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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.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.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.Self-reported information about demographic, phenotypic, and sun exposure measures captured using a survey completed at baseline, and polygenic risk score for melanoma.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.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.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.

PURPOSE Surgery for epithelial ovarian cancer (EOC) may activate stress-inflammatory responses that stimulate tumor growth and increase metastatic growth. Animal and in vitro studies have shown that inhibition of the catecholamine-induced inflammatory response via beta-adrenergic receptor blockade has antitumor potential in EOC. However, observational studies have reported mixed results. We assessed whether beta-blocker (BB) use at the time of primary ovarian cancer surgery was associated with improved survival in a large population-based study. MATERIALS AND METHODS Using linked administrative data, a population-based cohort of 3,844 Australian women age 50 years or older with a history of cardiovascular conditions who underwent surgery for EOC was followed for survival outcomes. The average treatment effect of selective BB (SBB) and nonselective BB (NSBB) supply at the time of surgery on survival was estimated from a causal inference perspective using covariate-balanced inverse probability of treatment weights with flexible parametric survival models that allowed for time-varying survival effects. RESULTS Around the time of surgery, 560 (14.5%) women were supplied a SBB and 67 (1.7%) were supplied a NSBB. At 2 years postsurgery, the survival proportion was 80% (95% CI, 68 to 88) for women dispensed NSBBs at surgery compared with 69% (95% CI, 67 to 70) for women not supplied NSBBs. The survival advantage appeared to extend to at least 8 years postsurgery. No association was observed for women dispensed a SBB around the time of surgery. CONCLUSION Perioperative supply of NSBBs appeared to confer a survival advantage for women age over 50 years with a history of cardiovascular conditions. Long-term clinical trials are required to confirm these findings.

Organ transplant recipients (OTRs) are at greater risk of basal cell carcinomas (BCCs) than non-OTRs, but histopathologic differences between BCCs in OTRs and the general population are largely unknown. We compared clinicopathologic features of BCCs in OTRs vs the general population in Queensland, Australia. Details of BCC tumors (site, size, level of invasion, subtype, biopsy procedure) were collected from histopathology reports in two prospective skin cancer studies, one in OTRs and one general-population-based. We used log-binomial regression models to estimate age- and sex-adjusted prevalence ratios (PR) with 95% confidence intervals (CIs) for BCC features. Overall, there were 702 BCCs in 200 OTRs and 1725 BCCs in 804 population cases. Of these, 327 tumors in 128 OTRs were higher risk BCCs (any head and neck BCC; ≥ 2 cm on trunk/extremities), more per person than 703 higher risk BCCs in 457 cases in the general population (chi-square p = 0.008). Among head/neck BCCs, OTRs were more likely than general population cases to have BCCs on scalp/ear than on face/lip/neck (PR = 1.5, 95%CI 1.2–1.8). Although aggressive subtypes were less common among higher risk BCCs in OTRs, BCCs invading beyond the dermis were almost twice as prevalent in OTRs (PR = 1.8, 95% CI 1.3–2.6) than the general population.

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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 (κw) = 0.87, 95% confidence interval [CI]: 0.81, 0.92). Items measuring sun exposure showed lower agreement (κw range 0.36‐0.54) compared with phenotypic characteristics (κw range 0.59‐0.87). Items relating to treatment of skin cancers demonstrated almost‐perfect test‐retest repeatability (e.g. excisions for skin cancers κw 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.

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.

We sought to describe trends in the incidence of invasive melanoma by histological subtype and thickness in two populations with different approaches to the early detection of melanoma (the US White population and Queensland, Australia). The incidence of thick melanoma (> 4.00 mm) increased over the period 1999–2018 at a faster rate than thinner melanomas in both populations, and the increase was driven primarily by increases in melanoma of the nodular subtype. Thin melanomas (< 1.00 mm) were overwhelmingly of the superficial spreading subtype, whereas thick melanomas (> 4.00 mm) were dominated by nodular 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.

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.

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.

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 thy...

STUDY QUESTION How does the risk of cardiovascular disease (CVD) vary with type and age of menopause? SUMMARY ANSWER Earlier surgical menopause (e.g. 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 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 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.

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.

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.

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.

Background Hysterectomy (surgical removal of the uterus) has been consistently associated with increased thyroid cancer risk. While there may be a biologic explanation, increased ascertainment (over-diagnosis) because of greater healthcare use by women having this procedure might also contribute to the observed increased risk. We explored this association considering indications for hysterectomy, age at hysterectomy, and the potential for the association to be mediated by increased contact with health professionals or increased thyroid function testing. Methods We recruited 730 women diagnosed with thyroid cancer and 785 age-matched population controls. We estimated odds ratios (OR) using logistic regression to assess the associations and used causal mediation analysis to investigate potential mediation. Results Prior hysterectomy was associated with an increased thyroid cancer risk (OR = 1.55, 95% CI: 1.14-2.12). When stratified by indication for hysterectomy, the increased risk was apparent only among those who had undergone hysterectomy for bleeding disorders (OR = 1.79, 95% CI: 1.26-2.56). Additionally, the association varied by age at hysterectomy ( Conclusions Hysterectomy for bleeding disorders was associated with an increased risk of thyroid cancer among women and a moderate proportion of this appeared due to frequent medical contact. Key messages The way in which women use health services probably explains at least some of the association between hysterectomy and risk of thyroid cancer.

Background A personal history of keratinocyte carcinoma (KC) has been reported as a risk factor for developing subsequent primary cutaneous and non-cutaneous malignancies. However most evidence to date stems from observational studies which are prone to bias, confounding and reverse causation. Our aim was to examine this association using different Mendelian randomization (MR) approaches. Methods We performed a one-sample MR analysis using individual-level data from the UK Biobank (n = 394,306). This analysis was then validated in an independent dataset in the QSkin cohort (n = 16,896). Using 64 independent genetic variants known to be associated with KC, we generated a polygenic risk score (PRS) for each participant in the UK Biobank and the QSkin cohort. We then performed two-sample MR analyses using genome-wide association study (GWAS) summary statistics. We tested the association between genetically predicted KC and risk of subsequent cancer using logistic regression. Results Results from one-sample MR analyses in the UK Biobank indicated that a personal history of KC was significantly associated with cancer overall (excluding melanoma) (OR: 1.15, 95% CI: 1.10-1.20, per doubling the prevalence of KC). The results from the two-sample MR corroborate the findings from the one-sample MR, although the risk estimate was lower (OR: 1.05, 95% CI: 1.03-1.07). Conclusions Our MR analyses suggest that genetically predicted KC is a risk factor for developing subsequent primary malignancies. Key messages A personal history of KC may serve as a proxy marker of inherited cancer risk.

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.

Background Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, has a five-year survival of ∼45%, and very few established modifiable risk factors. Some evidence suggests that bisphosphonates could have chemopreventive benefits, but few epidemiological studies have investigated the association between bisphosphonate use and incidence of EOC. Methods We conducted a nested case-control study using linked administrative data. We identified 9,367 women over 50 years diagnosed with EOC (cases) from 2004 to 2013, and for each case identified five controls from the Australian Medicare Enrolment database matched by age, state, area of residence, and area-level socioeconomic disadvantage. We assessed the associations between bisphosphonate use using dispensed prescription data (ever use, duration and dose) and EOC (overall, by histotype), adjusting for comorbidities and MHT use. We conducted sensitivity analyses in women with complete ascertainment of dispensing claims and for residents of one Australian state that had linked with data linked to hospital procedures, including oophorectomy. Results Our analyses show an inverse association between bisphosphonate use and risk of EOC overall (OR = 0.81, 95%CI:0.75-0.88), and for endometrioid (OR = 0.51, 95%CI:0.33-0.79) and serous (OR = 0.84, 95%CI:0.75-0.93) histotypes. There was some evidence that higher dose and duration were associated with a greater reduction in risk. Results from sensitivity analyses were not appreciably different. Conclusions Bisphosphonate use was associated with lower risk of EOC, suggesting bisphosphonates may reduce risk of ovarian cancer development. Key messages Bisphosphonates may protect against development of serous and endometrioid ovarian cancers.

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.We recruited 1013 people diagnosed with thyroid cancer and 1057 population controls frequency-matched on age and sex.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.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).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.

Keratoacanthomas are common keratinocyte skin tumours. However, there is little community-based data published on the clinical features of keratoacanthoma. The aim of this study was to describe the patient and tumour characteristics of keratoacanthomas, as well as their treatment patterns. Data were obtained from the QSkin Sun and Health study, a prospective cohort of 40,438 randomly sampled and consented participants aged 40-69 years in Queensland, Australia. In 2010, a baseline survey collected data, including demography, phenotype, ultraviolet radiation exposure, medical history and lifestyle. Histopathological reports of keratoacanthomas arising until 30 June 2014 were reviewed. In total, 584 participants developed 738 keratoacanthomas; 18% of participants developed multiple tumours. Common patient characteristics were male sex (58%), age ≥60 years (76%), fair skin (80%), and previous history of actinic keratoses/keratinocyte cancers (89%). Keratoacanthomas were commonly located on the legs/feet (48%), and rarely on the the head/neck (7%). Excision was the most frequently used surgical method (71%) Evidence of histopathological regression was reported in 67% of keratoacanthomas, suggesting a potential for spontan-eous resolution in a significant proportion of keratoacanthomas.

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.

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 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.

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.

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.

Objectives The major cause of mucosal squamous cell carcinomas of the head and neck (HNSCCs) has been attributed to human papillomavirus (HPV) infection. Here we investigate if microRNA expression in HNSCC can be used as a prognostic tool with or without HPV status. Materials and Methods We performed a discovery miRNA microarray (miRBase v.21) profiling of 52 tonsillar SCCs with TaqMan real-time PCR validation of 228 HNSCCs. Patients had a histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx or larynx. Logistic regression models were used to estimate the magnitude of the effect of association with clinical factors and miRNAs associated with HPV status. For recurrence and survival analysis, we used unadjusted and multivariable adjusted Cox proportional hazard regression models. Results Seventeen miRNAs were significantly associated with better prognosis in the discovery phase and were validated in the extended dataset. The best fitting model (AUC = 0.92) for HPV status included age, smoking, and miRNAs: miR-15b, miR-20b, miR-29a, miR-29c, miR-142, miR-146a and miR-205. Using Cox regression model for recurrence, miR-29a was associated with 49% increased risk of recurrence while miR-30e and miR-342 were associated with decreased risk of recurrence with HRs 0.92 (95% CI 0.85–0.99) and 0.84 (95% CI 0.73–0.98), respectively. Our best fitting model for survival included age, gender, alcohol consumption, N stage, recurrence, HPV status, together with miRNAs-20b, 29a, and 342. Conclusion miRNAs show potential to serve as usual biomarkers to predict the clinical course of patients with mucosal HNSCC.

Despite many epidemiologic studies in the past two decades investigating whether hormonal and reproductive factors increase risk of melanoma, the issue remains unresolved. Findings appear to differ according to study design, with positive findings generally limited to case-control studies, which are prone to selection and recall bias. Given the relative paucity of prospective data on the topic, we aimed to assess the relationship between hormonal and reproductive factors and subsequent risk of melanoma in a large population-based cohort of Australian women.