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Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

Background Studies of immigrants have provided unique opportunities for examining disparities in cancer screening and the impact of lifestyles and environmental exposures on cancer risk. Findings have been useful for planning cancer control strategies and generating etiological hypotheses. Although India is a leading source of immigration to British Columbia (BC), Canada, little is known about the cancer profiles of Indo-Canadians, information needed for planning health services and health promotion initiatives for this population.Methods Using data from three population-based cancer registries, cancer incidence was compared for four population groups (in each of Delhi and Mumbai, India; Indo-Canadians in BC, Canada; and the BC general population) over three time periods (1976-1985, 1986-1995 and 1996-2003). BC Indo-Canadians were identified by using Indian surnames.Results Age-standardized incidence rates (ASRs) for all cancers combined were lowest for men and women in Delhi and Mumbai, intermediate for BC Indo-Canadians, and highest for the BC general population. Ranking of common cancer sites and ASRs for Indo-Canadian men and women more closely resembled those for the BC general population, rather than those for either Delhi or Mumbai. ASRs and rankings of common cancer sites are presented by gender for the four population groups.Conclusions Cancer incidence patterns in BC Indo-Canadian men and women differed from those in India, being more similar to the BC general population. [ABSTRACT FROM AUTHOR]

The health care services and sociodemographic profiles of Chinese women residing in each of five neighborhoods of Vancouver and Richmond, British Columbia, were examined and compared to Pap testing rates. Information was collected from the provincial medical directory, the cervical cancer screening program, and a community-based survey. A total of 159 Chinese primary care physicians, 3 Chinese gynecologists, and 9 health clinics were identified within these neighborhoods and 769 Chinese women responded to the survey. Significant differences were found between neighborhoods in Pap testing rates, with Chinatown having the lowest rates. Differences between neighborhoods were also found in the availability of Chinese language health care services, sociodemographic profiles of the Chinese population, individual preferences and experiences with health care services, which were also related to Pap testing rates. The implications of these findings upon the planning of effective health care services within local neighborhoods are discussed. [ABSTRACT FROM AUTHOR]

Context: High nevus density is a risk factor for cutaneous malignant melanoma. Melanocytic nevi originate in childhood and are largely caused by solar exposure.Objective: To determine whether use of broad-spectrum, high-sun protection factor (SPF) sunscreen attenuates development of nevi in white children.Design: Randomized trial conducted June 1993 to May 1996.Setting and Participants: A total of 458 Vancouver, British Columbia, schoolchildren in grades 1 and 4 were randomized in 1993. After exclusion of nonwhite children and those lost to follow-up or with missing data, 309 children remained for analysis. Each child's nevi were enumerated at the start and end of the study in 1996.Intervention: Parents of children randomly assigned to the treatment group (n=222) received a supply of SPF 30 broad-spectrum sunscreen with directions to apply it to exposed sites when the child was expected to be in the sun for 30 minutes or more. Children randomly assigned to the control group (n=236) received no sunscreen and were given no advice about sunscreen use.Main Outcome Measure: Number of new nevi acquired during the 3 years of the study, compared between treatment and control groups.Results: Children in the sunscreen group developed fewer nevi than did children in the control group (median counts, 24 vs 28; P=.048). A significant interaction was detected between freckling and study group, indicating that sunscreen use was much more important for children with freckles than for children without. Modeling of the data suggests that freckled children assigned to a broad-spectrum sunscreen intervention would develop 30% to 40% fewer new nevi than freckled children assigned to the control group.Conclusions: Our data indicate that broad-spectrum sunscreens may attenuate the number of nevi in white children, especially if they have freckles. JAMA. 2000. [ABSTRACT FROM AUTHOR]

From mid 1997 to end of 1999, there was a sexually-transmitted infectious syphilis outbreak mainly in heterosexual people in British Columbia, Canada, that was concentrated in Vancouver. The rate across the province increased from less than 0.5 to 3.4 per 100000, and the rate in Vancouver reached 12.9 per 100000. We aimed to eliminate the syphillis outbreak by treating people at risk of infection. In 2000, a targeted mass treatment programme provided azithromycin (1.8 g orally) to 4384 at-risk residents in this city. After the programme, syphilis frequency fell significantly for 6 months (p=0.016), but rose again in 2001. Results from curve fitting analyses showed that the number of cases in 2001 (177) was higher than expected (0.0001

Background: Gastric and esophageal cancers are among the most lethal human malignancies. Their epidemiology is geographically diverse. This study compares the survival of gastric and esophageal cancer patients among several ethnic groups including Chinese, South Asians, Iranians and Others in British Columbia (BC), Canada., Methods: Data were obtained from the population-based BC Cancer Registry for patients diagnosed with invasive esophageal and gastric cancer between 1984 and 2006. The ethnicity of patients was estimated according to their names and categorized as Chinese, South Asian, Iranian or Other. Cox proportional hazards regression analysis was used to estimate the effect of ethnicity adjusted for patient sex and age, disease histology, tumor location, disease stage and treatment., Results: The survival of gastric cancer patients was significantly different among ethnic groups. Chinese patients showed better survival compared to others in univariate and multivariate analysis. The survival of esophageal cancer patients was significantly different among ethnic groups when the data was analyzed by a univariate test (p = 0.029), but not in the Cox multivariate model adjusted for other patient and prognostic factors., Conclusions: Ethnicity may represent underlying genetic factors. Such factors could influence host-tumor interactions by altering the tumor's etiology and therefore its chance of spreading. Alternatively, genetic factors may determine response to treatments. Finally, ethnicity may represent non-genetic factors that affect survival. Differences in survival by ethnicity support the importance of ethnicity as a prognostic factor, and may provide clues for the future identification of genetic or lifestyle factors that underlie these observations.

Introduction: Predict (www.predict.nhs.uk) is a prognostication and treatment benefit tool developed using UK cancer registry data. The aim of this study was to compare the 10-year survival estimates from Predict with observed 10-year outcome from a British Columbia dataset and to compare the estimates with those generated by Adjuvant! (www.adjuvantonline.com)., Method: The analysis was based on data from 3140 patients with early invasive breast cancer diagnosed in British Columbia, Canada, from 1989-1993. Demographic, pathologic, staging and treatment data were used to predict 10-year overall survival (OS) and breast cancer specific survival (BCSS) using Adjuvant! and Predict models. Predicted outcomes from both models were then compared with observed outcomes., Results: Calibration of both models was excellent. The difference in total number of deaths estimated by Predict was 4.1 percent of observed compared to 0.7 percent for Adjuvant!. The total number of breast cancer specific deaths estimated by Predict was 3.4 percent of observed compared to 6.7 percent for Adjuvant! Both models also discriminate well with similar AUC for Predict and Adjuvant! respectively for both OS (0.709 vs 0.712) and BCSS (0.723 vs 0.727). Neither model performed well in women aged 20-35., Conclusion: In summary Predict provided accurate overall and breast cancer specific survival estimates in the British Columbia dataset that are comparable with outcome estimates from Adjuvant! Both models appear well calibrated with similar model discrimination. This study provides further validation of Predict as an effective predictive tool following surgery for invasive breast cancer., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background/aim: The Dietary Guidelines for Americans Adherence Index (DGAI) 2005 was developed to assess the contribution of dietary patterns to chronic disease risk. The objective of this study was to evaluate the association of dietary patterns as measured by the DGAI 2005 with the esophageal squamous cell carcinoma (ESCC) risk in Iran., Methods: This case-control study was conducted on 50 ESCC cases and 100 hospital controls aged 40-75 years. Participants were interviewed using validated food frequency questionnaires and the DGAI score was calculated subsequently., Results: Generally, the mean DGAI 2005 score for this population was low (9.54 ± 1.79) and the control group scored significantly higher compared to the ESCC cases (p < 0.001). Being in the highest tertile of DGAI scores reduced the risk of ESCC by 31%. Consumption of salty, peppery, and sour foods in combination increased the ESCC risk by 7.23%, followed by consumption of fried/barbecued meals (OR 3.79; 95% CI 1.10-5.44; p < 0.001) and high-temperature food/beverages (OR 3.68; 95% CI 1.20-8.99; p < 0.001)., Conclusions: Consumption of a diet in accordance with dietary recommendations was associated with a lower risk of ESCC. Preventive strategies to reduce the ESCC risk in high-risk regions of the world should focus on overall dietary patterns and dietary habits in order to be effective., (Copyright © 2011 S. Karger AG, Basel.)

Background: Racial and ethnic disparities in breast cancer incidence, stage at diagnosis, survival and mortality are well documented; but few studies have reported on disparities in breast cancer treatment. This paper compares the treatment received by breast cancer patients in British Columbia (BC) for three ethnic groups and three time periods. Values for breast cancer treatments received in the BC general population are provided for reference., Methods: Information on patients, tumour characteristics and treatment was obtained from BC Cancer Registry (BCCR) and BC Cancer Agency (BCCA) records. Treatment among ethnic groups was analyzed by stage at diagnosis and time period at diagnosis. Differences among the three ethnic groups were tested using chi-square tests, Fisher exact tests and a multivariate logistic model., Results: There was no significant difference in overall surgery use for stage I and II disease between the ethnic groups, however there were significant differences when surgery with and without radiation were considered separately. These differences did not change significantly with time. Treatment with chemotherapy and hormone therapy did not differ among the minority groups., Conclusion: The description of treatment differences is the first step to guiding interventions that reduce ethnic disparities. Specific studies need to examine reasons for the observed differences and the influence of culture and beliefs.

Lynch syndrome is defined by the presence of germline mutations in mismatch repair (MMR) genes. Several models have been recently devised that predict mutation carrier status (Myriad Genetics, Wijnen, Barnetson, PREMM and MMRpro models). Families at moderate-high risk for harboring a Lynch-associated mutation, referred to the BC Cancer Agency (BCCA) Hereditary Cancer Program (HCP), underwent mutation analysis, immunohistochemistry and/or microsatellite testing. Seventy-two tested cases were included. Twenty-five patients were mutation positive (34.7%) and 47 were mutation negative (65.3%). Nineteen of 43 patients who were both microsatellite stable and normal on immunohistochemistry for MLH1 and MSH2 were also genotyped for mutations in these genes; all 19 were negative for MMR gene mutations. Model-derived probabilities of harboring a MMR gene mutation in the proband were calculated and compared to observed results. The area under the ROC curves were 0.75 (95%CI; 0.63-0.87), 0.86 (0.7-0.96), 0.89 (0.82-0.97), 0.89 (0.81-0.98) and 0.93 (0.86-0.99) for the Myriad, Barnetson, Wijnen, MMRpro and PREMM models, respectively. The Amsterdam II criteria had a sensitivity and specificity of 0.76 and 0.74, respectively, in this cohort. The PREMM model demonstrated the best performance for predicting carrier status based on the positive likelihood ratios at the >10%, >20% and >30% probability thresholds. In this referred cohort, the PREMM model had the most favorable concordance index and predictive performance for carrier status based on the positive LR. These prediction models (PREMM, MMRPro and Wijnen) may soon replace the Amsterdam II and revised Bethesda criteria as a prescreening tool for Lynch mutations.

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.

Background: Hepatitis B virus (HBV) is a growing health issue in Canada, especially given that population growth is now largely the result of immigration. Immigrants from countries with high HBV prevalence and low levels of HBV vaccination have an excess risk of liver disease and there is a need for increased diligence in HBV blood testing and possibly vaccination among these populations., Objective: This study describes the sociodemographic characteristics associated with a history of HBV testing and HBV vaccination in immigrants from several countries with high HBV prevalence who are attending English classes., Methods: 759 adult immigrants attending English as a Second Language classes completed a self-administered questionnaire asking about sociodemographic characteristics and history of HBV testing and HBV vaccination. Descriptive statistics and adjusted ORs were calculated to explore these associations., Results: 71% reported prior HBV testing, 8% reported vaccination without testing, and 21% reported neither testing nor vaccination. Age, education and country of birth all showed significant effects for both testing and vaccination., Conclusions: Health care practitioners need to be cognizant of HBV testing, and possibly vaccination, in some of their patients, including immigrants from countries with endemic HBV infection. Infected persons need to be identified by blood testing in order receive necessary care to prevent or delay the onset of liver disease as well as to adopt appropriate behaviours to reduce the risk of transmission to others. Close contacts of infected persons also require HBV testing and subsequent vaccination (if not infected) or medical management (if infected).

Background: Ethnicity is associated with genetic, environmental, lifestyle and social constructs. Difficult to define using a single variable, but strongly predictive of health outcomes and useful for planning healthcare services, it is often lacking in administrative databases, necessitating the use of a surrogate measure. A potential surrogate for ethnicity is birthplace. Our aim was to measure the agreement between birthplace and ethnicity among six major ethic groups as recorded at the population-based mammography service for British Columbia, Canada (BC)., Methods: We used records from the most-recent visits of women attending the Screening Mammography Program of British Columbia to cross-tabulate women's birthplaces and self-reported ethnicities, and separately considered results for the time periods 1990-1999 and 2000-2006. In general, we combined countries according to the system adopted by the United Nations, and defined ethnic groups that correspond to the nation groups. The analysis considered birthplaces and corresponding ethnicities for South Asia, East/Southeast Asia, North Europe, South Europe, East Europe, West Europe and all other nations combined. We used the kappa statistic to measure the concordance between self-reported ethnicity and birthplace., Results: Except for the 'Other' category, the most-common birthplace was East/Southeast Asia and the most-common ethnicity was East/Southeast Asian. The agreement between birthplace and self-reported ethnicity was poor overall, as evidenced by kappa scores of 0.22 in both 1990-1999 and 2000-2006. There was substantial agreement between ethnicity and birthplace for South Asians, excellent agreement for East/Southeast Asians, but poor agreement for Europeans., Conclusion: Birthplace can be used as a surrogate for ethnicity amongst people with South Asian and East/Southeast Asian ethnicity in BC.

Introduction: Primary breast cancer involving four or more axillary lymph nodes carries a poor prognosis. We hypothesized that use of an immunohistochemical biomarker scoring system could allow for identification of variable risk subgroups., Methods: Patients with four or more positive axillary nodes were identified from a clinically annotated tissue microarray of formalin-fixed paraffin-embedded primary breast cancers and randomized into a 'test set' and a 'validation set'. A prospectively defined prognostic scoring model was developed in the test set and was further assessed in the validation set combining expression for eight biomarkers by immunohistochemistry, including estrogen receptor, human epidermal growth factor receptors 1 and 2, carbonic anhydrase IX, cytokeratin 5/6, progesterone receptor, p53 and Ki-67. Survival outcomes were analyzed by the Kaplan-Meier method, log rank tests and Cox proportional-hazards models., Results: A total of 313 eligible patients were identified in the test set for whom 10-year relapse-free survival was 38.3% (SEM 2.9%), with complete immunohistochemical data available for 227. Tumor size, percentage of positive axillary nodes and expression status for the progesterone receptor, Ki-67 and carbonic anhydrase IX demonstrated independent prognostic significance with respect to relapse-free survival. Our combined biomarker scoring system defined three subgroups in the test set with mean 10-year relapse-free survivals of 75.4% (SEM 7.0%), 35.3% (SEM 4.1%) and 19.3% (SEM 7.0%). In the validation set, differences in relapse-free survival for these subgroups remained statistically significant but less marked., Conclusion: Biomarkers assessed here carry independent prognostic value for breast cancer with four or more positive axillary nodes and identified clinically relevant prognostic subgroups. This approach requires refinement and validation of methodology.

A genetic testing service can determine which members of a population might benefit most from cancer prevention. The eligibility criteria will affect the number of people who use a service and the proportion who test positive. This affects both the service's costs and benefits. The goal of this study was to create computer software that predicts the effect of eligibility restrictions on the performance of a genetic testing service. The software allows eligibility restrictions based on age, gender, and family history of disease. As performance measures, we considered the sensitivity and specificity of eligibility criteria to identify people with genetic cancer susceptibility, the likelihood of genetic susceptibility among people who are eligible for the service, and the likelihood of genetic susceptibility among people who are ineligible. We compared the performance predicted by our model with the observed performance of the Hereditary Cancer Program at the BC Cancer Agency, and studied the effects of changes to model parameters. There was good agreement between model predictions and observed outcomes, however, performance measures were affected by changes to the underlying model parameters. Computer software to predict the performance of a genetic testing service for cancer susceptibility is implemented on the website http://142.103.207.51:8080/gtsim.

Background: Chinese and South Asians are among the fastest growing minority populations in Canada; however little is known about the burden of cancer in these populations., Objective: The objective is to examine survival rates for breast, cervical and colorectal cancers in women within these two ethnic populations, as compared to the BC general population., Methods: Survival rates were calculated for three time periods in the Chinese, South Asian and BC general populations, using the BC cancer registry. Ethnicity within the registry was determined using surnames., Results: Survival rates for female breast, cervical and colorectal cancers have improved over time in all three population groups, however general differences were found among the groups. Chinese women had higher survival rates than both South Asians and all BC women for breast and cervical cancer, and intermediate survival rates between South Asians and all BC women for colorectal cancer. South Asian women had the highest survival rates for colorectal cancer, similar survival rates to all BC women for breast cancer, and lower survival rates for cervical cancer., Interpretation: Differences in the observed survival rates may be explained by variations in screening and early detection, treatment practices, and cancer biology. This is discussed more fully for each cancer site.

Purpose: Estrogen receptor (ER) expression predicts improved breast cancer-specific survival and reduced risk of recurrence and is targeted in breast cancer therapy. A high-quality antibody to identify ER-positive patients plays an important role in clinical decision making for women with breast cancer. This study evaluates immunohistochemistry using two anti-ER antibodies, a new rabbit monoclonal antibody (SP1) and the mouse monoclonal antibody (1D5), in relation to biochemical ER assay results and clinical data on survival and adjuvant systemic therapy., Patients and Methods: A population-based tissue microarray series of 4,150 invasive breast cancers was constructed. All patients had staging, pathology, treatment, and follow-up information. The median follow-up was 12.4 years and the median age at diagnosis 60 years. Survival analysis and log-rank tests were used to evaluate the prognostic value of ER status and correlations with clinical data., Results: Among the 4,105 samples interpretable for both antibodies, SP1 detected ER positivity in 69.5% and 1D5 in 63.1% of cases. Both monoclonal antibodies are demonstrated to be good prognostic indictors for breast cancer-specific and relapse-free survival. In multivariate analysis, including age, tumor size, grade, and lymphovascular and nodal status, SP1 was a better independent prognostic factor than 1D5. Among patients with discrepant ER results, the 8% of patients who were SP1 positive/1D5 negative showed good outcomes, and the 2% SP1-negative/1D5 positive had poor outcomes. Maintaining the same 92% specificity and 98% positive predictive value, SP1 is 8% more sensitive than 1D5 using biochemical assay as gold standard., Conclusion: SP1 represents an improved standard for ER immunohistochemistry assessment in breast cancer.

Background: There are several reasons that someone might be diagnosed with more than one primary cancer. The aim of this analysis was to determine combinations of cancer types that occur more often than expected. The expected values in previous analyses are based on age-and-gender-adjusted risks in the population. However, if cancer in people with multiple primaries is somehow different than cancer in people with a single primary, then the expected numbers should not be based on all diagnoses in the population., Methods: In people with two or more cancer types, the probability that a specific type is diagnosed was determined as the number of diagnoses for that cancer type divided by the total number of cancer diagnoses. If two types of cancer occur independently of one another, then the probability that someone will develop both cancers by chance is the product of the individual probabilities for each type. The expected number of people with both cancers is the number of people at risk multiplied by the separate probabilities for each cancer. We performed the analysis on records of cancer diagnoses in British Columbia, Canada between 1970 and 2004., Results: There were 28,159 people with records of multiple primary cancers between 1970 and 2004, including 1,492 people with between three and seven diagnoses. Among both men and women, the combinations of esophageal cancer with melanoma, and kidney cancer with oral cancer, are observed more than twice as often as expected., Conclusion: Our analysis suggests there are several pairs of primary cancers that might be related by a shared etiological factor. We think that our method is more appropriate than others when multiple diagnoses of primary cancer are unlikely to be the result of therapeutic or diagnostic procedures.

Purpose: Little is known about the potential adverse effects of interventions to reduce dietary fat. We examined the physical and emotional health effects, and social consequences experienced by women at high risk for breast cancer who had participated in a low-fat diet intervention, randomized, controlled trial for at least 5 years., Methods: Participants in the Canadian Diet and Breast Cancer Prevention Trial from British Columbia were mailed a survey questionnaire that included the validated Medical Outcomes Study 36-item Short Form Health Survey (SF-36) and Women's Health Questionnaire (WHQ), and a series of questions on health-related and social constructs. Responses were compared between the diet intervention and control groups by menopausal status., Results: Completed questionnaires were returned by 359 women in the diet intervention group and 382 in the control group. No significant differences were found between these groups for SF-36 and WHQ health outcomes, hair/nail changes, physical activity levels, family/friend support levels, and doctor visits. Significantly more women in the intervention group reported taking products for arthritis (other than pain medication), greater difficulty in maintaining eating habits in social situations and at work, greater stress, and guilt related to personal eating habits. These findings persisted for both premenopausal and postmenopausal women., Conclusion: Changes resulting from a low-fat diet intervention can be incorporated into women's daily lives with limited long-term negative effects.

The protein encoded by the MDM2 oncogene inhibits the function of p53, leading to increased cell growth, avoidance of apoptosis, tolerance of genetic instability, and resistance to chemotherapy. The present study was performed to evaluate the relationship between MDM2 protein expression and survival in breast carcinoma. Two series of cases were used in this study: the first to identify the cutoff to be used in the interpretation of MDM2 immunostaining and perform preliminary survival analysis, and a second, independent series, to validate the findings from the first series and to perform multivariate analysis. For both series, archival sections of tissue microarrays were stained with anti-MDM2 antibody (NeoMarkers, Fremont, CA, USA) and MDM2 staining intensity was scored semiquantitatively. In the first series, 49 of 362 (14%) interpretable cases were positive for MDM2 expression, with 35 (10%) showing weak positivity and 14 (4%) strong positivity. Patients with MDM2-positive tumours had a significantly worse disease-specific survival than patients with MDM2-negative tumours (P=0.0022, 10-year DSS 61% (95% CI: 45-73) vs 73% (95% CI: 67-77)). No significant difference in survival was observed between patients with strongly and weakly MDM2-positive tumours (P=0.3). Accordingly, in the independent validation series weak and strong MDM2 positivity were combined and considered to be MDM2 positive. MDM2 expression was seen in 230/1747 (13%) interpretable cases in this series, with a significant difference (P<0.0001) in DSS between MDM2-negative and MDM2-positive cases (10 year DSS 58% (95% CI: 51-64) vs 73% (95% CI: 70-75)). MDM2 was an independent prognostic marker (HR=1.35, P=0.02) in a Cox regression model including MDM2 expression, tumour grade, nodal status, ER status and tumour size. Immunohistochemical studies of MDM2 in more than 2000 breast carcinomas show that MDM2 is an independent negative prognostic marker.

Purpose: Adjuvant! (www.adjuvantonline.com) is a web-based tool that predicts 10-year breast cancer outcomes with and without adjuvant systemic therapy, but it has not been independently validated., Methods: Using the British Columbia Breast Cancer Outcomes Unit (BCOU) database, demographic, pathologic, staging, and treatment data on 4,083 women diagnosed between 1989 and 1993 in British Columbia with T1-2, N0-1, M0 breast cancer were abstracted and entered into Adjuvant! to calculate predicted 10-year overall survival (OS), breast cancer-specific survival (BCSS), and event-free survival (EFS) for each patient. Individual BCOU observed outcomes at 10 years were independently determined. Predicted and observed outcomes were compared., Results: Across all 4,083 patients, 10-year predicted and observed outcomes were within 1% for OS, BCSS, and EFS (all P > .05). Predicted and observed outcomes were within 2% for most demographic, pathologic, and treatment-defined subgroups. Adjuvant! overestimated OS, BCSS, and EFS in women younger than age 35 years (predicted-observed = 8.6%, 9.6%, and 13.6%, respectively; all P < .001) or with lymphatic or vascular invasion (LVI; predicted-observed = 3.6%, 3.8%, and 4.2%, respectively; all P < .05); these two prognostic factors were not automatically incorporated within the Adjuvant! algorithm. After adjusting for the distribution of LVI, using the prognostic factor impact calculator in Adjuvant!, 10-year predicted and observed outcomes were no longer significantly different., Conclusion: Adjuvant! performed reliably. Patients younger than age 35 or with known additional adverse prognostic factors such as LVI require adjustment of risks to derive reliable predictions of prognosis without adjuvant systemic therapy and the absolute benefits of adjuvant systemic therapy.

Background: Online Mendelian Inheritance in Man (OMIM) is a computerized database of information about genes and heritable traits in human populations, based on information reported in the scientific literature. Our objective was to establish an automated text-mining system for OMIM that will identify genetically-related cancers and cancer-related genes. We developed the computer program CGMIM to search for entries in OMIM that are related to one or more cancer types. We performed manual searches of OMIM to verify the program results., Results: In the OMIM database on September 30, 2004, CGMIM identified 1943 genes related to cancer. BRCA2 (OMIM *164757), BRAF (OMIM *164757) and CDKN2A (OMIM *600160) were each related to 14 types of cancer. There were 45 genes related to cancer of the esophagus, 121 genes related to cancer of the stomach, and 21 genes related to both. Analysis of CGMIM results indicate that fewer than three gene entries in OMIM should mention both, and the more than seven-fold discrepancy suggests cancers of the esophagus and stomach are more genetically related than current literature suggests., Conclusion: CGMIM identifies genetically-related cancers and cancer-related genes. In several ways, cancers with shared genetic etiology are anticipated to lead to further etiologic hypotheses and advances regarding environmental agents. CGMIM results are posted monthly and the source code can be obtained free of charge from the BC Cancer Research Centre website http://www.bccrc.ca/ccr/CGMIM

The current options available to BRCA1 mutation carriers can be classified as either cancer risk reduction or increased disease surveillance. Risk reduction might be preferable to young women. Increased surveillance might be more attractive to women when their cancer risk is highest. The aim of this report is to estimate the sensitivity, specificity and ability to detect carriers for a population-based BRCA1 testing program with eligibility based on family history of cancer, and examine the effect of age on the program's performance. A computer model was used to simulate the incidence of breast and ovarian cancer in a woman's family, based on her BRCA1 mutation carrier status. Age-specific estimates of the sensitivity and specificity for family history as an indicator of mutation status were applied to local population figures. Sensitivity of the program increased with the age of the proband and the size of her family. Sensitivity ranged from 0.33 for 20-year-olds with small families, to 0.98 for 60-year-olds with large families. Specificity was greater than 0.95, regardless of a woman's age or family size. If 0.12% of people carry a BRCA1 mutation, a province-wide testing program for people aged 20-69 with referrals based only on family history would have a sensitivity of 0.55. Only 2% of the genetic test results would be positive. The acceptability of a genetic testing program depends on its sensitivity and specificity, and on the options available to women who are found to carry a mutation. Compared with variation due to family size, the program sensitivity and specificity does not differ substantially amongst the various age groups.

Our objective was to determine work-related pre-menopausal breast cancer risks that depend on a woman's family history of the disease. In a large case-control study, 318 women with breast cancer and 340 healthy women completed a mailed questionnaire. All of the women were pre-menopausal and controls were matched to cases by age. All risk estimates were adjusted for women's smoking history and whether they reported a prior breast biopsy. There was an odds ratio (OR) of 6.9 (95% confidence interval: 1.5-31.9) for breast cancer among pre-menopausal women with no family history if they ever worked in material processing occupations. Among women with a family history of breast cancer, there was an OR of 6.4 (0.7-55.9) if they ever worked as miscellaneous salesclerks and salespersons of commodities, and an OR of 5.7 (0.6-50.9) if they ever worked in department stores. Despite changes in the OR, none of the estimates were significantly different in women with and without a family history.

Urokinase plasminogen activator (uPA) expression in breast cancer is associated with relapse and a reduction in disease-specific survival. Thus, efforts are under way to identify uPA inhibitors. By screening a chemical library of >1000 compounds, 17-allyaminogeldanamycin (17AAG) was identified as a potent inhibitor of uPA by the National Cancer Institute and is now in Phase I clinical trials. At this time, it remains unclear how 17AAG blocks uPA; one possibility is through disruption of the insulin-like growth factor I receptor (IGF-IR) pathway. This would be consistent with studies from our laboratory showing that activation of IGF-IR results in the induction of uPA protein. In the study described herein, we observed that IGF-IR and uPA were highly expressed in 87 and 55% of breast cancer by screening tumor tissue microarrays representing 930 cases. A significant proportion (52.1% = 354 of 680 cases, P < 0.0001) of the patients had tumors expressing both proteins. uPA alone (P = 0.033) or in combination with IGF-IR (P = 0.0104) was indicative of decreased disease-specific survival. Next, we demonstrated that treating MDA-MB-231 cells with increasing concentrations of 17AAG resulted in IGF-IR degradation (IC(50) = 1.0 micro M) and blocked signal transduction through the Akt and mitogen-activated protein kinase pathways. Finally, we found that 17AAG had a robust inhibitory effect on the production of uPA mRNAand protein in the presence of IGF-I. Thus, our study raises the possibility that 17AAG could prove to be an effective therapeutic agent for a large number of breast cancer patients by inhibiting the IGF-IR and ultimately uPA.

Painful sunburns are implicated in the pathogenesis of squamous cell carcinoma, basal cell carcinoma, and malignant melanoma. Chronic exposure to ultraviolet radiation is known as the most important risk factor for the development of actinic keratoses and squamous cell carcinoma. The purpose of the study was to assess the effect of painful sunburns and lifetime sun exposure on the development of actinic keratoses and seborrheic warts in relation to the development of squamous cell carcinoma and basal cell carcinoma, and on the development of melanocytic nevi and atypical nevi in relation to the development of malignant melanoma. We made use of a cohort of 966 individuals who participated in a case-control study to investigate environmental and genetic risk factors for skin cancer. Exposure measurements for sunlight were collected and actinic keratoses, seborrheic warts, melanocytic nevi, and atypical nevi were counted. Relative risks were estimated using exposure odds ratios from cross-tabulation. Multivariate logistic regression was used to adjust for potential confounders. The recall of painful sunburns before the age of 20 y was associated with an increased risk of squamous cell carcinoma, nodular basal cell carcinoma, and multifocal superficial basal cell carcinoma as well as actinic keratoses. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.5 (0.97; 2.3); 1.6 (1.1; 2.2); 2.6 (1.7; 3.8); and 1.9 (1.4; 2.6) for the three types of nonmelanoma skin cancer and actinic keratoses, respectively. Painful sunburns before the age of 20 y were also associated with an increased risk of malignant melanoma and the development of its precursors, melanocytic nevi and atypical nevi. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.4 (0.86; 2.1); 1.5 (1.1; 2.0); and 1.4 (0.88; 2.3) for malignant melanoma and the two types of precursors, respectively. Lifetime sun exposure was predominantly associated with an increased risk of squamous cell carcinoma (p-value for trend=0.03) and actinic keratoses (p-value for trend <0.0001) and to a lesser degree with the two types of basal cell carcinoma. By contrast, lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma, despite the fact that lifetime sun exposure did not diminish the number of melanocytic nevi or atypical nevi. Neither painful sunburns nor lifetime sun exposure were associated with an increased risk of seborrheic warts.

Smoking and ultraviolet radiation are known to have a detrimental effect on human skin. Important characteristics of the aging skin are elastosis and telangiectasia. The purpose of the study was to assess the relative importance of age per se, and the detrimental effects caused by sun exposure and smoking on the development of cutaneous elastosis and telangiectasia in a well-defined group of individuals. We made use of 966 individuals who participated in a case-control study to investigate environmental and genetic risk factors for skin cancer. Exposure measurements for sunlight and smoking were collected and the amount of elastosis and telangiectasia in the face and neck was recorded according to a four-graded score varying from none to severe. Relative risks were estimated using exposure odds ratios from cross-tabulation and logistic regression. Multivariate logistic regression was used to adjust for potential confounders. Among both sexes a strong association was observed between increasing age, sun exposure, and amount of elastosis. The association between increasing age, sun exposure, and amount of telangiectasia was strong among men, but less apparent among women. Smoking was also associated with elastosis among both sexes, and with telangiectasia predominantly among men. Intrinsic differences between men and women (e.g., hormones) or behavior differences (e.g., more frequent use of creams and cosmetics among women) could account for this apparent difference in the occurrence of telangiectasia. In contrast to elastosis, telangiectasia may not be a good marker of the aging skin, specifically not in women.

The BRCA1 gene and its relationship to family history of breast/ovarian cancer are difficult to study in a population because of practical and ethical issues. The paucity of information on BRCA1 in the general population was a major theme in a recent review of genetic testing in Canada. We develop a simulation model to mimic genetic inheritance and cancer incidence in the family of someone with a germline BRCA1 mutation. Given someone's age and family structure, our model simulates his or her family history in three steps: (1) determine which family members have the mutation, (2) determine the ages of family members and (3) determine which family members have breast/ovarian cancer. Each step involves random variation. Some parameters in our model are estimated using local (British Columbia, Canada) population data. The breast/ovarian cancer risk associated with BRCA1 mutations is estimated using values published in the literature. An example is provided to illustrate the model's application. The model incorporates results from genetics, demography and epidemiology, but requires several additional assumptions. Research to address these assumptions is recommended.

Some families seem to have an increased risk of several different cancers and a reduced risk of others. Either genetic predisposition or a shared environment may explain this familial clustering, and the type of cause can affect how family members should be advised. We used data from a case-control study to examine the risk of cancer in the mother, sisters and brothers of men with testicular cancer. Our results show a significant relative risk (RR=1.7; 95% confidence interval (CI): 1.05-2.6) of cancer for sisters of testicular cancer patients in comparison with the sisters of controls. When data were combined for brothers and sisters, the RR for all cancers was 1.53 (CI: 1.1-2.3). Despite the limitations of our data, there is evidence for cancer clustering in the families of testicular cancer patients. Unfortunately, the evidence is consistent with either a genetic or environmental etiology.

Background: An epidemiology unit was established in Aruba in 1994. The primary focus was the development of an infrastructure for both surveillance and health information data systems. This effort resulted in the first analysis of available skin cancer data., Methods: A retrospective study of cancer and particularly skin cancer cases at the local histopathology laboratory for the period 1980-1995 was performed. All available records with a cancer diagnosis were evaluated., Results: During the study period, an increase in age-adjusted rates for both men and women was observed for basal cell carcinomas and squamous cell carcinomas. No temporal trend was discerned for malignant melanoma or other skin cancers because the numbers of cases were small. Lesions were most often seen on the nose, face, and arm. Dermatologists provided the majority of skin cancer diagnoses and demonstrated the greatest diagnostic accuracy., Conclusions: The presence of a central histopathology laboratory may provide small island states, like Aruba, with important public health data. This first description of Aruba's skin cancer epidemiology provides information that may be utilized for future public health action.

The objective of this study was to determine whether paternal occupational exposure to chlorophenol fungicides and their dioxin contaminants is associated with childhood cancer in the offspring of sawmill workers. We used data from 23,829 British Columbian sawmill workers employed for at least 1 continuous year between 1950 and 1985 in 11 sawmills that used chlorophenates. Probabilistic linkage of the sawmill worker cohort to the provincial marriage and birth files produced an offspring cohort of 19,674 children born at least 1 year after the initiation of employment in the period 1952-1988. We then linked the offspring cohort to the British Columbia Cancer Registry. We included all malignancies in cases younger than 20 years of age that appeared on the cancer registry between 1969 and 1993. We calculated standardized incidence ratios (SIRs) using the British Columbia population as a reference. A nested case-control analysis assessed the effects of paternal cumulative exposure and windows of exposure on the risk of developing cancer in the offspring. We identified 40 cases of cancer during 259,919 person-years of follow-up. The all-cancer SIR was 1.0 [95% confidence interval (CI), 0.7-1.4]; the SIR for leukemia was 1.0 (CI, 0.5-1.8); and the SIR for brain cancer was 1.3 (CI, 0.6-2.5). The nested case-control analysis showed slightly increased risks in the highest categories of chlorophenol exposure, although none was statistically significant. Our analyses provide little evidence to support a relationship between the risk of childhood cancer and paternal occupational exposure to chlorophenate fungicides in British Columbian sawmills.

Background: Sunlight is the environmental exposure most often associated with squamous cell cancer (SCC) of the skin. It can be difficult to quantify the sunlight exposure of the skin because of the different types of clothing that may be worn. The problem is simplified for studies of SCC on the skin of the head and neck, where a hat is the only type of clothing that needs to be considered., Objective: The purpose of the study was to determine the risk for SCC of sunlight exposure on the skin of the head and neck, and the protective effect, if any, associated with wearing a hat., Methods: A case-control study of squamous cell carcinoma of the skin was conducted amongst men in the province of Alberta, Canada. Analysis was restricted to only those cases where cancer occurred on the head or neck, and their age and sex matched controls., Results: Ethnicity, non-sunexposed skin colour, and hair colour each significantly affected the SCC risk. An increased SCC risk was also associated with greater cumulative sunlight exposure and with sunburns experienced during the ages 5 to 15 years. The risk associated with sunlight exposure was significantly elevated in men who reported that they had always or usually worn a hat., Conclusion: As observed in previous studies, SCC on the skin of the head and neck is associated with host pigmentation, sunburns occurring in childhood, and sunlight exposure during adulthood. The risk observed for wearing a hat may be due to bias or confounding; however, hats remain an unproven means of protection against SCC on the skin of the head and neck.

Background and Purpose: Acetylsalicylic acid (ASA) can reduce the incidence of stroke and myocardial infarction by inhibiting platelet-fibrin thrombi in small blood vessels. To determine if ASA could reduce late effects of radiation therapy mediated by damage to small blood vessels, a prospective, placebo-controlled, double-blind trial was conducted in women with early breast cancer, receiving radiotherapy to the conserved breast., Materials and Methods: Cosmetic outcome and late radiotherapy effects were recorded prospectively for 186 women with T1 or T2, pathologically node-negative breast cancer treated with breast conservation and randomized to receive ASA (325 mg daily) or placebo for 1 year from the start of radiation therapy. Radiation was a tangent pair to the breast alone delivering a modal dose of 44 Gy in 16 daily fractions in 22-25 days., Results: Median follow-up is 6.5 years. The use of ASA has not had any effect on the acute (erythema, edema or discomfort) or late (induration, telangiectasia) effects of radiotherapy (all P > 0.10), the patients' or physicians' assessment of the cosmetic outcome (all P > 0.25) or rates of breast recurrence (P > 0.25)., Conclusion: ASA cannot be recommended to improve the outcome of radiotherapy complementing breast conserving surgery.

Background and Purpose: The number of fractions of radiation therapy (RT) used after breast conserving surgery varies widely and accounts for a significant proportion of the workload in a modern radiotherapy department. Internationally, 'standard' therapy ranges from 3 to 7 weeks of daily treatment with or without a boost. Short RT schedules have the attraction of reducing workload but raise concern about an increased risk of late effects and poorer cosmetic outcome., Materials and Methods: In a randomized trial, 186 women with T1 or T2, pathologically node-negative breast cancer had cosmetic and various normal tissue effects data collected prospectively. The breast RT prescription was 44 Gy in 16 daily fractions to a tangent pair., Results: Median follow-up is 6.7 years. Actuarial 5-year breast recurrence was 6%. Overall cosmetic results at 5 years were good or excellent in 89% and 96% as reported by physicians and patients, respectively, and were stable between 2 and 5 years. Breast discomfort, erythema, edema and induration were related to both surgery and RT. At 5 years, 20% had breast discomfort, 18% had induration, 6% had erythema and 3% had some degree of breast edema. Fewer patients had these effects at 5 years than immediately after primary surgery. The presence of induration prior to starting RT was associated with a greater likelihood of breast induration 3 or more years following RT (P = 0.02). Thirteen percent of patients, generally those with large breasts, developed mild inframammary telangiectasia by 5 years., Conclusions: Results are comparable to those reported from centers employing more conventional fractionation. Short fractionation produces acceptable cosmetic results for the majority of women if there are no contraindications to RT and in the absence of significant post-operative breast induration.

The role of non-sunlight-related risk factors for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin was investigated in a population-based, case-control study conducted among males in Alberta, Canada. In total, 180 SCC and 226 BCC cases and 406 randomly selected male controls, frequency matched by 5-year age groups to the cases, were interviewed by trained personnel using a standardized etiological questionnaire. Data were analyzed using conditional logistic regression techniques. After adjustment for age, skin and hair color, mother's ethnic origin, and sunlight exposure, elevated risks for SCC were seen in subjects exposed to insecticides [odds ratio (OR), highest tertile, 2.8; 95% confidence interval (CI), 1.4-5.6], herbicides (OR, highest tertile, 3.9; 95% CI, 2.2-6.9), and fungicides and seed treatments (OR, highest tertile, 2.4; 95% CI, 1.4-4.0), as well petroleum products, grease, and several other exposures. Elevated risks of BCC were seen in subjects exposed to fiberglass dust (OR, 2.0; 95% CI, 1.0-3.9) and dry cleaning agents (OR, 4.6 95% CI, 1.1-19.7). Prior nondiagnostic X-ray treatment for skin conditions increased risk of both cancers. Although solar UV radiation is known to be the major environmental exposure causing nonmelanocytic skin cancer, results of this study suggest that nonsolar factors may also be important.

Background and Design: Basal cell carcinoma (BCC) of the skin is the most common neoplasm in white populations, and solar radiation is generally accepted to be the dominant environmental risk factor for this disease. However, little information is available on the nature of the relationship between BCC and sunlight. The purpose of this study was to evaluate the nature of the relationship between sunlight exposure, pigmentary factors, and BCC of the skin. A population-based case-control study of 226 male patients with BCC diagnosed from January 1, 1983, through December 31, 1984, and 406 randomly selected male control subjects was conducted in Alberta, Canada. The study was conducted using a standardized questionnaire, administered in person by trained interviewers. Data were analyzed using conditional logistic regression methods., Results: After controlling for other host and pigmentary factors, the risk of BCC was increased in subjects with light skin color and those who freckled in childhood. A history of severe sunburn in childhood also increased risk. Subjects of southern European ethnic origin were at significantly lower risk of BCC. Surprisingly, no association was seen between mean annual cumulative summer sunlight exposure and risk of BCC. A significantly increased risk of BCC was seen in subjects with increased recreational sunlight exposure in adolescence and childhood (age, 0 to 19 years), although an inverse relationship was seen with lifetime recreation exposure. The relationship with childhood sun exposure was most pronounced among sun-sensitive subjects whose skin tended to burn rather than tan in the sun., Conclusions: The lack of association between cumulative sun exposure and BCC contradicts conventional wisdom about the cause of this tumor, and the increased risk with sun exposure at age 0 to 19 years suggests that childhood and adolescence may be critical periods for establishing adult risk for BCC.

Introduction and Design: Squamous cell carcinoma of the skin (SCC), a common cancer in white populations, is related to sunshine exposure; however, relatively little information is available on how timing and character of exposure affect the relationship. The purpose of this study was to investigate the nature of the relationship of SCC to individual solar UV exposure after control for phenotype and pigmentary factors. All newly diagnosed cases of SCC were in men aged 25 through 79 years, ascertained in the province of Alberta from January 1, 1983, through December 31, 1984, who were approached for participation; 80% completed a standardized etiologic interview that was conducted in their homes by a trained interviewer. Control subjects were chosen at random from the Alberta Health Care Insurance Plan subscribers list, matched only by sex (male) and age (within a 5-year age group). The response rate among controls was 71%., Results: Subjects with pale skin and red hair had an elevated risk of SCC. Subjects whose mother was of southern European ancestry had a reduced risk of SCC. After accounting for pigmentary factors, no association was seen between risk of SCC and cumulative lifetime sun exposure. However, a strong trend toward increasing risk was seen with increasing chronic occupational sun exposure in the 10 years prior to diagnosis., Conclusion: The results suggest that recent sun exposure (in the 10 years prior to diagnosis) may be important in accounting for individual risk of SCC.

Background and Methods: We examined the effect of adjuvant systemic therapy on survival after breast cancer among the residents of the Canadian province of British Columbia. Data on survival were collected for all women in whom breast cancer was diagnosed in British Columbia during each of three calendar years chosen to represent different province-wide treatment recommendations: 1974, when no adjuvant systemic therapy was recommended; 1980, when adjuvant chemotherapy was recommended only for premenopausal women with node-positive disease; and 1984, when adjuvant chemotherapy was also recommended for premenopausal women with node-negative disease and lymphatic, vascular, or neural invasion and tamoxifen was recommended for postmenopausal women with involved lymph nodes or lymphatic, vascular, or neural invasion unless their tumors were negative for estrogen receptors., Results: For women less than 50 years of age, disease-specific survival at seven years (i.e., with censoring of data on women who died from causes other than breast cancer) improved from 65.2 to 76.3 percent between 1974 and 1984 (P = 0.008), and overall survival improved from 64.8 to 74.6 percent (P = 0.02). For women from 50 through 89 years of age, disease-specific survival at seven years improved from 62.5 to 70.4 percent between 1980 and 1984 (P = 0.001), and overall survival improved from 53.9 to 58.3 percent (P = 0.05). The timing of the improvements in survival correlated with the introduction of adjuvant systemic therapy in each group., Conclusions: Survival among women with breast cancer improved significantly in a geographically defined population during the period when adjuvant systemic therapy became widely used.

Mussels were collected at high and low shore locations from two Mytilus edulis/Mytilus galloprovincialis populations, Croyde Bay and Whitsand Bay, in S.W. England. Genotype-dependent length-at-age values were determined. At high and low shore locations at both sites, M. edulis-like mussels had significantly smaller length-at-age values than M. galloprovincialis-like and putative F1 hybrid individuals. The putative F1 hybrids exhibited length-at-age values between those of the parental types, but much closer to those of M. galloprovincialis-like rather than M. edulis-like individuals. Genotype frequencies as a function of age were determined and relative viability coefficients estimated from comparisons of genotype frequencies of young versus old mussels. At high and low shore locations at both sites, the relative viability coefficient of M. galloprovincialis-like individuals was greater than that of M. edulis-like mussels. Putative F1 hybrids at both sites had relative viability coefficients intermediate between those of the parental types. These data indicate that the length-dependent variation in allozyme frequencies that characterizes sympatric populations can be attributed to a small but significant genotype-dependent difference in length-at-age values, but mostly to large and highly significant differences in viability.

Lead, cadmium and fluoride were determined in 210 samples of human milk and the mean and median levels and ranges found were 1.04 and 0.55 ng/g (range less than 0.05-15.8 ng/g) for lead, 0.08 and 0.06 ng/g (range less than 0.002-4.05 ng/g) for cadmium, and 7.08 and less than 4 ng/g (range less than 2-97 ng/g) for fluoride. For mothers taking no fluoride supplements and living in communities with fluoride (1 microgram/g) in the drinking-water, the mean fluoride level was 9.8 ng/g. Where no fluoride was present in the drinking-water, the mean level was 4.4 ng/g. Geometric means for all non-zero lead, cadmium and fluoride concentrations were 0.566, 0.063 and 12 ng/g, respectively. Statistical correlation of levels with some dietary and environmental factors showed that lead levels were most strongly correlated with the age of the house (P less than 0.001), with maternal exposure to heavy traffic for more than 5 yr (P = 0.011), and with coffee consumption (P = 0.034). Fluoride levels correlated strongly (P = 0.007) with the presence of fluoride in the drinking-water. Cadmium levels correlated strongly with exposure to cigarette smoke (P = 0.005 if the mother smoked and P = 0.003 if the father smoked and the mother did not smoke).