A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

The AusD Study: a population-based study of the determinants of serum 25-hydroxyvitamin D concentration across a broad latitude range.

Observational studies suggest that people with a high serum 25-hydroxyvitamin D (25(OH)D) concentration may have reduced risk of chronic diseases such as osteoporosis, multiple sclerosis, type 1 diabetes, cardiovascular disease, and some cancers. The AusD Study (A Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults) was conducted to clarify the relationships between ultraviolet (UV) radiation exposure, dietary intake of vitamin D, and serum 25(OH)D concentration among Australian adults residing in Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S), and Hobart (42.8°S). Participants aged 18-75 years were recruited from the Australian Electoral Roll between 2009 and 2010. Measurements were made of height, weight, waist:hip ratio, skin, hair, and eye color, blood pressure, and grip strength. Participants completed a questionnaire on sun exposure and vitamin D intake, together with 10 days of personal UV dosimetry and an associated sun-exposure and physical-activity diary that was temporally linked to a blood test for measurement of 25(OH)D concentration. Ambient solar UV radiation was also monitored at all study sites. We collected comprehensive, high-quality data from 1,002 participants (459 males, 543 females) assessed simultaneously across a range of latitudes and through all seasons. Here we describe the scientific and methodological issues considered in designing the AusD Study.

Postmenopausal hormone therapy and non-Hodgkin lymphoma: a pooled analysis of InterLymph case-control studies.

BACKGROUND: Non-Hodgkin lymphoma (NHL) subtypes, diffuse large B-cell (DLBCL) and follicular lymphoma (FL) have different sex ratios and are diagnosed at ages over 60 years; DLBCL is more common in men and diagnosed at older ages than FL, which occurs more among women. This analysis of postmenopausal women examines the relationship between postmenopausal hormone therapy and NHL. DESIGN: Self-reported use of postmenopausal hormone therapy from 2094 postmenopausal women with NHL and 2731 without were pooled across nine case-control studies (1983-2005) from North America, Europe and Japan. Study-specific odds ratios (OR) and 95% confidence intervals (CI) estimated using logistic regression were pooled using random-effects meta-analyses. RESULTS: Postmenopausal women who used hormone therapy were at decreased risk of NHL (pooled OR = 0.79, 95% CI 0.69-0.90). Risks were reduced when the age of starting was 50 years or older. There was no clear trend with number of years of use. Current users were at decreased risk while those stopping over 2 years before diagnosis were not. Having a hysterectomy or not did not affect the risk. Favourable effects were present for DLBCL (pooled OR = 0.66, 95% CI 0.54-0.80) and FL (pooled OR = 0.82, 95% CI 0.66-1.01). CONCLUSION: Postmenopausal hormone therapy, particularly used close to menopause, is associated with a decreased risk of NHL.

Occupational exposure to trichloroethylene and risk of non-Hodgkin lymphoma and its major subtypes: a pooled InterLymph [correction of IinterLlymph] analysis.

OBJECTIVES: We evaluated the association between occupational exposure to trichloroethylene (TCE) and risk of non-Hodgkin lymphoma (NHL) in a pooled analysis of four international case-control studies. METHODS: Overall, the pooled study population included 3788 NHL cases and 4279 controls. Risk of NHL and its major subtypes associated with TCE exposure was calculated with unconditional logistic regression and polytomous regression analysis, adjusting by age, gender and study. RESULTS: Risk of follicular lymphoma (FL), but not NHL overall or other subtypes, increased by probability (p=0.02) and intensity level (p=0.04), and with the combined analysis of four exposure metrics assumed as independent (p=0.004). After restricting the analysis to the most likely exposed study subjects, risk of NHL overall, FL and chronic lymphocytic leukaemia (CLL) were elevated and increased by duration of exposure (p=0.009, p=0.04 and p=0.01, respectively) and with the combined analysis of duration, frequency and intensity of exposure (p=0.004, p=0.015 and p=0.005, respectively). Although based on small numbers of exposed, risk of all the major NHL subtypes, namely diffuse large B-cell lymphoma, FL and CLL, showed increases in risk ranging 2-3.2-fold in the highest category of exposure intensity. No significant heterogeneity in risk was detected by major NHL subtypes or by study. CONCLUSIONS: Our pooled analysis apparently supports the hypothesis of an increase in risk of specific NHL subtypes associated with occupational exposure to TCE.

Menstrual and reproductive factors, and hormonal contraception use: associations with non-Hodgkin lymphoma in a pooled analysis of InterLymph case-control studies.

BACKGROUND: The two most common forms of non-Hodgkin lymphoma (NHL) exhibit different sex ratios: diffuse large B-cell lymphoma (DLBCL) occurs more frequently in men and follicular lymphoma (FL) more frequently in women. Looking among women alone, this pooled analysis explores the relationship between reproductive histories and these cancers. MATERIALS AND METHODS: Self-reported reproductive histories from 4263 women with NHL and 5971 women without NHL were pooled across 18 case-control studies (1983-2005) from North America, Europe and Japan. Study-specific odd ratios (ORs) and confidence intervals (CIs) were estimated using logistic regression and pooled using random-effects meta-analyses. RESULTS: Associations with reproductive factors were found for FL rather than NHL overall and DLBCL. In particular, the risk of FL decreased with increasing number of pregnancies (pooled OR(trend) = 0.88, 95% CI 0.81-0.96). FL was associated with hormonal contraception (pooled OR = 1.30, 95% CI 1.04-1.63), and risks were increased when use started after the age of 21, was used for <5 years or stopped for >20 years before diagnosis. DLBCL, on the other hand, was not associated with hormonal contraception (pooled OR = 0.87, 95% CI 0.65-1.16). CONCLUSIONS: Hormonal contraception is associated with an increased risk of FL but not of DLBCL or NHL overall.

Occupational exposure to power frequency magnetic fields and risk of non-Hodgkin lymphoma.

OBJECTIVES: To investigate the risk of non-Hodgkin lymphoma (NHL) using a job-exposure matrix (JEM) to assess exposure to occupational magnetic fields at the power frequencies of 50/60 Hz. METHODS: The study population consisted of 694 cases of NHL, first diagnosed between 1 January 2000 and 31 August 2001, and 694 controls from two regions in Australia, matched by age, sex and region of residence. A detailed occupational history was given by each subject. Exposure to power frequency magnetic fields was estimated using a population-based JEM which was specifically developed in the United States to assess occupational magnetic field exposure. The cumulative exposure distribution was divided into quartiles and adjusted odds ratios were calculated using the lowest quartile as the referent group. RESULTS: For the total work history, the odds ratio (OR) for workers in the upper quartile of exposure was 1.48 (95% CI 1.02 to 2.16) compared to the referent (p value for trend was 0.006). When the exposure was lagged by 5 years the OR was 1.59 (95% CI 1.07 to 2.36) (p value for trend was 0.003). Adjusting for other occupational exposures did not significantly alter the results. CONCLUSIONS: These findings provide weak support for the hypothesis that occupational exposure to 50/60 Hz magnetic fields increases the risk of NHL.

UV-radiation-specific p53 mutation frequency in normal skin as a predictor of risk of basal cell carcinoma.

BACKGROUND: A strong association has been found between skin cancer and exposure to UV radiation. The p53 tumor suppressor gene (also known as TP53), which is frequently mutated in human cancers, is believed to be an early target in UV radiation-associated skin carcinogenesis. We have previously developed a sensitive, polymerase chain reaction-based method capable of detecting and quantifying a UV radiation-specific mutation in the p53 gene (codons 247 and 248: AAC CGG --> AAT TGG) in normal skin. We have used this method to examine whether UV radiation-specific mutation frequency is associated with risk of basal cell carcinoma (BCC) and with sun exposure. METHODS: This case-control study in Australia involved 53 case subjects with BCC and 75 control subjects. DNA was isolated from normal skin (mirror-image anatomic site to the cancer site for case subjects and a randomly selected site for control subjects) and assayed for p53 mutation. Relationships between p53 mutation frequency and risk of BCC, sun sensitivity, or sun exposure were estimated by use of odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Case subjects were more likely to have a p53 mutation than control subjects (OR = 3.1; 95% CI = 1.3-7.1). In addition, the odds of BCC increased monotonically with increasing frequency of p53 mutation. No statistically significant associations could be demonstrated between p53 mutation frequency and age, sex, sensitivity to the sun, pigmentary characteristics, total lifetime sun exposure, or sun exposure to the biopsy site. CONCLUSIONS: Our results indicate that tandem CC --> TT mutations involving codons 247 and 248 of the p53 gene are associated with an increased risk of BCC but cannot be used as an accurate measure of total UV-radiation exposure.

Should women take part in clinical trials in breast cancer? Issues and some solutions.

PURPOSE: The purpose of this review is to consider the issues for women related to participation in clinical trials that evaluate the management of breast cancer and provide some recommendations for future initiatives to address the identified areas of concern. METHODS: The National Health and Medical Research Council (NHMRC) National Breast Cancer Centre hosted an international workshop to address the question "Clinical Trials in Breast Cancer: Should Women Take Part?" We also reviewed the literature on informed participation in clinical trials that was identified in a broadly based search that covered Medline, PsycLIT, and HealthPlan from 1986 to 1996. RESULTS AND CONCLUSION: When women are asked to participate in a clinical trial, they are faced with a number of questions and dilemmas. These include issues related to the conduct and ethical considerations of the trial; the effect of participation or nonparticipation on treatment; the roles of the doctor as clinician and as researcher; the process of informed consent; the timing of the request for participation; and the benefits and costs of participation. A number of steps are identified that could help women decide whether to participate in clinical trials. These include provision of community information about clinical trials; establishment of independent brokers and registers for clinical trials; consumer review of information and protocols and involvement in trials; review of the role of ethics committees; collection of data about the proportion of women currently recruited to clinical trials, their reasons for participating or declining, and their views about the process of recruitment and participation; models for optimal practice in recruiting women to clinical trials and encouraging ongoing participation in trials; evidence-based communication skills training for clinicians to teach skills to inform women adequately of clinical trial participation; and auspicing and promotion of trials by an independent agency.

Reproducibility of reported measurements of sun exposure in a case-control study.

We examined the reproducibility of the measurement of sun exposure in a cohort study of nonmelanocytic skin cancer in Geraldton, Western Australia. Two analyses were undertaken: a comparison of cutaneous sun damage with sun exposure reported at interview, and an analysis of test-retest reproducibility of reported exposure. Skin cancers and cutaneous indicators of sun damage (cutaneous microtopography and solar elastosis of the neck) were recorded at a survey in 1987. A case-control study was conducted in 1988 in which subjects were interviewed about their lifetime sun exposure. All subjects had European ancestry. A subset of these subjects was reinterviewed using the same interview schedule in 1993. The comparison of reported exposure with skin damage was restricted to 201 cases of basal cell carcinoma and 700 controls, all of whom were born in Australia and had no southern European ancestors. The analysis of test-retest reproducibility included 62 cases with basal cell carcinoma and 162 controls. After adjustment for the skin's sensitivity to sunlight, cutaneous microtopography explained 7% and solar elastosis of the back of the neck explained 13% of the variance in the reported time spent outdoors. The intraclass correlation between time spent outdoors reported in the two interviews was 0.77 [95% confidence interval (CI), 0.71-0.83], whereas for exposure to a specific anatomical site, it was 0.65 (95% CI, 0.55-0.73). The reported site-specific exposure was lower on the second occasion in controls but higher in cases. The hours of exposure on vacations and the proportion of exposure that occurred on nonworking days had poor reproducibility. Furthermore, cases reported a more intermittent pattern of weekly exposure on the first occasion than on the second, whereas the controls showed little difference in their pattern on the two occasions. The weighted kappa statistic for lifetime painful sunburns was 0.53 (95% CI, 0.41-0.66), and for lifetime number of blistering sunburns, it was 0.54 (95% CI, 0.44-0.65). Thus, the reported sun exposure showed only moderate agreement with biological markers of sun damage. Total sun exposure and, to a lesser extent, site-specific exposure showed good agreement on the two occasions. However, indicators of intermittent sun exposure had poor agreement, and sunburn had only fair agreement.

How much melanoma is caused by sun exposure?

Estimates have been made of the proportion of cutaneous malignant melanomas caused by sun exposure by comparing the observed incidence of melanoma with estimates of the incidence in the absence of sun exposure. The estimated proportions varied from 0.97 in males and 0.96 in females in Queensland, Australia, when the incidence on the whole body was compared with that on unexposed sites, to 0.68 when incidence in people born in Australia was compared with that in migrants to Australia from areas of lower sun exposure. A comparison of US Whites and US Blacks, in which the incidence in Blacks was taken as the incidence in unexposed Whites, gave estimates of 0.96 in males and 0.92 in females. It was estimated that some 59,000 (65%) of about 92,000 melanomas that occurred worldwide in 1985 were caused by sun exposure. This is probably a minimum estimate. That 20% of the world's melanomas are estimated to occur in Black African and Asian populations and are of unknown cause would justify studies of the causes of melanoma in these populations.

Ocular melanoma is not associated with CDKN2A or MC1R variants--a population-based study.

Germline variants in the melanocortin 1 receptor gene (MC1R) and the p16 gene (CDKN2A) are associated with an increased risk of cutaneous melanoma. The frequency of these germline variants was examined in a population-based, incident series of 62 ocular melanoma cases and ethnicity-matched population controls. In both cases and controls, 59% of individuals carried at least one MC1R variant and there were no significant differences in the frequency of any of the five most common variants of MC1R. We also found no significant differences between cases and controls in the frequency of any of the four most common variants of CDKN2A, and no melanoma case carried a deleterious germline CDKN2A mutation. Our findings argue against an important predisposing effect of the MC1R and CDKN2A genes for ocular melanoma.

Epidemiological evidence for a relationship between life events, coping style, and personality factors in the development of breast cancer.

OBJECTIVE: Review empirical evidence for a relationship between psychosocial factors and breast cancer development. METHODS: Standardised quality assessment criteria were utilised to assess the evidence of psychosocial predictors of breast cancer development in the following domains: (a) stressful life events, (b) coping style, (c) social support, and (d) emotional and personality factors. RESULTS: Few well-designed studies report any association between life events and breast cancer, the exception being two small studies using the Life Events and Difficulties Schedule (LEDS) reporting an association between severely threatening events and breast cancer risk. Seven studies show anger repression or alexithymia are predictors, the strongest evidence suggesting younger women are at increased risk. There is no evidence that social support, chronic anxiety, or depression affects breast cancer development. With the exception of rationality/anti-emotionality, personality factors do not predict breast cancer risk. CONCLUSION: The evidence for a relationship between psychosocial factors and breast cancer is weak. The strongest predictors are emotional repression and severe life events. Future research would benefit from theoretical grounding and greater methodological rigour. Recommendations are given.

Skin cancer.

It is estimated that 92,000 new cases of melanoma and 2,750,000 cases of nonmelanocytic skin cancer occur worldwide each year. Incidence of these cancers varies more than 100-fold from low rates in Asian populations to very high rates in the white population of Australia. Incidence of melanoma has been increasing in white populations by some 3% to 7% per year over the past 30 years; recent very sharp increases in some populations are probably due to early and increasing detection of cancers that were already there. Incidence of nonmelanocytic skin cancers probably is also increasing. Sun exposure is the main cause of skin cancer, accounting for at least 65% of melanomas worldwide and a much higher proportion in white populations. Pattern as well as amount of sun exposure is important in determining the risk of melanoma and probably also of basal cell carcinoma, with an intermittent pattern being associated with the greatest risk. There is increasing evidence that nonsolar sources of ultraviolet radiation, in particular sunlamps and sunbeds, increase the risk of melanoma, and PUVA therapy and exposure to ionizing radiation are established causes of nonmelanocytic skin cancer.

The epidemiology of UV induced skin cancer.

There is persuasive evidence that each of the three main types of skin cancer, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma, is caused by sun exposure. The incidence rate of each is higher in fairer skinned, sun-sensitive rather than darker skinned, less sun-sensitive people; risk increases with increasing ambient solar radiation; the highest densities are on the most sun exposed parts of the body and the lowest on the least exposed; and they are associated in individuals with total (mainly SCC), occupational (mainly SCC) and non-occupational or recreational sun exposure (mainly melanoma and BCC) and a history of sunburn and presence of benign sun damage in the skin. That UV radiation specifically causes these skin cancers depends on indirect inferences from the action spectrum of solar radiation for skin cancer from studies in animals and the action spectrum for dipyrimidine dimers and evidence that presumed causative mutations for skin cancer arise most commonly at dipyrimidine sites. Sun protection is essential if skin cancer incidence is to be reduced. The epidemiological data suggest that in implementing sun protection an increase in intermittency of exposure should be avoided, that sun protection will have the greatest impact if achieved as early as possible in life and that it will probably have an impact later in life, especially in those who had high childhood exposure to solar radiation.

Evaluation of linked cancer registry and hospital records of breast cancer.

BACKGROUND: Information on the treatment of women with breast cancer in Australia is generally available only from special surveys. Analysis of routinely collected datasets may be more timely and cost effective, if the data are sufficiently accurate and complete. OBJECTIVE: To evaluate the accuracy and completeness of data on treatment in linked records of breast cancer from two routinely collected datasets. METHODS: The NSW Department of Health linked NSW Central Cancer Registry (CCR) records for 2,636 women diagnosed with breast cancer in NSW in 1992 to all hospital admission records in the NSW In-patient Statistics Collection (ISC) from January 1991 to June 1994. We queried the original paper records of subsets of women to identify missing or miscoded information and cases not notified to the CCR. We also compared the treatment data with data collected independently from the medical records of 19% of the women. RESULTS: ISC records linked to 89% of the CCR records. The CCR had identified 94.9% of women with breast cancer treated as hospital in-patients and 83% of these women had surgical treatment recorded in the ISC. The linked dataset under-estimated the percentage of women having breast-conserving therapy (-4%) and slightly over-estimated the percentage having mastectomy (+1%). We estimated that 42% of women treated surgically for breast cancer had actually had breast-conserving surgery, compared with 39% in the original dataset. There was no evident bias by age or by urban or rural residence in the under-recording of breast conservation. There was 94% agreement on the type of surgery between the linked dataset and the independent dataset.

Occupational exposure to pesticides and risk of non-Hodgkin's lymphoma.

Pesticide exposure may be a risk factor for non-Hodgkin's lymphoma, but it is not certain which types of pesticides are involved. A population-based case-control study was undertaken in 2000-2001 using detailed methods of assessing occupational pesticide exposure. Cases with incident non-Hodgkin's lymphoma in two Australian states (n = 694) and controls (n = 694) were chosen from Australian electoral rolls. Logistic regression was used to estimate the risks of non-Hodgkin's lymphoma associated with exposure to subgroups of pesticides after adjustment for age, sex, ethnic origin, and residence. Approximately 10% of cases and controls had incurred pesticide exposure. Substantial exposure to any pesticide was associated with a trebling of the risk of non-Hodgkin's lymphoma (odds ratio = 3.09, 95% confidence interval: 1.42, 6.70). Subjects with substantial exposure to organochlorines, organophosphates, and "other pesticides" (all other pesticides excluding herbicides) and herbicides other than phenoxy herbicides had similarly increased risks, although the increase was statistically significant only for "other pesticides." None of the exposure metrics (probability, level, frequency, duration, or years of exposure) were associated with non-Hodgkin's lymphoma. Analyses of the major World Health Organization subtypes of non-Hodgkin's lymphoma suggested a stronger effect for follicular lymphoma. These increases in risk of non-Hodgkin's lymphoma with substantial occupational pesticide exposure are consistent with previous work.

Cutaneous melanoma.

Between the early 1960s and the late 1980s, the incidence of melanoma increased at a rate of 3-7% per year in populations of mainly European origin. Corresponding trends were observed in mortality. Higher rates of increase in incidence were observed in a few populations (eg 8.9% per year in Hawaii whites). With the exception of Japan and possibly Puerto Rico, incidence rates of melanoma have remained stable in the few populations of mainly non-European origin for which reliable incidence data were available. A comparison of age specific trends in incidence and mortality in populations of mainly European origin showed two general patterns: a continuous increase in incidence in all age groups but with moderation or cessation of the previous rising trend in mortality in younger people in more recent time periods (eg Canada, continental USA, Denmark and the UK) and recent moderation or cessation of both incidence and mortality trends in younger people (eg New Zealand and, possibly, Hawaii whites). The first of these two patterns appeared to be the most common. Studies of site specific trends in incidence in 13 populations indicate that the highest rates of increase have generally been for melanomas on the trunk and the lowest for those on the head and neck. There is weak evidence to suggest that the rate of increase on the lower limbs has been greater in women than in men. Studies of incidence trends in the 1980s by thickness of melanoma in seven populations show that relative and absolute incidence has increased most for the thinnest melanomas and least for the thickest lesions. Increasing detection, earlier diagnosis and a real rise may together explain the increase in incidence of melanoma. The increases in mortality suggest that incidence has really increased, and the recent moderation in mortality trends may be explained by improved survival from melanoma due, most likely, to increasingly early diagnosis. In some populations, it may also indicate that the incidence increases are coming to an end. The disproportionately increasing incidence of thin melanoma, the divergence between incidence and mortality trends and the recent sharp increases in incidence in some populations suggest that earlier diagnosis or greater detection of less aggressive melanomas may have contributed to the incidence trends. A progressive change from predominantly occupational to predominantly recreational patterns of sun exposure is the most likely cause of increasing real incidence of melanoma in populations of mainly European origin.