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 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.

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.

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.

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.

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 (

The use of nonsteroidal anti-inflammatory drugs and the risk of Barrett's oesophagus.

BACKGROUND: Epidemiological studies have consistently reported inverse associations between nonsteroidal anti-inflammatory drugs (NSAIDs) and oesophageal adenocarcinoma, but few have investigated associations with the precursor lesion, Barrett's oesophagus. AIM: To investigate the relationship between NSAID use and risk of Barrett's oesophagus. METHODS: We conducted a large population-based case-control study that collected information on patterns of intake for aspirin and non-aspirin NSAIDs during the past 5 years and other exposures from 285 patients with nondysplastic Barrett's oesophagus, 108 patients with dysplastic Barrett's oesophagus, and two separate control groups: 313 endoscopy patients with acute inflammatory changes ('inflammation controls') and 644 population controls. We calculated odds ratios (ORs) and 95% CIs using unconditional logistic regression. RESULTS: Use of aspirin was not associated with nondysplastic Barrett's oesophagus when compared with population (OR=1.01, 95% CI 0.71-1.43) or inflammation controls (OR=1.16, 95% CI 0.80-1.68). Whereas we observed significant risk reductions for use of non-aspirin NSAIDs when nondysplastic Barrett's oesophagus cases were compared with population controls (OR=0.69, 95% CI 0.49-0.97), the effect was weaker and nonsignificant when cases were compared with inflammation controls (OR=0.82, 95% CI 0.57-1.18), and no dose-response effects were present in either analysis. We found no evidence that aspirin or non-aspirin NSAID use conferred risk reductions for dysplastic Barrett's oesophagus, regardless of the control series. We excluded effect modification by known risk factors as an explanation for these null findings. CONCLUSIONS: We found little support for an inverse association between use of NSAIDs and Barrett's oesophagus. The question of whether or not these medications prevent the onset of Barrett's oesophagus remains open.

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.

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.

Aspirin and lung cancer risk in a cohort study of women: dosage, duration and latency.

Aspirin may reduce the risk of cancer at some sites but its effect at the lung is unclear. We prospectively examined associations between aspirin use and risk of lung cancer in 109,348 women in the Nurses' Health study from 1980 to 2004. During this time, 1,360 lung cancers were documented in participants 36-82 years of age. Aspirin use and smoking were assessed every 2 years. Risk of lung cancer was a non-significant 16% lower for regular aspirin users of one or two tablets per week and a significant 55% higher for users of 15 or more tablets per week compared with women who never regularly used aspirin. Results were similar when limited to never smokers. For both the low and high quantity aspirin users, risk of lung cancer did not decline or increase with longer durations of use, and associations attenuated as the latency period between aspirin assessment and lung cancer diagnosis was lengthened. Our findings, together with those from previous clinical trials and prospective studies, do not provide consistent evidence that aspirin influences the development of lung cancer and further investigation is required with adjustment for smoking.

Characterization of tumour-infiltrating lymphocytes and apoptosis in colitis-associated neoplasia: comparison with sporadic colorectal cancer.

The development of colorectal cancer is a major complication for patients with chronic idiopathic colitis. Colitis-associated tumours tend to occur at a younger age and be more aggressive than sporadic colorectal cancers. While we have previously associated the presence of tumour-infiltrating lymphocytes (TILs) and increased apoptosis in sporadic colorectal cancer with high-level microsatellite instability and improved prognosis, little is known of the relationship between these variables in colitis-associated colorectal cancer. The aim of this study was to correlate TILs and tumour cell apoptosis in colitis-associated neoplasms stratified according to microsatellite instability. Twenty tumour and 11 dysplastic samples resected from 21 patients with long-standing colitis were analysed for microsatellite instability at 10 microsatellite markers. TIL distribution (CD3, CD8) and function (granzyme B) were quantified by immunohistochemistry. Neoplastic cell apoptosis was assessed using the M30 CytoDEATH antibody. These findings were compared with 40 microsatellite stable (MSS) sporadic colorectal cancers previously evaluated for TILs and neoplastic apoptosis. Low-level microsatellite instability was found in 1/20 colitis-associated tumours. All other colitis-associated lesions were designated MSS. CD3(+) and CD8(+) TIL counts were significantly higher in colitis-associated lesions compared with MSS sporadic colorectal cancer (p < 0.0001, p = 0.001 respectively). Despite their higher TIL density, colitis-associated tumours were more likely to present late (Dukes' stage C or D) (p = 0.02). Functionally, colitis-associated TILs demonstrated significantly less granzyme B expression compared to sporadic cancers (p = 0.002). The level of tumour cell apoptosis was similar between the two groups (sporadic, 1.53%; colitis cancers, 1.45%). In conclusion, MSS colitis-associated tumours have a higher prevalence of CD3(+)/CD8(+) TILs but no associated increase in tumour cell killing by apoptosis. Unlike cytotoxic T cells in sporadic colorectal cancer, TILs do not appear to enhance the prognosis of colitis-associated colorectal cancer. This may be related to an impairment of granzyme B expression within these lesions.