Fasting insulin and endogenous hormones in relation to premenopausal breast density (Canada).

PURPOSE: Mammographic breast density (BD) is associated with increased risk of breast cancer. This study asks which circulating metabolic and reproductive biomarkers are associated with BD, particularly dense breast area, in premenopausal women not taking exogenous hormones. METHODS: In a cross-sectional study, 299 premenopausal women aged 40-49 completed questionnaires, provided a fasting blood sample, had height, weight, percentage body fat, waist and hip measurements taken, and attended a screening mammogram. Multivariate linear regression was used to calculate adjusted means for percentage BD, absolute dense and non-dense area, across categories of covariates, adjusted for day of menstrual cycle, age, parity, body mass index, percentage body fat, and ethnicity. RESULTS: Fasting insulin levels were inversely associated, and insulin-like growth factor-binding protein 1 levels directly associated with percentage BD, but lost statistical significance after multivariate adjustment. Sex hormone-binding globulin levels were directly associated with percentage BD, still significant after multivariate adjustment (p = 0.03). A significant inverse dose-response association was observed between progesterone levels and dense area (p < 0.01). CONCLUSIONS: Breast density in premenopausal women seems unrelated or inversely related to insulin resistance, levels of insulin-like growth factor 1 and its binding proteins, and levels of sex steroids; therefore, the mechanism by which radiodensity on a mammogram is related to breast cancer risk remains unclear.

Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant melanoma: a preliminary study.

A number of epidemiologic studies have suggested that exposure to polychlorinated biphenyls (PCB) and other organochlorine compounds (OCC) increase risk of cutaneous malignant melanoma (CMM). However, these studies have generally had no biologic measure of OCC exposure, and have been unable to control for sun exposure, the major known environmental risk factor for this disease. This preliminary study examined the relationship between OCC residues in plasma and risk of CMM adjusting for sun sensitivity and sun exposure. A case-control study of 80 CMM patients and 310 control subjects was conducted. Lifetime sun exposure information, along with data on pigmentation variables and sun sensitivity data was collected, along with a blood sample. Cases and controls were assayed for plasma levels of 14 PCB congeners and 11 organochlorine pesticide residues using gas chromatography. Strong associations were seen between risk of CMM and plasma levels of non-dioxin-like PCBs (Adjusted OR = 7.02; 95% CI: 2.30-21.43 for highest quartile) and several PCB congeners, organochlorine pesticides or metabolites. These associations persisted after control for sun sensitivity and sun exposure. Results from this investigation require independent confirmation in larger studies. However, they suggest that environmental factors other than UV radiation may play a role in genesis of CMM, and indicate that it may be productive to search for further agents which might increase risk.

Oviductal glycoprotein (OVGP1, MUC9): a differentiation-based mucin present in serum of women with ovarian cancer.

INTRODUCTION: Epithelial ovarian carcinomas are highly lethal because most are detected at late stages. A previous immunohistochemical analysis showed that oviductal glycoprotein 1 (OVGP1), a secretory product of the oviductal epithelium under estrogen dominance, is produced predominantly by borderline and low-grade malignant epithelial ovarian tumors. In the present study, we investigated OVGP1 as a possible serum marker for the detection of ovarian cancer. METHODS: We generated a highly specific monoclonal antibody, clone 7E10, to human OVGP1. Using 7E10 and a polyclonal antibody, a sandwich enzyme-linked immunosorbent assay was developed to assay OVGP1 levels in 135 normal sera, and sera from 21 benign tumors, 12 borderline tumors, and 87 ovarian cancers (18, grade 1-2 serous; 44, grade 3 serous; 10, mucinous; 10, clear cell; and 5, endometrioid). RESULTS: Using a 95% confidence interval cutoff from the mean of normal postmenopausal sera, median OVGP1 levels were elevated in the sera from 75% of the women with borderline tumors and 80% of the women with mucinous, 60% with clear cell, 59% with grade 1 and 2 serous, 22% with grade 3 serous, and 0% with endometrioid carcinomas. By stage, OVGP1 levels were highest in the sera from the borderline tumors, stage I and II serous carcinomas, and mucinous carcinomas. OVGP1 levels varied independently of cancer antigen 125 (CA125). CONCLUSIONS: Increases in OVGP1 serum levels vary with ovarian tumor histotypes and stages. Being differentiation based, OVGP1 seems to detect a different spectrum of ovarian epithelial cancers than other markers and thus should be a useful adjunct for more accurate detection, particularly of early serous ovarian cancers and mucinous carcinomas, which tend to lack increased CA125.

Ultraviolet radiation.

The major source of ultraviolet radiation is solar radiation or sunlight. However, exposure to artificial sources particularly through tanning salons is becoming more important in terms of human health effects, as use of these facilities by young people, has increased. The International Agency for Research on Cancer has noted that there is sufficient evidence from studies in animals and in man to establish ultraviolet radiation as a human carcinogen. Skin cancer has been the most commonly studied cancer site with respect to UV radiation. The nature and timing of sun exposure appear to be important determinants of both the degree of risk and the type of skin cancer. Cutaneous malignant melanoma and basal cell cancer are much more strongly related to measures of intermittent ultraviolet exposure (particularly those of childhood or adolescence) than to measures of cumulative exposure. In contrast, squamous cell cancer is more strongly related to constant or cumulative sun exposure. Lip cancer is causally related to lifetime sun exposure. It has been estimated that solar ultraviolet radiation accounts for approximately 93 percent of skin cancers and about half of lip cancers. This translates to approximately 4,500 life-threatening cancers (cutaneous malignant melanoma) per year in Canada, as well as 65,000 less serious cancers (basal cell cancer, squamous cell cancer and lip cancer). Appropriate clothing use, care not to sunburn and judicious use of sunscreens could prevent at least half of these and save approximately 450 lives per year. In addition, physician and public education programs can significantly increase the proportion of melanomas diagnosed early. Lesions that have not yet penetrated deeply are associated with a mortality rate of less than five percent. Several recent studies suggest a possible inverse relationship between ultraviolet radiation exposure and risk of non-Hodgkin lymphoma, colon, breast and prostate cancer, and investigators have speculated that this might be due to the higher serum levels of vitamin D stimulated by high lifetime sun exposure. Further, studies conducted within cohorts using stored pre-diagnostic serum suggest that those with high levels of vitamin D have lower incidence rates of a number of malignancies, particularly colon cancer. However, since serum vitamin D levels can be raised through the use of supplements without increasing risk for skin lip and other known UV-related cancers, changes to health policy with regard to exposure are not merited at this point. Further research is needed in this area.

Assessment of selection bias in the Canadian case-control study of residential magnetic field exposure and childhood leukemia.

The authors evaluated the role of selection bias in the 1999 Canadian case-control study of residential magnetic field exposure and childhood leukemia. They included cases, participating controls, and first-choice nonparticipating controls in their analyses. Exposure was assessed by wire coding, a classification system based on the distribution line characteristics near homes. Although an imperfect measure of magnetic field exposure, wire coding is the only method applicable to nonparticipating subjects. First-choice nonparticipant controls tended to be of lower socioeconomic status than their replacements (non-first-choice participant controls), and lower socioeconomic status was related to higher wire code categories. The odds ratios for developing childhood leukemia in the highest exposure category were 1.6 (95% confidence interval: 1.0, 2.6) when the actual participating controls were used and 1.3 (95% confidence interval: 0.8, 2.1) when the first-choice ideal controls were used, regardless of their participation. Overall, the authors conclude that, although there is some evidence for control selection or participation bias in the Canadian study, it is unlikely to explain entirely the observed association between magnetic field exposure and childhood leukemia. Inherent problems in exposure assessment for nonparticipating subjects, however, limit the interpretations of these results, and the role of selection bias cannot entirely be dismissed on the basis of these results alone.

Facilitated "fast track" referral reduces time from abnormal screening mammogram to diagnosis.

BACKGROUND: The Screening Mammography Program of British Columbia (SMPBC) implemented voluntary, facilitated referral to diagnostic imaging ("Fast Track") after testing 5 interventions to reduce time from an abnormal screening mammogram to diagnosis. The purpose of this study was to compare time intervals for patients evaluated through the Fast Track process with patients who were not. METHODS: Data were extracted from the SMPBC database for women with abnormal screens conducted from January 1, 2003 to June 30, 2005 (N = 40,292). After exclusions, 39,607 screens were analyzed. Median and 90th percentile times were calculated from abnormal screen to diagnosis and for three subintervals: abnormal screen to notification, notification to first assessment, and first assessment to diagnosis. RESULTS: One third of abnormal screens were investigated through Fast Track imaging facilities. Overall, the median time from abnormal screen to diagnosis was 8 days faster for Fast Track compared with non-Fast Track. There was no clinically significant difference in time from abnormal screen to notification. The median time from notification to first assessment was 1.1 weeks (Fast Track) compared with 2.4 weeks (non-Fast Track), a reduction of 9 days or 54% in the interval targeted by the Fast Track strategy. The time interval distribution from first assessment to diagnosis was significantly different only for those having a core biopsy (average 3 days faster for Fast Track). INTERPRETATION: Facilitated referral to diagnostic imaging reduces average time from notification of abnormal screen to first assessment by more than half. Additional strategies are needed to address diagnostic investigation beyond initial imaging procedures.

Twenty-four-hour light exposure and melatonin levels among shift workers.

OBJECTIVES: We sought to measure melatonin levels and 24-hour light intensity exposure in health care workers over a 7-day period in natural occupational and residential settings. METHODS: Five office workers and 17 nurses working either days or rotating night and day shifts wore a device to record light intensity exposure for one or two 7-day periods, completed a questionnaire, and provided three saliva samples for melatonin. RESULTS: Rotating shift workers had irregular light exposure patterns and abnormal melatonin levels compared with those working days. In addition to lower-than-normal melatonin levels during sleep periods, rotating shift workers exhibited higher-than-normal melatonin levels on arising and during work. Self-reported years of shift work were correlated with measured melatonin and light. CONCLUSIONS: Rotating shift work is supported as a surrogate for exposure to light-at-night and circadian disruption.

Insulin, macronutrient intake, and physical activity: are potential indicators of insulin resistance associated with mortality from breast cancer?

High levels of insulin have been associated with increased risk of breast cancer, and poorer survival after diagnosis. Data and sera were collected from 603 breast cancer patients, including information on diet and physical activity, medical history, family history, demographic, and reproductive risk factors. These data were analyzed to test the hypothesis that excess insulin and related factors are directly related to mortality after a diagnosis of breast cancer. The cohort was recruited from breast cancer patients treated at the British Columbia Cancer Agency between July 1991 and December 1992. Questionnaire and medical record data were collected at enrollment and outcomes were ascertained by linkage to the BC Cancer Registry after 10 years of follow-up. The primary outcome of interest was breast cancer-specific mortality (n = 112). Lifestyle data were analyzed using Cox proportional hazards regression models to relate risk factors to outcomes, controlling for potential confounders, such as age and stage at diagnosis. Data for biological variables were analyzed as a nested case-control study due to limited serum volumes, with at least one survivor from the same cohort as a control for each breast cancer death, matched on stage and length of follow-up. High levels of insulin were associated with poorer survival for postmenopausal women [odds ratio, 1.9; 95% confidence interval (CI), 0.7-6.6, comparing highest to lowest tertile, P trend = 0.10], while high dietary fat intake was associated with poorer survival for premenopausal women (relative risk, 4.8; 95% CI, 1.3-18.1, comparing highest to lowest quartile). Higher dietary protein intake was associated with better survival for all women (relative risk, 0.4; 95% CI, 0.2-0.8, comparing highest to lowest quartile).

Carbohydrates and colorectal cancer risk among Chinese in North America.

Previous studies have analyzed total carbohydrate as a dietary risk factor for colorectal cancer (CRC) but obtained conflicting results, perhaps attributable in part to the embedded potential confounder, fiber. The aim of this study was to analyze the nonfiber ("effective") carbohydrate component (eCarb) separately and to test the hypothesis that effective carbohydrate consumption is directly related to CRC risk. The data (473 cases and 1192 controls) were from a large, multicenter, case-control study of Chinese residing in North America. Multivariate logistic regression was used to perform a secondary analysis controlling for age; sex; consumption of fat, fiber, calcium, and total kilocalories; body mass (Quetelet's) index; family history; education; and years in North America. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate risk among subgroups by sex and cancer site. A statistically significant positive association was observed between eCarb consumption and risk of CRC in both men (OR, 1.7 comparing highest with lowest tertile of eCarb consumption; 95% CI, 1.1-2.7) and women (OR, 2.7; 95% CI, 1.5-4.8). As expected, the ORs for total carbohydrate were somewhat lower than those for effective carbohydrate, but the differences were not large. A sex difference in risk by colorectal subsite was observed, with risk concentrated in the right colon for women (OR, 6.5; 95% CI, 2.4-18.4) and in the rectum for men (OR, 2.4; 95% CI, 1.2-4.8). These data indicate that increased eCarb and total carbohydrate consumption are both associated with increased risk of CRC in both sexes, and that among women, relative risk appears greatest for the right colon, whereas among men, relative risk appears greatest for the rectum.

Breast cancer incidence and neighbourhood income.

BACKGROUND: In developed countries, women of higher socioeconomic status often have higher breast cancer incidence rates, compared with women of lower socioeconomic status. DATA AND METHODS: Data were extracted from the Canadian Cancer Registry for the 229,955 cases of adult female invasive breast cancer diagnosed from 1992 through 2004. Postal code at diagnosis was used to determine neighbourhood income quintile. Breast cancer incidence was examined by year, region, age and neighbourhood income quintile. Census data for 1991 on children ever born and British Columbia data for 2006 on first-time attendance at mammography screening were analyzed by neighbourhood income quintile. RESULTS: Residence in the lowest as opposed to the highest neighbourhood income quintile was associated with a 15% lower risk of being diagnosed with breast cancer. Higher income levels were associated with lower parity in 1991 and a higher prevalence of first-time screening mammography in British Columbia in 2006. INTERPRETATION: Canadian data support an association between the diagnosis of invasive breast cancer and neighbourhood income quintile. Parity and mammography screening may account for some differences in incidence.

Quality, quantity and harmony: the DataSHaPER approach to integrating data across bioclinical studies.

BACKGROUND: Vast sample sizes are often essential in the quest to disentangle the complex interplay of the genetic, lifestyle, environmental and social factors that determine the aetiology and progression of chronic diseases. The pooling of information between studies is therefore of central importance to contemporary bioscience. However, there are many technical, ethico-legal and scientific challenges to be overcome if an effective, valid, pooled analysis is to be achieved. Perhaps most critically, any data that are to be analysed in this way must be adequately 'harmonized'. This implies that the collection and recording of information and data must be done in a manner that is sufficiently similar in the different studies to allow valid synthesis to take place. METHODS: This conceptual article describes the origins, purpose and scientific foundations of the DataSHaPER (DataSchema and Harmonization Platform for Epidemiological Research; http://www.datashaper.org), which has been created by a multidisciplinary consortium of experts that was pulled together and coordinated by three international organizations: P³G (Public Population Project in Genomics), PHOEBE (Promoting Harmonization of Epidemiological Biobanks in Europe) and CPT (Canadian Partnership for Tomorrow Project). RESULTS: The DataSHaPER provides a flexible, structured approach to the harmonization and pooling of information between studies. Its two primary components, the 'DataSchema' and 'Harmonization Platforms', together support the preparation of effective data-collection protocols and provide a central reference to facilitate harmonization. The DataSHaPER supports both 'prospective' and 'retrospective' harmonization. CONCLUSION: It is hoped that this article will encourage readers to investigate the project further: the more the research groups and studies are actively involved, the more effective the DataSHaPER programme will ultimately be.

Light intensity exposure, sleep duration, physical activity, and biomarkers of melatonin among rotating shift nurses.

Long-term, night shiftwork has been identified as a potential carcinogenic risk factor. It is hypothesized that increased light at night exposure during shiftwork reduces melatonin production, which is associated with increased cancer risk. Sleep duration has been hypothesized to influence both melatonin levels and cancer risk, and it has been suggested that sleep duration could be used as a proxy for melatonin production. Finally, physical activity has been shown to reduce cancer risk, and laboratory studies indicate it may influence melatonin levels. A cross-sectional study of light exposure, sleep duration, physical activity, and melatonin levels was conducted among 61 female rotating shift nurses (work schedule: two 12 h days, two 12 h nights, five days off). Light intensity was measured using a light-intensity data logger, and sleep duration and physical activity were self-reported in a study diary and questionnaire. Melatonin concentrations were measured from urine and saliva samples. The characteristics of nurses working day and night shifts were similar. Light intensity was significantly higher during sleep for those working at night (p< 0.0001), while urinary melatonin levels following sleep were significantly higher among those working days (p = 0.0003). Mean sleep duration for nurses working during the day (8.27 h) was significantly longer than for those working at night (4.78 h, p< 0.0001). An inverse association (p = 0.002) between light exposure and urinary melatonin levels was observed; however, this was not significant when stratified by shift group. There was no significant correlation between sleep duration and melatonin, and no consistent relationship between physical activity and melatonin. Analysis of salivary melatonin levels indicated that the circadian rhythms of night workers were not altered, meaning peak melatonin production occurred at night. This study indicates that two nights of rotating shift work may not change the timing of melatonin production to the day among those working at night. Additionally, in this study, sleep duration was not correlated with urinary melatonin levels, suggesting it may not be a good proxy for melatonin production.

A true screening environment for review of interval breast cancers: pilot study to reduce bias.

PURPOSE: To retrospectively assess the feasibility of an uninformed review process to evaluate interval breast cancers and to compare the number of false-negative cancers detected at uninformed review with the number detected at standard informed review. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study, and informed consent was waived. Mammograms showing interval cancer were included in the daily work of radiologists in a high-volume screening center. Each of three experienced radiologists read studies in the normal screening environment, without knowledge that identifiers had been changed to conceal the fact that studies were not current (ie, uninformed review). Results were compared with the standard review procedure, in which mammograms showing interval cancers were mixed with normal mammograms and read in a panel of 17-20 interval cancers per 80 normal studies by radiologists who were aware that they were participating in a review process (ie, informed review). RESULTS: Of 21 interval cancers, six (29%) were interpreted as positive more often by the informed radiologists than by the uninformed radiologists. For 14 (67%) cancers, there was no difference in detection rate between the two groups, and one cancer (5%) was seen by one of the uninformed radiologists but by none of the informed radiologists. The screening environment review process was found to be feasible at the low volumes tested. CONCLUSION: The number of false-negative cancers was higher in the informed review than in the uninformed review. This result suggests that bias exists with the informed review process.

Socioeconomic status and childhood solid tumor and lymphoma incidence in Canada.

The authors examined the relation between neighborhood income, as a measure of socioeconomic status, and childhood cancer. Incident cases of childhood solid tumor and lymphoma in 1985-2001 were identified from provincial cancer registries in Canada. Residential postal codes at the time of diagnosis were used to assign cases to census neighborhoods. Person-years at risk were determined from quintiles of population by neighborhood income, sex, and 5-year age group, constructed using census population data. Poisson regression was used to calculate incidence rate ratios across neighborhood income quintiles. Compared with the incidence rate in the richest income quintile, moderately lower rate ratios of 0.73 (95% confidence interval: 0.63, 0.86) and 0.84 (95% confidence interval: 0.69, 1.04) were observed, respectively, for carcinomas and renal tumors in the poorest income quintile. No association was found for other types of cancer. Although a potential relation between socioeconomic status and childhood cancer cannot be excluded, the overall pattern seems compatible with random variation.