-5.90), p(trend) = 0.002 for DHEAS and 0.46 (0.20-1.05), p(trend) = 0.01 for SHBG after adjustment for body mass index, use of oral contraceptives and hormone replacement therapy. The results of our multicenter prospective study showed a strong direct association of circulating estrogens, androgens and an inverse association of SHBG levels with endometrial cancer in postmenopausal women. The effect of elevated androstenedione and testosterone levels on disease risk seems to be mediated mainly through their conversion to estrogens, although an independent effect of androgens on tumor growth cannot be ruled out, in particular in the years close to diagnosis
— id: 44750, year: 2004, vol: 108, page: 425, stat: Journal Article,

Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer
Lukanova, Annekatrin; Zeleniuch-Jacquotte, Anne; Lundin, Eva; Micheli, Andrea; Arslan, Alan A; Rinaldi, Sabina; Muti, Paola; Lenner, Per; Koenig, Karen L; Biessy, Carine; Krogh, Vittorio; Riboli, Elio; Shore, Roy E; Stattin, Par; Berrino, Franco; Hallmans, Goran; Toniolo, Paolo; Kaaks, Rudolf
2004 Jan 10;108(2):262-268, International journal of cancer
Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker of pancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-control study was nested within 3 cohorts in New York (USA), Umea (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronic hyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer
— id: 44751, year: 2004, vol: 108, page: 262, stat: Journal Article,

Neutral endopeptidase protein expression and prognosis in localized prostate cancer
Osman, Iman; Yee, Herman; Taneja, Samir S; Levinson, Benjamin; Zeleniuch-Jacquotte, Anne; Chang, Caroline; Nobert, Craig; Nanus, David M
2004 Jun 15;10(12 Pt 1):4096-4100, Clinical cancer research
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
— id: 44832, year: 2004, vol: 10, page: 4096, stat: Journal Article,

Circulating enterolactone and risk of breast cancer: a prospective study in New York
Zeleniuch-Jacquotte, A; Adlercreutz, H; Shore, R E; Koenig, K L; Kato, I; Arslan, A A; Toniolo, P
2004 Jul 5;91(1):99-105, British journal of cancer
It has been proposed that phyto-oestrogens protect against breast cancer. Lignans are the main class of phyto-oestrogens in Western diets. We conducted a case-control study of breast cancer and serum levels of the main human lignan, enterolactone, nested within a prospective cohort study, the New York University Women's Health Study. Serum samples collected at enrollment and stored at -80 degrees C were used. Among 14 275 participants, 417 incident breast cancer cases were diagnosed a median of 5.1 years after enrollment. Cohort members individually matched to the cases on age, menopausal status at enrollment, serum storage duration and, if premenopausal, day of menstrual cycle were selected as controls. No difference in serum enterolactone was observed between postmenopausal cases (median, 14.3 nmol l(-1)) and controls (14.5 nmol l(-1)), whereas premenopausal cases had higher levels (13.9 nmol l(-1)) than their matched controls (10.9 nmol l(-1), P-value=0.01). In the latter group, the odds ratio for the highest vs the lowest quintile of enterolactone was 1.7 (95% confidence interval (CI), 0.8-3.4; P-value for trend=0.05) and after adjustment for known risk factors for breast cancer was 1.6 (95% CI, 0.7-3.4; P-value for trend=0.13). We observed a moderate positive correlation between serum enterolactone and serum sex hormone-binding globulin in postmenopausal women (r=0.29 in controls (P<0.001) and r=0.14 in cases (P=0.04)), but no correlation with oestrogens or androgens. These results do not support a protective role of circulating lignans, in the range of levels observed, in the development of breast cancer.British Journal of Cancer (2004) 91, 99-105. doi:10.1038/sj.bjc.6601893 www.bjcancer.com
— id: 43220, year: 2004, vol: 91, page: 99, stat: Journal Article,

Postmenopausal levels of oestrogen, androgen, and SHBG and breast cancer: long-term results of a prospective study
Zeleniuch-Jacquotte, A; Shore, R E; Koenig, K L; Akhmedkhanov, A; Afanasyeva, Y; Kato, I; Kim, M Y; Rinaldi, S; Kaaks, R; Toniolo, P
2004 Jan 12;90(1):153-159, British journal of cancer
We assessed the association of sex hormone levels with breast cancer risk in a case-control study nested within the cohort of 7054 New York University (NYU) Women's Health Study participants who were postmenopausal at entry. The study includes 297 cases diagnosed between 6 months and 12.7 years after enrollment and 563 controls. Multivariate odds ratios (ORs) (95% confidence interval (CI)) for breast cancer for the highest quintile of each hormone and sex-hormone binding globulin (SHBG) relative to the lowest were as follows: 2.49 (1.47-4.21), P(trend)=0.003 for oestradiol; 3.24 (1.87-5.58), P(trend)<0.001 for oestrone; 2.37 (1.39-4.04), P(trend)=0.002 for testosterone; 2.07 (1.28-3.33), P(trend)<0.001 for androstenedione; 1.74 (1.05-2.89), P(trend)<0.001 for dehydroepiandrosterone sulphate (DHEAS); and 0.51 (0.31-0.82), P(trend)<0.001 for SHBG. Analyses limited to the 191 cases who had donated blood five to 12.7 years prior to diagnosis showed results in the same direction as overall analyses, although the tests for trend did not reach statistical significance for DHEAS and SHBG. The rates of change per year in hormone and SHBG levels, calculated for 95 cases and their matched controls who had given a second blood donation within 5 years of diagnosis, were of small magnitude and overall not different in cases and controls. The association of androgens with risk did not persist after adjustment for oestrone (1.08, 95% CI=0.92-1.26 for testosterone; 1.15, 95% CI=0.95-1.39 for androstenedione and 1.06, 95% CI=0.90-1.26 for DHEAS), the oestrogen most strongly associated with risk in our study. Our results support the hypothesis that the associations of circulating oestrogens with breast cancer risk are more likely due to an effect of circulating hormones on the development of cancer than to elevations induced by the tumour. They also suggest that the contribution of androgens to risk is largely through their role as substrates for oestrogen production
— id: 42623, year: 2004, vol: 90, page: 153, stat: Journal Article,

Circulating soluble Fas levels and risk of ovarian cancer
Akhmedkhanov, Arslan; Lundin, Eva; Guller, Seth; Lukanova, Annekatrin; Micheli, Andrea; Ma, Yuehong; Afanasyeva, Yelena; Zeleniuch-Jacquotte, Anne; Krogh, Vittorio; Lenner, Per; Muti, Paola; Rinaldi, Sabina; Kaaks, Rudolf; Berrino, Franco; Hallmans, Goran; Toniolo, Paolo
2003 Dec 22;3(1):33-33, BMC cancer
BACKGROUND: Dysregulation of apoptosis, specifically overexpression of soluble Fas (sFas), has been proposed to play a role in the development of ovarian cancer. The main objective of the present study was to evaluate serum sFas as a potential biomarker of ovarian cancer risk. METHODS: The association between serum sFas levels and the risk of ovarian cancer was examined in a case-control study nested within three prospective cohorts in New York (USA), Umea (Sweden), and Milan (Italy). Case subjects were 138 women with primary invasive epithelial ovarian cancer diagnosed between 2 months and 13.2 years after the initial blood donation. Control subjects were 263 women who were free of cancer, and matched the case on cohort, menopausal status, age, and enrollment date. Serum sFas levels were determined using a quantitative sandwich enzyme immunoassay. RESULTS: Serum sFas levels were similar in women subsequently diagnosed with ovarian cancer (median, 6.5 ng/mL; range, 4.4-10.2) and in controls (median, 6.8 ng/mL; range, 4.5-10.1). Statistically significant trends of increasing serum sFas with age were observed among cases (r = 0.39, p < 0.0001) and controls (r = 0.42, p < 0.0001). Compared to women in the lowest third, women in the highest third of serum sFas were not at increased risk of ovarian cancer after adjustment for potential confounders (odd ratio (OR), 0.87; 95% confidence interval (CI), 0.42-1.82). CONCLUSION: The results suggest that serum sFas may not be a suitable marker for identification of women at increased risk of ovarian cancer
— id: 44780, year: 2003, vol: 3, page: 33, stat: Journal Article,

Reliability of serum iron, ferritin, nitrite, and association with risk of renal cancer in women
Ali, M Aktar; Akhmedkhanov, Arslan; Zeleniuch-Jaquotte, Anne; Toniolo, Paolo; Frenkel, Krystyna; Huang, Xi
2003 ;27(2):116-121, Cancer detection & prevention
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
— id: 34537, year: 2003, vol: 27, page: 116, stat: Journal Article,

Reliability of follicle-stimulating hormone measurements in serum
Arslan, Alan A; Zeleniuch-Jacquotte, Anne; Lukanova, Annekatrin; Rinaldi, Sabina; Kaaks, Rudolf; Toniolo, Paolo
2003 Jun 18;1(1):49-49, Reproductive biology & endocrinology: RB&E.
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
— id: 38098, year: 2003, vol: 1, page: 49, stat: Journal Article,

Serum follicle-stimulating hormone and risk of epithelial ovarian cancer in postmenopausal women
Arslan, Alan A; Zeleniuch-Jacquotte, Anne; Lundin, Eva; Micheli, Andrea; Lukanova, Annekatrin; Afanasyeva, Yelena; Lenner, Per; Krogh, Vittorio; Muti, Paola; Rinaldi, Sabina; Kaaks, Rudolf; Berrino, Franco; Hallmans, Goran; Toniolo, Paolo
2003 Dec;12(12):1531-1535, Cancer epidemiology biomarkers & prevention
The 'gonadotropin hypothesis' postulates that gonadotropin overstimulation of ovarian epithelium results in its increased proliferation and subsequent malignant transformation. To address this hypothesis, we assessed the association between prediagnostic serum levels of follicle-stimulating hormone (FSH) and the risk of epithelial ovarian cancer in postmenopausal women who were part of a case-control study nested within three prospective cohorts in New York City, Umea, Sweden, and Milan, Italy. Case subjects were 88 women with primary invasive epithelial ovarian cancer diagnosed between 3 months and 13.1 years after the blood donation. Controls were 168 women who were free of cancer and matched the case on cohort, age, and enrollment date. Serum FSH was determined using a quantitative immunoradiometric assay. FSH concentrations were similar in women who subsequently received a diagnosis of epithelial ovarian cancer (median, 44.0 mIU/ml; range, 13.8-101.2) and in controls (median, 43.4 mIU/ml; range, 13.5-109.5; P = 0.17). Compared with women in the lowest third, women in the highest third of serum FSH were not at increased risk of epithelial ovarian cancer after an adjustment for potential confounders (odds ratio, 0.85; 95% confidence interval, 0.36-1.99). These observations provide no evidence for an association between circulating FSH and risk of epithelial ovarian cancer in postmenopausal women and do not appear to support the gonadotropin hypothesis of epithelial ovarian carcinogenesis
— id: 44779, year: 2003, vol: 12, page: 1531, stat: Journal Article,

A randomized, controlled six-month intervention study soy protein isolate in men with biochemical recurrence after radical prostatectomy
Bosland, MC; Zeleniuch-Jacquotte, A; Melamed, J; Lepor, H; Taneja, SS; Schmoll, J; Watanabe, H; Levinson, B; Walden, PD
2003 NOV ;12(11):1327S-1328S, Cancer epidemiology biomarkers & prevention
— id: 55376, year: 2003, vol: 12, page: 1327S, stat: Journal Article,

Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients
Drobnjak, Marija; Melamed, Jonathan; Taneja, Samir; Melzer, Kate; Wieczorek, Rosemary; Levinson, Benjamin; Zeleniuch-Jacquotte, Anne; Polsky, David; Ferrara, Jay; Perez-Soler, Roman; Cordon-Cardo, Carlos; Pagano, Michele; Osman, Iman
2003 Jul;9(7):2613-2619, Clinical cancer research
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
— id: 38153, year: 2003, vol: 9, page: 2613, stat: Journal Article,

Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer
Hochster, Howard; Chachoua, Abraham; Speyer, James; Escalon, Juliette; Zeleniuch-Jacquotte, Anne; Muggia, Franco
2003 Jul 15;21(14):2703-2707, Journal of clinical oncology
PURPOSE: To determine the activity of biweekly oxaliplatin, combined with weekly bolus fluorouracil (FU) and low-dose leucovorin (LV) chemotherapy (bFOL), as first-line therapy for patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients with measurable metastatic colorectal cancer; no previous therapy for advanced disease (adjuvant therapy allowed if >6 months since completion); and performance status 0, 1, or 2 were eligible and were treated with oxaliplatin 85 mg/m2 days 1 and 15 plus LV 20 mg/m2 over 10 to 20 minutes, followed by a 500 mg/m2 bolus dose of FU on days 1, 8, and 15 every 28 days. Patients underwent response evaluation by computed tomographic scan every 2 months. RESULTS: Forty-two patients were entered, and 41 patients were treated, including 20 men and 22 women, nine with previous adjuvant chemotherapy and four with radiation therapy. Three patients achieved complete response, and 23 patients achieved partial response, for a response rate of 63% (95% CI, 49% to 78%). Major toxicities included cumulative neuropathy grade 2 (24%) and grade 3 (12%; requiring discontinuation of oxaliplatin), diarrhea grade 3 to 4 (29%) and grade 3 to 4 hematologic toxicity (10%). Median time to progression was 9.0 months (95% confidence interval, 7.1 to 10.8 months) with median survival of 15.9 months (95% confidence interval, 11.4 to 19.7 months). CONCLUSION: The bFOL regimen seems to have activity comparable to be infusional programs of FU combined with oxaliplatin. Prospective trials are warranted to determine the relative merits of this schedule compared with the currently indicated schedules
— id: 44743, year: 2003, vol: 21, page: 2703, stat: Journal Article,

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women
Key, T J; Appleby, P N; Reeves, G K; Roddam, A; Dorgan, J F; Longcope, C; Stanczyk, F Z; Stephenson, H E Jr; Falk, R T; Miller, R; Schatzkin, A; Allen, D S; Fentiman, I S; Key, T J; Wang, D Y; Dowsett, M; Thomas, H V; Hankinson, S E; Toniolo, P; Akhmedkhanov, A; Koenig, K; Shore, R E; Zeleniuch-Jacquotte, A; Berrino, F; Muti, P; Micheli, A; Krogh, V; Sieri, S; Pala, V; Venturelli, E; Secreto, G; Barrett-Connor, E; Laughlin, G A; Kabuto, M; Akiba, S; Stevens, R G; Neriishi, K; Land, C E; Cauley, J A; Kuller, L H; Cummings, S R; Helzlsouer, K J; Alberg, A J; Bush, T L; Comstock, G W; Gordon, G B; Miller, S R; Longcope, C
2003 Aug 20;95(16):1218-1226, Journal of the National Cancer Institute
BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol
— id: 38442, year: 2003, vol: 95, page: 1218, stat: Journal Article,

Free estradiol and breast cancer risk in postmenopausal women: Comparison of measured and calculated values
Key, TJ; Appleby, PN; Reeves, GK; Roddam, AW; Dorgan, JF; Longcope, C; Stanczyk, FZ; Stephenson, HE; Falk, RT; Miller, R; Schatzkin, A; Allen, DS; Fentiman, IS; Key, TJ; Wang, DY; Thomas, HV; Hankinson, SE; Toniolo, P; Akhmedkhanov, A; Koenig, K; Shore, RE; Zeleniuch-Jacquotte, A; Berrino, F; Muti, P; Krogh, AMV; Sieri, S; Pala, V; Venturelli, E; Secreto, G; Barrett-Connor, E; Laughlin, GA; Kabuto, M; Stevens, RG; Neriishi, K; Land, CE; Cauley, JA; Kuller, LH; Helzlsouer, KJ; Alberg, AJ; Bush, TL; Comstock, GW; Gordon, GB; Miller, SR; Longcope, C
2003 DEC ;12(12):1457-1461, Cancer epidemiology biomarkers & prevention
Mathematical methods exist to determine the fractions of sex hormones bound to albumin, bound to sex hormone binding globulin (SHBG), or unbound, using total hormone concentration and SHBG concentration. We used data from eight prospective studies of postmenopausal women to assess the validity of these estimates for fractions of estradiol (E2) and to investigate the impact of using calculated values in breast cancer relative risk (RR) models. Comparisons were made between measured and calculated concentrations of free and non-SHBG-bound E2 in four studies. Relationships between the hormone fractions were investigated and a sensitivity analysis of the calculation performed. Breast cancer RRs were estimated using conditional logistic regression by quintiles of free E2. There is a high correlation (r > 0.91) between calculated and measured values of both free and non-SHBG-bound E2. The calculation is highly sensitive to total hormone concentration but is relatively insensitive to SHBG concentration. In studies with both measured and calculated values, the RRs of breast cancer by quintile of free E2 were almost identical for both estimates; using calculated values in all possible studies the RR in the highest compared with the lowest quintile of free E2 was 2.29 (95% confidence interval, 1.65-3.19). The mathematical method used to calculate fractions of E2 is valid, and RR analyses using calculated values produce similar results to those using measured values. This suggests that for epidemiological studies, it is only necessary to measure total E2 concentration and SHBG concentration, with hormone fractions being obtained by calculation, producing savings in cost, time, and serum
— id: 42543, year: 2003, vol: 12, page: 1457, stat: Journal Article,

Circulating levels of sex steroid hormones and risk of ovarian cancer
Lukanova, Annekatrin; Lundin, Eva; Akhmedkhanov, Arslan; Micheli, Andrea; Rinaldi, Sabina; Zeleniuch-Jacquotte, Anne; Lenner, Per; Muti, Paola; Biessy, Carine; Krogh, Vittorio; Berrino, Franco; Hallmans, Goran; Riboli, Elio; Kaaks, Rudolf; Toniolo, Paolo
2003 May 1;104(5):636-642, International journal of cancer
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
— id: 34538, year: 2003, vol: 104, page: 636, stat: Journal Article,

Risk of ovarian cancer in relation to prediagnostic levels of C-peptide, insulin-like growth factor binding proteins-1 and -2 (USA, Sweden, Italy)
Lukanova, Annekatrin; Lundin, Eva; Micheli, Andrea; Akhmedkhanov, Arslan; Rinaldi, Sabina; Muti, Paola; Lenner, Per; Biessy, Carine; Krogh, Vittorio; Riboli, Elio; Hallmans, Goran; Berrino, Franco; Zeleniuch-Jacquotte, Anne; Toniolo, Paolo; Kaaks, Rudolf
2003 Apr;14(3):285-292, Cancer causes & control. ccc
OBJECTIVE: To investigate the association of prediagnostic circulating levels of C-peptide, as a marker of pancreatic insulin secretion, and IGF binding proteins -1 and -2, as indicators of the biologically active IGF-I concentration, with risk of developing ovarian cancer. METHODS: The study was nested within three prospective cohorts in New York (USA), Umea (Sweden) and Milan (Italy). Case subjects were 132 women with primary invasive epithelial ovarian cancer diagnosed at least one year after blood donation. For each case, two control subjects were selected, matching the case subject on cohort, menopausal status, age and date of recruitment (n = 263). Only women who did not use exogenous hormones at blood donation were included in the study. RESULTS: Odds ratios and their 95% confidence intervals for risk of developing ovarian cancer over quartiles of peptides concentrations after adjustment for BMI and fasting were: 1.00, 0.66 (0.35-1.23), 0.96 (0.51-1.82) and 0.89 (0.44-1.81) for C-peptide; 1.00, 1.10 (0.58-2.09), 1.07 (0.55-2.04) and 0.79 (0.38-1.62) for IGFBP-1; and 1.00, 1.01 (0.54-1.89), 0.98 (0.51-1.88) and 0.87 (0.45-1.68) for IGFBP-2. In women who had ovarian cancer diagnosis before age 55 the ORs for the top tertiles of IGFBP-1 and IGFBP-2 were 0.51 (0.18-1.49) and 0.53 (0.18-1.54), respectively. CONCLUSIONS: This study does not support an independent direct etiological role of C-peptide in ovarian cancer pathogenesis, but suggests a possible protective effect of circulating IGFBP-1 and -2 in women who develop ovarian cancer before age 55
— id: 44781, year: 2003, vol: 14, page: 285, stat: Journal Article,

Changes in the presence of multiple markers of circulating melanoma cells correlate with clinical outcome in patients with melanoma
Reynolds, Sandra R; Albrecht, Jeff; Shapiro, Richard L; Roses, Daniel F; Harris, Matthew N; Conrad, Andrew; Zeleniuch-Jacquotte, Anne; Bystryn, Jean-Claude
2003 Apr;9(4):1497-1502, Clinical cancer research
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
— id: 34746, year: 2003, vol: 9, page: 1497, stat: Journal Article,

Vaccine-induced CD8+ T-cell responses to MAGE-3 correlate with clinical outcome in patients with melanoma
Reynolds, Sandra R; Zeleniuch-Jacquotte, Anne; Shapiro, Richard L; Roses, Daniel F; Harris, Matthew N; Johnston, Dean; Bystryn, Jean-Claude
2003 Feb;9(2):657-662, Clinical cancer research
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
— id: 34747, year: 2003, vol: 9, page: 657, stat: Journal Article,

Aspirin and lung cancer in women
Akhmedkhanov, A; Toniolo, P; Zeleniuch-Jacquotte, A; Koenig, K L; Shore, R E
2002 Jul 1;87(1):49-53, British journal of cancer
The association between aspirin use and lung cancer risk in women was examined in a case-control study nested in the New York University Women's Health Study, a large cohort in New York. Case subjects were all the 81 incident lung cancer cases who had provided information about aspirin use at enrollment and during the 1994-1996 follow up. Ten controls per case were randomly selected from among study participants who matched a case by age, menopausal status, and dates of enrollment and follow-up. Relative to no aspirin use, the odds ratio for lung cancer (all histological sub-types combined) among subjects who reported aspirin use three or more times per week for at least 6 months was 0.66 (95% confidence interval 0.34-1.28), after adjustment for smoking and education. A stronger inverse association was observed in analyses restricted to non-small cell lung cancer (adjusted odds ratio 0.39, 95% confidence interval 0.16-0.96). These results suggest that regular aspirin use might be inversely associated with risk of lung cancer in women, particularly the non-small cell sub-type
— id: 32489, year: 2002, vol: 87, page: 49, stat: Journal Article,

Chemoprevention strategies for prostate cancer
Bosland, Maarten C; McCormick, David L; Melamed, Jonathan; Walden, Paul D; Zeleniuch-Jacquotte, Anne; Lumey, L H
2002 Aug;11 Suppl 2(2):S18-S27, European journal of cancer prevention
Prostate cancer is the most common male malignancy in western countries. Although primary prevention of prostate cancer is not possible, screening using prostate-specific antigen (PSA) may eliminate prostate cancers by definitive treatments. Prevention of clinically detectable prostate cancer requires earlier chemoprevention interventions. Because prostate cancer is histologically present in 30-50% of 30- to 50-year-old men, effective chemoprevention needs to inhibit not only prostate carcinogenesis but also growth and progression of these cancers. A prostate carcinogenesis animal model has been used to screen chemopreventive agents; inhibitory effects were found with 9-cis-retinoic acid, dehydroepiandrosterone, fluasterone, and the Bowman-Birk inhibitor and an isoflavone mixture which both occur in soy. Such results can be used to select agents for clinical trials. Besides large-scale long-duration prevention trials, trials of short/intermediate duration using smaller cohorts prior to or following radical prostatectomy may provide excellent and cost-effective approaches for chemopreventive agent efficacy testing. Intervention prior to surgery allows measurements of intervention agents and intermediate end-points in the prostate. These peri-surgical trials only assess inhibition of growth and progression of preexisting cancer, not real preventive effects, but they focus on clinically significant cancers. Such trials are an essential step in the development of antiprostate cancer chemoprevention agents
— id: 34748, year: 2002, vol: 11 Suppl 2, page: S18, stat: Journal Article,

Insulin-like growth factor II and colorectal cancer risk in women
Hunt, Kelly J; Toniolo, Paolo; Akhmedkhanov, Arslan; Lukanova, Annekatrin; Dechaud, Henri; Rinaldi, Sabina; Zeleniuch-Jacquotte, Anne; Shore, Roy E; Riboli, Elio; Kaaks, Rudolf
2002 Sep;11(9):901-905, Cancer epidemiology biomarkers & prevention
Recently, a number of prospective studies showed evidence that the growth hormone/insulin-like growth factor I (IGF-I) axis may be important in the development of colorectal cancer. However, only a few studies have reported on the possible relationship of colorectal cancer risk with circulating levels of IGF-II, which are not growth hormone dependent and which do not vary with alterations in energy balance. In a case-control study of 102 cases and 200 matched controls nested within a cohort of 14,275 women in New York, we examined the relationship between colorectal cancer risk and prediagnostic serum levels of IGF-II. Conditional logistic regression analysis showed an odds ratio (OR) for colorectal cancer of 2.02 (95% confidence interval (CI): 0.83-4.93), comparing the upper to lower quintile of IGF-II. This association was slightly attenuated after excluding IGF-II measurements in serum samples taken within 1 year before case diagnosis (OR of 1.81; 95% CI: 0.71-4.64) and moderately attenuated after excluding IGF-II measurements in serum samples taken within 2 years before case diagnosis (OR of 1.47; 95% CI: 0.56-3.91). Adjustment for IGF-1, IGF binding protein (BP)-1, IGFBP-3, smoking, or body mass index did not substantially alter the association, whereas adjustment for IGFBP-2 moderately attenuated the relationship. Our results confirm those of three recent case-control studies, and collectively these results suggest a possible increase in colorectal cancer risk among subjects with comparatively elevated serum IGF-II. Mechanisms that might cause the increase in IGF-II levels are unknown but may include loss of parental imprinting of the IGF-II gene
— id: 34544, year: 2002, vol: 11, page: 901, stat: Journal Article,

Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies
Key, T; Appleby, P; Barnes, I; Reeves, G
2002 Apr 17;94(8):606-616, Journal of the National Cancer Institute
BACKGROUND: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. METHODS: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. RESULTS: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; P(trend)<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; P(trend)<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (P(trend) =.041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. CONCLUSION: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women
— id: 38580, year: 2002, vol: 94, page: 606, stat: Journal Article,

Long-term survival of stage IV melanoma patients treated with a polyvalent, shed antigen, melanoma vaccine
Laky, D; Shapiro, RL; Harris, MN; Roses, DF; Jacquotte, AZ; Reynolds, SR; Bystryn, J
2002 JUL ;119(1):240-240, Journal of investigative dermatology
— id: 55284, year: 2002, vol: 119, page: 240, stat: Journal Article,

Circulating levels of insulin-like growth factor-I and risk of ovarian cancer
Lukanova, Annekatrin; Lundin, Eva; Toniolo, Paolo; Micheli, Andrea; Akhmedkhanov, Arslan; Rinaldi, Sabina; Muti, Paola; Lenner, Per; Biessy, Carine; Krogh, Vittorio; Zeleniuch-Jacquotte, Anne; Berrino, Franco; Hallmans, Goran; Riboli, Elio; Kaaks, Rudolf
2002 Oct 20;101(6):549-554, International journal of cancer
Insulin-like growth factor (IGF)-I, a mitogenic and anti-apoptotic peptide, has been implicated in the development of several cancers. We hypothesized that high circulating IGF-I concentrations may be associated with an increased risk of ovarian cancer. A case-control study was nested within 3 prospective cohorts in New York (USA), Umea (Sweden) and Milan (Italy). One hundred thirty-two women with primary invasive epithelial ovarian cancer diagnosed at least 1 year after blood donation were case subjects. For each case, 2 control subjects were selected, matching the case subject on cohort, menopausal status, age and date of recruitment (n = 263). Only women who did not use exogenous hormones at blood donation were included in the study. There was no association between IGF-I concentrations and ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at a young age (<55), circulating IGF-I was directly and strongly associated with ovarian cancer risk (OR = 4.97; 95% CI = 1.22-20.2 for the top vs. the bottom IGF-I tertile after adjustment for parity, BMI categories and smoking). There was no significant association of IGF binding protein-3 with ovarian cancer risk. We found a strong direct relationship between circulating IGF-I levels and risk of developing ovarian cancer before age 55. Additional, larger studies of this association are needed to provide more precise estimates of effect
— id: 34543, year: 2002, vol: 101, page: 549, stat: Journal Article,

Body mass index in relation to ovarian cancer: a multi-centre nested case-control study
Lukanova, Annekatrin; Toniolo, Paolo; Lundin, Eva; Micheli, Andrea; Akhmedkhanov, Arslan; Muti, Paola; Zeleniuch-Jacquotte, Anne; Biessy, Carine; Lenner, Per; Krogh, Vittorio; Berrino, Franco; Hallmans, Goran; Riboli, Elio; Kaaks, Rudolf
2002 Jun 1;99(4):603-608, International journal of cancer
The incidence of ovarian cancer is up to 10 times higher in Western countries than in rural Asia and Africa. One common consequence of a Western lifestyle is the development of excessive body weight and obesity. A multi-centre prospective study was conducted to investigate the association between body mass index (BMI) and ovarian cancer risk. A case-control study was nested within 3 prospective cohorts in New York (USA), Umea (Sweden) and Milan (Italy). Information on anthropometry, demographic characteristics, medical history and lifestyle was obtained at the time of subjects' recruitment in each cohort. Women diagnosed with primary, invasive epithelial ovarian cancer from the 3 cohorts (n = 122) diagnosed 12 months or later after recruitment into the respective cohort served as case subjects. For each case subject, 2 control subjects that matched the case subject on cohort, menopausal status, age and date of recruitment were randomly identified. Data were analyzed by conditional logistic regression. There was an inverse association between BMI and ovarian cancer risk. For increasing quartiles of BMI above the lowest, the ORs were 0.62 (0.32-1.21), 0.59 (0.30-1.17) and 0.46 (0.23-0.92), p = 0.03. Analyses limited to women diagnosed 3 or more years after recruitment into the cohorts did not alter these findings. When obese women (BMI > 30) were compared to lean women (BMI < or = 23), the inverse association became stronger, with an OR of 0.38 (0.17-0.85), p < 0.02. There was some evidence of direct association of ovarian cancer with height, which was limited to cancers diagnosed before age 55. Our data suggest that increasing body weight may confer a protection against ovarian cancer
— id: 34545, year: 2002, vol: 99, page: 603, stat: Journal Article,

Meat and dairy food consumption and breast cancer: a pooled analysis of cohort studies
Missmer, Stacey A; Smith-Warner, Stephanie A; Spiegelman, Donna; Yaun, Shiaw-Shyuan; Adami, Hans-Olov; Beeson, W Lawrence; van den Brandt, Piet A; Fraser, Gary E; Freudenheim, Jo L; Goldbohm, R Alexandra; Graham, Saxon; Kushi, Lawrence H; Miller, Anthony B; Potter, John D; Rohan, Thomas E; Speizer, Frank E; Toniolo, Paolo; Willett, Walter C; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Hunter, David J
2002 Feb;31(1):78-85, International journal of epidemiology
BACKGROUND: More than 20 studies have investigated the relation between meat and dairy food consumption and breast cancer risk with conflicting results. Our objective was to evaluate the risk of breast cancer associated with meat and dairy food consumption and to assess whether non-dietary risk factors modify the relation. METHODS: We combined the primary data from eight prospective cohort studies from North America and Western Europe with at least 200 incident breast cancer cases, assessment of usual food and nutrient intakes, and a validation study of the dietary assessment instrument. The pooled database included 351,041 women, 7379 of whom were diagnosed with invasive breast cancer during up to 15 years of follow-up. RESULTS: We found no significant association between intakes of total meat, red meat, white meat, total dairy fluids, or total dairy solids and breast cancer risk. Categorical analyses suggested a J-shaped association for egg consumption where, compared to women who did not eat eggs, breast cancer risk was slightly decreased among women who consumed < 2 eggs per week but slightly increased among women who consumed > or = 1 egg per day. CONCLUSIONS: We found no significant associations between intake of meat or dairy products and risk of breast cancer. An inconsistent relation between egg consumption and risk of breast cancer merits further investigation
— id: 34749, year: 2002, vol: 31, page: 78, stat: Journal Article,

Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations
Rinaldi, Sabina; Geay, Annabelle; Dechaud, Henri; Biessy, Carine; Zeleniuch-Jacquotte, Anne; Akhmedkhanov, Arslan; Shore, Roy E; Riboli, Elio; Toniolo, Paolo; Kaaks, Rudolf
2002 Oct;11(10 Pt 1):1065-1071, Cancer epidemiology biomarkers & prevention
In this study, we validated measurements of free testosterone (fT) and free estradiol (fE(2)) concentrations calculated from total serum concentrations of testosterone (T), estradiol (E(2)), and sex hormone-binding globulin (SHBG), measured by direct, commercial radioimmunoassays, by comparison with reference measurements obtained by dialysis plus an in-house radioimmunoassay after extraction and chromatographic purification. The study was conducted in serum samples from 19 postmenopausal women who were part of an ongoing prospective cohort study. We also performed sensitivity analyses to examine the robustness of the theoretical calculations. Sensitivity analyses showed that in this population, competitive binding of dihydrotestosterone and total T could be ignored in the calculation of fE(2), and competitive binding by dihydrotestosterone does not need to be taken into account for calculation of fT. Furthermore, variations in albumin and SHBG concentrations had negligible effects on fT and fE(2) calculations. Values of fT and fE(2), calculated from total T and E(2) concentrations obtained by the same in-house radioimmunoassay used for the dialysis method, correlated highly with the measurements by dialysis (Pearson's coefficients of correlation above 0.97). When calculating fT and fE(2) using total T and total E(2) concentrations obtained by different direct radioimmunoassays, almost all kits gave good correlations with the reference method for fT (Pearson's r > 0.83), but only a few gave good correlations for fE(2) (Diagnostic System Laboratories and DiaSorin; r > 0.80). The direct radioimmunoassays giving the best correlation for fT and fE(2) with the dialysis method were those that best measured total concentrations of T and E(2). Furthermore, mean values of fT and fE(2) corresponded well to mean values by the reference method if SHBG measurements were also well calibrated. We conclude that in postmenopausal women, theoretical calculations are valid for the determination of fT and fE(2) concentrations and can give reliable estimation of cancer risk in epidemiological studies when the total concentrations of T, E(2), and SHBG are measured accurately
— id: 34542, year: 2002, vol: 11, page: 1065, stat: Journal Article,

Serum fatty acids and risk of breast cancer in a nested case-control study of the New York University Women's Health Study
Saadatian-Elahi, M; Toniolo, P; Ferrari, P; Goudable, J; Akhmedkhanov, A; Zeleniuch-Jacquotte, A; Riboli, E
2002 ;156(5):227-230, IARC scientific publications (Lyon)
— id: 34539, year: 2002, vol: 156, page: 227, stat: Journal Article,

Serum fatty acids and risk of breast cancer in a nested case-control study of the New York University Women's Health Study
Saadatian-Elahi, Mitra; Toniolo, Paolo; Ferrari, Pietro; Goudable, Joelle; Akhmedkhanov, Arslan; Zeleniuch-Jacquotte, Anne; Riboli, Elio
2002 Nov;11(11):1353-1360, Cancer epidemiology biomarkers & prevention
Migrant and experimental animal studies suggest that differences in breast cancer incidence rates may be related, in part, to intake of dietary fat. The experimental evidence indicates that total fat, saturated, and n-6 polyunsaturated fatty acids (PUFAs) may stimulate both mammary tumor growth and metastasis, whereas n-3 PUFAs may have a tumor-inhibiting effect. Overall, epidemiological studies do not appear to confirm such observations. Within a cohort of women in the New York University Women's Health Study, the fatty acid composition of serum phospholipids was analyzed by gas chromatography among 197 pre- and postmenopausal clinically identified breast cancer subjects and their matched controls. Individual fatty acids in serum phospholipids were expressed as a percentage of total fatty acids. No significant difference was observed in the proportion of saturated fatty acids (SFAs), monounsaturated fatty acids, or n-6 and n-3 PUFAs between cases and controls. After menopause, total SFAs were positively associated with the risk of breast cancer [odds ratio (OR) = 1.96, 95% confidence interval (CI): 0.73-5.25; P = 0.05] after adjustment for potential confounding factors. Myristc acid (C14:0) was suggestive of a small increase in breast cancer risk in premenopausal women (OR = 2.22, 95% CI: 0.78-6.31), whereas palmitic acid (C16:0) showed similar trends in postmenopausal women (OR = 2.57, 95% CI: 0.99-6.61). Overall, total PUFAs (n-6 and n-3) were suggestive of a small protective effect (OR = 0.59, 95% CI: 0.31-1.09). No significant associations were found between other fatty acids and the risk of breast cancer. The study suggested evidence of an association between serum levels of SFAs and the risk of breast cancer in postmenopausal women. Neither individual n-3 fatty acids of marine origin, eicosapentaenoic acid (C20:5 n-3), and docosahexaenoic acid (C22:6 n-3), nor n-6 PUFAs were related to cancer risk in this study
— id: 34540, year: 2002, vol: 11, page: 1353, stat: Journal Article,

Aspirin and epithelial ovarian cancer
Akhmedkhanov A; Toniolo P; Zeleniuch-Jacquotte A; Kato I; Koenig KL; Shore RE
2001 Dec;33(6):682-687, Preventive medicine
BACKGROUND: Epidemiological evidence suggests that chronic inflammation may influence ovarian carcinogenesis. The study objective was to examine the association between the commonly used anti-inflammatory drug aspirin and epithelial ovarian cancer. METHODS: The authors conducted a case-control study based in the New York University Women's Health Study cohort enrolled between 1985 and 1991 in New York City. After a median follow-up period of 12 years, 68 incident cases of epithelial ovarian cancer were identified. Data about regular aspirin use were collected during the 1994-1996 follow-up questionnaire. Using a case-control study design, 10 controls per case were randomly selected among study participants who matched the case by age and menopausal status. Conditional logistic regression analysis was used to study the relationships between aspirin and epithelial ovarian cancer by generating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Relative to no aspirin use, the OR for epithelial ovarian cancer among women who reported aspirin use three or more times per week for a period of at least 6 months was 0.60 (95% CI 0.26, 1.38), after adjustment for age at menarche, parity, oral contraceptive use, and first-degree family history of breast cancer before age 50. Among recent, within the previous 5 years, users of aspirin, the adjusted OR was 0.36 (95% CI 0.11, 1.18). CONCLUSION: Although confidence intervals included unity, the observed risk estimates seem to be compatible with previous studies suggesting that regular aspirin use could be inversely associated with risk of epithelial ovarian cancer
— id: 26517, year: 2001, vol: 33, page: 682, stat: Journal Article,

Luteinizing hormone, its beta-subunit variant, and epithelial ovarian cancer: the gonadotropin hypothesis revisited
Akhmedkhanov A; Toniolo P; Zeleniuch-Jacquotte A; Pettersson KS; Huhtaniemi IT
2001 Jul 1;154(1):43-49, American journal of epidemiology
The gonadotropin hypothesis postulates that excessive gonadotropin stimulation results in increased proliferation and subsequent malignant transformation of ovarian epithelium. The authors evaluated this hypothesis by analyzing the association between serum levels of wild-type luteinizing hormone (LH) and ovarian cancer risk. They also examined the relation between a variant of LH containing two missense point mutations (Trp(8)Arg and Ile(15)Thr) in its beta-subunit and ovarian cancer risk. Fifty-eight cases of epithelial ovarian cancer and 116 controls matched on age, menopausal status, and date of blood donation were included in a case-control study nested within the New York University Women's Health Study, a prospective cohort enrolled between 1985 and 1991 in New York City. Wild-type serum levels and variant LH status were determined by immunofluorometric assays in which monoclonal antibodies specific for wild-type and variant LH were used. Compared with women in the lowest tertile of wild-type LH, women in the highest tertile had a lower risk of ovarian cancer, after adjustment for potential confounders (odds ratio = 0.42, 95% confidence interval: 0.09, 2.09). Women heterozygous for variant LH were not at increased risk (adjusted odds ratio = 0.95, 95% confidence interval: 0.27, 3.34). The results suggest that neither wild-type LH levels nor variant LH status is associated with increased risk of epithelial ovarian cancer
— id: 21164, year: 2001, vol: 154, page: 43, stat: Journal Article,

Role of exogenous and endogenous hormones in endometrial cancer: review of the evidence and research perspectives
Akhmedkhanov A; Zeleniuch-Jacquotte A; Toniolo P
2001 Sep;943(3):296-315, Annals of the New York Academy of Sciences
Endometrial carcinoma is the most common cancer of the female reproductive organs in the United States. International comparisons reveal that the incidence of endometrial cancer vary widely between different countries with the highest rates observed in North America and Northern Europe, intermediate rates in Eastern Europe and Latin America, and lowest rates in Asia and Africa. International variation in endometrial cancer rates may represent differences in the distribution of known risk factors, which include obesity, postmenopausal estrogen replacement, ovarian dysfunction, diabetes mellitus, infertility, nulliparity, and tamoxifen use. Most of the risk factors for endometrial cancer can be explained within the framework of the unopposed estrogen hypothesis, which proposes that exposure to estrogens unopposed by progesterone or synthetic progestins leads to increased mitotic activity of endometrial cells, increased number of DNA replication errors, and somatic mutations resulting in malignant phenotype. Although the impact of exogenous hormone replacement was intensively studied during the last two decades, less is known about the effects of endogenous hormones in endometrial cancer. A review of available experimental, clinical, and epidemiologic data suggests that in addition to estrogens, other endogenous hormones, including progesterone, androgens, gonadotropins, prolactin, insulin, and insulin-like growth factors, may play a role in the pathogenesis of different histopathologic types of endometrial cancer
— id: 26645, year: 2001, vol: 943, page: 296, stat: Journal Article,

Chemoprevention trials in men with prostate-specific antigen failure or at high risk for recurrence after radical prostatectomy: Application to efficacy assessment of soy protein
Bosland MC; Kato I; Melamed J; Taneja S; Lepor H; Torre P; Walden P; Zeleniuch-Jacquotte A; Lumey LH
2001 Apr;57(4 Suppl 1):202-204, Urology
This article discusses the basic elements of chemoprevention trial designs using cohorts of men following radical prostatectomy who either have prostate-specific antigen (PSA) failure indicative of recurrence or are at high risk for recurrence (positive surgical margins, extracapsular extension, seminal vesicle invasion, positive lymph nodes, Gleason score of greater than or equal to 8, preoperative serum PSA less than 20 ng/mL). Two ongoing randomized, double-blind, placebo-controlled clinical trials with soy protein as intervention in these 2 populations are described. In the trial with men at high risk for recurrence, participants started intervention within 4 months after surgery and were followed for up to 2 years; primary endpoints were PSA failure rate and time-to-PSA failure. In the trial with men with PSA failure (PSA 0.1 to 2.0 ng/mL), participants received treatment for 8 months and the primary endpoint is rise in PSA over time. The strengths and limitations of these designs are discussed and interim experience using studies with soy protein as the intervention agent are summarized
— id: 18555, year: 2001, vol: 57, page: 202, stat: Journal Article,

Double-blind trial of a polyvalent, shed-antigen, melanoma vaccine
Bystryn JC; Zeleniuch-Jacquotte A; Oratz R; Shapiro RL; Harris MN; Roses DF
2001 Jul;7(7):1882-1887, Clinical cancer research
A polyvalent melanoma vaccine prepared from shed antigens stimulates humoral and cellular immune responses and improves survival compared with historical controls. We conducted a double-blind, prospectively randomized, placebo-controlled trial to assess whether this vaccine could slow the progression of resected melanoma. Thirty-eight patients with resected melanoma metastatic to regional nodes (American Joint Committee on Cancer stage III) who had a particularly poor prognosis on the basis of the nodes being clinically positive or two or more histologically positive nodes were randomly assigned in a 2:1 ratio to treatment with 40 microg of melanoma or placebo (human albumin) vaccine, both of which were bound to alum as an adjuvant. Immunizations were given intradermally into the extremities every 3 weeks x 4, monthly x 3, every 3 months x 2, and then every 6 months for 5 years or until disease progression. Twenty-four patients were treated with the melanoma, and 14 patients were treated with the placebo vaccine. The groups were evenly balanced with respect to prognostic factors. Median length of observation was 2.5 years. There was no local or systemic toxicity. By Kaplan-Meier analysis, median time to disease progression was two and a half times longer in patients treated with melanoma vaccine compared with that in patients treated with placebo vaccine, i.e., 1.6 years (95% confidence interval, 1.0-3.0 years) compared with 0.6 year [95% confidence interval, 0.3-1.9 year(s)]. By Cox proportional hazards analysis, this difference was significant at P = 0.03. Overall survival was 40% longer in the melanoma vaccine-treated group (median overall survival of 3.8 years versus 2.7 years), but this difference was not statistically significant. In a double-blind and placebo-controlled trial, these results suggest that immunization with a melanoma vaccine may be able to slow the progression of melanoma. Although statistically significant, these results must be interpreted with caution because they are based on a small number of patients
— id: 21126, year: 2001, vol: 7, page: 1882, stat: Journal Article,

Correspondence re: Giovannucci et al., A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol. Biomark. Prev., 9: 345-349, 2000
Kaaks R; Rinaldi S; Lukanova A; Akhmedkhanov A; Zeleniuch-Jacquotte A; Toniolo P
2001 Oct;10(10):1103-1104, Cancer epidemiology biomarkers & prevention
— id: 34547, year: 2001, vol: 10, page: 1103, stat: Journal Article,

A cross-sectional study of IGF-I determinants in women
Lukanova A; Toniolo P; Akhmedkhanov A; Hunt K; Rinaldi S; Zeleniuch-Jacquotte A; Haley NJ; Riboli E; Stattin P; Lundin E; Kaaks R
2001 Oct;10(5):443-452, European journal of cancer prevention
Evidence is accumulating that elevated circulating insulin-like growth factor I (IGF-I) is related to increased cancer risk. The identification of hormonal, reproductive and lifestyle characteristics influencing its synthesis and bioavailability is of particular interest. Data from 400 women, who served as controls in two case-control studies nested within the same prospective cohort study, were combined. IGF-I, IGF-binding proteins 1, 2 and 3 (IGFBP-1, -2, -3) and insulin were measured in serum samples from all subjects and cotinine in 186 samples. Age appears to be the most important determinant of total IGF-I levels in women. Anthropometric measures, such as body mass index (BMI) or waist-to-hip ratio (WHR) do not seem to influence total IGF-I concentrations in peripheral blood, but may modulate IGF-I bioavailability through insulin-dependent changes in IGFBP-1 and -2 concentrations. Age at menarche, phase of the menstrual cycle at blood draw, parity, menopause, past oral contraceptive or hormone replacement therapy use, and tobacco smoking do not appear to exert an independent effect on IGF-I and its binding proteins. There was some suggestion that regular physical activity may increase total IGF-I and that women with positive family history of breast cancer might have higher IGF-I levels than those without such diagnosis in their relatives
— id: 34546, year: 2001, vol: 10, page: 443, stat: Journal Article,

Reliability and validity of commercially available, direct radioimmunoassays for measurement of blood androgens and estrogens in postmenopausal women
Rinaldi S; Dechaud H; Biessy C; Morin-Raverot V; Toniolo P; Zeleniuch-Jacquotte A; Akhmedkhanov A; Shore RE; Secreto G; Ciampi A; Riboli E; Kaaks R
2001 Jul;10(7):757-765, Cancer epidemiology biomarkers & prevention
In large-scale epidemiological studies on endogenous sex steroids and cancer risk, direct immunoassays of circulating hormone levels have the advantage of being fast and comparatively inexpensive while requiring only small sample volumes. On the other hand, indirect assays after organic extraction and chromatographic prepurification have the advantage of reducing specific interferences and matrix effects and hence are thought to have better validity. We compared direct assays of testosterone (T, six different assays), Delta4-androstenedione (A, four assays), estrone (E(1), one assay), and 17beta-estradiol (E(2), five assays) with measurements obtained by an indirect assay in a representative subset of 20 postmenopausal women who were part of a large prospective cohort study. Within-batch reproducibilities of the subject rankings by relative hormone levels were good (intraclass correlations >0.89) for all direct assays tested. Between batches, reproducibilities generally were also acceptable (r > 0.80) to good (r > 0.90) in terms of Pearson's correlations. The between-batch reproducibility in terms of intraclass correlations was systematically lower in terms of Pearson's correlations, however, because of between-batch variations in the absolute scale of measurements. The relative validity of direct versus indirect assays in terms of the subjects' ranking by relative hormone levels was also high for most of the kits tested for T, A, and E(1) (Pearson's correlations between 0.70 and 0.89) but was high for only two kits of five tested for E(2) (correlations of 0.86 and 0.84). On an absolute scale, mean measurement values were generally higher for direct assays than for the indirect assay and, for each hormone, varied substantially, depending on the kit used. Overall, the results of this study show that, with careful selection, commercial kits for direct radioimmunoassays of steroid hormones in postmenopausal serum can be found that may allow a reliable estimation of relative risks in epidemiological studies. However, standardization of the absolute scale of assays remains problematic
— id: 34548, year: 2001, vol: 10, page: 757, stat: Journal Article,

Expression of cell cycle regulators p57(KIP2), cyclin D1, and cyclin E in epithelial ovarian tumors and survival
Rosenberg E; Demopoulos RI; Zeleniuch-Jacquotte A; Yee H; Sorich J; Speyer JL; Newcomb EW
2001 Aug;32(8):808-813, Human pathology
The search for new prognostic indicators is especially important in the diagnosis and treatment of ovarian cancer because clinicopathologic criteria currently used to predict survival are largely inadequate. We examined 2 groups of patients with epithelial ovarian cancer, 1 group of long-term survivors (>5 years), and 1 group of short-term survivors (<2 years) for levels of expression of the cell cycle regulators p57(KIP2), cyclin D1, and cyclin E and their relationship with survival. Our findings show that p57(KIP2) is not associated with prognosis, in contrast to p27(KIP1) expression, which is previously shown to be positively associated with long-term survival in univariate analysis (P =.001). Cyclin E expression, in contrast to cyclin D1 expression, is marginally associated with short-term survival in univariate analysis for a group of 53 women. Among the short-term survivors, 15 (65%) of 23 were positive for cyclin E expression, compared with only 11 (37%) of 30 long-term survivors (P = 0.054). This association remained significant (P =.04) in a logistic regression analysis adjusted simultaneously for performance status and extent of residual disease, the 2 strongest predictors of survival in our study. We also found a significant difference in the frequency of the cyclin E staining pattern between nonserous and serous ovarian tumor subtypes (P =.0002). Immunostaining for levels of cyclin E and p27(KIP1) expression may have potential as prognostic markers in the management of ovarian cancer
— id: 26681, year: 2001, vol: 32, page: 808, stat: Journal Article,

Types of dietary fat and breast cancer: a pooled analysis of cohort studies
Smith-Warner SA; Spiegelman D; Adami HO; Beeson WL; van den Brandt PA; Folsom AR; Fraser GE; Freudenheim JL; Goldbohm RA; Graham S; Kushi LH; Miller AB; Rohan TE; Speizer FE; Toniolo P; Willett WC; Wolk A; Zeleniuch-Jacquotte A; Hunter DJ
2001 Jun 1;92(5):767-774, International journal of cancer
Recently, there has been interest in whether intakes of specific types of fat are associated with breast cancer risk independently of other types of fat, but results have been inconsistent. We identified 8 prospective studies that met predefined criteria and analyzed their primary data using a standardized approach. Holding total energy intake constant, we calculated relative risks for increments of 5% of energy for each type of fat compared with an equivalent amount of energy from carbohydrates or from other types of fat. We combined study-specific relative risks using a random effects model. In the pooled database, 7,329 incident invasive breast cancer cases occurred among 351,821 women. The pooled relative risks (95% confidence intervals [CI]) for an increment of 5% of energy were 1.09 (1.00-1.19) for saturated, 0.93 (0.84-1.03) for monounsaturated and 1.05 (0.96-1.16) for polyunsaturated fat compared with equivalent energy intake from carbohydrates. For a 5% of energy increment, the relative risks were 1.18 (95% CI 0.99-1.42) for substituting saturated for monounsaturated fat, 0.98 (95% CI 0.85-1.12) for substituting saturated for polyunsaturated fat and 0.87 (95% CI 0.73-1.02) for substituting monounsaturated for polyunsaturated fat. No associations were observed for animal or vegetable fat intakes. These associations were not modified by menopausal status. These data are suggestive of only a weak positive association with substitution of saturated fat for carbohydrate consumption; none of the other types of fat examined was significantly associated with breast cancer risk relative to an equivalent reduction in carbohydrate consumption
— id: 34751, year: 2001, vol: 92, page: 767, stat: Journal Article,

Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies
Smith-Warner SA; Spiegelman D; Yaun SS; Adami HO; Beeson WL; van den Brandt PA; Folsom AR; Fraser GE; Freudenheim JL; Goldbohm RA; Graham S; Miller AB; Potter JD; Rohan TE; Speizer FE; Toniolo P; Willett WC; Wolk A; Zeleniuch-Jacquotte A; Hunter DJ
2001 Feb 14;285(6):769-776, JAMA
CONTEXT: Some epidemiologic studies suggest that elevated fruit and vegetable consumption is associated with a reduced risk of breast cancer. However, most have been case-control studies in which recall and selection bias may influence the results. Additionally, publication bias may have influenced the literature on associations for specific fruit and vegetable subgroups. OBJECTIVE: To examine the association between breast cancer and total and specific fruit and vegetable group intakes using standardized exposure definitions. DATA SOURCES/STUDY SELECTION: Eight prospective studies that had at least 200 incident breast cancer cases, assessed usual dietary intake, and completed a validation study of the diet assessment method or a closely related instrument were included in these analyses. DATA EXTRACTION: Using the primary data from each of the studies, we calculated study-specific relative risks (RRs) that were combined using a random-effects model. DATA SYNTHESIS: The studies included 7377 incident invasive breast cancer cases occurring among 351 825 women whose diet was analyzed at baseline. For comparisons of the highest vs lowest quartiles of intake, weak, nonsignificant associations were observed for total fruits (pooled multivariate RR, 0.93; 95% confidence interval [CI], 0.86-1.00; P for trend =.08), total vegetables (RR, 0.96; 95% CI, 0.89-1.04; P for trend =.54), and total fruits and vegetables (RR, 0.93; 95% CI, 0.86-1.00; P for trend =.12). No additional benefit was apparent in comparisons of the highest and lowest deciles of intake. No associations were observed for green leafy vegetables, 8 botanical groups, and 17 specific fruits and vegetables. CONCLUSION: These results suggest that fruit and vegetable consumption during adulthood is not significantly associated with reduced breast cancer risk
— id: 34752, year: 2001, vol: 285, page: 769, stat: Journal Article,

Serum carotenoids as biomarkers of fruit and vegetable consumption in the New York Women's Health Study
van Kappel AL; Steghens JP; Zeleniuch-Jacquotte A; Chajes V; Toniolo P; Riboli E
2001 Jun;4(3):829-835, Public health nutrition
OBJECTIVE: To investigate the usefulness of serum carotenoids as biomarkers of fruit and vegetable consumption. DESIGN:: Reproducibility study on three repeat measurements of serum carotenoids. Correlation analysis of carotenoids and dietary food intake, and regression analysis of potential predictive parameters for serum carotenoid levels. SETTING: New York, USA. SUBJECT:: Women participating in the New York Women's Health Study, a prospective study of sex hormones, diet and breast cancer. Forty-eight women with three repeat blood samples and 302 women having a blood sample and a dietary history questionnaire (including 47 subjects from the reproducibility study). RESULTS: Serum carotenoid concentrations were highly reproducible between one- and two-year repeat samples. Estimated fruit and vegetable consumption was positively correlated with serum carotenoid concentrations but correlation coefficients were low. Consumption of fruit was predictive for serum levels of beta-carotene, alpha-carotene and beta-cryptoxanthin, while vegetable consumption was predictive for serum beta-carotene, lutein, zeaxanthin and lycopene. Serum concentrations of cholesterol and triglycerides were predictive for serum carotenoids but adjustment for their levels had little or no influence on the correlation between fruit and vegetable consumption and serum carotenoid concentrations. CONCLUSIONS: One single serum measurement of alpha-carotene, beta-carotene and lutein can accurately rank subjects according to their usual serum level. Serum concentrations, however, correlate only moderately with estimated dietary intake of fruits or vegetables and should therefore be used with caution as biomarkers of fruit and vegetable intake
— id: 34750, year: 2001, vol: 4, page: 829, stat: Journal Article,

Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study
Zeleniuch-Jacquotte A; Akhmedkhanov A; Kato I; Koenig KL; Shore RE; Kim MY; Levitz M; Mittal KR; Raju U; Banerjee S; Toniolo P
2001 Apr 6;84(7):975-981, British journal of cancer
We assessed the association of postmenopausal serum levels of oestrogens and sex hormone-binding globulin (SHBG) with endometrial cancer risk in a case-control study nested within the NYU Women's Health Study cohort. Among 7054 women postmenopausal at enrolment, 57 cases of endometrial cancer were diagnosed a median of 5.5 years after blood donation. Each case was compared to 4 controls matched on age, menopausal status at enrolment, and serum storage duration. Endometrial cancer risk increased with higher levels of oestradiol (odds ratio = 2.4 in highest vs lowest tertile, P for trend = 0.02), percent free oestradiol (OR = 3.5, P< 0.001), and oestrone (OR = 3.9, P< 0.001). Risk decreased with higher levels of percent SHBG-bound oestradiol (OR = 0.43, P = 0.03) and SHBG (OR = 0.39, P = 0.01). Trends remained in the same directions after adjusting for height and body mass index. A positive association of body mass index with risk was substantially reduced after adjusting for oestrone level. Our results indicate that risk of endometrial cancer increases with increasing postmenopausal oestrogen levels but do not provide strong support for a role of body mass index independent of its effect on oestrogen levels.
— id: 21217, year: 2001, vol: 84, page: 975, stat: Journal Article,

Genetic variant of luteinizing hormone and risk of breast cancer in older women [In Process Citation]
Akhmedkhanov A; Toniolo P; Zeleniuch-Jacquotte A; Pettersson K; Huhtaniemi I
2000 Aug;9(8):839-842, Cancer epidemiology biomarkers & prevention
A genetic variant of luteinizing hormone (LH) characterized by two point mutations in codons 8 (TGG-->CGG) and 15 (ATC-->ACC) of the LH beta-subunit gene has been described recently. As compared with wild-type LH, the variant LH appears to have higher in vitro bioactivity but a shortened circulatory half-life, and it has been reported to affect circulating levels of sex hormones. Our purpose was to determine whether the variant form of LH is associated with an altered risk of breast cancer. This hypothesis was addressed in a case-control study nested within a prospective cohort that included 270 cases of breast cancer and twice as many matching control subjects. The study was limited to subjects diagnosed at age 50 years or older. The LH status was determined by the combination of two immunofluorometric assays of serum using monoclonal antibodies. Frequency of the variant LH was similar in breast cancer cases and controls (11.5% versus 10.7%). In conditional regression models, the presence of the variant LH was not associated with a considerable increase of breast cancer risk (odds ratio, 1.07; 95% confidence interval, 0.68-1.69). Adjustment for potential confounders did not notably change the risk estimate (odds ratio, 1.11; 95% confidence interval, 0.69-1.78). These observations do not appear to support the hypothesis that this particular variant of LH is associated with altered risk of breast cancer diagnosed at age 50 years and older
— id: 11536, year: 2000, vol: 9, page: 839, stat: Journal Article,

Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women
Kaaks R; Toniolo P; Akhmedkhanov A; Lukanova A; Biessy C; Dechaud H; Rinaldi S; Zeleniuch-Jacquotte A; Shore RE; Riboli E
2000 Oct 4;92(19):1592-1600, Journal of the National Cancer Institute
BACKGROUND: Leading a Western lifestyle, being overweight, and being sedentary are associated with an increased risk of colorectal cancer. Recent theories propose that the effects of these risk factors may be mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I. To test this hypothesis, we conducted a case-control study nested within a cohort of 14 275 women in New York. METHODS: We used blood samples that had been obtained from these women from March 1985 through June 1991 and stored in a biorepository. C-peptide (a marker for insulin secretion), IGF-I, and IGF-binding proteins (IGFBPs)-1, -2, and -3 were assayed in the serum of 102 women who subsequently developed colorectal cancer and 200 matched control subjects. Logistic regression was used to relate cancer risk to these peptide levels, by adjustment for other risk factors. All statistical tests used are two-sided. RESULTS: Colorectal cancer risk increased with increasing levels of C-peptide (P:(trend) =.001), up to an odds ratio (OR) of 2. 92 (95% confidence interval [CI] = 1.26-6.75) for the highest versus the lowest quintiles, after adjustment for smoking. For colon cancer alone (75 case subjects and 146 control subjects), ORs increased up to 3.96 (95% CI = 1.49-10.50; P:(trend) <.001) for the highest versus the lowest quintiles. A statistically significant decrease in colorectal cancer risk was observed for increasing levels of IGFBP-1 (P:(trend) =.02; OR in the upper quintile = 0.48 [95% CI = 0.23-1. 00]), as well as for the highest quintile of IGFBP-2 levels (P:(trend) =.06; OR = 0.38 [95% CI = 0.15-0.94]). Colorectal cancer risk showed a modest but statistically nonsignificant positive association with levels of IGF-I and was statistically significantly increased for the highest quintile of IGFBP-3 (OR = 2.46 [95% CI = 1. 09-5.57]). CONCLUSIONS: Chronically high levels of circulating insulin and IGFs associated with a Western lifestyle may increase colorectal cancer risk, possibly by decreasing IGFBP-1 and increasing the bioactivity of IGF-I
— id: 34552, year: 2000, vol: 92, page: 1592, stat: Journal Article,

Risk of iron overload among middle-aged women
Kato I; Dnistrian AM; Schwartz M; Toniolo P; Koenig K; Shore RE; Zeleniuch-Jacquotte A; Akhmedkhanov A; Riboli E
2000 May;70(3):119-125, International journal for vitamin & nutrition research
Iron overload, expressed as increased body iron stores, has been recognized as a potential hazard because it promotes the generation of oxygen radicals. We analyzed factors associated with serum ferritin levels (an indicator of body iron stores) among middle-aged women with a high prevalence of nutrient supplement use. Serum ferritin concentrations were determined on automated immunoassay for 487 healthy women with the mean age of 57 years who participated in the New York University Women's Health Study. The mean serum ferritin concentration in postmenopausal women was more than twice that in premenopausal women. Serum ferritin concentrations progressively increased with advancing age, but adjustment for menopausal status considerably weakened this association. Among non-dietary factors, nonwhite ethnicity, obesity and cigarette smoking were positively associated with serum ferritin concentrations. After adjustment for these factors and for menopausal status, serum ferritin levels were positively associated with meat intake and multivitamin use and inversely associated with breakfast cereal consumption. However, none of these lifestyle factors positively associated with serum ferritin levels had a significant impact on serum ferritin levels above 100 ng/ml (approximately equal to median concentration). Our results suggest that iron overload seems unlikely among middle aged women through their diet and nutritional supplements
— id: 34554, year: 2000, vol: 70, page: 119, stat: Journal Article,

Diet, smoking and anthropometric indices and postmenopausal bone fractures: a prospective study
Kato I; Toniolo P; Zeleniuch-Jacquotte A; Shore RE; Koenig KL; Akhmedkhanov A; Riboli E
2000 Feb;29(1):85-92, International journal of epidemiology
OBJECTIVE: Bone fractures are an important cause of morbidity and mortality among the elderly in the US. The present study assesses the possible role of a number of risk factors for postmenopausal bone fractures. METHODS: We analysed the relationships of anthropometric, demographic and lifestyle factors with the risk of bone fracture among 6250 postmenopausal women in a prospective cohort study, the New York University Women's Health Study. RESULTS: After an average of 7.6 years of follow-up, 1025 new incident bone fractures were reported, including 34 hip and 159 wrist fractures (incidence rates; 71.6 and 334.7 per 105 woman-years, respectively). The risk of fracture increased with increasing age, body height and total fat intake, while it was significantly lower among obese and African American women. The relative risk among African Americans was 0.45 (95% CI: 0.32-0.63) compared with non-African Americans. Women taller than 170 cm had a 64% increase in risk of fractures, as compared with those under 155 cm. These associations were generally more pronounced when fractures were limited to those at the hip and wrist. CONCLUSIONS: The present study provides an indication for a potential role of dietary fat in the development of postmenopausal fractures and further evidence to support protective effects of obesity, short stature and African American ethnicity
— id: 10348, year: 2000, vol: 29, page: 85, stat: Journal Article,

Psychotropic medication use and risk of hormone-related cancers: the New York University Women's Health Study
Kato I; Zeleniuch-Jacquotte A; Toniolo PG; Akhmedkhanov A; Koenig K; Shore RE
2000 Jun;22(2):155-160, Journal of public health medicine
BACKGROUND: The use of psychotropic medications may increase the risk of hormone-related cancers in females through increased gonadotropin secretion, but the data from epidemiologic studies are limited to evaluate the hypothesis. METHODS: The association between the use of psychotropic medications and cancer incidence was studied in a prospective cohort study that involves 15,270 women who participated in mammographic screening. The relative risks (RR) and 95 per cent confidence intervals (CIs) for cancer associated with the use of psychotropic medications were estimated by the Cox's proportional hazard model. RESULTS: During an average of 7.3 years of follow-up, 1,130 incident cases of cancer were identified, including 566 breast, 67 endometrial and 47 ovarian cancers. The use of any type of psychotropic medication at baseline was associated with increased risks of breast [relative risk (RR) = 1.39, 95 per cent CI 1.11-1.74], endometrial (RR=1.71; 95 per cent CI 0.93-3.14) and ovarian (RR= 1.48, 95 per cent CI 0.69-3.16) cancers, whereas no increase in risk was observed for other cancers (RR = 1.06). When the subjects were divided by menopausal status at baseline, premenopausal women tended to have higher risk of all hormone-related cancers (RR = 1.73, 95 per cent CI 1.27-2.35) than postmenopausal women (RR=1.23, 95 per cent CI 0.94-1.62). The magnitude of the RR associated with the use of these medications did not change by length of follow-up. Analysis by type of medication did not find that the association was limited to specific types. CONCLUSION: The observed association needs to be confirmed in further studies based on more detailed medication history
— id: 34553, year: 2000, vol: 22, page: 155, stat: Journal Article,

Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice
Perez-Soler R; Kemp B; Wu QP; Mao L; Gomez J; Zeleniuch-Jacquotte A; Yee H; Lee JS; Jagirdar J; Ling YH
2000 Dec;6(12):4932-4938, Clinical cancer research
The lack of tumor models that can reliably predict for response to anticancer agents remains a major deficiency in the field of experimental cancer therapy. Although heterotransplants of certain human solid tumors can be successfully grown in nude mice, they have never been appropriately explored for prediction of in vivo chemosensitivity to anticancer agents. We determined the tumor response rate and studied the influence of several biological and molecular tumor parameters on the in vivo sensitivity to paclitaxel in a series of heterotransplanted human non-small cell lung cancer (NSCLC) tumors. One hundred consecutive resected NSCLC tumors were heterotransplanted s.c. in nude mice. The in vivo sensitivity to i.v. paclitaxel (60 mg/kg every 3 weeks) was studied in 34 successfully grown heterotransplants. Treatment started when the tumors reached a size of 5 mm in diameter, and strict standard clinical criteria (>50% shrinkage in tumor weight or cross-sectional surface) were used to define tumor response. Baseline multidrug resistance protein (MRP), Her-2/neu, and epidermal growth factor receptor (EGFR) expression, and pre- and posttherapy bax and bcl-2 expression were determined by Western blot analysis. p53 status was determined by sequencing. The overall take rate was 46% (95% confidence interval, 36-56%) and was significantly higher (P < 0.05) for squamous carcinoma tumors (75%) than for adenocarcinoma tumors (30%) and bronchoalveolar tumors (23%). The heterotransplants were morphologically very similar to the original tumors. The response rate to paclitaxel was 21% (95% confidence interval, 9-38%). Baseline tumor parameters associated with response were no Her-2/neu expression (none of the responding tumors expressed Her-2/neu versus 48% of the nonresponding tumors, P = 0.05) and baseline bcl-2 expression (all responding tumors expressed bcl-2 versus only 43% of the nonresponding tumors, P = 0.02). There was a trend toward a higher response rate in bax-positive tumors, and MRP- and EGFR-negative tumors, but it was not statistically significant. The response was independent of baseline p53 status and baseline mitotic index. Responding tumors had a higher bax/bcl-2 ratio 24 h after therapy, but the difference was only marginally significant (2.8 for responding tumors versus 1.1 for nonresponding tumors, P = 0.07). The extent of mitotic arrest at 24 h after therapy was not associated with response. Human NSCLC heterotransplants are morphologically identical to the original tumors and have a response rate to paclitaxel that is equivalent to that reported in Phase II studies in patients with advanced NSCLC treated with single-agent paclitaxel. NSCLC heterotransplants deserve to be explored to evaluate new agents for lung cancer and to predict clinical response on an individual basis in selected groups of patients
— id: 34753, year: 2000, vol: 6, page: 4932, stat: Journal Article,

Serum insulin-like growth factor-I and breast cancer
Toniolo P; Bruning PF; Akhmedkhanov A; Bonfrer JM; Koenig KL; Lukanova A; Shore RE; Zeleniuch-Jacquotte A
2000 Dec 1;88(5):828-832, International journal of cancer
Insulin-like growth factor I (IGF-I) is a systemic hormone with potent mitogenic and anti-apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre-menopausal ages. In a prospective case-control study nested within a cohort of New York City women, IGF-I, IGF-binding protein 3 (IGFBP-3) and C peptide were measured in frozen serum samples from 172 pre-menopausal and 115 post-menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post-menopausal breast cancer was not associated with serum IGF-I, IGFBP-3 or C-peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF-I in pre-menopausal women. The odds ratio (OR) for the highest quartile of IGF-I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91-2. 81]. The OR decreased to 1.49 (95% CI 0.80-2.79) after adjustment for IGFBP-3. In analyses restricted to subjects who were pre-menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07-4.94). Adjustment for IGFBP-3 reduced the OR to 1.90 (95% CI 0.82-4.42). There was no association between pre-menopausal breast cancer and IGFBP-3, IGF-I:IGFBP-3 ratio or non-fasting levels of C peptide. Elevated circulating levels of IGF-I may be an indicator of increased risk of breast cancer occurring before age 50
— id: 34550, year: 2000, vol: 88, page: 828, stat: Journal Article,

Risk of breast cancer and organochlorine exposure
Wolff MS; Zeleniuch-Jacquotte A; Dubin N; Toniolo P
2000 Mar;9(3):271-277, Cancer epidemiology biomarkers & prevention
A prospective investigation of breast cancer and organochlorine (OC) exposures was undertaken in the New York University Women's Health Study. Cases (n = 148) and individually matched controls (n = 295) were identified among women whose blood had been obtained 6 months or more prior to breast cancer diagnosis. In addition, among 84 cases and 196 controls, two or more consecutive annual blood samples were available to estimate half-lives of 1,1-dichloro-2,2-bis(p-chlorophenyl) ethene (DDE) and polychlorinated biphenyls (PCBs). Cases and controls had similar levels of DDE (geometric mean, 6.95 versus 7.27 ng/ml; lipid-adjusted geometric mean, 977 versus 1100 ng/g) and PCBs (5.04 versus 4.97 ng/ml; lipid-adjusted geometric mean, 683 versus 663 ng/g). These differences remained nonsignificant when estrogen receptor status of tumors was considered. DDE and PCB half-lives did not differ in case versus control patients. In control patients, DDE and PCB half-lives were strongly correlated (r(s) = 0.71), and the half-life of DDE (but not that of PCB) was inversely correlated with body mass index (BMI), yet the blood serum levels of PCB (but not those of DDE) were correlated with BMI. We conclude that there is no evidence for an association of breast cancer risk with DDE or PCB levels in blood (based on samples collected during the period 1987-1992) nor with their elimination half-lives. However, changes in DDE and PCBs over time are influenced by metabolism, BMI, and current OC exposures, and each may affect interpretation of OC levels in risk assessment models
— id: 34754, year: 2000, vol: 9, page: 271, stat: Journal Article,

Reliability of fatty acid composition in human serum phospholipids
Zeleniuch-Jacquotte A; Chajes V; Van Kappel AL; Riboli E; Toniolo P
2000 May;54(5):367-372, European journal of clinical nutrition
OBJECTIVE: We examined the reliability of the fatty acid composition of serum phospholipids in the New York University Women's Health Study, a prospective study of sex hormones, diet and breast cancer. DESIGN: Non-fasting serum samples collected at three yearly visits, in 46 healthy women, and stored at -80 degrees C for 7-12 y, were included in the study. Serum phospholipid fatty acid composition was measured by capillary gas chromatography. RESULTS: For the 20 individual fatty acids measured, the reliability coefficients were less than 0.50 for four, between 0.50 and 0.70 for nine, and greater than 0.70 for seven. Among the major fatty acids, arachidonic and alpha-linolenic acids had high reliability coefficients (0.71 and 0. 72, respectively), palmitic, oleic, linoleic, eicosapentaenoic and docosahexaenoic acids had intermediate coefficients (0.57, 0.69, 0. 62, 0.64 and 0.66, respectively), whereas stearic acid had the lowest coefficient (0.15). The reliability coefficients for total monounsaturated fats, omega-6 and omega-3 fatty acids were moderately high (0.66, 0.53 and 0.66, respectively), whereas the coefficients for total saturated fats and total polyunsaturated fats were low (0.31 and 0.43, respectively). CONCLUSIONS: These results indicate that the fatty acid composition of serum phospholipids can be a useful tool in epidemiologic studies, although for most fatty acids a single determination is associated with some error in measurement that should be taken into account at the design and analysis stages. Storage for up to 12 y at -80 degrees C preserved polyunsaturated fatty acids from oxidation very well
— id: 10347, year: 2000, vol: 54, page: 367, stat: Journal Article,

Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study
Kato I; Dnistrian AM; Schwartz M; Toniolo P; Koenig K; Shore RE; Akhmedkhanov A; Zeleniuch-Jacquotte A; Riboli E
1999 Apr;79(11-12):1917-1922, British journal of cancer
Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case-control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After adjusting for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27-0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83-3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92-4.29). The potentially protective effects of folate need to be confirmed in clinical trials
— id: 6090, year: 1999, vol: 79, page: 1917, stat: Journal Article,

Epidemiologic correlates of serum folate and homocysteine levels among users and non-users of vitamin supplement
Kato I; Dnistrian AM; Schwartz M; Toniolo P; Koenig K; Shore RE; Zeleniuch-Jacquotte A; Akhmedkhanov A; Riboli E
1999 Sep;69(5):322-329, International journal for vitamin & nutrition research
Lower serum folate and higher serum homocysteine levels are known risk factors for various conditions. Thus, epidemiologic correlates with these measurements were studied for 256 multivitamin users and 230 non-users who were middle-aged women. Both serum folate and homocysteine levels increased with advancing age in both multivitamin users (P < 0.01 and P < 0.01) and non-users (P = 0.08 and P < 0.01). Among non-users, higher intake of vegetables, fruits, cold cereals and total protein were associated positively with serum folate and inversely with homocysteine levels. There were 25-74% increases in serum folate and 10-15% decreases in serum homocysteine between 1st and 4th quartiles of intake of these food/nutrients. In addition, 26% lower serum folate and 18% higher serum homocysteine were observed for those smoking 20 or more cigarettes per day compared with non-smokers. Among multivitamin users, body weight was correlated inversely with serum folate (P < 0.01) and positively with serum homocysteine levels (P = 0.04), while no correlates were found among lifestyle factors. Regular use of multivitamins increased serum folate about fourfold and decreased homocysteine twofold. These results suggest that multivitamin use can offset the effects of an unhealthy lifestyle on these serum markers, and that levels of serum folate and homocysteine can also be favorably influenced by healthier diet and abstinence from smoking
— id: 6221, year: 1999, vol: 69, page: 322, stat: Journal Article,

Iron intake, body iron stores and colorectal cancer risk in women: a nested case-control study
Kato I; Dnistrian AM; Schwartz M; Toniolo P; Koenig K; Shore RE; Zeleniuch-Jacquotte A; Akhmedkhanov A; Riboli E
1999 Mar 1;80(5):693-698, International journal of cancer
Accumulated evidence suggests that increased body iron stores may increase the risk of colorectal cancer, possibly via catalyzing oxidation reactions. We examined the relationship between iron status and colorectal cancer in a case-control study nested within the New York University Women's Health Study cohort. For 105 incident cases of colorectal cancer with an average follow-up of 4.7 years and 523 individually matched controls, baseline levels of serum iron, ferritin, total iron binding capacity (TIBC) and transferrin saturation were determined as indicators of body iron stores, and total iron intake was assessed based on their diet and supplement intake. Overall, there were no associations between the risk of colorectal cancer and any of these indices except for serum ferritin, which showed a significant inverse association. When analyzed by subsite, there was an increasing trend in risk of cancer of the proximal colon with increasing total iron intake (p-value for trend = 0.04). In addition, a significantly increased risk of colorectal cancer associated with higher total iron intake [odds ratio (OR) = 2.50; 95% confidence interval (CI): 1.06-5.87] was observed among subjects with higher intake of total fat. Our results do not support a role of increased body iron stores in the development of colorectal cancer, but suggest that luminal exposure to excessive iron may possibly increase the risk in combination with a high fat diet
— id: 7363, year: 1999, vol: 80, page: 693, stat: Journal Article,

Comparison of active and cancer registry-based follow-up for breast cancer in a prospective cohort study
Kato I; Toniolo P; Koenig KL; Kahn A; Schymura M; Zeleniuch-Jacquotte A
1999 Feb 15;149(4):372-378, American journal of epidemiology
The authors compared the relative effectiveness of two distinct follow-up designs in prospective cohort studies--the active approach, based on direct contact with study subjects, and the passive approach, based on record linkages with population-based cancer registries--utilizing available information from the New York University Women's Health Study (WHS) and the New York State Cancer Registry (NYSCR). The analyses were limited to breast cancer cases identified during the period 1985-1992, for which follow-up was considered reasonably complete by both the WHS and the NYSCR. Among 12,947 cohort members who reported a New York State address, 303 pathologically confirmed cases were identified through active follow-up and 284 through record linkage. Sixty-three percent of cancers were identified by both sources, 21% by the WHS only, and 16% by the NYSCR only. The agreement was appreciably better for invasive cancers. The percentage of cases identified only by the NYSCR was increased among subjects whose active follow-up was incomplete, as well as among nonwhites, obese patients, and parous patients. This suggests that relying on either type of follow-up alone may introduce certain biases in evaluating risk factors for breast cancer. Combining both approaches appears to be a better strategy in prospective cohort studies
— id: 7364, year: 1999, vol: 149, page: 372, stat: Journal Article,

Epidemiologic correlates with menstrual cycle length in middle aged women
Kato I; Toniolo P; Koenig KL; Shore RE; Zeleniuch-Jacquotte A; Akhmedkhanov A; Riboli E
1999 Oct;15(9):809-814, European journal of epidemiology
While irregular menstruations have been associated with lower cumulative exposure to the ovarian steroids, shorter regular cycles have been postulated to increase the cumulative exposure. Epidemiological correlates with menstrual patterns were analyzed among 4900 premenopausal women aged 45 or younger from the New York University Women's Health Study. The length of regular menstrual cycles increased with increasing age at menarche, body mass index and parity, but decreased with age, nonwhite racial background and current smoking. The likelihood of irregular cycles increased with increasing age, body mass index and number of cigarettes smoked per day. With adjustment for age, body mass index and number of cigarettes smoked per day, the risk of irregular cycles was marginally positively associated with total fat intake
— id: 10358, year: 1999, vol: 15, page: 809, stat: Journal Article,

Onset of natural menopause - Response
Kato, I; Toniolo, P; Akhmedkhanov, A; Koenig, KL; Shore, R; Zeleniuch-Jacquotte, A
1999 DEC ;52(12):1291-1292, Journal of clinical epidemiology
— id: 53844, year: 1999, vol: 52, page: 1291, stat: Journal Article,

Expression of the cell cycle inhibitor p27KIP1 is a new prognostic marker associated with survival in epithelial ovarian tumors
Newcomb EW; Sosnow M; Demopoulos RI; Zeleniuch-Jacquotte A; Sorich J; Speyer JL
1999 Jan;154(1):119-125, American journal of pathology
This case-control study was designed to identify factors associated with long-term survival. We examined two groups of patients with epithelial ovarian cancer, one group of long-term survivors (> 5 years) and one group of short-term survivors (< 2 years), for levels of expression of p53 and p27KIP1 proteins (as both proteins have been shown to be independent prognostic markers in tumors other than ovary) and the relationship with patient survival. Our findings show that p27KIP1 expression, in contrast to p53 expression, is positively associated with long-term survival in univariate analysis (P = 0.001), in analyses stratified by residual disease (P = 0.02) or performance status (P = 0.02), the two strongest prognostic factors for ovarian cancer, as well as multivariate analysis (P = 0.002) adjusting simultaneously for age, tumor stage, residual disease, performance status, and grade of differentiation. Therefore, immunostaining for levels of p27KIP1 expression may have potential as a new prognostic factor in the management of ovarian cancer
— id: 7414, year: 1999, vol: 154, page: 119, stat: Journal Article,

In vivo sensitivity to paclitaxel (P) in human non-small cell lung cancer (NSCLC) heterotransplants (HT's): Role of Her-2, bax and bcl-2
Perez-Soler, R; Ling, Y H; Mao, L; Wu, Q P; Zeleniuch-Jacquotte, A; Kemp, B
1999 Apr 10-14;40:186-186, Proceedings (American Association for Cancer Research)
— id: 15919, year: 1999, vol: 40, page: 186, stat: Journal Article,

Randomized, double-blind, clinical trial of a polyvalent melanoma vaccine in patients with stage III melanoma
Bystryn, JC; Oratz, R; Shapiro, R; Harris, M; Roses, D; Jacquotte, A
1998 APR ;110(4):498-498, Journal of investigative dermatology
— id: 53522, year: 1998, vol: 110, page: 498, stat: Journal Article,

Randomized, double-blind phase III trial of a polyvalent, shed, melanoma antigen vaccine in stage III melanoma
Bystryn, JC; Oratz, R; Shapiro, RL; Harris, MN; Roses, DF; Jacquotte, A; Chen, DL; Rivas, M
1998 AUG 25 ;9(4):84-84, Annals of oncology
— id: 53387, year: 1998, vol: 9, page: 84, stat: Journal Article,

Prospective study of factors influencing the onset of natural menopause
Kato I; Toniolo P; Akhmedkhanov A; Koenig KL; Shore R; Zeleniuch-Jacquotte A
1998 Dec;51(12):1271-1276, Journal of clinical epidemiology
Late or early menopause has been implicated in risk of several chronic diseases in women. To study factors influencing the onset of natural menopause, the authors analyzed the follow-up data of 4694 premenopausal women who enrolled in the New York University Women Study at ages 34-61. In an average of 5.4 years of observation, there were 2035 incidences of menopause, with the median age of 51.3 years. Current smokers experienced menopause 0.75 years earlier than never-smokers. Those who smoked more than 10 cigarettes per day had a 40% increase in risk of earlier menopause. In contrast, women who had three or more children experienced menopause 0.86 years later than nulliparous women, and Jewish women, 0.66 years later than Catholic women. There was also a modest increase in the age at menopause with increasing body mass index. This prospective study provides solid epidemiologic evidence that several factors other than cigarette smoking have impact on the onset of natural menopause
— id: 6062, year: 1998, vol: 51, page: 1271, stat: Journal Article,

Pharmacodynamics of topoisomerase I inhibition: Western blot determination of topoisomerase I and cleavable complex in patients with upper gastrointestinal malignancies treated with topotecan
Liebes L; Potmesil M; Kim T; Pease D; Buckley M; Fry D; Cho J; Adler H; Dar K; Zeleniuch-Jacquotte A; Hochster H
1998 Mar;4(3):545-557, Clinical cancer research
Analogues of camptothecins are specific inhibitors of eukaryotic DNA topoisomerase I (topo I) that lead to DNA damage and, eventually, cellular cytotoxicity. Camptothecin analogues bind to this target enzyme in the course of its normal function and stabilize the DNA-enzyme adduct to form a 'cleavable complex.' Preclinical experiments using Western blot analyses have shown cleavable complex formation to be the key intermediate step in topo I inhibition. In this series of experiments, it was our goal to convert this laboratory technique into a useful clinical assay, allowing measurement of the target enzyme and detection of the key intermediate in clinical specimens taken from patients being treated with the topo I inhibitor topotecan. Because available antibodies were not sufficiently sensitive at the start of this project, we identified a highly specific human SCL-70 antibody from a patient with scleroderma, which allowed quantitative determination of topo I copy number in HeLa and HT-29 cell lines. Additional refinements of the Western blot technique were accomplished to improve signal:noise ratio. In surgical tumor specimens, we found the median topo I level to be 30.1 x 10(5) copies/cell for gastric adenocarcinomas, compared to 18.4 x 10(5) copies/cell for normal gastric mucosae in the same samples. For lung adenocarcinoma, the median protein level was 21.5 x 10(5) copies/cell, compared with the normal tissue counterpart protein level of 12.7 x 10(5) copies/cell. The median tumor:normal ratios from paired samples of these tumor types were 1.51 and 1.84, respectively. As part of a Phase II study evaluating the efficacy of topotecan (1.5-2.0 mg/m2 daily for 5 days) in upper gastrointestinal malignancies, we obtained tumor and normal mucosa biopsies in 11 patients with gastric or esophageal cancer, 30 min after administration on day 4 or 5. Three patients with gastric adenocarcinoma had stable disease as their best response, with the remainder of patients progressing. Improvement in Western blotting methodology allowed the quantitation of topo I levels in these gastric and esophageal cancer biopsies, which could be augmented by brief heating to release complexed topo I. We were also able to directly visualize high molecular weight topo I-containing bands, which were shown to be cleavable complexes by heat reversal, with restoration of the topo I Mr 100,000 band. Using this heat reversal technique, we determined the presence of cleavable complex in a total of 7 of 11 patient biopsy samples (5 tumors and 2 normal mucosae). In patients treated with topotecan on this dose and schedule, we determined that a median of 73% of the total tumor topo I was involved in cleavable complex (range, 18.3-91%). The intensity of the Mr 100,000 topo I band in biopsy specimens of patients receiving topotecan represented 'free' or noncomplexed topo I. The median copy number for the residual, noncomplexed topo I (n = 11) was 7.36 x 10(5) copies/cell, significantly less than the median of 30.1 x 10(5) copies/cell for random tumor specimens from patients with gastric adenocarcinomas (P < 0.001). Pharmacodynamic analysis demonstrated a negative correlation between the noncomplexed topo I copy number and topotecan area under the curve (Spearman rank test: r(s) = -0.81, P = 0.003). Nonlinear regression analyses of these data were best fit with an inhibitory maximum effect model, yielding parameter estimates for Emax and EC50 of 29.3 x 10(5) copies/cell (coefficient of variation = 22%) and 43.1 ng x h/ml (coefficient of variation = 27%), respectively. Through a series of careful modifications and refinements, we have improved the Western blot assay for topo I for use in clinical monitoring. We have demonstrated the ability to directly visualize cleavable complex in patients being treated with topo I inhibitor therapy and have directly quantitated free topo I, as well as the key topo I intermediate (cleavable complex), in biopsy specimens obtained from pat
— id: 57194, year: 1998, vol: 4, page: 545, stat: Journal Article,

Reliability of serum measurements of lignans and isoflavonoid phytoestrogens over a two-year period
Zeleniuch-Jacquotte A; Adlercreutz H; Akhmedkhanov A; Toniolo P
1998 Oct;7(10):885-889, Cancer epidemiology biomarkers & prevention
We examined the distribution and long-term reliability of serum measurements of the two main human lignans, enterolactone and enterodiol, and the isoflavonoid phytoestrogens daidzein, genistein, equol, and O-Desmethylangolensin in the New York University Women's Health Study, a prospective cohort study of sex hormones and breast cancer. Serum samples collected at three yearly visits in 30 premenopausal and 30 postmenopausal women who had not been diagnosed with cancer or cardiovascular disease were included in the study. Assays were carried out by ion-exchange chromatography and capillary gas chromatography-mass spectrometry. Levels of isoflavonoid phytoestrogens were low, often at or below the sensitivity level of the assay. The reliability coefficients for these compounds were also low (< or =0.30). The median levels of enterodiol and enterolactone were 1.52 nmol/liter and 20.2 nmol/liter, respectively, and were comparable with the levels observed in omnivorous Finnish women living in the Helsinki area. A substantial number of women, though, had fairly high levels: for instance, 15% of the assays showed levels of enterolactone greater than the mean level observed in vegetarian Finnish women, i.e., 89.1 nmol/liter (H. Adlercreutz et al., Cancer Detec. Prev., 18: 259-271, 1994). The reliability coefficient of a single measurement of enterolactone was moderately high (0.55), suggesting that serum measurements of this compound could be a useful tool in prospective epidemiological studies with access to repeated blood or serum specimens. For instance, the reliability coefficient of the average of three measurements of enterolactone would be 0.79, a level considered acceptable in light of the other sources of error that are present in epidemiological studies (W. Willett, Stat. Med., 8: 1031-1040, 1989)
— id: 7470, year: 1998, vol: 7, page: 885, stat: Journal Article,

Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study
Hochster H; Liebes L; Speyer J; Sorich J; Taubes B; Oratz R; Wernz J; Chachoua A; Blum RH; Zeleniuch-Jacquotte A
1997 Aug;3(8):1245-1252, Clinical cancer research
Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming 'cleavable complex,' a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 'free' topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of </=20 cm2 were entered at the 0.6 mg/m2/day level. Cohorts of four patients were entered until the maximum tolerated dose was determined. Peripheral blood was sampled weekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot. For previously untreated patients, the dose-limiting toxicity was myelosuppression at the dose of 0.8 mg/m2/day. Anemia was seen as a cumulative effect. Unexpected nonhematological toxicity was not observed. topo-1 level analysis by Western blot in 11 cycles with weekly measurements showed progressive decrement in the percentage of free topo-1 (compared to baseline value) during weeks 1, 2, and 3. The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at week 2, and 77% (P = 0.016) at week 3. At week 4, off drug treatment, the median percentage of decrease from baseline was only 14%. Additional analysis of free topo-1 level as a function of both area under the curve (P = 0.005) and day of infusion (P = 0.003) demonstrated a significant relationship by regression analysis using a linear mixed effects model. In this Phase I study of topotecan prolonged infusion, hematological toxicity remained dose limiting without evidence of previously described nonhematological toxicity. The recommended Phase II dose is 0.7 mg/m2/day for 21 days every 28 days for previously untreated patients and 0.6 mg/m2/day for those with limited prior therapy. Western blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, which reached statistical significance by week 3. Within 1 week of stopping infusion, topo-1 levels return to baseline. A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated. These data suggest that prolonged administration of topo-1 inhibitory drugs results in sustained depletion of free topo-1 enzyme as measured by Western Blot analysis, which may be an important consideration in the clinical use of these agents. Direct randomized, comparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy
— id: 56951, year: 1997, vol: 3, page: 1245, stat: Journal Article,

Correcting for measurement error in the analysis of case-control data with repeated measurements of exposure
Kim MY; Zeleniuch-Jacquotte A
1997 Jun 1;145(11):1003-1010, American journal of epidemiology
The authors present a technique for correcting for exposure measurement error in the analysis of case-control data when subjects have a variable number of repeated measurements, and the average is used as the subject's measure of exposure. The true exposure as well as the measurement error are assumed to be normally distributed. The method transforms each subject's observed average by a factor which is a function of the measurement error parameters, prior to fitting the logistic regression model. The resulting logistic regression coefficient estimate based on the transformed average is corrected for error. A bootstrap method for obtaining confidence intervals for the true regression coefficient, which takes into account the variability due to estimation of the measurement error parameters, is also described. The method is applied to data from a nested case-control study of hormones and breast cancer
— id: 7179, year: 1997, vol: 145, page: 1003, stat: Journal Article,

Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women
Zeleniuch-Jacquotte A; Bruning PF; Bonfrer JM; Koenig KL; Shore RE; Kim MY; Pasternack BS; Toniolo P
1997 Jun 1;145(11):1030-1038, American journal of epidemiology
The authors examined the relation between postmenopausal serum levels of testosterone and dehydroepiandrosterone sulfate (DHEAS) and subsequent risk of breast cancer in a case-control study nested within the New York University Women's Health Study cohort. A specific objective of their analysis was to examine whether androgens had an effect on breast cancer risk independent of their effect on the biologic availability of estrogen. A total of 130 cases of breast cancer were diagnosed prior to 1991 in a cohort of 7,054 postmenopausal women who had donated blood and completed questionnaires at a breast cancer screening clinic in New York City between 1985 and 1991. For each case, two controls were selected, matching the case on age at blood donation and length of storage of serum specimens. Biochemical analyses were performed on sera that had been stored at -80 degrees C since sampling. The present report includes a subset of 85 matched sets, for whom at least 6 months had elapsed between blood donation and diagnosis of the case. In univariate analysis, testosterone was positively associated with breast cancer risk (odds ratio (OR) for the highest quartile = 2.7, 95% confidence interval (CI) 1.1-6.8, p < 0.05, test for trend). However, after including % estradiol bound to sex hormone-binding globulin (SHBG) and total estradiol in the statistical model, the odds ratios associated with higher levels of testosterone were considerably reduced, and there was no longer a significant trend (OR for the highest quartile = 1.2, 95% CI 0.4-3.5). Conversely, breast cancer risk remained positively associated with total estradiol levels (OR for the highest quartile = 2.9, 95% CI 1.0-8.3) and negatively associated with % estradiol bound to SHBG (OR for the highest quartile = 0.05, 95% CI 0.01-0.19) after adjustment for serum testosterone levels. These results are consistent with the hypothesis that testosterone has an indirect effect on breast cancer risk, via its influence on the amount of bioavailable estrogen. No evidence was found of an association between DHEAS and risk of breast cancer in postmenopausal women
— id: 7290, year: 1997, vol: 145, page: 1030, stat: Journal Article,

Potentiation of melanoma vaccine activity by IL-2 liposomes
Bystryn JC; Oratz R; Shapiro RL; Johnston D; Harris MN; Roses DF; Zeleniuch-Jacquotte A; Chen DF; Lax A
1996 ;106(4):845-845 #235, Journal of investigative dermatology
— id: 25218, year: 1996, vol: 106, page: 845, stat: Journal Article,

Potentiation of melanoma vaccine activity by IL-2 liposomes
Bystryn, JC; Oratz, R; Shapiro, R; Johnston, D; Harris, M; Roses, D; ZeleniuchJacquotte, A; Chen, DL; Lax, A
1996 APR ;106(4):235-235, Journal of investigative dermatology
— id: 98386, year: 1996, vol: 106, page: 235, stat: Journal Article,

Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity [published erratum appears in J Clin Oncol 1996 Dec;14(12):3175]
Wasserheit C; Frazein A; Oratz R; Sorich J; Downey A; Hochster H; Chachoua A; Wernz J; Zeleniuch-Jacquotte A; Blum R; Speyer J
1996 Jul;14(7):1993-1999, Journal of clinical oncology
PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients
— id: 7058, year: 1996, vol: 14, page: 1993, stat: Journal Article,

A PROSPECTIVE-STUDY OF ENDOGENOUS ESTROGENS AND BREAST-CANCER IN POSTMENOPAUSAL WOMEN - REPLY
LEVITZ, M; BANERJEE, S; KOENIG, K; SHORE, RE; TONIOLO, P; ZELENIUCHJACQUOTTE, A
1995 SEP 20 ;87(18):1414-1415, Journal of the National Cancer Institute
— id: 86758, year: 1995, vol: 87, page: 1414, stat: Journal Article,

Evidence for an effect of human leukocyte antigens on susceptibility to Kaposi's sarcoma related to charge and peptide-binding properties of class I molecules
Marmor M; Winchester R; Zeleniuch-Jacquotte A; Weiss SH; Krasinski K; Saxinger WC; Friedman-Kien A; William DC; Demopoulos R
1995 Oct;9(10):1194-1195, AIDS
— id: 9091, year: 1995, vol: 9, page: 1194, stat: Journal Article,

Improved survival of patients with melanoma with an antibody response to immunization to a polyvalent melanoma vaccine
Miller K; Abeles G; Oratz R; Zeleniuch-Jacquotte A; Cui J; Roses DF; Harris MN; Bystryn JC
1995 Jan 15;75(2):495-502, Cancer
BACKGROUND. Melanoma vaccine treatment appears to slow the progression of melanoma in some patients, particularly in patients in whom it stimulates cellular antimelanoma immune responses. The relationship of vaccine-induced antibody responses to clinical outcome is less clear. The purpose of this study was to investigate the clinical relevance of antibody responses to melanoma vaccine immunization. METHODS. Eighty-two evaluable patients with surgically resected American Joint Committee on Cancer Stage III malignant melanoma were immunized to a partially purified, polyvalent, melanoma antigen vaccine. Antimelanoma antibodies were measured by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis before vaccine treatment and 1 week after the fourth immunization. RESULTS. Vaccine treatment induced or augmented antibody responses to melanoma in 32 (39%) of the patients. The antibodies were directed to one or more antigens of 38-43, 75, 110, 150 and/or 210 kDs, which previously have been shown to be expressed preferentially in cultured human melanoma cells. The median disease free survival of patients with a vaccine-induced antibody response to one or more of these antigens was 5.4 years compared with 1.4 years for nonresponders (P = 0.06), and 5-year overall survival was 71% compared with 44%, respectively (P = < 0.01). As determined by Cox multivariate analysis, the difference in overall survival was independent of disease severity or of immunologic competence as evaluated by ability to be sensitized to dinitrochlorobenzene. The difference in survival between antibody responders and nonresponders improved with time. CONCLUSIONS. The antibody response to vaccine treatment is an immune marker of vaccine activity that appears to be predictive of a later reduction in the recurrence of melanoma and is unrelated to the vaccine's ability to induce cellular immune responses. This finding suggests that vaccine treatment may be effective in slowing the progression of melanoma in some patients and that the protective effect is mediated partly by vaccine-induced antimelanoma antibodies
— id: 12813, year: 1995, vol: 75, page: 495, stat: Journal Article,

Effect of DETOX as an adjuvant for melanoma vaccine
Schultz N; Oratz R; Chen D; Zeleniuch-Jacquotte A; Abeles G; Bystryn JC
1995 Apr;13(5):503-508, Vaccine
The identification of effective adjuvants is critical for tumor vaccine development. Towards this end, we examined whether the immunogenicity of a melanoma vaccine could be potentiated by DETOX, an adjuvant consisting of monophosphoryl lipid A (MPL) and purified mycobacterial cell-wall skeleton (CWS). Nineteen patients with resected stage III melanoma were immunized with a polyvalent melanoma antigen vaccine (40 micrograms) admixed with DETOX, q3 wks x 4. Seven patients received vaccine + low-dose DETOX (10 micrograms MPL + 100 micrograms CWS) and 12 received vaccine + high-dose DETOX (20 micrograms MPL + 200 micrograms CWS). A non-randomized control group of 35 patients was treated similarly with 40 micrograms vaccine + alum. One week after the fourth vaccine immunization, melanoma antibodies were increased over baseline in 7/7 (100%) patients treated with vaccine + low-dose DETOX, 8/12 (67%) patients treated with vaccine + high-dose DETOX, and in 4/19 (21%) of vaccine + alum patients. For the entire DETOX group, the antibody response rate was 15/19 (79%) compared 4/19 (21%) in the alum group (p < 0.001). In contrast, a strong delayed-type hypersensitivity (DTH) response (> or = 15 mm increase in DTH response over baseline) was induced in 50% of the entire DETOX group versus in 47% of the alum group. Median disease-free (DF) survival for the entire DETOX group was 17.8 months compared with 32.1 months in the alum group (p < 0.05). In conclusion, DETOX markedly potentiated antibody but had little effect on DTH responses to melanoma vaccine immunization. It did not appear to improve disease-free survival in comparison to alum in this non-randomized study
— id: 6745, year: 1995, vol: 13, page: 503, stat: Journal Article,

A prospective study of endogenous estrogens and breast cancer in postmenopausal women
Toniolo PG; Levitz M; Zeleniuch-Jacquotte A; Banerjee S; Koenig KL; Shore RE; Strax P; Pasternack BS
1995 Feb 1;87(3):190-197, Journal of the National Cancer Institute
BACKGROUND: Circumstantial evidence links endogenous estrogens to increased risk of breast cancer in women, but direct epidemiologic support is limited. In particular, only a few small prospective studies have addressed this issue. PURPOSE: Our purpose was to assess breast cancer risk in relation to circulating levels of the two major endogenous estrogens, estrone and estradiol, measured before the clinical onset of the disease. METHODS: The association between serum levels of estrogens and the risk of breast cancer was examined in a prospective cohort study of 14,291 New York City women, 35-65 years of age, who received screening for breast cancer at the time of blood sampling and who had not been diagnosed with breast cancer. During the first 5 1/2 years of study, we identified 130 breast cancers among the postmenopausal group (7063 women, 35,509 person-years). The case subjects and twice as many postmenopausal control subjects were included in a case-control study nested within the cohort. Biochemical analyses for percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), total estradiol, estrone, and follicle-stimulating hormone were performed on sera that had been kept at -80 degrees C since sampling. RESULTS: For increasing quartiles of total estradiol, the odds ratio (ORs) of breast cancer, as adjusted for Quetelet index (weight in kilograms divided by the square of the height in meters), were 1.0, 0.9, 1.8, and 1.8 (P value for trend = .06); the ORs for increasing quartiles of estrone were 1.0, 2.2, 3.7, and 2.5 (P value for trend = .06). For increasing quartiles of free estradiol, defined as the fraction of estradiol that is not bound to proteins, the Quetelet index-adjusted ORs of breast cancer were 1.0, 1.4, 3.0, and 2.9 (P value for trend < .01). When we considered the percent of estradiol bound to SHBG, the Quetelet index-adjusted ORs were 1.0, 0.70, 0.40, and 0.32 (P value for trend < .01), thus suggesting a strong protective effect. These associations persisted or became even stronger when analyses were restricted to women whose samples had been drawn 2 or more years before breast cancer diagnosis. CONCLUSIONS: These data represent the first confirmation in a large prospective epidemiologic study of a link between circulating estrogens and breast cancer risk. Although estrogen levels appeared to fall within the conventional limits of normality in all women under study, those who subsequently developed breast cancer tended to show higher levels of estrone, total estradiol, and free estradiol, and a lower percent of estradiol bound to SHBG than women who remained free of cancer. IMPLICATIONS: Factors that increase endogenous estrogen production or reduce the binding of estradiol to SHBG may increase a woman's risk of developing breast cancer later in life
— id: 57459, year: 1995, vol: 87, page: 190, stat: Journal Article,

Endogenous estrogens and risk of breast cancer by estrogen receptor status: a prospective study in postmenopausal women
Zeleniuch-Jacquotte A; Toniolo P; Levitz M; Shore RE; Koenig KL; Banerjee S; Strax P; Pasternack BS
1995 Dec;4(8):857-860, Cancer epidemiology biomarkers & prevention
A positive association between postmenopausal serum levels of total estradiol, percentage of free estradiol, and percentage of estradiol not bound to sex hormone-binding globulin (SHBG) and breast cancer risk was recently reported by the New York University Women's Health Study (P. Toniolo et al., J. Natl. Cancer Inst., 87: 190-197, 1995). Data from this prospective study are used to assess whether the observed associations differ according to estrogen receptor (ER) status of the tumor. Between 1985 and 1991, 7063 postmenopausal women donated blood and completed questionnaires at a large breast cancer screening clinic in New York City. Before 1991, 130 cases of first primary breast cancer were identified by active follow-up of the cohort. For each case, two controls were selected, matching the case on age at first blood donation and length of storage of specimens. Biochemical analyses were performed on sera that had been stored at -80 degrees since sampling. ER information was abstracted from pathology reports. Separate statistical analyses were conducted of ER-positive, ER-negative, and ER-unknown groups (53, 23, and 54 matched sets, respectively). In each of the 3 groups, the mean estradiol and the mean percentage of free estradiol were greater (21-28% and 6-7%, respectively) in cases than in controls. Conversely, the mean percentage of estradiol bound to SHBG was 9-12% lower in cases than in controls. The logistic regression coefficients measuring the strength of the association between estradiol and its free and SHBG-bound fractions and breast cancer risk were similar in the ER-positive, ER-negative, and ER-unknown groups. These data suggest that in postmenopausal women, the association of endogenous estrogens with breast cancer risk is independent of the ER status of the tumor. This result is more compatible with the hypothesis of a progression from ER-positive to ER negative tumors than with the hypothesis that ER status identifies two distinct types of breast cancer
— id: 56859, year: 1995, vol: 4, page: 857, stat: Journal Article,

ENDOGENOUS ESTROGENS AND RISK OF BOAST CANCER BY ESTROGEN-RECEPTOR STATUS
ZELENIUCHJACQUOTTE, A; TONIOLO, P; LEVITZ, M; SHORE, R; KOENIG, K; BANERJEE, S; STRAX, P; PASTERNACK, B
1995 JUN 1 ;141(11):S15-S15, American journal of epidemiology
— id: 87280, year: 1995, vol: 141, page: S15, stat: Journal Article,

Induction of cytolytic antibodies to melanoma by immunization to a polyvalent melanoma antigen vaccine
Cui J; Chen D; Oratz R; Zeleniuch-Jacquotte A; Harris M; Roses D; Bystryn J-C
1994 ;3(4):175-182, Vaccine research
This study was conducted to examine whether immunization to a melanoma vaccine can induce antibodies that are functionally effective in killing melanoma cells. A group of 79 evaluable patients with surgically resected AJCC stage III melanoma were immunized every 3 weeks to a polyvalent melanoma antigen vaccine (40 mug/immunization). Cytolytic antibodies to melanoma cells, assayed by europium-based complement-dependent cytolysis before vaccine treatment and 1 week following the fourth immunization, were detected in 7 patients (9%) before vaccine treatment but in none of 17 control individuals. Vaccine treatment induced or increased the level of these antibodies in 37 patients (47%; p = 0.0001). Vaccine-induced cytolytic antibodies were predominantly directed to melanoma cells. There was no correlation between the induction of these antibodies and improved clinical outcome. These results indicate that melanoma vaccine treatment can induce antibodies that have the functional ability to kill melanoma cells in vitro but suggest that the induction of such cytolytic antibodies is not associated with a delay in the progression of melanoma
— id: 25185, year: 1994, vol: 3, page: 175, stat: Journal Article,

EFFECT OF ASPIRIN ON RISK OF STROKE OR DEATH IN WOMEN WHO HAVE SUFFERED CEREBRAL-ISCHEMIA
JONAS, S; ZELENIUCHJACQUOTTE, A
1994 MAY-JUN ;4(3):157-162, Cerebrovascular diseases
A meta-analysis was performed on the results of randomized placebo-controlled clinical trials of the effect of aspirin on occurrence of stroke or death in people who previously had suffered cerebral ischemia. The data from 8 such trials (a total of 5,287 subjects) shows a beneficial effect overall: the odds ratio is 0.82; 95% confidence interval (CI) 0.72-0.94; p < 0.01. When men are analyzed separately (n = 3,691) the benefit of aspirin is also statistically significant: odds ratio = 0.82; 95% CI = 0.70-0.96; p = 0.01. The analysis for women (n = 1,596) shows a similar odds ratio (0.82), but this result does not reach statistical significance in the smaller female cohort (95% CI = 0.63-1.05; p 0.12). On the basis of these data and in the absence of a valid biological hypothesis for an effect in women different from that in men, we consider justified the recommendation that aspirin be used to reduce the rate of occurrence of stroke or death in women as well as in men who have suffered cerebral ischemia
— id: 52427, year: 1994, vol: 4, page: 157, stat: Journal Article,

PROSPECTIVE-STUDY OF SERUM PROLACTIN AND BREAST-CANCER
KOENIG, K; TONIOLO, P; BRUNING, P; BONFRER, J; SHORE, R; ZELENIUCHJACQUOTTE, A; PASTERNACK, B
1993 OCT 15 ;138(8):601-601, American journal of epidemiology
— id: 52160, year: 1993, vol: 138, page: 601, stat: Journal Article,

Contralateral ovary in unilateral ovarian carcinoma: a search for preneoplastic lesions
Mittal KR; Zeleniuch-Jacquotte A; Cooper JL; Demopoulos RI
1993 Jan;12(1):59-63, International journal of gynecological pathology
Contralateral ovaries from patients with unilateral ovarian carcinoma were examined and compared to ovaries from age-matched control patients without ovarian carcinoma. The number of inclusion cysts were increased in ovaries from patients with ovarian carcinoma compared to the controls (p < 0.01). In addition, inclusions from cases with ovarian carcinoma showed serous differentiation more frequently than the controls (p < 0.01; odds ratio = 10.0; 95% confidence interval = 1.2-78.1). An age-related increase in the number of inclusion cysts was seen in the study group but not in the control group. These findings support a role of surface inclusion cysts in the genesis of ovarian carcinoma
— id: 29008, year: 1993, vol: 12, page: 59, stat: Journal Article,

PROSPECTIVE-STUDY OF ENDOGENOUS ESTROGENS AND BREAST-CANCER
TONIOLO, P; LEVITZ, M; JACQUOTTE, A; KOENIG, K; SHORE, R; PASTERNACK, B
1993 OCT 15 ;138(8):601-601, American journal of epidemiology
— id: 52159, year: 1993, vol: 138, page: 601, stat: Journal Article,

HLA-B35 is associated with accelerated progression to AIDS
Itescu S; Mathur-Wagh U; Skovron ML; Brancato LJ; Marmor M; Zeleniuch-Jacquotte A; Winchester R
1992 ;5(1):37-45, Journal of acquired immune deficiency syndrome
To investigate the influence of HLA specificities on the rate of progression and outcome of human immunodeficiency virus (HIV) infection, we performed (a) a case-control study in 1989-1990 of HIV-seropositive individuals stratified by both risk behavior and ethnic background, (b) a longitudinal cohort study of HIV-infected male homosexuals enrolled in 1981-1982, and (c) an analysis of individuals with a diffuse infiltrative CD8 lymphocytosis syndrome. In the case-control study, there was a significantly higher frequency of HLA-B35 among intravenous drug users, but not homosexuals, who developed illnesses meeting the case definition for AIDS compared with asymptomatic HIV-positive controls, regardless of ethnic status. In the longitudinal study, HLA-B35-positive homosexuals had a significantly increased rate of progression to AIDS and decreased survival over a 7-year period compared with those without this specificity. Finally, there was a significantly decreased frequency of HLA-B35 in individuals with the diffuse infiltrative lymphocytosis syndrome, a clinically and genetically distinctive disorder occurring in HIV infection in which a low rate of progression to opportunistic infections was found. The high rate of salivary and lacrimal gland lymphoma in this group suggests that there is dissociation between the presence of HLA-B35 and the development of particular AIDS-defining conditions. We conclude that HLA-B35 is a risk factor for more rapid progression to AIDS, particularly opportunistic infections and Kaposi's sarcoma, operating in groups with high rates of newly acquired HIV infections such as New York City male homosexuals in 1981-1982, and intravenous drug users in 1989-1990.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 9103, year: 1992, vol: 5, page: 37, stat: Journal Article,

ICRF-187 permits longer treatment with doxorubicin in women with breast cancer [published erratum appears in J Clin Oncol 1992 May;10(5):867]
Speyer JL; Green MD; Zeleniuch-Jacquotte A; Wernz JC; Rey M; Sanger J; Kramer E; Ferrans V; Hochster H; Meyers M; et al
1992 Jan;10(1):117-127, Journal of clinical oncology
PURPOSE: To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS: Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS: We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION: By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety
— id: 13730, year: 1992, vol: 10, page: 117, stat: Journal Article,

Consolidation with intraperitoneal cisplatin in first-line therapy of advanced ovarian cancer
Beller U; Speyer J; Colombo N; Sorich J; Wernz J; Hochster H; Zeleniuch-Jacquotte A; Porges R; Beckman EM
1991 May;9(5):809-817, Journal of clinical oncology
Seventy-five patients with advanced epithelial ovarian cancer were treated with a combined modality regimen of systemic, induction chemotherapy followed by intraperitoneal therapy (IPT). All patients underwent initial surgery for staging and/or cytoreduction followed by cisplatin 20 mg/m2 intravenously (IV) for 5 days and cyclophosphamide 600 mg/m2 on day 4 every 3 to 4 weeks for two to four cycles. Patients were then evaluated for IPT and, if eligible, had an intraperitoneal (IP) catheter placed. IPT consisted of cisplatin 60 mg/m2 in 2 L on day 1 and IV cyclophosphamide 600 mg/m2 on day 2 every 3 weeks for three to six cycles. Patients who demonstrated a clinical complete response (CCR) were then referred for second-look laparotomy (SLL). Of 71 patients who completed the induction phase, 53 (75%) were eligible for IPT, and 49 patients entered the therapy phase. Toxicity of the combined modality approach was acceptable and did not differ from our previous experience using the same drugs systemically. Thirty-two of the 49 patients who completed IPT achieved a CCR, which was confirmed by SLL in 20 patients. Twenty recurrences were documented in the 32 CCR patients, 13 occurred in patients after SLL. Projected median survival of all patients is 38 months. Median survival correlated with amount of residual disease following initial surgery (23 months for bulky v 45 months for minimal residual; P less than .001) and with performance status ([PS]; 24 months for PS 2, 3 v greater than 46 months for PS O; P less than .001). Patients who presented with bulky tumors were less likely to reach the consolidation IPT phase. Incorporation of IP cisplatin into the first-line regimen for treatment of ovarian cancer does not appear to have major impact on the survival of all treated patients when compared with our historical control series. Combined IV and IPT cisplatin and cyclophosphamide is feasible with acceptable toxicity. Its impact on response and survival may be limited to only 'good-prognosis' patients
— id: 14031, year: 1991, vol: 9, page: 809, stat: Journal Article,

A prospective randomized trial of ICRF-187 for prevention of cumulative doxorubicin-induced cardiac toxicity in women with breast cancer
Speyer JL; Green MD; Sanger J; Zeleniuch-Jacquotte A; Kramer E; Rey M; Wernz JC; Blum RH; Hochester H; Meyers M; et al
1990 Sep;17(2-3):161-163, Cancer treatment reviews
— id: 15688, year: 1990, vol: 17, page: 161, stat: Journal Article,

[Adjuvant chemotherapy of colorectal cancer: what can be learned from meta-analysis?]
Buyse M; Zeleniuch-Jacquotte A; Chalmers TC
1989 ;76(9):1021-1028, Bulletin du cancer
— id: 34755, year: 1989, vol: 76, page: 1021, stat: Journal Article,

The potential role of nutritional factors in the induction of immunologic abnormalities in HIV-positive homosexual men
Moseson M; Zeleniuch-Jacquotte A; Belsito DV; Shore RE; Marmor M; Pasternack B
1989 ;2(3):235-247, Journal of acquired immune deficiency syndrome
The literature is briefly summarized as to how several nutrients affect immune function, susceptibility to infection, and cancer susceptibility or progression. Nutritional deficiencies can impair immunity and so influence susceptibility to infectious agents, including ones that are common and relatively virulent in acquired immune deficiency syndrome (AIDS) patients. A variety of nutrients affect several of the immune functions that are defective in human immunodeficiency virus (HIV)-infected individuals. For example, beta-carotene increased the number of CD4+ cells; vitamin E decreased the number of CD8+ cells and increased the CD4+/CD8+ ratio; vitamin D decreased the CD4+/CD8+ ratio; and iron increased the number of peripheral lymphocytes in humans receiving supplementation. Furthermore, nutritional deficiencies can influence gastrointestinal function, while infectious diseases can influence nutrient requirements by altering the efficiency of absorption and the rate of tissue metabolism. Malnutrition, depressed serum zinc levels, and intestinal nutrient malabsorption have been found in AIDS patients. The above findings suggest that dietary manipulations might diminish the immune defects in HIV infection and enhance resistance to opportunistic infections. However, dietary alterations in immune defects are generally not well quantified and may be small relative to the magnitude of the defects observed in AIDS patients. Because conflicting or adverse effects have been reported for some nutrients, recommendations for dietary supplementation in HIV-infected individuals are premature and possibly hazardous. Further studies are much needed to relate dietary nutrient intakes to clinical outcomes
— id: 9114, year: 1989, vol: 2, page: 235, stat: Journal Article,

Adjuvant therapy of colorectal cancer. Why we still don't know
Buyse M; Zeleniuch-Jacquotte A; Chalmers TC
1988 Jun 24;259(24):3571-3578, JAMA
All randomized controlled trials of adjuvant therapy of colorectal cancer, published up to December 1986 in English, were reviewed. Eight trials compared radiotherapy groups with control groups in rectal cancer (3062 patients), and 17 trials compared chemotherapy groups with control groups in colorectal cancer (6791 patients). The results of trials testing radiotherapy or chemotherapy were combined. Fluorouracil-containing regimens resulted in a small benefit of therapy in terms of overall survival, with a mortality odds ratio of 0.83 in favor of therapy (95% confidence interval, 0.70 to 0.98). All other combinations of trials failed to show statistically significant differences between treated and control patients, even though the odds of death tended to be slightly lower in treated patients, especially those with rectal tumors. Some overall survival benefit from adjuvant therapy cannot be excluded, but it is likely small. Such small benefit, if real, would be far from negligible in a common case of malignancy with long survival expectancy. Trials much larger than those published up to now are needed
— id: 34757, year: 1988, vol: 259, page: 3571, stat: Journal Article,

Topical mechlorethamine therapy for early stage mycosis fungoides
Ramsay DL; Halperin PS; Zeleniuch-Jacquotte A
1988 Oct;19(4):684-691, Journal of the American Academy of Dermatology
One hundred seventeen patients with mycosis fungoides were treated with topical mechlorethamine hydrochloride. The probability of achieving a clinically apparent remission within 2 years of therapy was 75.8% in patients with stage I disease, 44.6% in patients with stage II disease, and 48.6% in patients with stage III disease. Patients with stage I disease achieved complete remission sooner (median, 6.5 months) than patients with stage II (median, 41.1 months) or stage III (median, 39.1 months) disease. The median time to relapse was 44.5 months. Sixty-eight patients (58.1%) developed a delayed hypersensitivity reaction, but only one patient had to discontinue therapy as a consequence. No appreciable differences were seen in the probability to achieve complete remission or time to complete remission as stratified by gender, substage, or the development of a delayed hypersensitivity reaction. Survival analysis revealed that the probability of surviving at 5 years was 89% for all patients. These findings compare favorably with results with other treatments for early stage mycosis fungoides
— id: 10943, year: 1988, vol: 19, page: 684, stat: Journal Article,

Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer
Speyer JL; Green MD; Kramer E; Rey M; Sanger J; Ward C; Dubin N; Ferrans V; Stecy P; Zeleniuch-Jacquotte A; et al.
1988 Sep 22;319(12):745-752, New England journal of medicine
Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC + ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference). Eleven patients on the FDC + ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC + ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions
— id: 34756, year: 1988, vol: 319, page: 745, stat: Journal Article,