Citations

AbstractCalcium channel blockers block calcium signal-mediated apoptosis. It is hypothesized that the use of these drugs may be associated with the development of cancer. This study investigated the association between daily use of calcium channel blockers and prostate cancer in a community-based cohort of men who participated in a longitudinal study of lower urinary tract symptoms. Study subjects were men ages 40 to 79 years by January 1, 1990, and were randomly selected from Olmsted County in Minnesota. At baseline, participants underwent an interview to determine all medications taken on a daily basis, including calcium channel blockers and to elicit a family history of prostate cancer. During follow-up, all men with a histological diagnosis of prostate cancer were identified through patient self-report and by a review of the complete medical record. Over 12,668 person years of follow-up, 15 (6.8%) of 220 calcium channel blocker users and 120 (10.5%) of 1142 nonusers developed prostate cancer (P = 0.09; odds ratio, 0.62; 95% confidence interval, 0.36–1.10). With adjustment for age and family history of prostate cancer, the risk (odds ratio, 95% confidence interval) of prostate cancer was 0.55 (0.31–0.97) in calcium channel blocker users compared with nonusers. In analyses stratified by family history of prostate cancer, the risk of prostate cancer was 0.45 (0.23–0.88) in men without a family history and 2.64 (0.82–8.47) in men with a family history of prostate cancer (P = 0.006). These findings suggest an association between prostate cancer and daily use of calcium channel blockers that varies by family history of prostate cancer.

Abstract Objective: Predictors of quality of life (QOL) in patients with metastatic colorectal cancer are lacking. The insulin-like growth factor (IGF) family of proteins is associated with QOL in noncancer populations. We sought to study whether these proteins are associated with QOL in patients with colorectal cancer. Method: We used a cohort of 526 patients with metastatic colorectal cancer treated with combination chemotherapy. Plasma samples of IGF-I, IGF-II, IGF binding protein-3, and C-peptide were collected before initiation of chemotherapy. QOL was measured by the uniscale instrument and the Symptom Distress Scale at baseline and throughout treatment. Results: Baseline plasma levels of IGF-I and IGF-II before initiation of chemotherapy were significantly associated with several important baseline QOL measures in patients with metastatic colorectal cancer. Patients with lower levels of IGF-I reported increased distress with regard to appearance, appetite, cough, and nausea intensity after adjustment for potential confounders. Similarly, decreased levels of IGF-II were predictive of worse quality related to appearance, appetite, fatigue, nausea frequency and intensity, pain frequency, and composite Symptom Distress Scale score. IGF binding protein-3 and C-peptide were not predictive of baseline QOL. Baseline biomarkers were not associated with subsequent changes in QOL during treatment. Higher body mass index was significantly associated with superior baseline QOL in several areas; nonetheless, the association of IGF-I and IGF-II with baseline QOL measures remained significant even after controlling for baseline body mass index. Conclusion: Baseline plasma IGF-I and IGF-II are significantly associated with symptom distress. Whether this association is simply reflective of patient nutritional status and/or disease burden or represents an independent biological effect of IGFs on QOL remains uncertain. Nonetheless, these data suggest that molecular biomarkers may be useful predictors of QOL in cancer patients.

Abstract Background: Adult mammographic percent density is one of the strongest known risk factors for breast cancer. In utero exposure to high levels of endogenous estrogens (or other pregnancy hormones) has been hypothesized to increase breast cancer risk in later life. We examined the hypothesis that those factors associated with higher levels of estrogen during pregnancy or shortly after birth are associated with higher mammographic breast density in adulthood. Methods: We analyzed data on 1,893 women from 360 families in the Minnesota Breast Cancer Family Study who had screening mammograms, risk factor data, over age 40, and no history of breast cancer. Prenatal and perinatal risk factor data were ascertained using a mailed questionnaire. Mammographic percent density and dense area were estimated from the mediolateral oblique view using Cumulus, a computer-assisted thresholding program. Linear mixed effects models incorporating familial correlation were used to assess the association of risk factors with percent density, adjusting for age, weight, and other breast cancer risk factors, all at time of mammography. Results: The mean age at mammography was 60.4 years (range, 40-91 years), and 76% were postmenopausal. Among postmenopausal women, there was a positive association of birthweight with percent density (P trend <0.01), with an adjusted mean percent density of 17.1% for <2.95 kg versus 21.0% for ≥3.75 kg. There were suggestive positive associations with gestational age (mean percent density of 16.7% for preterm birth, 20.2% for term birth, and 23.0% for late birth; P trend = 0.07), maternal eclampsia/preeclampsia (mean percent density of 19.9% for no and 14.6% for yes; P = 0.16), and being breast-fed as an infant (mean percent density of 18.2% for never and 20.0% for ever; P = 0.08). There was no association of percent density with maternal age, birth order, maternal use of alcohol or cigarettes, or neonatal jaundice. Except for being breast-fed, these associations showed similar but attenuated trends among premenopausal women, although none were statistically significant. The results for dense area paralleled the percent density results. The associations of gestational age and being breast-fed as an infant with percent density attenuated when included in the same model as birthweight. Conclusions: Birthweight was positively associated with mammographic breast density and dense area among postmenopausal women and more weakly among premenopausal women, suggesting that it may be a marker of this early life exposure. These results offer some support to the hypothesis that pregnancy estrogens or other pregnancy changes may play a role in breast cancer etiology, and suggest that these factors may act in part through long-term effects on breast density.

Abstract Context: Environmental exposure to herbicides has been hypothesized to contribute to the long-term increase in non-Hodgkin lymphoma (NHL). Objective: To estimate the effects of residential herbicide exposure on NHL risk. Design: Population-based case-control study. Setting: Iowa and metropolitan Detroit, Los Angeles, and Seattle, 1998 to 2000. Participants: NHL patients ages 20 to 74 years and unaffected residents identified by random digit dialing and Medicare eligibility files. Main Outcome Measures: Computer-assisted personal interviews (1,321 cases, 1,057 controls) elicited data on herbicide use at each home occupied since 1970. Levels of 2,4-dichlorophenoxy-acetic acid and dicamba were measured in dust taken from used vacuum cleaner bags in the current home (679 cases, 510 controls who had owned at least half of their carpets for ≥5 years). Results: Herbicide use on the lawn or garden was similar among cases and controls (adjusted relative risk, 1.02; 95% confidence interval, 0.84-1.23). Estimated risk did not increase with greater duration, frequency, or total number of applications of herbicides to the lawn, the garden, or to both combined. Risk was not elevated for respondents who applied the herbicides themselves and not for those exposed during the 1970s, 1980s, or 1990s. We detected 2,4-dichlorophenoxy-acetic acid equally often in homes of cases and controls (78%). We found dicamba in homes of 15% of cases and 20% of controls. We also found no elevation in risk among the respondents who had the highest dust levels and highest self-reported exposures. We found no consistent patterns for specific histologies. Conclusions: We found no detectable excess associated with residential exposures. Residential herbicide exposures are unlikely to explain the long-term increase in NHL.

Abstract Background: The International Lymphoma Epidemiology Consortium (InterLymph) provides an opportunity to analyze the relationship between cigarette smoking and non-Hodgkin lymphoma with sufficient statistical power to consider non-Hodgkin lymphoma subtype. The results from previous studies of this relationship have been inconsistent, likely due to the small sample sizes that arose from stratification by disease subtype. To clarify the role of cigarette smoking in the etiology of non-Hodgkin lymphoma, we conducted a pooled analysis of original patient data from nine case-control studies of non-Hodgkin lymphoma conducted in the United States, Europe, and Australia. Methods: Original data were obtained from each study and uniformly coded. Risk estimates from fixed-effects and two-stage random-effects models were compared to determine the impact of interstudy heterogeneity. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived from unconditional logistic regression models, controlling for study center, age, sex, and race. Results: In our pooled study population of 6,594 cases and 8,892 controls, smoking was associated with slightly increased risk estimates (OR, 1.07; 95% CI, 1.00-1.15). Stratification by non-Hodgkin lymphoma subtype revealed that the most consistent association between cigarette smoking and non-Hodgkin lymphoma was observed among follicular lymphomas (n = 1452). Compared with nonsmokers, current smokers had a higher OR for follicular lymphoma (1.31; 95% CI, 1.12-1.52) than former smokers (1.06; 95% CI, 0.93-1.22). Current heavy smoking (≥36 pack-years) was associated with a 45% increased OR for follicular lymphoma (1.45; 95% CI, 1.15-1.82) compared with nonsmokers. Conclusions: Cigarette smoking may increase the risk of developing follicular lymphoma but does not seem to affect risk of the other non-Hodgkin lymphoma subtypes we examined. Future research is needed to determine the biological mechanism responsible for our subtype-specific results.

AbstractMost esophageal adenocarcinomas arise within Barrett's esophagus but the cause of this increasingly prevalent condition remains unknown. Early detection improves survival and discriminant screening markers for Barrett's esophagus and cancer are needed. This study was designed to explore the natural history of eyes absent 4 (EYA4) gene methylation in the neoplastic progression of Barrett's esophagus and to evaluate methylated EYA4 as a candidate marker. Aberrant promoter methylation of EYA4 was studied by methylation-specific PCR using bisulfite-treated DNA from esophageal adenocarcinomas, Barrett's esophagus, and normal epithelia, and then confirmed by sequencing. Eight cancer cell lines were treated with the demethylation agent 5-aza-2′-deoxycytidine, and EYA4 mRNA expression with and without treatment was quantified by real-time reverse-transcription PCR. EYA4 hypermethylation was detected in 83% (33 of 40) of esophageal adenocarcinomas and 77% (27 of 35) of Barrett's tissues, but only in 3% (2 of 58) of normal esophageal and gastric mucosa samples (P < 0.001). The unmethylated cancer cell lines had much higher EYA4 mRNA expression than the methylated cancer cell lines. Demethylation caused by 5-aza-2′-deoxycytidine increased the mRNA expression level by a median of 3.2-fold in methylated cells, but its effect on unmethylated cells was negligible. Results indicate that aberrant promoter methylation of EYA4 is very common during tumorigenesis in Barrett's esophagus, occurs in early metaplasia, seems to be an important mechanism of down-regulating EYA4 expression, and represents an intriguing candidate marker for Barrett's metaplasia and esophageal cancer.

Abstract Obesity and adult weight gain are well-established risk factors for postmenopausal breast cancer. Although there are a few studies demonstrating the contribution of adult weight gain to breast cancer risk, whether weight gain during a critical time period is specifically associated with risk, or whether subsequent weight loss among women who have gained weight will reduce the excess risk, is not firmly established. We investigated the association of changes in weight (loss or gain in excess of 5% of body weight) using two risk factor models: (a) age 18 to 30 years and age 30 years to menopause and (b) age 30 years to menopause and after the menopause to the baseline study in 1986 on risk of postmenopausal breast cancer in a prospective cohort of 33,660 postmenopausal women in Iowa. Over 15 years of follow-up, 1,987 cases of breast cancer occurred. Data were analyzed using proportional hazards regression models adjusted for established breast cancer risk factors. The most frequently observed pattern of body weight over time was a consistent increase; these women were observed to have the highest rates of breast cancer and served as the reference category for all comparisons. The lowest-risk groups were (a) women who maintained or lost weight from age 18 to 30 years and then lost weight from age 30 years to menopause [risk ratio (RR), 0.36; 95% confidence interval (95% CI), 0.22-0.60] and (b) women who maintained or lost weight from age 30 years to menopause and then lost weight after the menopause (RR, 0.48; 95% CI, 0.22-0.65). Women who gained weight from age 30 years to menopause but then lost weight after the menopause experienced risk reductions (RR, 0.77; 95% CI, 0.64-0.92) although perhaps slightly smaller in magnitude than women who maintained their weight in both time intervals (RR, 0.63; 95% CI, 0.55-0.73). Women who gained weight from age 18 to 30 years and then lost weight from age 30 years to menopause had comparable risk reductions (RR, 0.61; 95% CI, 0.46-0.8) with women who maintained their weight in both time intervals (RR, 0.73; 95% CI, 0.64-0.84). Women who gained weight during the period from age 30 years to menopause but who had stable weight after menopause had rates similar to the reference group. These data suggest prevention of weight gain between age 18 years and menopause or weight loss and maintenance during these years reduces risk of postmenopausal breast cancer.

Abstract A possible role for SV40, a macaque polyomavirus, in non-Hodgkin lymphoma (NHL) in humans was raised recently by the reported detection of SV40 DNA in tumor tissue. Animals with SV40-induced tumors frequently produce high-level antibodies against T antigen, the SV40 oncoprotein. In this study, we assessed whether SV40 T antibody measured in humans supported a relationship between SV40 and NHL. Subjects were sampled from a U.S. population-based case-control study of NHL, according to presence of antibodies against capsids of SV40 and BK, a related human polyomavirus (n = 85 cases, n = 95 controls). T antibody was measured by enzyme immunoassay. We also evaluated serum specimens from SV40-infected and SV40-uninfected macaques (n = 19 and n = 8, respectively), SV40-uninfected hamsters (n = 5), and hamsters with SV40-induced tumors (n = 10). Hamsters with SV40-induced tumors all produced robust SV40 T antibody [median absorbance, 0.99), whereas SV40-uninfected hamsters and macaques had much lower levels (median absorbance, 0.05 and 0.04, respectively). NHL cases, controls, and SV40-infected macaques resembled these latter two groups, generally showing only low-level T antibody (median absorbance, 0.03, 0.04, and 0.04, respectively). Overall, only five cases (6%) and five controls (5%) had T antibody responses classified as seropositive (odds ratio, 1.2; 95% confidence interval, 0.3-4.6). Interestingly, all 10 humans with T antibody responses also showed antibody responses to BK capsid. We found no association between the presence of T antibody and NHL, arguing against SV40 as a cause of NHL. Infrequent and low-level T antibody responses among humans could represent cross-reactivity to BK virus T antigen.

Abstract Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecologic cancers in the United States. Because women who are diagnosed with early stage disease have a better prognosis than women diagnosed with late stage disease, early detection represents a potentially practical approach to reduce the mortality associated with EOC. Unfortunately, no single screening test has proven to be effective for this purpose, and a valid and feasible screening program to detect early stage EOC in the general population has not yet been devised. Consequently, research has focused on coupling two or more screening modalities to improve program validity and feasibility. Serum cancer antigen 125 (CA125) and a soluble isoform of the epidermal growth factor receptor (p110 sEGFR) have been studied individually as biomarkers of ovarian cancer. In this study, we compare serum CA125 levels and sEGFR concentrations in women with EOC to women with benign gynecologic conditions of ovarian and non-ovarian origin. We show that serum sEGFR concentrations are lower in patients with EOC than in women with benign gynecologic conditions, whereas serum CA125 levels are higher in patients to EOC compared with women with benign gynecologic conditions. These data also reveal that age and serum sEGFR concentrations modify the association between CA125 levels and EOC versus benign gynecologic disease. Hence, age- and sEGFR-dependent CA125 cutoff thresholds improve the ability of CA125 to discern EOC patients from women with benign ovarian tumors and non-ovarian gynecologic conditions. Our analyses show that parallel testing with fixed sEGFR and CA125 cutoff thresholds optimizes sensitivity to detect EOC, whereas serial testing with age- and sEGFR-dependent CA125 cutoff thresholds optimizes test specificity, and overall accuracy to discern patients with EOC from women with benign ovarian and non-ovarian gynecologic conditions. The combined use of serologic sEGFR and CA125, thus, has improved utility for screening and diagnosing EOC, which may increase the positive predictive value of a multimodal screening program that incorporates these biomarkers to detect and subsequently differentiate benign from malignant ovarian tumors.

AbstractFolate receptor α (FRα) expression in epithelial ovarian cancer may be related to folate intake. We examined this association using multivitamin intake, a proxy for folic acid, and assessed whether the relation was modified by alcohol intake, a folate agonist. Cases (n = 148) with suspected epithelial ovarian cancer, of ages ≥20 years, were seen at Mayo Clinic, Minnesota, between 2000 and 2004; those with tumor specimens (n = 108) were included in analyses. Outpatient controls (n = 148) without cancer and with at least one ovary intact were matched to cases by age (within 5 years) and state of residence. Multivitamin (≥4 pills/wk) and weekly alcohol (≥5 drinks) intakes were assessed. Tumor specimens were analyzed immunohistochemically for FRα. Multivariable rate ratios (RR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression. In case-control analysis, the RRs of multivitamin intake with absent/weak/moderate and strong-expressing FRα tumors were 0.30 (95% CI, 0.12-0.70) and 0.47 (95% CI, 0.24-0.91), respectively. For alcohol, the associations were 0.84 (95% CI, 0.24-2.86) and 1.65 (95% CI, 0.69-3.93), respectively. In case-case analysis, the RR associated with developing strong-expressing versus other FRα tumors was 3.13 (95% CI, 1.14-8.65) for multivitamins and 1.58 (95% CI, 0.45-5.60) for alcohol. The data did not support evidence for an interaction between multivitamin and alcohol intake with risk of developing a strong-expressing FRα tumor. The association of multivitamin intake with ovarian cancer may depend on FRα expression level.