Search

Importance: An increasing number of people develop more than 1 primary melanoma, yet to date, no population-based prospective cohort studies have reported on risk factors for developing first vs second primary melanomas., Objective: To compare the clinical characteristics of first and second melanomas and then to estimate the relative risks of developing 1 vs multiple melanomas associated with demographic, phenotypic, sun exposure, and genetic factors., Design, Setting, and Participants: This population-based prospective cohort study included men and women aged 40 to 69 years recruited in 2011 and followed up until December 2018 in Queensland, Australia. Data analysis was performed from February to July 2022., Exposures: Self-reported information about demographic, phenotypic, and sun exposure measures captured using a survey completed at baseline, and polygenic risk score for melanoma., Main Outcomes and Measures: Incident first or second primary melanoma diagnosis, and histologic and clinical characteristics thereof. The Wei-Lin-Weissfeld model for recurrent events was used to estimate the association of each factor with the risks of first and second primary melanoma., Results: A total of 38 845 patients (mean [SD] age at baseline, 56.1 [8.2] years; 17 775 men and 21 070 women) were included in the study. During a median follow-up period of 7.4 years, 1212 (3.1%) participants had a single primary melanoma diagnosis, and 245 (0.6%) had a second primary melanoma diagnosis. Second melanomas were more likely than first melanomas to be in situ; for invasive tumors, second melanomas were more likely to be thin (ie, ≤1 mm) than first melanomas. Having many moles at age 21 years (self-reported using visual scoring tool) was more strongly associated with second (hazard ratio [HR], 6.36; 95% CI, 3.77-10.75) than first primary melanoma (HR, 3.46; 95% CI, 2.72-4.40) (P value for difference between the HRs = .01). A high genetic predisposition (ie, polygenic risk score in tertile 3) was also more strongly associated with second (HR, 3.28; 95% CI, 2.06-5.23) than first melanoma (HR, 2.06; 95% CI, 1.71-2.49; P = .03). Second melanomas were more strongly associated with a history of multiple skin cancer excisions (HR, 2.63; 95% CI, 1.80-3.83) than first melanomas (HR, 1.86; 95% CI, 1.61-2.16; P = .05). For all other phenotypic characteristics and sun exposure measures, similarly elevated associations with first vs second melanomas were observed., Conclusions and Relevance: Findings of this cohort study suggest that within the general population, the presence of many nevi and having a high genetic predisposition to melanoma were associated with the highest risks of developing second primary melanomas.

Background: Melanoma incidence has been rising in populations with predominantly European ancestry (White), speculated to be partly driven by heightened detection of indolent tumors. If in situ melanomas are destined to evolve to invasive cancers, detecting and removing them should deplete the pool of invasive lesions, and people with in situ melanoma should, on average, be younger than those with invasive melanoma., Methods: We analyzed long-term incidence trends (1982-2018) for in situ and invasive melanomas in 3 predominantly White populations with high, medium, and low melanoma rates: Queensland (Australia), United States White, and Scotland. We calculated the incidence rate ratio (IRR) of in situ to invasive melanomas and estimated the contributions of age, period, and cohort effects. We compared age at diagnosis of in situ vs invasive melanomas overall and stratified by sex and anatomic site., Results: In all 3 populations, the in situ to invasive incidence rate ratio increased statistically significantly from less than 0.3 in 1982 to 1.95 (95% confidence interval [CI] = 1.88 to 2.02) in Queensland, 0.93 (95% CI = 0.90 to 0.96) in the US White population, and 0.58 (95% CI = 0.54 to 0.63) in Scotland in 2018. The mean age at diagnosis of in situ melanomas was the same or higher than invasive melanomas for almost all time periods among men and women and on all body sites except the lower limbs., Conclusions: The increasing ratio of in situ to invasive melanoma incidence over time, together with the high (and increasing) mean age at diagnosis of in situ melanomas, is consistent with more indolent lesions coming to clinical attention than in previous eras., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Cutaneous melanomas are common cancers in white-skinned populations, and early detection is promoted as a means of reducing morbidity and mortality. There is concern that increased skin screening is leading to overdiagnosis of indolent melanomas with low risk of lethality. The extent of melanoma overdiagnosis associated with screening is unknown., Objectives: To estimate possible overdiagnosis by comparing subsequent melanoma incidence and biopsy rates among people subjected to skin screening those who were not., Methods: We recruited 43 762 residents of Queensland, Australia, aged 40-69 years, with no prior history of melanoma, selected at random from a population register in 2010. At baseline, participants completed a comprehensive melanoma risk factor survey and were asked if their skin had been examined by a doctor in the 3 years prior to baseline. We calculated incidence and relative risk of histologically confirmed melanoma (invasive and in situ) in years 2-7 of follow-up, obtained through linkage to the cancer registry. In secondary analyses, we measured biopsy rates in years 2-6 of follow-up. We used propensity score analysis to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs)., Results: In total, 28 155 participants underwent skin screening prior to baseline. We observed 967 first-incident melanomas (381 invasive) during 197 191 person-years of follow-up. Those screened had higher rates of melanoma (aHR 1·29, 95% CI 1·02-1·63) and subsequent skin biopses (aHR 1·85, 95% CI 1·69-2·04) than unscreened participants. The higher risk associated with skin screening was evident for in situ melanoma (aHR 1·45, 95% CI 1·09-1·92) but not invasive melanoma (aHR 1·05, 95% CI 0·72-1·54). In secondary analyses, where screening was defined as having a skin biopsy in the first year after baseline, we observed significantly increased risks of melanoma (aHR 1·53, 95% CI 1·23-1·89) and subsequent biopsies (aHR 2·64, 95% CI 2·46-2·84) relative to those who did not have a biopsy., Conclusions: People who undergo skin screening subsequently experience higher rates of biopsies and melanoma (especially in situ melanoma), even after adjusting for all known risk factors, consistent with overdiagnosis. What is already known about this topic? Cutaneous melanomas are common cancers in white-skinned populations for which early detection is promoted as a means of reducing morbidity and mortality. There is concern that increased surveillance is leading to the overdiagnosis of indolent melanomas that are not destined to be lethal. The extent of melanoma overdiagnosis associated with surveillance is not known. What does this study add? People subjected to skin examinations by a doctor or who undergo skin biopsies subsequently have higher numbers of biopsies and higher rates of melanoma than people not subjected to either, even after adjusting for all known risk factors. These findings suggest that heightened surveillance leads to a proportion of melanomas being diagnosed that otherwise may not have come to clinical attention., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

A longitudinal follow-up design was used to study the psychological distress and coping among 168 individuals immediately after the national lockdown and after 6 months of the pandemic. Psychological distress was measured using the Depression, Anxiety, and Stress Scale (DASS-21). The coping strategies used were measured by the Brief-COPE, and Intolerance of Uncertainty Scale (IUS-12) was employed to measure response to uncertainty. On follow-up, the prevalence rates for severe/very severe levels of depression, anxiety, and stress had increased substantially from time 1 to time 2. The stepwise multivariate regression analyses revealed that the change in the three DASS-21 scores over time was primarily predicted by intolerance of uncertainty as measured by the IUS-12 and dysfunctional style as assessed by the coping Brief-COPE. There is a need to implement public health policies that promote psychological resilience among high-risk groups., Competing Interests: None

Background: There are few readily modifiable risk factors for epithelial ovarian cancer; preclinical studies suggest bisphosphonates could have chemopreventive actions. Our study aimed to assess the association between use of nitrogen-based bisphosphonate medicine and risk of epithelial ovarian cancer, overall and by histotype., Methods: We conducted a case-control study nested within a large, linked administrative dataset including all Australian women enrolled for Medicare, Australia's universal health insurance scheme, between July 2002 and December 2013. We included all women with epithelial ovarian cancer diagnosed at age 50 years and older between July 1, 2004, and December 31, 2013 (n = 9367) and randomly selected up to 5 controls per case, individually matched to cases by age, state of residence, area-level socioeconomic status, and remoteness of residence category (n = 46 830). We used prescription records to ascertain use of nitrogen-based bisphosphonates (ever use and duration of use), raloxifene, and other osteoporosis medicines (no nitrogen-based bisphosphonates, strontium and denosumab). We calculated adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression., Results: Ever use of nitrogen-based bisphosphonates was associated with a reduced risk of epithelial ovarian cancer compared with no use (OR = 0.81, 95% CI = 0.75 to 0.88). There was a reduced risk of endometrioid (OR = 0.51, 95% CI = 0.33 to 0.79) and serous histotypes (OR = 0.84, 95% CI = 0.75 to 0.93) but no association with the mucinous or clear cell histotypes., Conclusion: Use of nitrogen-based bisphosphonates was associated with a reduced risk of endometrioid and serous ovarian cancer. This suggests the potential for use for prevention, although validation of our findings is required., (© The Author(s) 2022. Published by Oxford University Press.)

Numerous epidemiologic studies have reported positive associations between higher nevus counts and internal cancers. Whether this association represents a true relationship or is due to bias or confounding by factors associated with both nevus counts and cancer remains unclear. We used germline genetic variants for nevus count to test whether this phenotypic trait is a risk-marker for cancer. We calculated polygenic risk scores (PRS) for nevus counts using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 17 427). The association between the nevus PRS and each cancer site was assessed using logistic regression adjusted for the effects of age, sex and the first five principal components. In both cohorts, those in the highest nevus PRS quartile had higher risks of melanoma than those in the lowest quartile (UK Biobank odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.29-1.55; QSkin OR 1.58, 95% CI: 1.29-1.94). We also observed increases in risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with higher nevus PRS quartiles (BCC UK Biobank OR 1.38, 95% CI: 1.33-1.44; QSkin OR 1.20, 95% CI: 1.05-1.38 and SCC UK Biobank OR 1.41, 95% CI: 1.28-1.55; QSkin OR 1.44, 95% CI: 1.19-1.77). We found no consistent evidence that nevus count PRS were associated with risks of developing internal cancers. We infer that associations between nevus counts and internal cancers reported in earlier observational studies arose because of unmeasured confounding or other biases., (© 2021 UICC.)

Objectives: To review the most recent population-based estimates of keratinocyte cancer incidence in Australia, to describe the trends over time and to calculate lifetime risk of developing these skin cancers., Methods: We conducted a literature search of PubMed/MEDLINE from 2001 to August 2021 to identify relevant literature. We defined eligible articles as those reporting population-based studies of adults and excluded studies that reported only on high-risk or paediatric populations, or on incidence of precursor or related lesions. We summarised identified studies qualitatively. We calculated lifetime risk of developing keratinocyte cancer using the methods of Cancer Research UK, adjusting for multiple primaries and the competing risk of death., Results: We identified six eligible studies. In the absence of compulsory notifications of keratinocyte cancer to state and territory cancer registries in Australia, all estimates of national incidence rates of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) have limitations. The most recent population-based estimates of people annually affected for the period 2011-2014 (BCC: 770/100 000 person years; SCC: 271/100 000 person years) represent the lower end of the possible range of incidence rates nationally. Because many people are affected by multiple lesions, the lesion-based incidence estimates are more than double the person-based rates (BCC: 1565/100 000 person years; SCC: 580/100 000 person years). Analyses of temporal trends in treatment rates (excisions, cryotherapy/curettage) show increases over time, most marked for people aged 55 years or older. We estimate that 69% of Australians will have at least one excision for histologically confirmed keratinocyte cancer in their lifetime (60% to age 79 years)., Conclusion: The available evidence on national incidence rates is out of date and of moderate quality, but indicates very high rates of keratinocyte cancer in Australia. We recommend that population-based cancer registries work towards statutory notification and routine reporting of keratinocyte cancer in Australia., Competing Interests: None declared.

Australia and Aotearoa New Zealand have the highest incidence of melanoma and KC in the world. We undertook a cost-of-illness analysis using Markov decision-analytic models separately for melanoma and keratinocyte skin cancer (KC) for each country. Using clinical pathways, the probabilities and unit costs of each health service and medicine for skin cancer management were applied. We estimated mean costs and 95% uncertainty intervals (95% UI) using Monte Carlo simulation. In Australia, the mean first-year costs of melanoma per patient ranged from AU$644 (95%UI: $642, $647) for melanoma in situ to AU$100,725 (95%UI: $84,288, $119,070) for unresectable stage III/IV disease. Australian-wide direct costs to the Government for newly diagnosed patients with melanoma were AU$397.9 m and AU$426.2 m for KCs, a total of AU$824.0 m. The mean costs per patient for melanoma ranged from NZ$1450 (95%UI: $1445, $1456) for melanoma in situ to NZ$77,828 (95%UI $62,525, $94,718) for unresectable stage III/IV disease. The estimated total cost to New Zealand in 2021 for new patients with melanoma was NZ$51.2 m, and for KCs, was NZ$129.4 m, with a total combined cost of NZ$180.5 m. These up-to-date national healthcare costs of melanoma and KC in Australia and New Zealand accentuate the savings potential of successful prevention strategies for skin cancer.

Objective: Smoking has been associated with a reduced risk of thyroid cancer, but whether the association varies between higher- and lower-risk cancers remains unclear. We aimed to assess the association between smoking and risk of thyroid cancer overall as well as by tumour BRAF mutational status as a marker of potentially higher-risk cancer., Design and Patients: We recruited 1013 people diagnosed with thyroid cancer and 1057 population controls frequency-matched on age and sex., Methods: Multivariable logistic regression was used to assess the association overall and in analyses stratified by tumour characteristics. We used sensitivity analysis to assess the potential for selection bias., Results: We found little evidence of an association with current smoking (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.69-1.26; current vs. never smoking), but a higher number of pack-years of smoking was associated with a lower risk of thyroid cancer (OR = 0.75; 95% CI: 0.57-0.99; ≥20 pack-years vs. never). However, after correcting for potential selection bias, we observed a statistically significant inverse association between current smoking and risk of thyroid cancer (bias-corrected OR = 0.65; 95% CI: 0.51-0.83). Those with BRAF-positive cancers were less likely to be current smokers than those with BRAF-negative cancers (prevalence ratio: 0.79; 95% CI: 0.62-0.99)., Conclusion: We found smoking was inversely related to thyroid cancer risk and, in particular, current smoking was associated with a reduced risk of potentially more aggressive BRAF-positive than the likely more indolent BRAF-negative papillary thyroid cancers., (© 2021 John Wiley & Sons Ltd.)

Relatively little is known about the epidemiology of Merkel cell carcinoma (MCC) with regard to international trends in incidence, specifically relating to differences by age, sex, and anatomic site. We examined the trends in sex-specific incidence of MCC in the United States, Australia, New Zealand, Scotland, and Norway over a 20-year period (1997-2016) as well as the site-specific incidence trends in the United States. We used Joinpoint regression models to estimate the average annual percentage change in the incidence. In the total United States population, we observed an average annual percentage change of 2.7% (95% confidence interval [CI] = 2.0-3.3) for MCC, with sex-specific incidence increasing from 0.55 to 1.03 per 100,000 in men and from 0.28 to 0.45 per 100,000 in women. MCC incidence also increased in Queensland, Australia (average annual percentage change 1.8%, 95% CI = 0.7-2.8), New Zealand (2.0%, 95% CI = 0.4-3.7), Scotland (3.7%, 95% CI = 2.0-5.5), and Norway (4.0%, 95% CI = 2.1-5.9). In all populations, MCC incidence was higher in men than in women. Between 1993 and 2016 in the United States, the incidence of MCC of the head and neck and upper and lower limbs increased in both sexes. Despite being an uncommon malignancy, our analyses show that MCC incidence is steadily increasing both in areas of low and those of high ambient UVR levels., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the test-retest repeatability of a self-completed survey with items capturing skin cancer risk factors., Methods: We invited 238 randomly selected participants of the QSkin II cohort to complete the baseline survey a second time. Responses were compared using kappa statistics and intraclass correlation coefficients to quantify agreement for categorical and continuous variables, respectively. We compared the performance of key items with that observed in an earlier repeatability study using the same survey instrument in an independent cohort., Results: Measures of phenotypic characteristics had moderate to almost-perfect test-retest repeatability (e.g. eye colour weighted kappa (κ w ) = 0.87, 95% confidence interval [CI]: 0.81, 0.92). Items measuring sun exposure showed lower agreement (κ w range 0.36-0.54) compared with phenotypic characteristics (κ w range 0.59-0.87). Items relating to treatment of skin cancers demonstrated almost-perfect test-retest repeatability (e.g. excisions for skin cancers κ w 0.85, 95%CI: 0.80, 0.89). In aggregate, the repeatability of key items was very similar across the two independent repeatability samples., Conclusion: Fair to almost-perfect repeatability for self-reported skin cancer risk factors was robust across independent and temporally distant cohorts. Implications for public health: These self-assessed risk factors for skin cancer are repeatable and suitable for use in clinical practice and research., (© 2021 The Authors.)

Background: Patient medical out-of-pocket expenses are thought to be rising worldwide yet data describing trends over time is scant. We evaluated trends of out-of-pocket expenses for patients in Australia with one of five major cancers in the first-year after diagnosis., Methods: Participants from the QSKIN Sun and Health prospective cohort Study with a histologically confirmed breast, colorectal, lung, melanoma, or prostate cancer diagnosed between 2011 and 2015 were included (n = 1965). Medicare claims data on out-of-pocket expenses were analysed using a two-part model adjusted for year of diagnosis, health insurance status, age and education level. Fisher price and quantity indexes were also calculated to assess prices and volumes separately., Results: On average, patients with cancer diagnosed in 2015 spent 70% more out-of-pocket on direct medical expenses than those diagnosed in 2011. Out-of-pocket expenses increased significantly for patients with breast cancer (mean AU$2513 in 2011 to AU$6802 in 2015). Out-of-pocket expenses were higher overall for individuals with private health insurance. For prostate cancer, expenses increased for those without private health insurance over time (mean AU$1586 in 2011 to AU$4748 in 2014) and remained stable for those with private health insurance (AU$4397 in 2011 to AU$5623 in 2015). There were progressive increases in prices and quantities of medical services for patients with melanoma, breast and lung cancer. For all cancers, prices increased for medicines and doctor attendances but fluctuated for other medical services., Conclusion: Out-of-pocket expenses for patients with cancer have increased substantially over time. Such increases were more pronounced for women with breast cancer and those without private health insurance. Increased out-of-pocket expenses arose from both higher prices and higher volumes of health services but differ by cancer type. Further efforts to monitor patient out-of-pocket costs and prevent health inequities are required., (© 2021. The Author(s).)

Background: Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites., Methods: In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants., Results: Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13-1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03-1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort., Conclusion: Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Hysterectomy has been associated with increased thyroid cancer risk but whether this reflects a biological link or increased diagnosis of indolent cancers due to greater medical contact remains unclear., Methods: We recruited 730 women diagnosed with thyroid cancer and 785 age-matched population controls. Multivariable logistic regression was used to assess the association overall, and by tumour BRAF mutational status as a marker of potentially higher-risk cancers. We used causal mediation analysis to investigate potential mediation of the association by healthcare service use., Results: Having had a hysterectomy was associated with an increased risk of thyroid cancer (odds ratio [OR] = 1.45, 95 % confidence interval [CI] 1.07-1.96). When stratified by indication for hysterectomy, the risk appeared stronger for those who had a hysterectomy for menstrual disorders (OR = 1.67, 95 % CI 1.17-2.37) but did not differ by tumour BRAF status. Approximately 20 % of the association between hysterectomy and thyroid cancer may be mediated by more frequent use of healthcare services., Conclusions: The observed increased risk of thyroid cancer among those with hysterectomy may be driven, at least partly, by an altered sex steroid hormone milieu. More frequent healthcare service use by women with hysterectomy accounts for only a small proportion of the association., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Oral infection with human papillomavirus (HPV) is likely to underpin the rapidly rising incidence of oropharyngeal squamous cell carcinoma; however, there are few data describing the natural history of oral HPV infection. We recruited 704 participants aged 20 to 70 years from worksites, universities and primary care practices in Brisbane, Australia. Participants completed questionnaires at baseline, 12 and 24 months and donate four saliva samples at baseline, 6, 12 and 24 months for HPV polymerase chain reaction testing and typing. We estimated the prevalence of oral HPV infection at baseline, incidence of new infections among those HPV-negative at baseline, clearance rate and persistent infections. At baseline, 10.7% of participants had oral HPV infections from 26 different HPV types. Sexual behaviours were associated with oral HPV infection, including more partners for passionate kissing (29 or more; odds ratio [OR] 3.4, 95% confidence interval [CI] 1.5-8.0), and giving and receiving oral sex (16 or more; OR 5.4, 95% CI 1.6-17.7 and OR 5.6, 95% CI 1.6-18.7, respectively). Of 343 participants, HPV-free at baseline and with subsequent saliva samples, 87 (25%) acquired new infections over the 24 months. Sixty-eight of 87 people included in the clearance analysis (78%) cleared their oral HPV infections. Clearance was associated with being a nonsmoker (OR 12.7, 95% CI 1.3-122.8), and no previous diagnosis of a sexually transmitted infection (OR 6.2, 95% CI 2.0-19.9). New oral infections with HPV in this sample were not rare. Although most infections were cleared, clearance was not universal suggesting a reservoir of infection exists that might predispose to oropharyngeal carcinogenesis., (© 2020 UICC.)

Background: Primary care skin cancer clinics facilitate early treatment of melanoma in Australia. We investigated the clinical and histopathological features of melanomas diagnosed and treated in an established clinic in Brisbane., Methods: Retrospective audit of medical records of patients diagnosed with in situ or invasive primary cutaneous melanoma in a primary care clinic specializing in skin cancer, 2000-2017. Demographic and clinical data were standardly extracted by a medically-trained investigator. We used descriptive analyses to assess characteristics of patients and melanomas, and examine surgical management according to tumour thickness., Results: Of 380 patients (median age 57 years; 57 % male) newly diagnosed with 497 histologically-confirmed primary cutaneous melanomas, 369 were in situ and 128 invasive. Of the 369 in situ melanomas, 143 (39 %) were on the trunk and 87 (24 %) on the head and neck; 247 (67 %) were diagnosed by shave biopsy; and 141 (38 %) referred for wide local excision (WLE). Of the 128 invasive melanomas, only 21 (16 %) had thickness ≥ 0.8 mm and these occurred more often on head and neck than thin invasive melanomas (p = 0.02). The majority of invasive melanomas were diagnosed by excision biopsy, and WLE was carried out in a median of 3 days (melanomas ≥ 0.8 mm) and 2 days (<0.8 mm). The doctor detected the majority of in situ (83 %) and thin invasive (73 %) melanomas during surveillance, compared with 48 % of thicker invasive melanomas ≥ 0.8 mm (p < 0.001)., Conclusion: In Australia, specialised primary care practice plays a major role in detection and treatment of early primary melanoma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: Keratoacanthoma (KA) is a common and generally benign keratinocyte skin tumor. Reports of the incidence rates of KA are scant. In addition, the risk factors for KA are not well understood, although associations with UV radiation exposure and older age have been described., Objective: To investigate the incidence rate of KA and the risk factors for developing KA., Design, Setting, and Participants: The study included data from 40 438 of 193 344 randomly selected residents of Queensland, Australia, who participated in the QSkin Sun and Health (QSkin) prospective population-based cohort study. All participants completed a baseline survey between 2010 and 2011 and were ages 40 to 69 years at baseline. Histopathologic reports of KA were prospectively collected until June 30, 2014, through data linkage with pathologic records. Cox proportional hazards models were used to identify risk factors associated with KA while controlling for potential confounding variables. Data were analyzed from January 2 to April 8, 2020., Exposures: Demographic characteristics, phenotypes, UV radiation exposure, medical history, and lifestyle., Results: Among 40 438 participants (mean [SD] age, 56 [8] years; 18 240 men [45.1%]), 596 individuals (mean [SD] age, 62 [6] years; 349 men [58.6%]) developed 776 KA tumors during a median follow-up period of 3.0 years (interquartile range, 2.8-3.3 years). The person-based age-standardized incidence rate for KA in the age-restricted cohort was 409 individuals per 100 000 person-years (based on the 2001 Australian population). Risk factors after adjustment for potential confounders were older age (age ≥60 years vs age <50 years; hazard ratio [HR], 6.38; 95% CI, 4.65-8.75), male sex (HR, 1.56; 95% CI, 1.33-1.84), fair skin (vs olive, dark, or black skin; HR, 3.42; 95% CI, 1.66-7.04), inability to tan (vs ability to tan deeply; HR, 1.69; 95% CI, 1.19-2.40), previous excisions of keratinocyte cancers (ever had an excision vs never had an excision; HR, 6.28; 95% CI, 5.03-7.83), current smoking (vs never smoking, HR, 2.02; 95% CI, 1.59-2.57), and high alcohol use (≥14 alcoholic drinks per week vs no alcoholic drinks per week; HR, 1.42; 95% CI, 1.09-1.86)., Conclusions and Relevance: This is, to date, the first large prospective population-based study to report the incidence rate and risk factors for KA. The high person-based incidence rate (409 individuals per 100 000 person-years) highlights the substantial burden of KA in Queensland, Australia. Furthermore, the study's findings suggest that older age (≥60 years), male sex, UV radiation-sensitive phenotypes, indications of high sun exposure (eg, previous keratinocyte cancer excisions), smoking, and high alcohol use are independent risk factors for the development of KA.

Background: Menopausal vasomotor symptoms (ie, hot flashes and night sweats) have been associated with unfavorable risk factors and surrogate markers of cardiovascular disease, but their association with clinical cardiovascular disease events is unclear., Objective: To examine the associations between different components of vasomotor symptoms, timing of vasomotor symptoms, and risk of cardiovascular disease., Study Design: We harmonized and pooled individual-level data from 23,365 women in 6 prospective studies that contributed to the International Collaboration for a Life Course Approach to Women's Reproductive Health and Chronic Disease Events consortium. Women who experienced cardiovascular disease events before baseline were excluded. The associations between frequency (never, rarely, sometimes, and often), severity (never, mild, moderate, and severe), and timing (before or after age of menopause; ie, early or late onset) of vasomotor symptoms and incident cardiovascular disease were analyzed. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals., Results: In the adjusted model, no evidence of association was found between the frequency of hot flashes and incident cardiovascular disease, whereas women who reported night sweats "sometimes" (hazard ratio, 1.22; 95% confidence interval, 1.02-1.45) or "often" (hazard ratio, 1.29; 95% confidence interval, 1.05-1.58) had higher risk for cardiovascular disease. Increased severity of either hot flashes or night sweats was associated with higher risk of cardiovascular disease. The hazards ratios of cardiovascular disease in women with severe hot flashes, night sweats, and any vasomotor symptoms were 1.83 (95% confidence interval, 1.22-2.73), 1.59 (95% confidence interval, 1.07-2.37), and 2.11 (95% confidence interval, 1.62-2.76), respectively. Women who reported severity of both hot flashes and night sweats had a higher risk for cardiovascular disease (hazard ratio, 1.55; 95% confidence interval, 1.24-1.94) than those with hot flashes alone (hazard ratio, 1.33; 95% confidence interval, 0.94-1.88) and night sweats alone (hazard ratio, 1.32; 95% confidence interval, 0.84-2.07). Women with either early-onset (hazard ratio, 1.38; 95% confidence interval, 1.10-1.75) or late-onset (hazard ratio, 1.69; 95% confidence interval, 1.32-2.16) vasomotor symptoms had an increased risk for incident cardiovascular disease compared with women who did not experience vasomotor symptoms., Conclusion: Severity rather than frequency of vasomotor symptoms (hot flashes and night sweats) was associated with increased risk of cardiovascular disease. Vasomotor symptoms with onset before or after menopause were also associated with increased risk of cardiovascular disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Thyroid cancer incidence has increased in many parts of the world since the 1980s, as has the prevalence of obesity. Evidence suggests that people with greater body size have higher thyroid cancer risk. However, it is unclear whether this association is causal or is driven by over-diagnosis of indolent cancers, because overweight/obese people use health services more frequently than those of normal weight, thus conferring greater opportunity for incidental diagnosis. Assessing whether obesity is associated with higher-risk thyroid cancers might help clarify this issue. Methods: We recruited 1013 people diagnosed with thyroid cancer between 2013 and 2016 and 1057 population controls, frequency matched by sex and age group. We used logistic regression to assess the association between body mass index (BMI) and overall thyroid cancer risk as well as by tumor BRAF mutational status as a marker of potentially higher-risk cancer. Results: Overall, obesity was associated with greater risk of thyroid cancer (odds ratio [OR] = 1.72; 95% confidence interval [CI 1.37-2.16] for obese vs. normal BMI). The association with obesity was significantly stronger for BRAF -mutation positive than BRAF -negative papillary thyroid cancers (PTCs; OR = 1.71 [CI 1.17-2.50] for BRAF- positive vs. BRAF -negative cancers). The increased risks associated with overweight/obesity did not vary by histological subtypes or presence/absence of adverse tumor histologic features. Conclusions: Greater risk of BRAF -mutated PTCs among those with high BMI suggests that the association may not merely reflect greater health care service use and indicates an independent relationship between obesity and clinically important thyroid cancer.

Study Question: How does the risk of cardiovascular disease (CVD) vary with type and age of menopause?, Summary Answer: Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause., What Is Known Already: Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear., Study Design, Size, Duration: Pooled individual-level data of 203 767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis., Participants/materials, Setting, Methods: Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35-39, 40-44, 45-49, 50-54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause., Main Results and the Role of Chance: Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16-1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50-54 years, women with surgical menopause before 35 (2.55, 2.22-2.94) and 35-39 years (1.91, 1.71-2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23-2.05 and 1.51, 1.33-1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT., Limitations, Reasons for Caution: Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results., Wider Implications of the Findings: In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD., Study Funding/competing Interest(s): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background/objectives: Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most commonly encountered cancers in fair-skinned populations worldwide. Perineural invasion is associated with worse outcomes for patients with BCC or SCC. Estimates of perineural invasion prevalence range widely, likely reflecting non-representative patient samples. We sought to determine the prevalence of perineural invasion in BCC and SCC in the general population, as well as among cancers arising in solid organ transplant recipients., Methods: We retrospectively analysed histopathology reports of BCC and SCC from patients enrolled in the QSkin Study (a population-based cohort of 43 794 Queensland residents recruited 2010-2011) and the Skin Tumours in Allograft Recipients (STAR) study (a cohort of 509 high-risk kidney or liver transplant recipients at the Princess Alexandra Hospital, Brisbane, recruited 2012-2014.) We estimated the prevalence of perineural invasion (and 95% confidence interval) in BCC and SCC, respectively, and identified clinical factors associated with perineural invasion., Results: In QSkin, we observed 35 instances of perineural invasion in 9850 histopathologically confirmed BCCs (0.36%) and 9 instances of perineural invasion in 3982 confirmed SCC (0.23%) lesions. In the STAR cohort, we identified 4 lesions with perineural invasion in 692 BCCs (0.58%) and 16 reports of perineural invasion in 875 SCC lesions (1.9%)., Conclusions: These data suggest that the overall prevalence of perineural invasion in keratinocyte cancer is low, although perineural invasion prevalence may be slightly higher among organ transplant recipients when compared to the general population., (© 2020 The Australasian College of Dermatologists.)

Background: Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach., Methods: We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height., Results: Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91-1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02-1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results., Conclusions: These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant., Objectives: To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions., Methods: Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly sampled from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure., Results: Among participants with genetic data (n = 15 373), 420 (2·7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4·4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk., Conclusions: An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3·16, 95% confidence interval 1·39-7·22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with divergent pathways for melanoma development. Linked Comment: Cust. Br J Dermatol 2020; 183:205-206. Plain language summary available online., (© 2019 British Association of Dermatologists.)

Purpose: Keratinocyte cancers are exceedingly common in high-risk populations, but accurate measures of incidence are seldom derived because the burden of manually reviewing pathology reports to extract relevant diagnostic information is excessive. Thus, we sought to develop supervised learning algorithms for classifying basal and squamous cell carcinomas and other diagnoses, as well as disease site, and incorporate these into a Web application capable of processing large numbers of pathology reports., Methods: Participants in the QSkin study were recruited in 2011 and comprised men and women age 40-69 years at baseline (N = 43,794) who were randomly selected from a population register in Queensland, Australia. Histologic data were manually extracted from free-text pathology reports for participants with histologically confirmed keratinocyte cancers for whom a pathology report was available (n = 25,786 reports). This provided a training data set for the development of algorithms capable of deriving diagnosis and site from free-text pathology reports. We calculated agreement statistics between algorithm-derived classifications and 3 independent validation data sets of manually abstracted pathology reports., Results: The agreement for classifications of basal cell carcinoma (κ = 0.97 and κ = 0.96) and squamous cell carcinoma (κ = 0.93 for both) was almost perfect in 2 validation data sets but was slightly lower for a third (κ = 0.82 and κ = 0.90, respectively). Agreement for total counts of specific diagnoses was also high (κ > 0.8). Similar levels of agreement between algorithm-derived and manually extracted data were observed for classifications of keratoacanthoma and intraepidermal carcinoma., Conclusion: Supervised learning methods were used to develop a Web application capable of accurately and rapidly classifying large numbers of pathology reports for keratinocyte cancers and related diagnoses. Such tools may provide the means to accurately measure subtype-specific skin cancer incidence.

Importance: Men and women develop melanoma at different rates on different body sites, with variation across countries, but explanations for these disparities remain elusive., Objective: To test whether observed differences in melanoma incidence between men and women vary by population, age, or anatomic site., Design: Cross-sectional analysis of sex- and site-specific temporal trends in melanoma incidence over 3 decades was conducted for men and women diagnosed with invasive melanoma in the US (limited to white race), Canada, Australia, New Zealand, the UK, Sweden, Norway, and Denmark. Using cancer registry data, male to female incidence rate ratios (IRRs) were calculated overall and by anatomic site, and Joinpoint regression models were used to estimate the annual percentage rate changes in sex- and site-specific incidence in each population. Incidence rates were standardized to the US 2000 population. Data on the incidence between January 1, 1982, and December 31, 2015, were obtained; analysis was conducted from March 1 to October 15, 2019., Main Outcomes and Measures: Male to female IRRs and annual percentage change in rates., Results: Total melanoma incidence was higher in men than women in US individuals (limited to white race), Canada, Australia, and New Zealand, but not in Denmark, the UK, Norway, and Sweden. In all populations, men had higher rates of melanoma of the head and neck and trunk than women (male to female IRR >1), but lower melanoma rates on the lower limbs (ie, male to female IRR approximately 0.5). The male to female IRR increased log linearly with age, with excess melanomas in women younger than 45 years in all populations (eg, IRR for 20-24 y age group, 0.3 in Denmark and 0.7 in Australia), and excess melanomas in men older than 69 years (eg, IRR for 70-74 y age group, 1.1 in Denmark and 2.1 in the US white population). The age at which the melanoma incidence in men exceeded the melanoma incidence in women differed by population, being achieved the earliest in Australia (45-49 years) and latest in Denmark (65-69 years)., Conclusions and Relevance: In predominantly fair-skinned populations, melanoma incidence appears to differ systematically and consistently between men and women by age and anatomic site.

Background: Population-based incidence and mortality studies of cutaneous squamous cell carcinoma (SCC) have been few owing to the commonness of the disease, and rare deaths making accurate mortality statistics difficult., Objectives: Our aim was to summarize SCC incidence and mortality in populations across three continents, exemplified by Australia, the United States (US) and Germany., Methods: We estimated age-specific and age-standardized (Australian Standard 2001 Population) incidence and mortality rates per 100 000 person-years., Results: Squamous cell carcinoma incidence is plateauing or falling in Australia, stable in the United States (2013-2015) and rising in Germany (2007-2015). Current incidence estimates in men and women are 341 and 209, 497 and 296, and 54 and 26, respectively, for the three countries. Incidence increases strongly with age in all countries. Mortality of non-melanoma skin cancer appears to be increasing in Germany and stable in Australia (unavailable for the US population)., Conclusions: Squamous cell carcinoma is an important health issue, particularly among older men, with incidence exceeding most other cancers. More precise and uniform population-based studies of incidence and mortality are needed to better quantify the impact of SCC on healthcare systems worldwide and to gauge the effect of new treatments such as anti-PD1 therapy on mortality., (© 2019 European Academy of Dermatology and Venereology.)

Background: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease., Methods: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40-44 years (early menopause), 45-49 years (relatively early), 50-51 years (reference category), 52-54 years (relatively late), and 55 years or older (late menopause)., Findings: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50-51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38-1·73; p<0·0001), early menopause (age 40-44 years; 1·30, 1·22-1·39; p<0·0001), and relatively early menopause (age 45-49 years; 1·12, 1·07-1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62-2·20; p<0·0001) and early menopause (1·40, 1·27-1·54; p<0·0001), but were attenuated at age 60-69 years, with no significant association observed at age 70 years and older., Interpretation: Compared with women who had menopause at age 50-51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women., Funding: Australian National Health and Medical Research Council., (© 2019 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY NC ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background/objective: To describe the clinical settings in which keratinocyte cancers are excised in Queensland and describe the types of practitioners who excise them; to examine costs; and to identify predictors of hospital admission., Methods: We used linked data for participants from the QSkin study (n = 43 794), including Medicare claims and Queensland hospital admissions relating to treatment episodes for incident keratinocyte cancers from July 2011 to June 2015. We used multinomial logistic regression to measure associations between demographic and clinical characteristics and treatment setting. The median costs of Medicare claims (AU$) were calculated., Results: During 4 years of follow-up, there were 18 479 skin cancer excision episodes among 8613 people. Most excisions took place in private clinical rooms (89.7%), the remainder in hospitals (7.9% private; 2.4% public). Compared with other anatomical sites, skin cancers on the nose, eyelid, ear, lip, finger or genitalia were more likely to be treated in hospitals than in private clinical rooms (public hospital OR 5.7; 95%CI 4.5-7.2; private hospital OR 8.3; 95%CI 7.3-9.4). Primary care practitioners excised 83% of keratinocyte cancers, followed by plastic surgeons (9%) and dermatologists (6%). The median Medicare benefit paid was $253 in private clinical rooms and $334 in private hospitals. Out-of-pocket payments by patients treated in private hospitals were fourfold higher than those in private clinical rooms ($351 vs $80)., Conclusions: Most keratinocyte cancers are excised in primary care, although more than 10% of excisions occur in hospital settings., (© 2019 The Australasian College of Dermatologists.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been postulated as chemopreventive agents for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), but findings from observational studies have been inconsistent, and clinical trial data are scant., Objectives: To examine the association between aspirin and NSAID (nonaspirin) use and the risk of BCC and SCC in a large cohort specifically designed for skin cancer outcomes., Methods: We used data from the QSkin Study, a prospective cohort of 43 764 residents of Queensland, Australia (34 630 were included in this study and 23 581 were used in our primary analyses). We used Cox proportional hazards models to estimate the hazard ratios (HRs) between self-reported aspirin and NSAID use 1 year prior to study baseline and the first histologically confirmed BCC or SCC for high-risk (history of skin cancer excisions or more than five actinic lesions treated) and average-to-low-risk participants (no history of skin cancer excision and at most five actinic lesions treated)., Results: After a median of 3 years of follow-up, 3421 participants developed BCC and 1470 SCC (2288 BCC and 932 SCC with complete covariate information). Among the high-risk group (1826 BCC and 796 SCC), compared with never use, frequent (at least weekly) NSAID use was associated with reduced risk of BCC (HR 0·84, 95% confidence interval 0·71-0.99) but not SCC. Aspirin use was associated with reduced risk of SCC (HR 0·77, 95% confidence interval 0·64-0·93) only among infrequent (less than weekly) users and was not associated with BCC. We observed no association between NSAID or aspirin use and the risk of BCC or SCC among average-to-low-risk participants., Conclusions: While some weakly inverse associations were observed between prior use of aspirin or NSAIDs and skin cancer, the inconsistent patterns of associations do not provide convincing evidence that these medications reduce subsequent skin cancer risk. Further data on doses, duration and long-term follow-up may help us to comprehend the cumulative dose effect., (© 2019 British Association of Dermatologists.)

Sunscreen when applied at the recommended concentration (2 mg/cm 2 ) has been shown to block the harmful molecular effects of ultraviolet radiation (UVR) in vivo. In real world conditions, however, sunscreen is often not applied/reapplied sufficiently to yield protection. This field study tested the effectiveness of UV detection stickers to prevent sunburn and improve reapplication of sunscreen. During the Ashes Cricket Test match event (November 2017) in Brisbane, Australia interested spectators were recruited into the control group on DAY-1 and during subsequent days (DAY-2, DAY-3, DAY-4) new participants were recruited into the UV-Sticker group. Participants in both groups were provided with free sunscreen and participants in the UV-Sticker group were additionally provided with a UV detection sticker. Primary outcomes were self-reported sunburns and reapplication of sunscreen. Secondary endpoints included satisfaction with the UV detection stickers. 813 participants enrolled in the study, and complete data is available for 428 participants (52.6% response rate, n = 369 UV detection sticker, n = 59 control). Participants provided with a UV detection sticker were more likely to re-apply sunscreen than controls (80% vs 68%, p = 0.04); but do not reduce sunburn rates. UV detection stickers may improve sunscreen re-application in a high UV-environment. Trial registration: Australian and New Zealand clinical trials register (ACTRN12617001572358)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Early menopause is associated with an increased risk of subsequent cardiovascular disease (CVD). Few studies have investigated the converse. We examined whether premenopausal CVD events are associated with early age at menopause. We pooled the individual data of 177,131 women from nine studies. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRR) and 95% confidence intervals (CI) for the associations between age at onset of premenopausal CVD events-including coronary heart disease (CHD) and stroke-and age at natural menopause. Altogether 1561 (0.9%) premenopausal participants reported CVD events (including 1130 CHD and 469 stroke) at a mean age of 41.3 years. Compared with women without any premenopausal CVD events, women who experienced a first CVD event before age 35 years had a twofold risk of menopause before age 45 years (early menopause); adjusted RRR (95% CI) of 1.92 (1.17, 3.14) for any CVD, 1.86 (1.01, 3.43) for CHD and 2.17 (1.43, 3.30) for stroke. Women who experienced a first premenopausal CVD event after age 40 years underwent a natural menopause at the expected age (around 51 years). These associations were robust to adjustment for smoking status, BMI, educational level, race/ethnicity, age at menarche, parity, hypertension and family history of CVD. For premenopausal women, a first CVD event before age 35 years is associated with a doubling of the risk of an early menopause, while a first CVD event occurred after 35 years indicates a normal menopause at around 51 years. Shared genetic and environmental factors (such as smoking), as well as compromised vasculature following CVD events, may contribute to this outcome.

Background: The incidence of thyroid cancer has rapidly increased, and ecological evidence suggests this is due in some part to over-diagnosis. Understanding pathways to diagnosis could help determine whether unnecessary diagnosis can be avoided., Methods: A population-based sample (n = 1007) of thyroid cancer patients diagnosed between July 2013 and August 2016 was recruited from Queensland, Australia (response rate 67%). Information from structured telephone interviews was used to describe diagnostic pathways for thyroid cancer, to investigate factors associated with diagnostic pathways, and to assess the most prevalent modes of diagnoses by which the lowest-risk, potentially over-diagnosed thyroid cancers (intrathyroidal microcarcinomas) are detected., Results: Only 38% of participants presented with symptoms potentially related to thyroid cancer. Older age at diagnosis was associated with a lower prevalence of symptomatic diagnosis (prevalence ratio [PR] = 0.46 [confidence interval (CI) 0.31-0.68] for 70-79 vs. <30 years), as was frequent medical contact, while living in rural/regional areas was associated with a higher prevalence of symptomatic diagnosis (PR = 1.17 [CI 1.00-1.37] for rural/regional areas vs. major cities). Symptomatic diagnosis also occurred more for those whose tumors had adverse histopathological features (larger size, lymph node involvement, lymphovascular invasion). The likelihood of diagnosis of intrathyroidal microcarcinomas was greatest for those having surgical resection or monitoring for benign thyroid disease (PR = 3.87 [CI 2.81-5.32] and PR = 2.21 [CI 1.53-3.18], respectively)., Conclusions: A minority of newly detected thyroid cancer cases were diagnosed because of symptoms. Access to medical care and factors related to cancer aggressiveness were associated with how diagnoses occurred. The likelihood of diagnosing the lowest-risk thyroid cancers was higher in situations related to management of other thyroid conditions. Adherence to thyroid management guidelines could reduce some thyroid cancer over-diagnosis, but ultimately better diagnostic tools are needed to differentiate between indolent cancers and those of clinical significance.

Importance: Concerns around possible overdiagnosis and overtreatment of differentiated thyroid cancer (DTC) have been raised. Issues concerning health-related quality of life (HRQOL) after diagnosis and treatment of DTC are understudied in this patient group., Objective: To better understand the range of HRQOL outcomes, including possible adverse effects of treatment, associated with diagnosis and treatment of DTC and whether these outcomes vary by type of surgery received., Design, Setting, and Participants: This content analysis assessed responses to an open-ended question about outcomes and concerns after DTC diagnosis and treatment among patients ascertained from the major postsurgical thyroid cancer treatment center and the population-based Cancer Registry in Queensland, Australia. Participants were aged 18 to 79 years and recently diagnosed with throid cancer. Responses underwent analysis to identify and code emergent themes to describe HRQOL issues and adverse effects of treatment experienced. Quantitative analysis was used to explore whether surgery type was associated with HRQOL issues and/or adverse effects of treatment. Of 1416 eligible patients, 1005 (71.0%) participated. Data were collected from July 1, 2013, through August 31, 2016, and analyzed from January 11 through April 9, 2018., Main Outcomes and Measures: Issues concerning HRQOL., Results: The analysis included 1005 patients (72.2% female [n = 726]; mean [SD] age, 52 [14.0 years) with DTC. Most patients were diagnosed with papillary thyroid cancer (889 of 1003 [88.6%]), had tumors smaller than 2 cm in size (564 of 1000 [56.4%]), and received a total thyroidectomy (791 of 1005 [78.7%]). Overall, 775 patients (77.1%) reported HRQOL issues after diagnosis and treatment of DTC. The following 4 main themes emerged from content analysis of patient responses: physical (663 [66.0%]), psychological (187 [18.6%]), lifestyle (82 [8.2%]), and no issue or adverse effect (246 [24.5%]). Patients who had a total thyroidectomy (without neck dissection) were 1.5 times (odds ratio, 1.49; 95% CI, 1.04-2.12) more likely to report an HRQOL issue or an adverse effect of treatment compared with patients who underwent a hemithyroidectomy., Conclusions and Relevance: According to results of this study, patients diagnosed with DTC report wide-ranging HRQOL issues; these are more prevalent among patients who have total thyroidectomies rather than hemithyroidectomies. For patients with small, localized DTCs, hemithyroidectomy may offer fewer adverse effects of treatment and better HRQOL outcomes than total thyroidectomy. It appears that issues with HRQOL should be considered by patients and physicians when deciding on the best treatment approach after a diagnosis of DTC.

To delineate causal pathways for melanoma, it is essential to derive unbiased estimates of risk. Extant knowledge derives largely from case-control studies with potential for bias. In a population-based prospective study (QSkin, n = 38,854), we assessed melanoma risks associated with pigmentation characteristics and other phenotypes, and we explored additive interactions. We fitted Cox proportional hazards models to adjust for other factors to estimate the independent effects of each characteristic on melanoma risk. During a mean follow-up of 3.5 years, 642 (1.5%) participants developed melanoma (253 invasive, 389 in situ). The characteristics most strongly associated with invasive melanoma were self-reported nevus density at age 21 years (many vs. no moles hazard ratio [95% confidence interval] = 4.91 [2.81-8.55]), inability to tan (no tan vs. deep tan, hazard ratio [95% confidence interval] = 3.39 [1.85-6.20]), and red hair color (vs. black, hazard ratio [95% confidence interval] = 3.11 [1.50-6.43]). Propensity to sunburn was not associated with melanoma after tanning inability was adjusted for. People with both high nevus density and a history of multiple keratinocyte cancers had significantly higher melanoma risks than those with only one of those traits. We infer that melanoma risk is more strongly related to nevus density and inability to tan than susceptibility to sunburn., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hysterectomy is a common surgical procedure, predominantly performed when women are between 30 and 50 years old. One in 3 women in Australia has had a hysterectomy by the time they are 60 years old, and 30% have both ovaries removed at the time of surgery. Given this high prevalence, it is important to understand the long-term effects of hysterectomy. In particular, women who have a hysterectomy/oophorectomy at younger ages are likely to be premenopausal or perimenopausal and may experience greater changes in hormone levels and a shortened reproductive lifespan than women who have a hysterectomy when they are older and postmenopausal. Use of menopausal hormone therapy after surgery may compensate for these hormonal changes. To inform clinical decisions about postsurgery management of women who have a hysterectomy prior to menopause (ie, average age at menopause 50 years), it is useful to compare women with a hysterectomy to women with no hysterectomy and to stratify the hysterectomy status by whether or not women have had a bilateral oophorectomy, or used menopausal hormone therapy., Objective: We sought to investigate whether women who had a hysterectomy with ovarian conservation or a hysterectomy and bilateral oophorectomy before the age of 50 years were at a higher risk of premature all-cause mortality compared to women who did not have this surgery before the age of 50 years. We also sought to explore whether use of menopausal hormone therapy modified these associations., Study Design: Women from the midcohort (born 1946 through 1951) of the Australian Longitudinal Study on Women's Health were included in our study sample (n = 13,541). Women who reported a hysterectomy (with and without both ovaries removed) before the age of 50 years were considered exposure at risk and compared with women who did not report these surgeries before age 50 years. To explore effect modification by use of menopausal hormone therapy we further stratified hysterectomy status by menopausal hormone therapy use. Risk of all-cause mortality was assessed using inverse-probability weighted Cox regression models., Results: During a median follow-up of 21.5 years, there were 901 (6.7%) deaths in our study sample. Overall, there was no difference in all-cause mortality between women who reported a hysterectomy with ovarian conservation (hazard ratio, 0.86; 95% confidence interval, 0.72-1.02) or women who reported a hysterectomy and bilateral oophorectomy (hazard ratio, 1.02; 95% confidence interval, 0.78-1.34) and women with no hysterectomy. When stratified by menopausal hormone therapy use, women with hysterectomy and ovarian conservation before the age of 50 years were not at higher risk of all-cause mortality compared to no hysterectomy, regardless of menopausal hormone therapy use status. In contrast, among nonusers of menopausal hormone therapy only, women who reported a hysterectomy-bilateral oophorectomy before the age of 50 years were at a higher risk of death compared to women with no hysterectomy (hazard ratio, 1.81; 95% confidence interval, 1.01-3.25)., Conclusion: Hysterectomy with ovarian conservation before the age of 50 years did not increase risk of all-cause mortality. Among nonmenopausal hormone therapy users only, hysterectomy and bilateral oophorectomy before the age of 50 years was associated with a higher risk of death., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause., Methods and Findings: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias., Conclusions: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JEC is a director of Dietary Assessment Ltd, a University of Leeds spin out company to support measurement of dietary intake. All other authors have declared that no competing interests exist.

Background: Many women experience both vasomotor menopausal symptoms (VMS) and depressed mood at midlife, but little is known regarding the prospective bi-directional relationships between VMS and depressed mood and the role of sleep difficulties in both directions., Methods: A pooled analysis was conducted using data from 21 312 women (median: 50 years, interquartile range 49-51) in eight studies from the InterLACE consortium. The degree of VMS, sleep difficulties, and depressed mood was self-reported and categorised as never, rarely, sometimes, and often (if reporting frequency) or never, mild, moderate, and severe (if reporting severity). Multivariable logistic regression models were used to examine the bi-directional associations adjusted for within-study correlation., Results: At baseline, the prevalence of VMS (40%, range 13-62%) and depressed mood (26%, 8-41%) varied substantially across studies, and a strong dose-dependent association between VMS and likelihood of depressed mood was found. Over 3 years of follow-up, women with often/severe VMS at baseline were more likely to have subsequent depressed mood compared with those without VMS (odds ratios (OR) 1.56, 1.27-1.92). Women with often/severe depressed mood at baseline were also more likely to have subsequent VMS than those without depressed mood (OR 1.89, 1.47-2.44). With further adjustment for the degree of sleep difficulties at baseline, the OR of having a subsequent depressed mood associated with often/severe VMS was attenuated and no longer significant (OR 1.13, 0.90-1.40). Conversely, often/severe depressed mood remained significantly associated with subsequent VMS (OR 1.80, 1.38-2.34)., Conclusions: Difficulty in sleeping largely explained the relationship between VMS and subsequent depressed mood, but it had little impact on the relationship between depressed mood and subsequent VMS.

Background: Risk stratification can improve the efficacy and cost-efficiency of screening programs for early detection of cancer. We sought to derive a risk stratification tool for melanoma that was suitable for the general population using only self-reported information., Methods: We used melanoma risk factor information collected at baseline from QSKIN, a prospective cohort study of Queensland adults age 40 to 69 years at recruitment (n = 41 954). We examined two separate outcomes: 1) invasive melanomas and 2) all melanomas (invasive + in situ) obtained through data linkage to the cancer registry. We used stepwise Cox proportional hazards modeling to derive the risk models in a randomly selected two-thirds sample of the data set and assessed model performance in the remaining one-third validation sample., Results: After a median follow-up of 3.4 years, 655 (1.6%) participants developed melanoma (257 invasive, 398 in situ). The prediction model for invasive melanoma included seven terms. At baseline, the strongest predictors of invasive melanoma were age, sex, tanning ability, number of moles at age 21 years, and number of skin lesions treated destructively. The model for "all melanomas" (ie, invasive and in situ) included five additional terms. Discrimination in the validation data set was high for both models (C-index = 0.69, 95% confidence interval [CI] = 0.62 to 0.76, and C-index = 0.72, 95% CI = 0.69 to 0.75, respectively), and calibration was acceptable., Conclusions: Such a tool could be used to target surveillance activities to those at highest predicted risk of developing melanoma over a median duration of 3.4 years.

Aim: To examine the prospective associations between aspects of a woman's reproductive history and incident diabetes., Methods: We pooled individual data from 126 721 middle-aged women from eight cohort studies contributing to the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE). Associations between age at menarche, age at first birth, parity and menopausal status with incident diabetes were examined using generalized linear mixed models, with binomial distribution and robust variance. We stratified by body mass index (BMI) when there was evidence of a statistical interaction with BMI., Results: Over a median follow-up of 9 years, 4073 cases of diabetes were reported. Non-linear associations with diabetes were observed for age at menarche, parity and age at first birth. Compared with menarche at age 13 years, menarche at ≤10 years was associated with an 18% increased risk of diabetes (relative risk [RR] 1.18, 95% confidence interval [CI] 1.02-1.37) after adjusting for BMI. After stratifying by BMI, the increased risk was only observed in women with a BMI ≥25 kg/m 2 . A U-shaped relationship was observed between parity and risk of diabetes. Compared with pre-/peri-menopausal women, women with a hysterectomy/oophorectomy had an increased risk of diabetes (RR 1.17, 95% CI 1.07-1.29)., Conclusions: Several markers of a woman's reproductive history appear to be modestly associated with future risk of diabetes. Maintaining a normal weight in adult life may ameliorate any increase in risk conferred by early onset of menarche., (© 2018 John Wiley & Sons Ltd.)

A proportion of cutaneous melanomas display neval remnants on histologic examination. Converging lines of epidemiologic and molecular evidence suggest that melanomas arising from nevus precursors differ from melanomas arising de novo. In a large, population-based study comprising 636 cutaneous melanomas subjected to dermatopathology review, we explored the molecular, host, and environmental factors associated with the presence of neval remnants. We found that nevus-associated melanomas were significantly associated with younger age at presentation, non-brown eye color, trunk site, thickness of less than 0.5 mm, and BRAF V600E mutation. Compared with patients with de novo melanomas, those with nevus-associated tumors were more likely to self-report many moles on their skin as a teenager (odds ratio = 1.94, 95% confidence interval = 1.01-3.72) but less likely to report many facial freckles (odds ratio = 0.49, 95% confidence interval = 0.25-0.96). They also had high total nevus counts (odds ratio = 2.18, 95% confidence interval = 1.26-3.78). On histologic examination, nevus-associated melanomas exhibited less dermal elastosis in adjacent skin compared with de novo melanomas (odds ratio = 0.55, 95% confidence interval = 0.30-1.01). These epidemiologic data accord with the emerging molecular paradigm that nevus-associated melanomas arise through a distinct sequence of causal events that differ from those leading to other cutaneous melanomas., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Current evidence on the association between body mass index (BMI) and age at menopause remains unclear. We investigated the relationship between BMI and age at menopause using data from 11 prospective studies. A total of 24,196 women who experienced menopause after recruitment was included. Baseline BMI was categorised according to the WHO criteria. Age at menopause, confirmed by natural cessation of menses for ≥ 12 months, was categorised as < 45 years (early menopause), 45-49, 50-51 (reference category), 52-53, 54-55, and ≥ 56 years (late age at menopause). We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CI) for the associations between BMI and age at menopause. The mean (standard deviation) age at menopause was 51.4 (3.3) years, with 2.5% of the women having early and 8.1% late menopause. Compared with those with normal BMI (18.5-24.9 kg/m 2 ), underweight women were at a higher risk of early menopause (RRR 2.15, 95% CI 1.50-3.06), while overweight (1.52, 1.31-1.77) and obese women (1.54, 1.18-2.01) were at increased risk of late menopause. Overweight and obesity were also significantly associated with around 20% increased risk of menopause at ages 52-53 and 54-55 years. We observed no association between underweight and late menopause. The risk of early menopause was higher among obese women albeit not significant (1.23, 0.89-1.71). Underweight women had over twice the risk of experiencing early menopause, while overweight and obese women had over 50% higher risk of experiencing late menopause.

Aims: There is limited longitudinal research that has looked at the longer term incidence of depressive symptoms, comparing women with a hysterectomy to women without a hysterectomy. We aimed to investigate the association between hysterectomy status and the 12-year incidence of depressive symptoms in a mid-aged cohort of Australian women, and whether these relationships were modified by use of exogenous hormones., Methods: We used generalised estimating equation models for binary outcome data to assess the associations of the incidence of depressive symptoms (measured by the 10-item Centre for Epidemiologic Studies Depression Scale) across five surveys over a 12-year period, in women with a hysterectomy with ovarian conservation, or a hysterectomy with bilateral oophorectomy compared with women without a hysterectomy. We further stratified women with hysterectomy by their current use of menopausal hormone therapy (MHT). Women who reported prior treatment for depression were excluded from the analysis., Results: Compared with women without a hysterectomy (n = 4002), both women with a hysterectomy with ovarian conservation (n = 884) and women with a hysterectomy and bilateral oophorectomy (n = 450) had a higher risk of depressive symptoms (relative risk (RR) 1.20; 95% confidence interval (CI) 1.06-1.36 and RR 1.44; 95% CI 1.22-1.68, respectively). There were differences in the strength of the risk for women with a hysterectomy with ovarian conservation, compared with those without, when we stratified by current MHT use. Compared with women without a hysterectomy who did not use MHT, women with a hysterectomy with ovarian conservation who were also MHT users had a higher risk of depressive symptoms (RR 1.57; 95% CI 1.31-1.88) than women with a hysterectomy with ovarian conservation but did not use MHT (RR 1.17; 95% CI 1.02-1.35). For women with a hysterectomy and bilateral oophorectomy, MHT use did not attenuate the risk. We could not rule out, however, that the higher risk seen among MHT users may be due to confounding by indication, i.e. MHT was prescribed to treat depressive symptoms, but their depressive symptoms persisted., Conclusions: Women with a hysterectomy (with and without bilateral oophorectomy) have a higher risk of new incidence of depressive symptoms in the longer term that was not explained by lifestyle or socio-economic factors.

Background: Previous studies suggest that smokers have lower risks of cutaneous melanoma than nonsmokers, but data from population-based prospective studies are scarce. We investigated associations between smoking and melanoma in a cohort study purpose-designed to investigate skin cancer outcomes. Methods: Participants with no prior history of melanoma ( n = 38,697) completed a risk factor survey at baseline (2011). Patients were followed through linkage to the cancer registry. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between smoking (including intensity, duration, time since quitting) and melanoma using multivariate Cox proportional hazards regression, accounting for death as a competing event. Results: During a mean follow-up of 3.5 years, invasive melanomas developed in 247 participants. Compared with never smokers, former smokers (but not current smokers) had lower risks of invasive melanoma (HR 0.76; 95% CI, 0.57-1.01). Among former smokers, risks were lower with greater quantity of cigarettes smoked (HR 0.75; 95% CI, 0.56-0.98 per 10 cigarettes/day). No association was observed with duration of smoking while longer time since quitting was associated with a relative risk of melanoma that was not significantly different from the null (HR 1.18; 95% CI, 0.91-1.51, for every 10 years since quitting). Conclusions: We observed complex associations between smoking and melanoma, with some suggestion that former smokers had lower risks than never or current smokers. The apparent inverse association among former smokers may be due to residual confounding, although surveillance bias or biological effects cannot be excluded entirely. Impact: Smoking does not increase the risk of cutaneous melanoma. Cancer Epidemiol Biomarkers Prev; 27(8); 874-81. ©2018 AACR ., (©2018 American Association for Cancer Research.)