Skin cancers are the most frequent cancers in fair-skinned populations, but we can prevent them.

Cancers of the skin are the most commonly occurring cancers in humans. In fair-skinned populations, up to 95% of keratinocyte skin cancers and 70-95% of cutaneous melanomas are caused by ultraviolet radiation and are thus theoretically preventable. Currently, however, there is no comprehensive global advice on practical steps to be taken to reduce the toll of skin cancer. To address this gap, an expert working group comprising clinicians and researchers from Africa, America, Asia, Australia, and Europe, together with learned societies (European Association of Dermato-Oncology, Euromelanoma, Euroskin, European Union of Medical Specialists, and the Melanoma World Society) reviewed the extant evidence and issued the following evidence-based recommendations for photoprotection as a strategy to prevent skin cancer. Fair skinned people, especially children, should minimise their exposure to ultraviolet radiation, and are advised to use protective measures when the UV index is forecast to reach 3 or higher. Protective measures include a combination of seeking shade, physical protection (e.g. clothing, hat, sunglasses), and applying broad-spectrum, SPF 30 + sunscreens to uncovered skin. Intentional exposure to solar ultraviolet radiation for the purpose of sunbathing and tanning is considered an unhealthy behaviour and should be avoided. Similarly, use of solaria and other artificial sources of ultraviolet radiation to encourage tanning should be strongly discouraged, through regulation if necessary. Primary prevention of skin cancer has a positive return on investment. We encourage policymakers to communicate these messages to the general public and promote their wider implementation.

Age group-specific changes in keratinocyte cancer treatment rates in Australia, 2012-2021: a retrospective cohort study based on MBS claims data.

OBJECTIVES: To examine recent changes in the numbers of Medicare-subsidised keratinocyte cancer excisions, particularly for younger people exposed to primary prevention campaigns since the early 1980s. STUDY DESIGN: Retrospective cohort study; analysis of administrative data. SETTING, PARTICIPANTS: Analysis of Medicare Benefits Schedule (MBS) claims data for procedures related to the diagnosis and treatment of keratinocyte cancer in Australia, 2012-2021. MAIN OUTCOME MEASURES: Age-standardised rates for MBS-subsidised claims for first surgical squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) excisions, Mohs surgery, surgical excisions of benign lesions, skin biopsies, and cryotherapy or serial curettage of premalignant and malignant lesions, overall, and by sex, state/territory, and age group; average annual percentage change in rate for time intervals determined by joinpoint regression. RESULTS: In men, the age-standardised rate of BCC/SCC excisions increased by 1.9% (95% confidence interval [CI], 1.4-2.4%) per year during 2012-2019 (from 2931 to 3371 per 100 000 men) and then declined by 3.8% (95% CI, 0.5-7.0%) per year during 2019-2021 (to 3152 per 100 000). In women, the age-standardised rate increased by 2.2% (95% CI, 1.7-2.8%) per year during 2012-2019 (from 1798 to 2093 per 100 000 women); the decline to 1967 excisions per 100 000 women in 2021 was not statistically significant. BCC/SCC excision rates declined for men under 55 years of age (by 1.0-3.4% per year) and women under 45 years of age (by 1.7-2.3% per year). Age-standardised biopsy rates increased during 2012-2021 in all age groups (by 2.8-6.9% per year). CONCLUSIONS: Rates of MBS-subsidised treatment for keratinocyte cancers increased during 2012-2019, but BCC/SCC treatment rates declined among younger Australians, who have probably been exposed to less sunlight than earlier generations because of public health interventions and population-wide lifestyle changes related to technology use.

Genetic predisposition to childhood obesity does not influence the risk of developing skin cancer in adulthood.

The relationship between body mass index (BMI) and melanoma and other skin cancers remains unclear. The objective of this study was to employ the Mendelian randomization (MR) approach to evaluate the effects of genetically predicted childhood adiposity on the risk of developing skin cancer later in life. Two-sample MR analyses were conducted using summary data from genome-wide association study (GWAS) meta-analyses of childhood BMI, melanoma, cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). We used the inverse-variance-weighted (IVW) methods to obtain a pooled estimate across all genetic variants for childhood BMI. We performed multiple sensitivity analyses to evaluate the potential influence of various assumptions on our findings. We found no evidence that genetically predicted childhood BMI was associated with risks of developing melanoma, cSCC, or BCC in adulthood (OR, 95% CI: melanoma: 1.02 (0.93-1.13), cSCC 0.94 (0.79-1.11), BCC 0.97 (0.84-1.12)). Our findings do not support the conclusions from observational studies that childhood BMI is associated with increased risks of melanoma, cSCC, or BCC in adulthood. Intervening on childhood adiposity will not reduce the risk of common skin cancers later in life.

Genetic Analysis of Perceived Youthfulness Reveals Differences in How Men's and Women's Age Is Assessed.

Skin aging is a natural process that occurs over time but can be accelerated by sun exposure. Measuring skin age in a large population can provide insight into the extent of skin damage from sun exposure and skin cancer risk. Understanding the genetics of skin aging, within and across sexes (males and females), could improve our understanding of the genetic drivers of both skin aging and skin cancer. We used UK Biobank data to examine the genetic overlap between perceived youthfulness and traits relevant to actinic photoaging. Our GWAS identified 22 genome-wide significant loci for women and 43 for men. The genetic correlation (rg) between perceived youthfulness in men and women was significantly less than unity (rg = 0.75, 95% confidence interval = 0.69-0.80), suggesting a gene-by-sex interaction. In women, perceived youthfulness was modestly correlated with keratinocyte cancer (rg = -0.19) and skin tanning (rg = 0.18). In men, perceived youthfulness was correlated with male-pattern baldness (rg = -0.23). This suggests that the genetic architecture of perceived youthfulness may differ between sexes, with genes influencing skin tanning and skin cancer susceptibility driving the difference in women, whereas genes influencing male-pattern baldness and other puberty-related traits drive the difference in men. We recommend that future genetic analysis of skin aging include a sex-stratified component.

Balancing the risks and benefits of sun exposure: A revised position statement for Australian adults.

OBJECTIVE: To describe the development of a new position statement regarding balancing the risks and benefits of sun exposure for Australian adults. METHODS: We conducted a Sun Exposure Summit in March 2021, with presentations from invited experts and a workshop including representation from academic, clinical, policy, and patient stakeholder organisations. The group considered advice about balancing the risks and benefits of sun exposure for Australian adults and developed a revised consensus position statement. RESULTS: The balance of risks and benefits of sun exposure is not the same for everybody. For people at very high risk of skin cancer, the risks of exposure likely outweigh the benefits; sun protection is essential. Conversely, people with deeply pigmented skin are at low risk of skin cancer but at high risk of vitamin D deficiency; routine sun protection is not recommended. For those at intermediate risk of skin cancer, sun protection remains a priority, but individuals may obtain sufficient sun exposure to maintain adequate vitamin D status. CONCLUSIONS: The new position statement provides sun exposure advice that explicitly recognises the differing needs of Australia's diverse population. IMPLICATIONS FOR PUBLIC HEALTH: Mass communication campaigns should retain the focus on skin cancer prevention. The new position statement will support the delivery of personalised advice.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

International patterns and trends in the incidence of melanoma and cutaneous squamous cell carcinoma, 1989-2020.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) and melanoma have different associations with sun exposure. OBJECTIVES: To compare trends in the incidence rates of cSCC and melanoma, to provide insight into changing patterns of exposure to ultraviolet radiation (UVR). METHODS: We compared trends in the incidence of cSCC and melanoma in seven susceptible populations residing at mid-to-high latitudes: Finland, Norway, Sweden, Denmark, Scotland, the Netherlands and Tasmania (Australia). We fitted Joinpoint models to describe trends in age-standardized incidence rates for melanoma and cSCC and calculated the average annual percentage rate of change for the period 1989-2020 (1989-2018 for Tasmania). We calculated the incident rate ratio (IRR) as the ratio of the age-standardized rates (European Standard Population) for cSCC to melanoma and conducted age-period-cohort modelling to compare age, period and cohort effects. RESULTS: The ratio of cSCC-to-melanoma incidence increased with proximity to the equator and over time. In the most recent time period, the incidence of cSCC was higher than the incidence of melanoma for men and women in all seven populations. While the ratio of cSCC-to-melanoma incidence was higher for men vs. women, in most countries the cSCC-to-melanoma IRR increased over time to a greater extent in women than in men. Melanoma incidence was higher among younger people and cSCC incidence was higher among older people; the age at which the incidence of cSCC overtook the incidence of melanoma was progressively younger with proximity to the equator. CONCLUSIONS: Despite concerted international efforts to preserve the ozone layer over the past four decades resulting in significant reductions in surface ultraviolet B at mid-latitudes, the incidence of skin cancer, particularly cSCC, continues to rise in those regions. Our findings are consistent with a stronger association with age-associated cumulative sun exposure for cSCC vs. melanoma and suggest that women are currently receiving greater UV radiation exposure than in the past.

Genetic variants for smoking behaviour and risk of skin cancer.

Observational studies have suggested that smoking may increase the risk of cutaneous squamous cell carcinoma (cSCC) while decreasing the risks of basal cell carcinoma (BCC), and melanoma. However, it remains possible that confounding by other factors may explain these associations. The aim of this investigation was to use Mendelian randomization (MR) to test whether smoking is associated with skin cancer, independently of other factors. Two-sample MR analyses were conducted to determine the causal effect of smoking measures on skin cancer risk using genome-wide association study (GWAS) summary statistics. We used the inverse-variance-weighted estimator to derive separate risk estimates across genetic instruments for all smoking measures. A genetic predisposition to smoking initiation was associated with lower risks of all skin cancer types, although none of the effect estimates reached statistical significance (OR 95% CI BCC 0.91, 0.82-1.01; cSCC 0.82, 0.66-1.01; melanoma 0.91, 0.82-1.01). Results for other measures were similar to smoking initiation with the exception of smoking intensity which was associated with a significantly reduced risk of melanoma (OR 0.67, 95% CI 0.51-0.89). Our findings support the findings of observational studies linking smoking to lower risks of melanoma and BCC. However, we found no evidence that smoking is associated with an elevated risk of cSCC; indeed, our results are most consistent with a decreased risk, similar to BCC and melanoma.

Uncovering the complex relationship between balding, testosterone and skin cancers in men.

Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to greater exposure to ultraviolet radiation or indicate a role for androgenic pathways in the pathogenesis of skin cancers. We dissected this relationship via Mendelian randomization (MR) analyses, using genetic data from recent male-only meta-analyses of cutaneous melanoma (12,232 cases; 20,566 controls) and keratinocyte cancers (KCs) (up to 17,512 cases; >100,000 controls), followed by stratified MR analysis by body-sites. We found strong associations between MPB and the risk of KC, but not with androgens, and multivariable models revealed that this relationship was heavily confounded by MPB single nucleotide polymorphisms involved in pigmentation pathways. Site-stratified MR analyses revealed strong associations between MPB with head and neck squamous cell carcinoma and melanoma, suggesting that sun exposure on the scalp, rather than androgens, is the main driver. Men with less hair covering likely explains, at least in part, the higher incidence of melanoma in men residing in countries with high ambient UV.

Health care service use by people diagnosed with invasive melanoma in Queensland: a benefit incidence analysis.

OBJECTIVE: To quantify differences, by residential remoteness and socio-economic status, in health care service use by people diagnosed with invasive melanoma in Queensland. DESIGN: Benefit incidence analysis of CancerCostMod data, comprising Queensland Cancer Registry data linked with Queensland Hospital Admitted Patient Data Collection (QHAPDC), Medicare Benefits Schedule (MBS), and Pharmaceutical Benefits Scheme (PBS) data. SETTING, PARTICIPANTS: Adults (18 years or older) newly diagnosed with invasive melanoma in Queensland during 1 July 2011 - 31 June 2015 and alive three years after diagnosis. MAIN OUTCOME MEASURES: Concentration curves and indices quantifying differences by residential postcode-based remoteness (Australian Statistical Geography Standard - Remoteness Area) and socio-economic disadvantage (Index of Relative Socioeconomic Disadvantage) in hospital admissions (overall and by type) and use of MBS (overall and by type) and PBS services during the three years following diagnosis of invasive melanoma. RESULTS: A total of 13 145 adults diagnosed with invasive melanoma during 2011-15 were alive three years after the diagnosis. Public hospital admissions were more frequent for people living in areas of greater socio-economic disadvantage (concentration index, -0.15; 95% confidence interval [CI], -0.19 to -0.12) or outside major cities (concentration index, -0.10; 95% CI, -0.13 to -0.06); private hospital admissions (concentration index, 0.11; 95% CI, 0.07-0.15) and specialist consultations (concentration index, 0.08; 95% CI, 0.07-0.10) were more frequent in areas of lesser disadvantage and in major cities (private hospital admissions: 0.10; 95% CI, 0.06-0.13; specialist services: 0.07; 95% CI, 0.06-0.09). Differences in other melanoma health care service use by residential remoteness and socio-economic disadvantage were not statistically significant. CONCLUSIONS: Variation in health care service use by Queenslanders with primary diagnoses of invasive melanoma by residential socio-economic disadvantage and remoteness were generally minor. Our analysis suggests that access to health care for people with melanoma is fairly equitable in Queensland.

Comparative age-period-cohort analysis.

BACKGROUND: Cancer surveillance researchers analyze incidence or mortality rates jointly indexed by age group and calendar period using age-period-cohort models. Many studies consider age- and period-specific rates in two or more strata defined by sex, race/ethnicity, etc. A comprehensive characterization of trends and patterns within each stratum can be obtained using age-period-cohort (APC) estimable functions (EF). However, currently available approaches for joint analysis and synthesis of EF are limited. METHODS: We develop a new method called Comparative Age-Period-Cohort Analysis to quantify similarities and differences of EF across strata. Comparative Analysis identifies whether the stratum-specific hazard rates are proportional by age, period, or cohort. RESULTS: Proportionality imposes natural constraints on the EF that can be exploited to gain efficiency and simplify the interpretation of the data. Comparative Analysis can also identify differences or diversity in proportional relationships between subsets of strata ("pattern heterogeneity"). We present three examples using cancer incidence from the United States Surveillance, Epidemiology, and End Results Program: non-malignant meningioma by sex; multiple myeloma among men stratified by race/ethnicity; and in situ melanoma by anatomic site among white women. CONCLUSIONS: For studies of cancer rates with from two through to around 10 strata, which covers many outstanding questions in cancer surveillance research, our new method provides a comprehensive, coherent, and reproducible approach for joint analysis and synthesis of age-period-cohort estimable functions.

Does genetic risk modify the effect of skin screening on melanoma detection rates?

BACKGROUND: Skin screening is associated with higher melanoma detection rates, a potential indicator of overdiagnosis, but it remains possible that this effect is due to confounding by genetic risk. OBJECTIVES: To compare melanoma incidence among screened vs. unscreened participants within tertiles of genetic risk. METHODS: We investigated melanoma incidence in the QSkin study, a prospective cohort study which for this analysis comprised 15 283 participants aged 40-69 years with genotype data and no prior history of melanoma. We calculated a polygenic score (PGS) for melanoma. We first calculated the age-standardized rate (ASR) of melanoma within PGS tertiles, and then measured the association between skin examination and melanoma detection by calculating the hazard ratio (HR) and 95% confidence interval (95% CI), overall and within PGS tertiles. RESULTS: Melanoma incidence increased with PGS (ASR per 100 000 per year): tertile 1 = 442; tertile 2 = 519; tertile 3 = 871. We found that the HRs for all melanomas (i.e. in situ and invasive) associated with skin examination differed slightly across PGS tertiles [age- and sex-adjusted tertile 1 HR 1.88 (95% CI 1.26-2.81); tertile 2 HR 1.70 (95% CI 1.20-2.41); tertile 3 HR 1.96 (95% CI 1.43-2.70); fully adjusted tertile 1 HR 1.14 (95% CI 0.74-1.75); tertile 2 HR 1.21 (95% CI 0.82-1.78); tertile 3 HR 1.41 (95% CI 1.00-1.98)], but these differences were not statistically significant. HRs for in situ melanoma associated with skin examination were similar across PGS tertiles. For invasive melanomas, the point estimates appeared to be highest in PGS tertile 3 in both the minimally adjusted (age, sex) and fully adjusted models; however, these apparent differences were also not statistically significant. CONCLUSIONS: Genetic risk predicts subsequent melanoma incidence, and is weakly associated with screening behaviour, but it does not explain the higher rate of melanoma detection between screened and unscreened people.

High-risk Prognostic Tumor Features of Squamous Cell Carcinomas in Organ Transplant Recipients Compared With the General Population.

Importance: The extent to which major high-risk features of squamous cell carcinomas (SCCs) in organ transplant recipients (OTRs) differ from SCCs in the general population is not known. Objective: To quantify the relative frequency of perineural invasion, invasion below the dermis, lack of cellular differentiation, and tumor diameter greater than 20 mm in SCCs in OTRs and the general population, by anatomic site. Design, Setting, and Participants: This dual-cohort study in Queensland, Australia, included a cohort of OTRs at high risk of skin cancer ascertained from 2012 to 2015 (Skin Tumours in Allograft Recipients [STAR] study) and a population-based cohort ascertained from 2011 (QSkin Sun and Health Study). The STAR study comprised population-based lung transplant recipients and kidney and liver transplant recipients at high risk of skin cancer recruited from tertiary centers and diagnosed with histopathologically confirmed SCC from 2012 to 2015. The QSkin participants were recruited from Queensland's general adult population, and primary SCCs diagnosed from 2012 to 2015 were ascertained through Medicare (national health insurance scheme) and linked with histopathology records. Data analysis was performed from July 2022 to April 2023. Main Outcomes and Measures: Prevalence ratio (PR) of head/neck location, perineural invasion, tumor invasion to/beyond subcutaneous fat, poor cellular differentiation, and tumor diameter greater than 20 mm among SCCs in OTRs vs the general population. Results: There were 741 SCCs excised from 191 OTRs (median [IQR] age, 62.7 [56.7-67.1] years; 149 [78.0%] male) and 2558 SCCs from 1507 persons in the general population (median [IQR] age, 63.7 [58.0-68.8] years; 955 [63.4%] male). The SCCs developed most frequently on the head/neck in OTRs (285, 38.6%), but on arms/hands in the general population (896, 35.2%) (P < .001). After adjusting for age and sex, perineural invasion was more than twice as common in OTRs as in population cases (PR, 2.37; 95% CI, 1.70-3.30), as was invasion to/beyond subcutaneous fat (PR, 2.37; 95% CI, 1.78-3.14). Poorly vs well-differentiated SCCs were more than 3-fold more common in OTRs (PR, 3.45; 95% CI, 2.53-4.71), and prevalence of tumors greater than 20 mm vs 20 mm or smaller was moderately higher in OTRs (PR, 1.52; 95% CI, 1.08-2.12). Conclusions and Relevance: In this dual-cohort study, SCCs in OTRs had significantly worse prognostic features than SCCs in the general population, reinforcing the necessity of early diagnosis and definitive management of SCCs in OTRs.

Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial.

OBJECTIVE: To investigate whether supplementing older adults with monthly doses of vitamin D alters the incidence of major cardiovascular events. DESIGN: Randomised, double blind, placebo controlled trial of monthly vitamin D (the D-Health Trial). Computer generated permuted block randomisation was used to allocate treatments. SETTING: Australia from 2014 to 2020. PARTICIPANTS: 21 315 participants aged 60-84 years at enrolment. Exclusion criteria were self-reported hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, taking >500 IU/day supplemental vitamin D, or unable to give consent because of language or cognitive impairment. INTERVENTION: 60 000 IU/month vitamin D3 (n=10 662) or placebo (n=10 653) taken orally for up to five years. 16 882 participants completed the intervention period: placebo 8270 (77.6%); vitamin D 8552 (80.2%). MAIN OUTCOME MEASURES: The main outcome for this analysis was the occurrence of a major cardiovascular event, including myocardial infarction, stroke, and coronary revascularisation, determined through linkage with administrative datasets. Each event was analysed separately as secondary outcomes. Flexible parametric survival models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: 21 302 people were included in the analysis. The median intervention period was five years. 1336 participants experienced a major cardiovascular event (placebo 699 (6.6%); vitamin D 637 (6.0%)). The rate of major cardiovascular events was lower in the vitamin D group than in the placebo group (hazard ratio 0.91, 95% confidence interval 0.81 to 1.01), especially among those who were taking cardiovascular drugs at baseline (0.84, 0.74 to 0.97; P for interaction=0.12), although the P value for interaction was not significant (<0.05). Overall, the difference in standardised cause specific cumulative incidence at five years was -5.8 events per 1000 participants (95% confidence interval -12.2 to 0.5 per 1000 participants), resulting in a number needed to treat to avoid one major cardiovascular event of 172. The rate of myocardial infarction (hazard ratio 0.81, 95% confidence interval 0.67 to 0.98) and coronary revascularisation (0.89, 0.78 to 1.01) was lower in the vitamin D group, but there was no difference in the rate of stroke (0.99, 0.80 to 1.23). CONCLUSIONS: Vitamin D supplementation might reduce the incidence of major cardiovascular events, although the absolute risk difference was small and the confidence interval was consistent with a null finding. These findings could prompt further evaluation of the role of vitamin D supplementation, particularly in people taking drugs for prevention or treatment of cardiovascular disease. TRIAL REGISTRATION: ACTRN12613000743763.

Patterns and cost of care according to keratinocyte cancer risk stratification in a volunteer population screening clinic: Real-world data from the TRoPICS study.

BACKGROUND: Risk prediction tools have been developed for keratinocyte cancers (KCs) to effectively categorize individuals with different levels of skin cancer burden. Few have been clinically validated nor routinely used in clinical settings. OBJECTIVES: To assess whether risk prediction tool categories associate with interventions including chemoprophylaxis for skin cancer, and health-care costs in a dermatologist-run screening clinic. METHODS: Adult participants who presented to a walk-in screening facility were invited to participate. A self-completed KC risk prediction tool was used to classify participants into one of the five risk categories. Participants subsequently underwent full skin examination by a dermatologist. Dermatological interventions and skin cancer-related medical prescriptions were documented. Total health-care costs, both to the health-care system and patients were evaluated. RESULTS: Of the 507 participants recruited, 5-fluorouracil cream and nicotinamide were more frequently prescribed in the higher risk groups as chemoprophylaxis (p < 0.005). A significant association with high predicted risk was also observed in the use of cryotherapy and curettage and cautery (p < 0.05). The average health-care costs associated with a skin check visit increased from $90 ± 37 (standard deviation) in the lowest risk group to $149 ± 97 in the highest risk group (p < 0.0001). CONCLUSIONS: We observed a positive association between higher predicted risk of skin cancer and the prescription of chemoprophylaxis and health-care costs involved with opportunistic community skin cancer screening. A clinical use of risk stratification may be to provide an opportunity for clinicians to discuss skin cancer prevention and chemoprophylaxis with individual patients.

The diagnosis and initial management of melanoma in Australia: findings from the prospective, population-based QSkin study.

OBJECTIVES: To determine the proportions of newly diagnosed melanomas treated by different medical specialist types, to describe the types of excisions performed, and to investigate factors associated with treating practitioner specialty and excision type. DESIGN, SETTING: Prospective cohort study; analysis of linked data: baseline surveys, hospital, pathology, Queensland Cancer Register, and Medical Benefits Schedule databases. PARTICIPANTS: Random sample of 43 764 Queensland residents aged 40-69 years recruited during 2011, with initial diagnoses of in situ or invasive melanoma diagnosed to 31 December 2019. MAIN OUTCOME MEASURES: Treating practitioner type and treatment modality for first incident melanoma; second and subsequent treatment events for the primary melanoma. RESULTS: During a median follow-up of 8.4 years (interquartile range, 8.3-8.8 years), 1683 eligible participants (720 women, 963 men) developed at least one primary melanoma (in situ melanoma, 1125; invasive melanoma, 558), 1296 of which (77.1%) were initially managed in primary care; 248 were diagnosed by dermatologists (14.8%), 83 by plastic surgeons (4.9%), 43 by general surgeons (2.6%), and ten by other specialists (0.6%). The most frequent initial procedures leading to histologically confirmed melanoma diagnosis were first excision (854, 50.7%), shave biopsy (549, 32.6%), and punch biopsy (178, 10.6%); 1339 melanomas (79.6%) required two procedures, 187 (11.1%) three. Larger proportions of melanomas diagnosed by dermatologists (87%) or plastic surgeons (71%) were in people living in urban areas than of those diagnosed in primary care (63%); larger proportions of melanomas diagnosed by dermatologists or plastic surgeons than of those diagnosed in primary care were in people with university degrees (45%, 42% v 23%) or upper quartile clinical risk scores (63%, 59% v 47%). CONCLUSIONS: Most incident melanomas in Queensland are diagnosed in primary care, and nearly half are initially managed by partial excision (shave or punch biopsy). Second or third, wider excisions are undertaken in about 90% of cases.