Does polygenic risk influence associations between sun exposure and melanoma? A prospective cohort analysis.

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.

Aspirin and nonsteroidal anti-inflammatory drug use and keratinocyte cancers: a large population-based cohort study of skin cancer in Australia.

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.

Incidence and mortality for cutaneous squamous cell carcinoma: comparison across three continents.

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.

Increasing thyroid cancer incidence in Queensland, Australia 1982-2008 - true increase or overdiagnosis?

BACKGROUND: Thyroid cancer incidence has been increasing worldwide. Some suggest greater ascertainment of indolent tumours is the only driver, but others suggest there has been a true increase. Increases in Australia appear to have been among the largest in the world, so we investigated incidence trends in the Australian state of Queensland to help understand reasons for the rise. METHODS: Thyroid cancers diagnoses in Queensland 1982-2008 were ascertained from the Queensland Cancer Registry. We calculated age-standardized incidence rates (ASR) and used Poisson regression to estimate annual percentage change (APC) in thyroid cancer incidence by socio-demographic and tumour-related factors. RESULTS: Thyroid cancer ASR in Queensland increased from 2·2 to 10·6/100 000 between 1982 and 2008 equating to an APC of 5·5% [95% confidence interval (CI) 4·7-6·4] in men and 6·1% (95% CI 5·5-6·6) in women. The rise was evident, and did not significantly differ, across socio-economic and remoteness-of-residence categories. The largest increase seen was in the papillary subtype in women (APC 7·9%, 95% CI 7·3-8·5). Incidence of localized and more advanced-stage cancers rose over time although the increase was greater for early-stage cancers. CONCLUSION: There has been a marked increase in thyroid cancer incidence in Queensland. The increase is evident in men and women across all adult age groups, socio-economic strata and remoteness-of-residence categories as well as in localized and more advanced-stage cancers. Our results suggest 'overdiagnosis' may not entirely explain rising incidence. Contemporary aetiological data and individual-level information about diagnostic circumstances are required to further understand reasons for rising thyroid cancer incidence.

Prevalence and determinants of frequent gastroesophageal reflux symptoms in the Australian community.

Frequent gastroesophageal reflux (GER) causes chronic inflammation and damages esophageal mucosa, which can lead to Barrett's esophagus. It has also been consistently found to be a strong risk factor for esophageal adenocarcinoma. The prevalence of GER appears to vary; however, population-based Australian studies investigating the symptoms are limited. This study aimed to estimate the population prevalence and identify the determinants of frequent GER symptoms in the Australian population. Self-reported information on the frequency of reflux symptoms were collected from 1,580 adults from a population register. We estimated age- and sex-standardized prevalence of occasional (

Gastro-oesophageal reflux symptoms and the risks of oesophageal cancer: are the effects modified by smoking, NSAIDs or acid suppressants?

OBJECTIVE: To measure the extent to which risks of oesophageal cancers associated with gastro-oesophageal reflux (GOR) are modified by common factors including smoking, non-steroidal anti-inflammatory drugs (NSAIDs) and acid suppressant medications. DESIGN AND SETTING: Population-based case-control study. PARTICIPANTS: Cases were patients with oesophageal (OAC; n = 365) or gastro-oesophageal junction (GOJAC; n = 426) adenocarcinomas, or squamous cell carcinomas (OSCC; n = 303). Controls were sampled from a population register (n = 1580). MAIN OUTCOME MEASURE: Odds ratio and 95% confidence interval. RESULTS: Frequent (at least weekly) symptoms of GOR were associated with significant 6.4-fold, 4.6-fold and 2.2-fold increased risks of OAC, GOJAC and OSCC, respectively. Under models examining effects of combined exposure, patients with frequent GOR symptoms who were also heavy smokers had markedly higher OAC risks (OR = 12.3, 95% CI 6.3 to 24.0) than those with frequent GOR who did not smoke (OR = 6.8, 95% CI 3.6 to 12.9). Similar patterns were observed for GOJAC and OSCC. Among people with frequent GOR symptoms, regular use of aspirin/NSAIDs was associated with almost two-thirds lower OAC risks (OR = 4.8, 95% CI 2.5 to 9.2) than non-users (13.9, 95% CI 6.5 to 30.0). In contrast, among those with frequent GOR symptoms, users of acid suppressants had similar OAC risks (OR 7.8, 95% CI 5.2 to 11.8) to non-users (OR 5.3, 95% CI 3.2 to 9.0). CONCLUSIONS: People experiencing frequent GOR symptoms have markedly increased risks of OAC and GOJAC, and this effect may be greater amongst smokers. Use of aspirin and NSAIDs, but not acid suppressants, significantly reduced the risks of oesophageal cancers associated with GOR.

MicroRNA expression is associated with human papillomavirus status and prognosis in mucosal head and neck squamous cell carcinomas.

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.

Does type 2 diabetes influence the risk of oesophageal adenocarcinoma?

Since hyperinsulinaemia may promote obesity-linked cancers, we compared type 2 diabetes prevalence among oesophageal adenocarcinoma (OAC) patients and population controls. Diabetes increased the risk of OAC (adjusted odds ratio 1.59, 95% confidence interval (CI) 1.04-2.43), although the risk was attenuated after further adjusting for body mass index (1.32, 95% CI 0.85-2.05).

Leptin and the risk of Barrett's oesophagus.

BACKGROUND: Obesity is associated with increased risks of Barrett's oesophagus and oesophageal adenocarcinoma. Alterations in serum leptin and adiponectin, obesity-related cytokines, have been linked with several cancers and have been postulated as potential mediators of obesity-related carcinogenesis; however, the relationship with Barrett's oesophagus remains unexplored. METHODS: Serum leptin and adiponectin concentrations were measured on two subsets of participants within a case-control study conducted in Brisbane, Australia. Cases were people aged 18-79 years with histologically confirmed Barrett's oesophagus newly diagnosed between 2003 and 2006. Population controls, frequency matched by age and sex to cases, were randomly selected from the electoral roll. Phenotype and medical history data were collected through structured, self-completed questionnaires. Odds ratios (OR) and 95% CI were calculated using multivariable logistic regression analysis. RESULTS: In the pilot analysis (51 cases, 67 controls) risks of Barrett's oesophagus were highest among those in the highest quartile of serum leptin (OR 4.6, 95% CI 0.6 to 33.4). No association was seen with adiponectin. In the leptin validation study (306 cases, 309 controls), there was a significant threefold increased risk of Barrett's oesophagus among men in the highest quartile of serum leptin (OR 3.3, 95% CI 1.7 to 6.6) and this persisted after further adjustment for symptoms of gastro-oesophageal reflux (OR 2.4, 95% CI 1.1 to 5.2). In contrast, the risk of Barrett's oesophagus among women decreased with increasing serum leptin concentrations. CONCLUSIONS: High serum leptin is associated with an increased risk of Barrett's oesophagus among men but not women. This association is not explained simply by higher body mass or gastro-oesophageal reflux among cases. The mechanism remains to be determined.

Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus.

OBJECTIVE: To measure the relative risks of adenocarcinomas of the oesophagus and gastro-oesophageal junction associated with measures of obesity, and their interactions with age, sex, gastro-oesophageal reflux symptoms and smoking. DESIGN AND SETTING: Population-based case-control study in Australia. PATIENTS: Patients with adenocarcinomas of the oesophagus (n = 367) or gastro-oesophageal junction (n = 426) were compared with control participants (n = 1580) sampled from a population register. MAIN OUTCOME MEASURE: Relative risk of adenocarcinoma of the oesophagus or gastro-oesophageal junction. RESULTS: Risks of oesophageal adenocarcinoma increased monotonically with body mass index (BMI) (p(trend) <0.001). Highest risks were seen for BMI >or=40 kg/m2 (odds ratio (OR) = 6.1, 95% CI 2.7 to 13.6) compared with "healthy" BMI (18.5-24.9 kg/m2). Adjustment for gastro-oesophageal reflux and other factors modestly attenuated risks. Risks associated with obesity were substantially higher among men (OR = 2.6, 95% CI 1.8 to 3.9) than women (OR = 1.4, 95% CI 0.5 to 3.5), and among those aged <50 years (OR = 7.5, 95% CI 1.7 to 33.0) than those aged >or=50 years (OR = 2.2, 95% CI 1.5 to 3.1). Obese people with frequent symptoms of gastro-oesophageal reflux had significantly higher risks (OR = 16.5, 95% CI 8.9 to 30.6) than people with obesity but no reflux (OR = 2.2, 95% CI 1.1 to 4.3) or reflux but no obesity (OR = 5.6, 95% 2.8 to 11.3), consistent with a synergistic interaction between these factors. Similar associations, but of smaller magnitude, were seen for gastro-oesophageal junction adenocarcinomas. CONCLUSIONS: Obesity increases the risk of oesophageal adenocarcinoma independently of other factors, particularly among men. From a clinical perspective, these data suggest that patients with obesity and frequent symptoms of gastro-oesophageal reflux are at especially increased risk of adenocarcinoma.

Hysterectomy and incidence of depressive symptoms in midlife women: the Australian Longitudinal Study on Women's Health.

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.

TNFalpha and IL10 SNPs act together to predict disease behaviour in Crohn's disease.

BACKGROUND: The cytokines tumour necrosis factor (TNF)alpha and interleukin (IL)10 have been implicated in the pathogenesis of Crohn's disease (CD), with increased concentrations reported in patients with active disease. However, limited data exist on their effects on disease phenotype in the same population. Certain single nucleotide polymorphisms (SNPs) within the promoter region of the IL10 (-1082G/A, -592C/A) and TNFalpha (-308G/A, -857C/T) genes have been associated with altered levels of circulating IL10 and TNFalpha. METHODS: We conducted an Australian based case-control study (304 CD patients; 231 healthy controls) of these four SNPs. Further investigation of two SNPs was conducted using a logistic regression analysis. RESULTS: We identified a possible association of both IL10 SNPs and TNFalpha-857 with CD. Further investigation of a relationship with disease severity showed a significant association of higher producing IL10-1082G and TNFalpha-857C alleles with stricturing behaviour, which was strongest when these alleles were combined and persisted after multivariate analysis (p = 0.007; odds ratio (OR) 2.37, 95% CI 1.26 to 4.43). In addition, the TNFalpha-857CC genotype was independently associated with familial CD (p = 0.03; OR 3.12; 95% CI 1.15 to 8.46). CONCLUSION: These two SNPs may help to predict disease behaviour in CD patients, which may be clinically useful in shaping treatment of the disease at an earlier stage.

Ratio of male to female births in the offspring of BRCA1 and BRCA2 carriers.

A recent report based on 68 families, including 17 with mutations in BRCA1, suggested that there was an excess of female offspring born to BRCA1 mutation carriers. We have examined the gender ratio among offspring of 511 mutation carriers from 116 BRCA1 families, 77 and 39 from Australia and the United States, respectively. We found no evidence for a significant deviation from the expected proportion of female offspring in the Australian pedigrees, but there was an excess of female offspring in pedigrees from the USA. Ascertainment bias probably explains this bias, rather than a link with X-chromosome inactivation as previously suggested, because the families from the USA were ascertained for the purposes of linkage studies whereas those from Australia were ascertained through Familial Cancer Clinics to which they had been referred for clinical genetic counseling and mutation testing.

Proliferation, apoptosis, and survival in high-level microsatellite instability sporadic colorectal cancer.

Sporadic colorectal cancer (CRC) characterized by high-level DNA microsatellite instability (MSI-H) has a favorable prognosis. The reason for this MSI-H survival advantage is not known. The aim of this study was to correlate proliferation, apoptosis, and prognosis in CRC stratified by MSI status. The proliferative index (PI) was measured by immunohistochemical staining with the Ki-67 antibody in a selected series of 100 sporadic colorectal cancers classified according to the level of MSI as 31 MSI-H, 29 MSI-Low (MSI-L), and 40 microsatellite stable (MSS). The Ki-67 index was significantly higher in MSI-H cancers (P < 0.0001) in which the PI was 90.1 +/- 1.2% (mean +/- SE) compared with 69.5 +/- 3.1% and 69.5 +/- 2.3% in MSI-L and MSS subgroups, respectively. There was a positive linear correlation between the apoptotic index (AI) and PI (r = 0.51; P < 0.001), with MSI-H cancers demonstrating an increased AI:PI ratio indicative of a lower index of cell production. A high PI showed a trend toward predicting improved survival within MSI-H cancers (P = 0.09) but did not predict survival in MSI-L or MSS cancers. The AI was not associated with survival in any MSI subgroup. In conclusion, this is the first study to show that sporadic MSI-H cancers are characterized by a higher AI:PI ratio and increased proliferative activity compared with MSI-L and MSS cancers, and that an elevated PI may confer a survival advantage within the MSI-H subset.

Winter intervention against Aedes aegypti (Diptera: Culicidae) larvae in subterranean habitats slows surface recolonization in summer.

At semiarid Charters Towers, north Queensland, Australia, the importance of Aedes aegypti (L.) in wells was assessed in relation to the colonization of surface habitats during the wet season. From April to July 1999, 10 wells (five positive for Ae. aegypti) were monitored to assess their status and larvae population numbers therein. All surface containers located within a 100 m radius of each well were removed, treated with s-methoprene or sealed to prevent the utilization of these containers by mosquitoes. These inner cores were surrounded by outer zones for a further 100 m in which surface containers were left untreated but all subterranean habitats were treated. Ovitraps were monitored monthly in the inner cores for 36 wk from August 1999 to April 2000 and differences in the proportions of ovitraps positive for Ae. aegypti and Ochlerotatus notoscriptus (Skuse) were analyzed by logistic regression. Analysis of the proportions of ovitraps positive for Ae. aegypti near positive wells indicated significantly greater colonization from November to March (the wet season), compared with those situated near Ae. aegypti negative wells. As Oc. notoscriptus were not produced from subterranean sites, comparisons of the proportions of ovitraps positive for Oc. notoscriptus in positive and negative inner cores provided an indication of the relative productivity of the uncontrolled surface containers in the outer zones. Differences in the utililization of ovitraps by Oc. notoscriptus among positive and negative cores were observed during only one month (March), when oviposition was greater in ovitraps in the negative cores, compared with the positive cores. Best subsets linear regression analysis of the proportion of ovitraps positive forAe. aegypti against meteorological variables (rainfall, mean wind speed, mean relative humidity, mean minimum, and maximum temperature) during the week of ovitrapping indicated that minimum temperature and wind speed accounted for 63.4% of the variability. This study confirms that for semiarid towns such as Charters Towers, the practice of treating a relatively small number of key subterranean habitats during winter will significantly affect Ae. aegypti recolonization of surface container habitats during summer, the period of greatest risk for dengue.

Secondary burn reconstruction: recent advances with microvascular free flaps, regional flaps, and specialized grafts.

A representative series of cases are presented which demonstrate secondary reconstructive plastic surgery procedures for the burn victim utilizing microvascular free flaps, regional flaps, and specialized skin grafts. The unstable burn scar of the lower extremity could be managed either by a microvascular free-flap transfer, a muscle transfer, a myocutaneous flap transfer, or a reverse dermis graft, or overgrafting. In the present day, there are many treatment modalities available to us. Long-term wearing of the Jobst pressure stocking is essential in many cases to minimize the hypertrophic burn scar. In our experience, Kenalog injection into a hypertrophic burn scar always has resulted in improvement of the condition although it is usually necessary to give multiple injections into the hypertrophic burn scar at eight week intervals. We have never known Kenalog to fail to improve a hypertrophic scar by flattening it out to a significant extent, but it may take a year or more of injections to accomplish this goal. Microvascular surgery is most definitely a team effort requiring at least two fully trained microvascular surgeons, plus experienced operating room personnel. One microvascular surgeon harvests the free flap, and the other microvascular surgeons prepares the recipient area. Both microvascular surgeons participate in the multiple anastomoses that are required. A microvascular laboratory is essential to the success of a microvascular team, and constant practice is mandatory to maintain and enhance these precision skills. The primary burn surgeon ideally must always keep in mind ways to minimize functional and aesthetic deformity and to continue to improve the quality of life of the burn victim.