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.

Impact of weight change and weight cycling on risk of different subtypes of endometrial cancer.

AIM: Obesity is an established risk factor for endometrial cancer. Associations tend to be stronger for the endometrioid subtype. The role of adult weight change and weight cycling is uncertain. Our study aimed to determine whether there is an association between different adult weight trajectories, weight cycling and risk of endometrial cancer overall, and by subtype. METHODS: We analysed data from the Australian National Endometrial Cancer study, a population-based case-control study that collected self-reported information on height, weight at three time points (age 20, maximum and 1 year prior to diagnosis [recent]), intentional weight loss/regain (weight cycling) from 1398 women with endometrial cancer and 1538 controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression analysis. RESULTS: Relative to women who maintained a stable weight during adulthood, greater weight gain after the age of 20 was associated with increased risk of endometrial cancer (OR for gain 40+kg all subtypes 5.3, 95% CI 3.9-7.3; endometrioid 6.5, 95% CI 4.7-9.0). The strongest associations were observed among women who were continually overweight from the age of 20 (all subtypes OR 3.6, 95% CI 2.6-5.0). Weight cycling was associated with increased risk, particularly among women who had ever been obese (OR 2.9 95% CI 1.8-4.7), with ~3-fold risks seen for both endometrioid and non-endometrioid tumour subtypes. Women who had intentionally lost weight and maintained that weight loss were not at increased risk. CONCLUSION: These results suggest that higher adult weight gain, and perhaps weight cycling, independently increase the risk of endometrial cancer, however women who lost weight and kept that weight off were not at increased risk.

Intake of omega-3 and omega-6 fatty acids and risk of ovarian cancer.

OBJECTIVES: Limited experimental evidence suggests that omega-3 polyunsaturated (n-3) fatty acids inhibit the proliferation of ovarian cancer cells in vitro, whereas omega-6 polyunsaturated (n-6) fatty acids have been shown to promote carcinogenesis, but epidemiological studies to date have been inconclusive. Our aim was to evaluate the role of polyunsaturated fatty acids in ovarian carcinogenesis. METHODS: Participants in the Australian Ovarian Cancer Study (1,366 cases and 1,414 population controls) self-completed risk factor and food frequency questionnaires. Logistic regression models were used to calculate adjusted odds ratio (OR) and 95 % confidence intervals (CI). RESULTS: We found no association between intake of total n-3 fatty acids from foods, or the individual n-3 fatty acids-alpha-linolenic, eicosapentaenoic, docosapentaenoic, docosahexaenoic acids-and ovarian cancer risk. High intake of total n-6 fatty acids was inversely associated with risk (OR for highest vs. lowest category 0.78, 95 % CI 0.60-1.00, p-trend 0.04); however, the association was restricted to n-6 fatty acids from avocado, vegetables, and nuts. Neither higher intake of the individual n-6 fatty acids nor the ratio of n-3 to n-6 fatty acids was associated with ovarian cancer risk. We found no evidence that risk varied by supplement use. CONCLUSIONS: Our data provide no evidence of a protective role for n-3 fatty acids in ovarian carcinogenesis. The benefit, if any, of higher intake of n-6 fatty acids is due to general properties of the food sources, rather than due to the n-6 fatty acids per se.

Folate and related micronutrients, folate-metabolising genes and risk of ovarian cancer.

BACKGROUND/OBJECTIVE: Folates are essential for DNA synthesis and methylation, and thus may have a role in carcinogenesis. Limited evidence suggests folate-containing foods might protect against some cancers and may partially mitigate the increased risk of breast cancer associated with alcohol intake, but there is little information regarding ovarian cancer. Our aim was to evaluate the role of folate and related micronutrients, polymorphisms in key folate-metabolising genes and environmental factors in ovarian carcinogenesis. SUBJECTS/METHODS: Participants in the Australian Ovarian Cancer Study (1363 cases, 1414 controls) self-completed risk factor and food-frequency questionnaires. DNA samples (1638 cases, 1278 controls) were genotyped for 49 tag single-nucleotide polymorphisms (SNPs) in the methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and MTR reductase (MTRR) genes. Logistic regression models were used to generate adjusted odds ratios and 95% confidence intervals. RESULTS: We saw no overall association between the intake of folate, B vitamins or other methyl donors and ovarian cancer risk, although increasing folate from foods was associated with reduced risk among current smokers (P(trend)=0.03) and folic acid intake was associated with borderline significant increased risks among women who consumed ≥1 standard alcoholic drinks/day (odds ratio (OR)=1.64; 95% confidence interval (CI) 1.05-2.54, P(trend)=0.05). Two SNPs (rs7365052, rs7526063) showed borderline significant inverse associations with ovarian cancer risk; both had very low minor allele frequencies. There was little evidence for interaction between genotype and micronutrient intake or for variation between different histological subtypes of ovarian cancer. CONCLUSIONS: Our data provide little evidence to support a protective role for folate in ovarian carcinogenesis but suggest further evaluation of the joint effects of folic acid and alcohol is warranted.

Work/life balance and health: the Nurses and Midwives e-cohort Study.

BACKGROUND: Nursing and midwifery are demanding professions. Efforts to understand the health consequences and workforce needs of these professions are urgently needed. Using a novel electronic approach, the Nurses and Midwives e-cohort Study (NMeS) aims to investigate longitudinally Australian and New Zealand nurses' and midwives' work/life balance and health. This paper describes NMeS participation; provides key baseline demographic, workforce and health indicators; compares these baseline descriptions with external norms; and assesses the feasibility of the electronic approach. METHODS: From 1 April 2006 to 31 March 2008, nurses in Australia and New Zealand, and midwives in Australia were invited to participate. Potential participants were directed to a purpose-built NMeS Internet site, where study information was provided and consent sought. Once obtained, a range of standardized tools combined into one comprehensive electronic questionnaire was elicited. RESULTS: Overall, 7633 (2.3%) eligible nurses and midwives participated (6308 from Australia and 1325 from New Zealand) from a total pool of 334,400. Age, gender, occupational and health profiles were similar between countries and to national figures. However, some differences were noted; for instance, Queensland participants were over-represented, while Victorian and South Australian participants were under-represented, and 28.2% of Australians were in high strain positions compared with 18.8% of New Zealanders. CONCLUSIONS: Using an internationally novel web-based approach, a large cohort, which appears generally similar to population norms, has been established. Provided participant retention is adequate, the NMeS will provide insight into understanding the drivers of nurses' and midwives' workforce retention and work-related factors associated with their health.

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.

The influence of reproductive and hormonal factors on ovarian cancer survival.

Reproductive and hormonal exposures are known to influence ovarian carcinogenesis, but little is known about the effect of these factors on survival. We have studied survival according to hormonal and reproductive history in a population-based cohort of 676 Australian women aged 18-79, newly diagnosed with invasive epithelial ovarian cancer in the early 1990s. In order to place our findings in context, we have also undertaken a systematic review of the pertinent literature. Detailed information about each woman's reproductive and contraceptive history was obtained from pregnancy and contraceptive calendars at the time of diagnosis. Cox regression was used to obtain multivariate adjusted hazard ratios (HR) and 95% confidence intervals (CI). A total of 419 (62%) of the 676 women died during the follow-up (giving a 5-year survival proportion of 44%). Apart from better survival for women who had ever breastfed (multivariate HR 0.74, 95% CI 0.55-0.98), we found no association between survival from invasive ovarian cancer and a range of hormonal and gynecological factors including parity, use of oral contraceptives, and histories of tubal sterilization or hysterectomy. Systematic review of the literature generally supported the lack of influence of these factors on survival from ovarian cancer. We conclude that, except for a possible survival advantage among women with a history of breastfeeding, reproductive and hormonal exposures prior to diagnosis do not influence survival from invasive ovarian cancer, in contrast to their substantial effects on etiology of this disease.

Does birth weight predict childhood diet in the Avon longitudinal study of parents and children?

STUDY OBJECTIVE: Low birth weight predicts cardiovascular disease in adulthood, and one possible explanation is that children with lower birth weight consume more fat than those born heavier. Therefore, the objective of this study was to investigate associations between birth weight and childhood diet, and in particular, to test the hypothesis that birth weight is inversely related to total and saturated fat intake. DESIGN: Prospective cohort study. SETTING: South west England. PARTICIPANTS: A subgroup of children enrolled in the Avon longitudinal study of parents and children, with data on birth weight and also diet at ages 8, 18, 43 months, and 7 years (1152, 998, 848, and 771 children respectively). MAIN RESULTS: Associations between birth weight and diet increased in strength from age 8 to 43 months, but had diminished by age 7 years. Fat, saturated fat, and protein intakes were inversely, and carbohydrate intake was positively associated with birth weight at 43 months of age, after adjusting for age, sex, and energy intake. After adjustment for other confounders, all associations were weakened, although there was still a suggestion of a relation with saturated fat (-0.48 (95% CI -0.97, 0.02) g/day per 500 g increase in birth weight. Similar patterns were seen in boys and girls separately, and when the sample was restricted to those with complete data at all ages. CONCLUSIONS: A small inverse association was found between birth weight and saturated fat intake in children at 43 months of age but this was not present at 7 years of age. This study therefore provides little evidence that birth weight modifies subsequent childhood diet.

Changes in survival after breast cancer: improvements in diagnosis or treatment?

We have compared 5-year survival rates in two cohorts of women diagnosed with breast cancer in Brisbane, Australia, between 1981-1984 and 1990-1994. Tumours diagnosed in the early 1990s were significantly smaller and less likely to have nodal involvement than those diagnosed 10 years earlier (P<0.0001). The size difference was particularly striking for women aged over 50 at diagnosis, those targeted for screening. Five-year survival was greater among women diagnosed in the 1990s (84% vs. 74%; hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.46-0.81). After adjusting for the effects of tumour size and nodal status this difference was reduced, but women diagnosed more recently still showed improved survival (HR 0.75; 95% CI 0.56-1.01) and disease-free survival (HR 0.72; 0.56-0.92) at 5 years. This suggests that both earlier diagnosis and changes in breast cancer treatment have contributed to improved breast cancer survival.

Self-reported difficulty in conceiving as a measure of infertility.

BACKGROUND: This study aimed to explore the meaning and potential use of women's self-reported difficulties in conceiving as a measure of infertility in epidemiological studies, and to compare women's stated reasons for infertility with information in their medical records. METHODS: Data were available from a population-based case-control study of ovarian cancer involving 1638 women. The sensitivity and specificity of women's self-reported infertility were calculated against their estimated fertility status based on detailed reproductive histories. Self-reported reasons for infertility were compared with diagnoses documented in women's medical records. RESULTS: The sensitivity of women's self-reported difficulty in conceiving was 66 and 69% respectively when compared with calendar-derived and self-reported times taken trying to conceive; its specificity was 95%. Forty-one (23%) of the 179 women for whom medical records were available had their self-reported fertility problem confirmed. Self-reported infertility causes could be compared with diagnoses in medical records for only 22 of these women. CONCLUSIONS: Self-reported difficulty conceiving is a useful measure of infertility for quantifying the burden of fertility problems experienced in the community. Validation of reasons for infertility is unlikely to be feasible through examination of medical records. Improved education of the public regarding the availability and success rates of infertility treatments is proposed.

Body size and ovarian cancer: case-control study and systematic review (Australia).

OBJECTIVE: Although increased body mass is an established risk factor for a variety of cancers, its relation with cancer of the ovary is unclear. We therefore investigated the association between measures of body mass index (BMI) and ovarian cancer risk. METHODS: Data from an Australian case-control study of 775 ovarian cancer cases and 846 controls were used to examine the association with BMI. We have also summarized the results from a number of other studies that have examined this association. RESULTS: There was a significant increased risk of ovarian cancer with increasing BMI, with women in the top 15% of the BMI range having an odds ratio (OR) of 1.9 (95% confidence interval (CI), 1.3-2.6) compared with those in the middle 30%. Stratifying by physical activity showed a stronger effect among inactive women (OR = 3.0, 95% CI 1.3-6.9). The overall effect was consistent with the findings of most prior population-based case-control studies, while cohort studies reported positive effects closer to the null. Hospital-based studies gave variable results. CONCLUSIONS: Taken together, the evidence is in favor of a small to moderate positive relation between high BMI and occurrence of ovarian cancer.

Reproduction-related risk factors for mucinous and nonmucinous epithelial ovarian cancer.

The proposition that mucinous ovarian cancer has an etiology distinct from that of other histologic types has been evaluated using data from a population-based case-control study of epithelial ovarian cancer conducted in 1990--1993 among Australian women aged 18--79 years. The protective effects of parity and oral contraceptive use were greater in nonmucinous than in mucinous ovarian tumors. However, these differences appeared to be driven largely by the effect of ovulatory life, which was positively associated with nonmucinous tumors only. An association with family history of breast and/or ovarian cancer also appeared to be restricted to nonmucinous cancers. These results lend support to the hypothesis that mucinous and nonmucinous ovarian tumors develop via different causal mechanisms.

The occurrence of autoimmune diseases in patients with multiple sclerosis and their families.

The aims of this study were to determine whether the occurrence of autoimmune diseases is increased in patients with multiple sclerosis (MS) and their families and whether this is influenced by the type of MS. We conducted a case-control study using a questionnaire design to determine whether the prevalence of 11 autoimmune diseases is increased in patients with MS and their first-degree relatives compared to a random population control group and their first-degree relatives. We found that the total combined prevalence of the 11 autoimmune diseases was higher in the MS patients than in the controls, with an odds ratio of 1.7 (95% confidence interval 0.9-3.2; P = 0.10) increasing to 1.9 (1.0-3.5; P = 0.05) after adjusting for age. For persons aged under 60 years, the odds ratio was 2.3 (1.1-4.6). We also found that there was a significant increase in the total combined prevalence of the autoimmune diseases in the first-degree relatives of MS patients compared to the first-degree relatives of the control group (P = 0.003, odds ratio 2.2, confidence interval 1.3-3.7). Patients with primary progressive MS did not differ from patients with relapsing-remitting or secondary progressive MS in the personal or familial occurrence of autoimmune disease. In conclusion, although there were sources of possible bias, this study suggests that individuals with MS have a genetic predisposition to autoimmunity in general.

Hormone replacement therapy and risk of epithelial ovarian cancer.

It has been suggested that oestrogen replacement therapy is associated with risk of epithelial ovarian cancer of the endometrioid type. Using data from an Australian population-based case-control study, the relation between unopposed oestrogen replacement therapy and epithelial ovarian cancer, both overall and according to histological type, was examined. A total of 793 eligible incident cases of epithelial ovarian cancer diagnosed from 1990 to 1993 among women living in Queensland, New South Wales and Victoria were identified. These were compared with 855 eligible female controls selected at random from the electoral roll, stratified by age and geographic region. Trained interviewers administered standard questionnaires to obtain detailed reproductive and contraceptive histories, as well as details about hormone replacement therapy and pelvic operations. No clear associations were observed between use of hormone replacement therapy overall and risk of ovarian cancer. Unopposed oestrogen replacement therapy was, however, associated with a significant increase in risk of endometrioid or clear cell epithelial ovarian tumours (odds ratio (OR) 2.56; 95% confidence interval (CI) 1.32-4.94). In addition, the risk associated with oestrogen replacement therapy was much larger in women with an intact genital tract (OR 3.00; 95% CI 1.54-5.85) than in those with a history of either hysterectomy or tubal ligation. Post-menopausal oestrogen replacement therapy may, therefore, be a risk factor associated with endometrioid and clear cell tumours in particular. Additionally, the risk may be increased predominantly in women with an intact genital tract. These associations could reflect a possible role of endometriosis in the development of endometrioid or clear cell ovarian tumours.

Milk consumption, galactose metabolism and ovarian cancer (Australia).

OBJECTIVES: It has been suggested that increased exposure to galactose, due to high consumption of dairy foods or reduced galactose metabolism, is associated with the development of ovarian cancer. We have investigated this in a large case-control study conducted in three Australian states between 1990 and 1993. METHODS: Approximately 800 histologically-confirmed cases, 800 community controls and 300 controls recruited through breast-screening clinics completed dietary questionnaires. Approximately 100 cases and all breast-screening controls also provided a blood sample for analysis of galactose-1-phosphate-uridyltransferase (GALT). RESULTS: Ovarian cancer risk was positively associated with increasing consumption of whole milk and other full-fat dairy foods, but was not associated with consumption of low-fat dairy foods and was inversely related to consumption of skimmed milk. There was no association between ovarian cancer and GALT except among women with abnormally low GALT who had a non-significant 2.5-fold increased risk of ovarian cancer. CONCLUSIONS: These data do not support the hypothesis that galactose plays a major role in the development of ovarian cancer and suggest that reported associations between milk consumption and ovarian cancer are due to the fat content of milk and not to lactose or galactose. An increased risk of ovarian cancer in women with abnormally low levels of GALT cannot, however, be ruled out.

Risk of colorectal adenomas in patients with a family history of colorectal cancer: some implications for screening programmes.

BACKGROUND AND AIMS: Most colorectal cancers (CRC) arise in colorectal adenomas. A case-control study was conducted to see whether a family history of CRC is associated with a higher prevalence of colorectal adenomas. SUBJECTS: Subjects were drawn from all patients who underwent colonoscopy at the Royal Brisbane Hospital between 1980-1982 and 1985, and included 141 cases with colorectal adenomas diagnosed at colonoscopy and 882 controls who were free of polyps at colonoscopy. METHODS: The prevalence of family history of CRC was compared between patients with adenomas and negative colonoscopy controls. RESULTS: Overall, patients with one first degree relative with CRC were at no greater risk for adenomas at colonoscopy than patients with no family history (odds ratio (OR) = 0.8, 95% confidence intervals (CI) = 0.4, 1.5). Patients with two or more affected first degree relatives had a more than doubled risk for adenomas (OR = 2.3, 95% CI = 0.5, 8.2), and were also more likely to carry moderately or severely dysplastic adenomas (OR = 14.1, 95% CI = 2.0, 62.9). CONCLUSIONS: These findings are consistent with the hypothesis that some families, in addition to those with familial adenomatous polyposis, have an increased susceptibility to develop colorectal adenomas, and that adenomas in such families may have a greater tendency to undergo malignant transformation.

Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site.

The mammalian N-methyl-D-aspartate (NMDA) receptor complex is though to consist of an NR1 subunit in combination with one or more of the four NR2 subunits (A, B, C, and D). When corresponding cDNAs are expressed in Xenopus oocytes, ion channels with the characteristic profile of NMDA receptors are formed. The receptor is unique in requiring two coagonists, glutamate and glycine, for activation of the channel. We have used site-directed mutagenesis to study amino acids in the human NR1 subunit that contribute to the glycine binding site of the NMDA receptor without affecting the agonist site for glutamate. Mutations to D481 and K483 produced receptors with up to 160-fold lower affinities for glycine, as well as other agonists and partial agonists, without affecting maximum current size or the degree of agonist efficacy. The D481A mutation also led to 40-50-fold lower affinities for two structurally diverse glycine site antagonists. From these data we propose that the carboxyl group of this aspartate interacts with the amino moiety of glycine and the equivalent group contained in other agonists and antagonists.

A novel allosteric modulatory site on the GABAA receptor beta subunit.

Cloning of cDNAs that code for GABAA receptor subunits has revealed multiple receptor populations constructed from different subunit combinations. On native rat and cloned human GABAA receptors, the anticonvulsant compound loreclezole strongly potentiated GABA-mediated chloride currents. Using different combinations of human GABAA receptor subunits expressed in Xenopus oocytes and transfected 293 cells, loreclezole was highly selective for receptors containing the beta 2 or beta 3 subunit over those containing the beta 1 subunit. Loreclezole was demonstrated to act at a site distinct from the benzodiazepine, barbiturate, and steroid sites with a unique subunit dependence. These results describe a previously unidentified modulatory site on the GABAA receptor beta subunit that allows pharmacological discrimination of different GABAA receptor subpopulations in the brain and provides a new target for putative anticonvulsant/anxiolytic drugs.