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Observational studies suggest that higher serum 25-hydroxyvitamin D concentration may be associated with lower risk of cataract. However, no randomized controlled trials (RCTs) have assessed the effect of vitamin D supplementation on the incidence of cataract. We aimed to assess whether vitamin D supplementation reduces the incidence of cataract surgery.We conducted an ancillary study of D-Health Trial, a randomized, double-masked, placebo-controlled trial of monthly vitamin D for the prevention of all-cause mortality conducted from 2014 to 2020 within the Australian general population.We invited 421,207 men and women aged 60-84 years to participate; including an additional 1,896 volunteers, 40,824 expressed interest. Those with hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia or sarcoidosis, or who were taking500 international units (IU) supplemental vitamin D per day were excluded. 21,315 people were randomized. 1,390 participants did not fulfil the eligibility criteria for this analysis (linked data available, no cataract within first 6 months) leaving 19,925 included. The median follow-up was 5 years. .60,000 IU of vitamin DThe primary outcome for this analysis was the first surgical treatment for cataract, ascertained through linkage to universal health insurance records and hospital data.Among 19,925 participants eligible for the analysis of incident cataract (mean age 69.3 years, 46% women) 3,668 (18.4%) underwent cataract surgery during follow-up (n=1,841 (18.5%) of the vitamin D group and n=1,827 (18.3%) of the placebo group). The incidence of cataract surgery was similar between the two groups (incidence rate 41.6 and 41.1 per 1,000 person-years in the vitamin D and placebo groups, respectively; hazard ratio 1.02; 95% CI 0.95 to 1.09). In pre-specified subgroup analyses, the effect of vitamin D supplementation on the incidence of cataract surgery was not modified by age, sex, body mass index, predicted serum 25-hydroxyvitamin D concentration, or ambient ultraviolet radiation.Routinely supplementing older adults who live in an area with a low prevalence of vitamin D deficiency with high-dose vitamin D is unlikely to reduce the need for cataract surgery.

The presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery.This analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS.Menopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53).The association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy.

Objective To evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association. Methods We conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs). Results Overall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99). Conclusions The hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.

Objective The Measure of Ovarian Symptoms and Treatment (MOST-T35) is a patient-reported symptom index, developed and validated in the context of palliative chemotherapy for recurrent ovarian cancer (OC). We aimed to develop and validate a version suitable for surveillance of symptoms following first-line treatment for OC to support clinical follow-up. Methods In a prospective study of women following completion of first-line chemotherapy for OC, patients completed MOST-T35 every 3 months for up to 3.5 years and other patient-reported outcome measures. Construct validity (Spearman's correlations), discriminative validity (t-tests/ANOVAs assessing differences between clinically distinct groups), ability to detect clinically important symptoms (receiver operating characteristic analysis), and responsiveness (t-tests examining change) were assessed. Results Data from 726 women who received ≥3 cycles of chemotherapy, did not progress within 3 months, and completed ≥one MOST-T35 were analysed. The revised version, MOST-S26, has 26 items and 5 multi-item indexes: peripheral neuropathy (MOST-NTx), disease or treatment-related (MOST-DorT), abdominal (MOST-Abdo), and psychological symptoms (MOST-Psych), and MOST-Wellbeing, plus 9 individual items. Construct validity was confirmed (r range = 0.43–0.88). Discriminative validity confirmed expected differences between groups. MOST-NTx and MOST-Psych detected improvements in peripheral neuropathy and psychological symptoms respectively, whereas MOST-Abdo detected worsening of abdominal symptoms pre-recurrence. Conclusions This study developed and validated the MOST-S26, for surveillance of women in follow-up after first-line chemotherapy for OC. MOST-S26 reliably detected improvement in symptoms of peripheral neuropathy, psychological distress and may detect symptoms of relapse. Administration of MOST-S26 in follow-up consultations could identify concerning symptoms and facilitate timely and appropriate intervention.

Summary Background Observational studies have linked vitamin D deficiency with acute respiratory tract infection, but results from randomised controlled trials are heterogeneous. We analysed data from the D-Health Trial to determine whether supplementing older Australian adults, recruited from the general population, with monthly doses of vitamin D reduced the risk, duration, and severity of acute respiratory tract infections. Methods We used data from the D-Health Trial, a randomised, double-blind, placebo-controlled trial of monthly vitamin D supplementation, for which acute respiratory infection was a pre-specified trial outcome. Participants were supplemented and followed for up to 5 years. The trial was set within the Australian general population, using the Commonwealth Electoral Roll as the sampling frame, but also allowing some volunteers to participate. Participants were men and women aged 60 to 79 years (with volunteers up to age 84 years). Participants were randomly assigned to receive either vitamin D or placebo (1:1) using computer-generated permuted block randomisation, which was stratified by age, sex, and state. This was an automated process and the assignment list was not visible to study staff or investigators. Active and placebo gel capsules, identical in appearance to ensure masking, were labelled A and B and the code was not available to study staff or investigators. Participants were asked to report occurrence of acute respiratory symptoms over the previous month via annual surveys, and a subset of participants completed 8-week respiratory symptom diaries in winter. As part of our process to maintain blinding, a random sample of participants was selected for analysis of survey data and a separate sample selected for analysis of diary data. Blood samples were obtained from a random sample of participants (about 450 per group per year) and serum 25-hydroxy vitamin D (25[OH]D) concentrations were measured to monitor adherence. We used regression models to estimate odds ratios (OR), rate ratios, and rate differences. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763. Findings Between Jan 13, 2014, and May 26, 2015, 421 207 invitations were sent, 40 824 people were interested in participating, and 21 315 participants were recruited and randomised. Of the 16 000 participants selected for potential analysis of survey data, 15 373 were included in the analysis; 295 in the vitamin D group and 332 in the placebo group who were missing data for all five annual surveys were excluded from the analysis. Of the 3800 selected for potential analysis of diary data, 3070 were invited to complete the diaries because 730 had already withdrawn. 2598 people were included in the analysis; 218 people in the vitamin D group and 254 in the placebo group were missing data and were therefore excluded from the analysis. In blood samples collected from randomly sampled participants throughout the trial, the mean serum 25(OH)D concentration was 114·8 (SD 30·3) nmol/L in the vitamin D group and 77·5 (25·2) nmol/L in the placebo group. Vitamin D supplementation did not reduce the risk of acute respiratory tract infection (survey OR 0·98, 95% CI 0·93 to 1·02; diary OR 0·98, 0·83 to 1·15). Analyses of diary data showed reductions in the overall duration of symptoms and of severe symptoms, but these were small and unlikely to be clinically significant. Interpretation Monthly bolus doses of 60 000 IU of vitamin D did not reduce the overall risk of acute respiratory tract infection, but could slightly reduce the duration of symptoms in the general population. These findings suggest that routine vitamin D supplementation of a population that is largely vitamin D replete is unlikely to have a clinically relevant effect on acute respiratory tract infection. Funding National Health and Medical Research Council.

After treatment for ovarian cancer, women want to know when they will feel 'normal' again. Our objective was to document the proportions of women with high levels of physical and emotional symptoms at the end of treatment, determine if/when they return to normal and identify groups at risk of persistent symptoms/delayed recovery.Women in the OPAL (Ovarian cancer Prognosis And Lifestyle) study who received ≥3 cycles of first-line chemotherapy and completed patient-reported outcome (PRO) questionnaires on or 6 weeks after completing chemotherapy (baseline) were included in this analysis (n = 527). PRO measures included anxiety, depression, insomnia, fatigue and wellbeing (quality-of-life) at baseline, 3, 6, 9 and 18 months post-baseline. Group-based trajectory models identified clusters of individuals who followed similar patterns. Logistic and Cox regression identified factors associated with persistent symptoms and delayed recovery, respectively.At baseline, 57% of women reported moderate-to-severe fatigue, 22% anxiety, 20% depression, 14% clinical insomnia and 45% had quality-of-life scores significantly lower than the general population. Between 50 and 75% of individual PRO scores normalised within six months, with the exception of emotional wellbeing (42%), but approximately two-in-five women still had at least one persistently poor PRO at 18 months. Women with more severe symptoms at baseline, who were younger, or had a history of anxiety/depression were more likely to have persistent symptoms or delayed recovery.Two-in-five women might never fully return to 'normal' after completing primary treatment for ovarian cancer. Those with risk factors should be triaged for early supportive interventions.

Objectives Insomnia is common in women with ovarian cancer but there are limited prospective data on the frequency and degree of impact on patients. Our objective was to determine the prevalence of insomnia over the first three years after a diagnosis of ovarian cancer; and the relationship between insomnia and quality of life. Methods OPAL (Ovarian cancer, Prognosis And Lifestyle) is a prospective study of Australian women with epithelial ovarian cancer; 894 provided information on insomnia symptoms, medications and quality of life at three, six, nine, 12, 24 and 36 months after diagnosis. Generalised linear mixed models were used to determine the relationship between insomnia and quality of life measured at the same time and three months later. Results One-quarter of women reported symptoms consistent with clinical insomnia within three years after diagnosis and an additional 13% regularly used sleep medication (total 36% affected). Excluding 7% who reported insomnia symptoms before diagnosis, 22% reported new insomnia, which reduced to 17% when also excluding women on chemotherapy. The proportion of women with clinical (14%) or subclinical (28%) insomnia symptoms was highest at three months after diagnosis. Compared to women with no insomnia, those with clinical insomnia had significantly lower quality of life measured at the same time (8.4 points lower, 95% CI: 7.2–9.5), and three months later (5.5 points lower, 95% CI: 3.4–7.6). Conclusions Over a third of women with ovarian cancer likely experience insomnia after diagnosis; this may persist and is associated with poorer quality of life.

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend

To determine the impact of chemotherapy dose reductions and dose delays on progression-free survival (PFS) in women with ovarian cancer receiving first line chemotherapy in a real world prospective cohort study.Patients with newly diagnosed epithelial ovarian (or peritoneal, fallopian tube) cancer enrolled in a national Australian prospective study, OPAL, who commenced three-weekly carboplatin (AUC 5 or 6) and paclitaxel 175 mg/m634 evaluable patients, 309 commenced CP and 325 DD-CP. Patient's age was similar in the two groups (median 62 years, range 21-79). All planned chemotherapy doses were completed by 66% vs 40% (p 0.001) in the CP and DD-CP groups respectively. There was at least one treatment delay in 28% vs 58% (p 0.001) in the CP and DD-CP groups, respectively, and 29% vs 49% (p 0.001), respectively, required at least a 15% dose reduction for either carboplatin or paclitaxel. Median PFS was 29.2 [22.9, 43.8] and 21.5 [19.4, 23.1] months in the CP and DD-CP groups respectively. Adjusting for age, histology and FIGO stage PFS did not differ between treatment groups. Median PFS was similar in patients irrespective of dose reduction or dose delay.Patients receiving DD-CP required more dose reductions and delays due to haematological toxicities and lower completion rates than CP without significant difference in median PFS between CP and DD-CP. Median PFS was similar in patients irrespective of dose reduction or dose delay.

Objective Although a high proportion of women with advanced stage ovarian cancer die within five years, approximately 30% will survive longer than this. The factors contributing to exceptional survival are currently poorly understood. The viewpoints of ovarian cancer survivors were qualitatively explored to determine the factors they felt have influenced their exceptional ovarian cancer survival. Methods Four focus groups, one each in Los Angeles (California), Ann Arbor (Michigan), New York (New York) and Edmonton (Alberta, Canada), were conducted with women who had survived at least five years. Physical activity, diet, meditation, prayer, treatment, complementary medicine, and side effects were explored in semi-structured discussions. The audiotaped sessions were transcribed and coded and then analyzed using Dedoose Version 8.0.35, a qualitative analysis software. Results Of the 26 women who participated, 23 had advanced stage disease. Three overarching themes emerged: (a) survivors had improved their ‘lifestyles’, including but not limited to fitness and diet; (b) survivors were able to draw on strong support systems, which included family, friends, support groups, faith communities, and healthcare workers; and (c) survivors had a strong life purpose, which manifested as positivity, taking charge of their lives, and advocating for themselves. Conclusions Long-term survivors have varying experiences with their cancer, but identified lifestyle modification, motivation and persistence, strong life purpose, and strong support systems as key elements in their better survival. These preliminary findings indicate the need for further prospective studies to determine whether meaningful differences exist between short term and long term survivors on these characteristics.

ObjectiveAlthough endometrial cancer (EC) is associated with relatively good survival rates overall, women diagnosed with high-risk subtypes have poor outcomes. We examined the relationship between lifestyle factors and subsequent all-cause, cancer-specific and non-cancer related survival.MethodsIn a cohort of 1359 Australian women diagnosed with incident EC between 2005 and 2007 pre-diagnostic information was collected by interview at recruitment. Clinical and survival information was abstracted from women's medical records, supplemented by linkage to the Australian National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific survival (EC death vs. non-EC death) associated with each exposure, overall and by risk group (low-grade endometrioid vs. high-grade endometrioid and non-endometrioid).ResultsAfter a median follow-up of 7.1 years, 179 (13%) women had died, with 123 (69%) deaths from EC. As expected, elevated body mass index (BMI), diabetes and the presence of other co-morbidities were associated with a significantly increased risk of all-cause and non-cancer related death. Women with diabetes had higher cancer-specific mortality rates (HR 2.09, 95% CI 1.31–3.35), particularly those who had were not obese (HR 4.13, 95% CI 2.20–7.76). The presence of ≥2 other co-morbidities (excluding diabetes) was also associated with increased risk of cancer-specific mortality (HR 3.09, 95% CI 1.21–7.89). The patterns were generally similar for women with low-grade and high-grade endometrioid/non-endometrioid EC.ConclusionOur findings demonstrate the importance of diabetes, other co-morbidities and obesity as negative predictors of mortality among women with EC but that the risks differ for cancer-specific and non-cancer related mortality.

Objective To measure association between endometrial carcinoma ER and PR status and endometrial cancer (EC) survival, accounting for inter-observer variation. Methods The intensity and proportion of tumor cell expression of ER and PR in ECs were assessed independently and semi-quantitatively by two pathologists using digital images of duplicate tumor tissue microarrays (TMAs). Cases with inconsistent initial assessment were reviewed and final scoring agreed. The association between overall and EC-specific survival and hormone receptor expression (intensity, proportion and combined) was assessed using Cox regression analysis. The C-index was used to evaluate model discrimination with addition of ER and PR status. Results Tumor ER and PR analysis was possible in 659 TMAs from 255 patients, and in 459 TMAs from 243 patients, respectively. Initial ER and PR scoring was consistent in 82% and 80% of cases, respectively. In multivariate analyses decreased ER and PR expression was associated with increased tumor-related mortality. Associations reached statistical significance for ER proportion score (P=0.05), ER intensity score (P=0.003), and PR combined score (P=0.04). Decreased expression of combined ER/PR expression was associated with poorer EC-specific survival than decreased expression of either hormone receptor alone (P=0.005). However, hormone receptor status did not significantly improve mortality prediction in individual cases. Conclusion ER and PR expression combined, using cut-points that capture variation in scoring and across cores, is significantly associated with EC-specific survival in analyses adjusting for known prognostic factors. However, at the individual level, ER and PR expression does not improve mortality prediction.

Background Many cancers are caused by exposure to lifestyle, environmental, and occupational factors. Earlier studies have estimated the number of cancers occurring in a single year which are attributable to past exposures to these factors. However, there is now increasing appreciation that estimates of the future burden of cancer may be more useful for policy and prevention. We aimed to calculate the future number of cancers expected to arise as a result of exposure to 23 modifiable risk factors. Methods We used the future excess fraction (FEF) method to estimate the lifetime burden of cancer (2016–2098) among Australian adults who were exposed to modifiable lifestyle, environmental, and occupational risk factors in 2016. Calculations were conducted for 26 cancer sites and 78 cancer-risk factor pairings. Results The cohort of 18.8 million adult Australians in 2016 will develop an estimated 7.6 million cancers during their lifetime, of which 1.8 million (24%) will be attributable to exposure to modifiable risk factors. Cancer sites with the highest number of future attributable cancers were colon and rectum (n = 717,700), lung (n = 380,400), and liver (n = 103,200). The highest number of future cancers will be attributable to exposure to tobacco smoke (n = 583,500), followed by overweight/obesity (n = 333,100) and alcohol consumption (n = 249,700). Conclusion A significant proportion of future cancers will result from recent levels of exposure to modifiable risk factors. Our results provide direct, pertinent information to help determine where preventive measures could best be targeted.

Globally, ovarian cancer is the seventh most common cancer in women and the eighth most common cause of cancer death, with five-year survival rates below 45%. Although age-standardised rates are stable or falling in most high-income countries, they are rising in many low and middle income countries. Furthermore, with increasing life-expectancy, the number of cases diagnosed each year is increasing. To control ovarian cancer we need to understand the causes. This will allow better prediction of those at greatest risk for whom screening might be appropriate, while identification of potentially modifable causes provides an opportunity for intervention to reduce rates. In this paper we will summarise the current state of knowledge regarding the known and possible causes of epithelial ovarian cancer and discuss some of the main theories of ovarian carcinogenesis. We will also briefly review the relationship between lifestyle and survival after a diagnosis of ovarian cancer.

Purpose Family history of pancreatic adenocarcinoma is an established risk factor for the disease. However, associations of pancreatic cancer with other familial cancers are less clear. We analyzed data from the Queensland Pancreatic Cancer Study (QPCS), an Australian population-based case-control study, to investigate associations between family history of various cancer types and risk of pancreatic cancer. Materials and methods Our study included 591 pancreatic cancer patients and 646 controls, all of whom self-reported the histories of cancer in their first-degree relatives. We used logistic regression to estimate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Based on our results, we conducted a systematic literature review using the Medline (OVID) database to identify articles pertaining to the association between family history of melanoma and risk of pancreatic cancer. A meta-analysis including associations in five published studies, unpublished results from a study co-author and the QPCS results was then performed using the DerSimonian and Laird random-effects model. Results Cases were more likely than controls to report a family history of pancreatic cancer (OR 2.20, 95% CI 1.16–4.19) and melanoma (OR 1.74, 95% CI 1.03–2.95), but not of breast, ovarian, respiratory, other gastrointestinal or prostate cancer. Meta-analysis of melanoma family history and pancreatic cancer risk yielded an OR of 1.22 (95% CI 1.00–1.51). Conclusions Our results yield further evidence of increased risk of pancreatic cancer in those with family histories of the disease. We also provide suggestive evidence of an association between family history of melanoma and risk of pancreatic cancer.

Basal cell and squamous cell carcinomas of the skin are the commonest cancers in humans, yet no validated tools exist to estimate future risks of developing keratinocyte carcinomas. To develop a prediction tool, we used baseline data from a prospective cohort study (n = 38,726) in Queensland, Australia, and used data linkage to capture all surgically excised keratinocyte carcinomas arising within the cohort. Predictive factors were identified through stepwise logistic regression models. In secondary analyses, we derived separate models within strata of prior skin cancer history, age, and sex. The primary model included terms for 10 items. Factors with the strongest effects were >20 prior skin cancers excised (odds ratio 8.57, 95% confidence interval [95% CI] 6.73–10.91), >50 skin lesions destroyed (odds ratio 3.37, 95% CI 2.85–3.99), age ≥ 70 years (odds ratio 3.47, 95% CI 2.53–4.77), and fair skin color (odds ratio 1.75, 95% CI 1.42–2.15). Discrimination in the validation dataset was high (area under the receiver operator characteristic curve 0.80, 95% CI 0.79–0.81) and the model appeared well calibrated. Among those reporting no prior history of skin cancer, a similar model with 10 factors predicted keratinocyte carcinoma events with reasonable discrimination (area under the receiver operator characteristic curve 0.72, 95% CI 0.70–0.75). Algorithms using self-reported patient data have high accuracy for predicting risks of keratinocyte carcinomas.

Background Hysterectomy is one of the most commonly performed gynecological surgeries, with an estimated 30% of women in Australia undergoing the procedure by age 70. In the USA, about 45% of women have a hysterectomy in their lifetime. Some studies have suggested this procedure increases the risk of premature mortality. With many women making the decision to have a hysterectomy for a benign indication each year, additional research is needed to clarify whether there are long-term health consequences of hysterectomy. Objective Our aim was to examine the association between hysterectomy for benign indications, with or without removal of the ovaries, and cause-specific and all-cause mortality. Study Design Our cohort of 666,588 women comprised the female population of Western Australia with linked hospital and health records from 1970 to 2015. We used Cox regression models to assess the association between hysterectomy and all-cause, cardiovascular disease, cancer and other mortality by oophorectomy type (categorized as none, unilateral and bilateral), with no hysterectomy or oophorectomy as the reference group. We repeated these analyses using hysterectomy without oophorectomy as the reference group. We also investigated whether associations varied by age at the time of surgery, although small sample size precluded this analysis in women who had a hysterectomy with unilateral salpingo-oophorectomy. In our main analysis, women who had hysterectomy and/or oophorectomy undertaken as part of treatment for cancer were retained in the analysis and considered unexposed to that surgery. As a sensitivity analysis, we censored procedures undertaken for cancer. Results Compared to no surgery, having a hysterectomy without oophorectomy before age 35 was associated with an increase in all-cause mortality (HR=1.29, 95% CI:1.19-1.40); for surgery after age 35, there was an inverse association (35-44 years: HR=0.93, 95%CI:0.89,0.97). Similarly, hysterectomy with bilateral salpingo-oophorectomy was associated with increased all-cause mortality when undertaken before age 45 (35-44 years: HR=1.15, 95%CI:1.04-1.27), but decreased mortality rates when surgery was undertaken after age 45. In our sensitivity analysis, censoring gynecological surgeries for cancer resulted in many cancer-related deaths being excluded for women who did not have surgery for benign indications, and thus increased the hazard ratios for the associations between both hysterectomy without oophorectomy and hysterectomy with bilateral salpingo-oophorectomy and risk of all-cause and cancer-specific mortality. The sensitivity analysis therefore potentially biased the results in favor of no surgery. Conclusion Among women having surgery for benign indications, hysterectomy without oophorectomy performed prior to 35 years and hysterectomy with bilateral salpingo-oophorectomy performed prior to 45 years were associated with an increase in all-cause mortality. These procedures are not associated with poorer long-term survival when performed at older ages.

There are strong associations between a number of reproductive factors and hormone-related cancers such as breast, ovarian and endometrial cancer, but most of these factors (e.g. numbers of pregnancies, age at first birth) cannot pragmatically be modified for the purposes of cancer prevention. Breastfeeding has marked effects on maternal reproductive hormones, has been inversely linked to breast and ovarian cancer and, unlike many other reproductive exposures, can be promoted to women for its public health and individual benefits. In the Second Expert Report on Food, Nutrition, Physical Activity and the Prevention of Cancer1 and subsequent Continuous Update Project (CUP),2 the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) concluded that there was convincing evidence that breastfeeding decreases risk of maternal pre- and post-menopausal breast cancer, but also concluded that the evidence for a causal association between breastfeeding and ovarian cancer1,3 was only “limited-suggestive”. This latter conclusion was based on their meta-analysis of three cohort studies4–6 which showed a non-significant 10% reduction in risk for ever versus never breastfeeding (relative risk [RR] 0.90; 95% confidence interval [CI] 0.75–1.08).3 However, results of another recently published meta-analysis of three cohort studies5,7,8 (only one of which5 was included in the WCRF review) suggested that each additional month of breastfeeding was associated with a significant 1.02% reduction in risk of ovarian cancer.9 There are several biologically plausible mechanisms by which breastfeeding might reduce risk of breast and ovarian cancers. Lactation causes differentiation of breast epithelial cells so they may be less susceptible to neoplastic transformation;2 ductal epithelial cells also exfoliate during lactation potentially eliminating those with DNA-damage.2 Furthermore, breastfeeding suppresses gonadotrophins, thereby lowering endogenous oestrogen and progesterone, and these hormones are thought to play an important role in the development of breast neoplasia.2 For ovarian cancer, most data suggest that repeated exposure of the ovarian/fallopian tube epithelium (many ovarian cancers may actually arise from the fallopian tube) to the effects of recurrent ovulation and/or reproductive hormones have an important role in carcinogenesis. In suppressing gonadotrophins and ovulation, lactation should decrease exposure of the ovary/fallopian tube to most factors postulated to have a strong causative role in cancer development.10 Our aim was to estimate the proportion of cancers attributable to little or no breastfeeding by parous women. Based on our a priori decision to limit our primary analyses to exposure-cancer relationships that either the WCRF or International Agency for Research on Cancer (IARC) had concluded were causal, in our primary analysis we estimated only the proportion of breast cancers diagnosed in 2010 that were attributable to little or no breastfeeding by women who had children. On the assumption that further studies will likely strengthen the evidence for a protective causal association between breastfeeding and ovarian cancer, we have undertaken a supplementary analysis to calculate PAF estimates for ovarian cancer.

Objectives: To estimate the population attributable fraction (PAF) and numbers of cancers occurring in Australia in 2010 attributable to tobacco smoking, both personal and by a partner. Methods: We used a modified Peto-Lopez approach to calculate the difference between the number of lung cancer cases observed and the number expected assuming the entire population developed lung cancer at the same rate as never smokers. For cancers other than lung, we applied the standard PAF formula using relative risks from a large cohort and derived notional smoking prevalence. To estimate the PAF for partners' smoking, we used the standard formula incorporating the proportion of non-smoking Australians living with an ever-smoking partner and relative risks associated with partner smoking. Results: An estimated 15,525 (13%) cancers in Australia in 2010 were attributable to tobacco smoke, including 8,324 (81%) lung, 1,973 (59%) oral cavity and pharynx, 855 (60%) oesophagus and 951 (6%) colorectal cancers. Of these, 136 lung cancers in non-smokers were attributable to partner tobacco smoke. Conclusions: More than one in eight cancers in Australia is attributable to tobacco smoking and would be avoided if nobody smoked. Implications: Strategies to reduce the prevalence of smoking remain a high priority for cancer control.

Objectives: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to menopausal hormone therapy (MHT) use. Methods: We estimated the population attributable fraction for cancers causally associated with MHT (breast, endometrium, ovary), and the proportion of colorectal cancers prevented by MHT. We used standard formulae incorporating Australian prevalence data, relative risks of cancer associated with MHT and cancer incidence. We also estimated potential change in cancer incidence under two hypothetical scenarios whereby 25% fewer Australian women used MHT, or women exclusively used oestrogen-only MHT. Results: An estimated 539 cancers in Australia in 2010 were attributable to MHT: 453 breast, 67 endometrial and 19 ovarian cancers equating to 3.4%, 3.1% and 1.6% of each cancer type, respectively. In contrast, MHT may have prevented 52 colorectal cancers. If 25% fewer women used MHT, then 141 cancers may have been avoided. If women exclusively used oestrogen-only MHT then 240 cancers may have been avoided. Conclusions: MHT use caused more than 500 cancers in Australian women in 2010 and prevented ∼50 colorectal cancers. Implications: MHT use continues to cause an excess of cancers. The risks, benefits, regimen and treatment duration should be carefully considered for each woman before MHT is commenced.

Identifying people at high risk of melanoma is important for targeted prevention activities and surveillance. Several tools have been developed to classify melanoma risk, but few have been independently validated. We assessed the discriminatory performance of six melanoma prediction tools by applying them to individuals from two independent data sets, one comprising 762 melanoma cases and the second a population-based sample of 42,116 people without melanoma. We compared the model predictions with actual melanoma status to measure sensitivity and specificity. The performance of the models was variable with sensitivity ranging from 97.7 to 10.5% and specificity from 99.6 to 1.3%. The ability of all the models to discriminate between cases and controls, however, was generally high. The model developed by MacKie et al. (1989) had higher sensitivity and specificity for men (0.89 and 0.88) than women (0.79 and 0.72). The tool developed by Cho et al. (2005) was highly specific (men, 0.92; women, 0.99) but considerably less sensitive (men, 0.64; women, 0.37). Other models were either highly specific but lacked sensitivity or had low to very low specificity and higher sensitivity. Poor performance was partly attributable to the use of non-standardized assessment items and various differing interpretations of what constitutes "high risk".

Aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease tumor progression in pre-clinical models of ovarian cancer, however the influence of these drugs on survival in women following a diagnosis of ovarian cancer is unknown. We included 1305 Australian women diagnosed with incident invasive epithelial ovarian cancer, recruited into a population-based case-control study. Use of aspirin, nonaspirin NSAIDs and acetaminophen in the 5 years preceding ovarian cancer diagnosis was assessed from self-reports. Deaths were ascertained up to October 2011 via linkage with the Australian National Death Index. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CI). During a mean follow-up time of 4.9 years (SD 2.8 years), there were 834 deaths, of which 779 (93% of deaths) were from ovarian cancer. We found uniformly inverse, but non-significant, HRs for ever use in the last five years of aspirin, nonaspirin NSAIDs and acetaminophen compared with no use (adjusted HRs 0.92 [95% CI 0.81-1.06], 0.91 [95% CI 0.80-1.05] and 0.91 [95% CI 0.69-1.20], respectively). There was no evidence of any dose response trends. The results remained unchanged when we limited the outcome to ovarian cancer mortality. Associations did not differ by histologic subtype, age at diagnosis or stage. Given current interest in the role of aspirin and nonaspirin NSAIDs in cancer survival these results are noteworthy given they are the first to investigate these associations in women with ovarian cancer. Our results provide no strong evidence that pre-diagnostic use of aspirin or nonaspirin NSAIDs are associated with improved survival in women with ovarian cancer.

Objective To quantitatively assess and compare the quality of life (QoL) of women with a self-reported diagnosis of lower limb lymphedema (LLL), to women with lower limb swelling (LLS), and to women without LLL or LLS following treatment for endometrial cancer. Methods 1399 participants in the Australian National Endometrial Cancer Study were sent a follow-up questionnaire 3–5years after diagnosis. Women were asked if they had experienced swelling in the lower limbs and, if so, whether they had received a diagnosis of lymphedema by a health professional. The 639 women who responded were categorized as: Women with LLL (n=68), women with LLS (n=177) and women without LLL or LLS (n=394). Multivariable-adjusted generalized linear models were used to compare women's physical and mental QoL by LLL status. Results On average, women were 65years of age and 4years after diagnosis. Women with LLL had clinically lower physical QoL ( M =41.8, SE =1.4) than women without LLL or LLS ( M =45.1, SE =0.8, p =.07), however, their mental QoL was within the normative range ( M =49.6; SE =1.1 p =1.0). Women with LLS had significantly lower physical ( M =41.0, SE =1.0, p =.003) and mental QoL ( M =46.8; SE =0.8, p M =50.6, SE =0.8). Conclusion Although LLL was associated with reductions in physical QoL, LLS was related to reductions in both physical and mental QoL 3–5years after cancer treatment. Early referral to evidence-based lymphedema programs may prevent long-term impairments to women's QoL.

Background: Observational data suggested that supplementation with vitamin D could reduce risk of infection, but trial data are inconsistent. Objective: We aimed to examine the effect of oral vitamin D supplementation on antibiotic use. Design: We conducted a post hoc analysis of data from pilot D-Health, which is a randomized trial carried out in a general community setting between October 2010 and February 2012. A total of 644 Australian residents aged 60–84 y were randomly assigned to receive monthly doses of a placebo (n = 214) or 30,000 (n = 215) or 60,000 (n = 215) IU oral cholecalciferol for #12 mo. Antibiotics prescribed during the intervention period were ascertained by linkage with pharmacy records through the national health insurance scheme (Medicare Australia). Results: People who were randomly assigned 60,000 IU cholecalciferol had nonsignificant 28% lower risk of having antibiotics prescribed at least once than did people in the placebo group (RR: 0.72; 95% CI: 0.48, 1.07). In analyses stratified by age, in subjects aged $70 y, there was a significant reduction in antibiotic use in the highdose vitamin D compared with placebo groups (RR: 0.53; 95% CI: 0.32, 0.90), whereas there was no effect in participants ,70 y old (RR: 1.07; 95% CI: 0.58, 1.97) (P-interaction ¼ 0.1). Conclusion: Although this study was a post hoc analysis and statistically nonsignificant, this trial lends some support to the hypothesis that supplementation with 60,000 IU vitamin D/mo is associated with lower risk of infection, particularly in older adults. The trial was registered at the Australian New Zealand Clinical Trials Registry (anzctr.org.au) as ACTRN12609001063202. Am J Clin Nutr doi: 10.3945/ajcn.113.063271.

HE4 has emerged as a promising biomarker in gynaecological oncology. The purpose of this study was to evaluate serum HE4 as a biomarker for high-risk phenotypes in a population-based endometrial cancer cohort.Peri-operative serum HE4 and CA125 were measured in 373 patients identified from the prospective Australian National Endometrial Cancer Study (ANECS). HE4 and CA125 were quantified on the ARCHITECT instrument in a clinically accredited laboratory. Receiver operator curves (ROC), Spearman rank correlation coefficient, and chi-squared and Mann-Whitney tests were used for statistical analysis. Survival analysis was performed using Kaplan-Meier and Cox multivariate regression analyses.Median CA125 and HE4 levels were higher in stage III and IV tumours (p0.001) and in tumours with outer-half myometrial invasion (p0.001). ROC analysis demonstrated that HE4 (area under the curve (AUC)=0.76) was a better predictor of outer-half myometrial invasion than CA125 (AUC=0.65), particularly in patients with low-grade endometrioid tumours (AUC 0.77 vs 0.64 for CA125). Cox multivariate analysis demonstrated that elevated HE4 was an independent predictor of recurrence-free survival (HR=2.40, 95% CI 1.19-4.83, p=0.014) after adjusting for stage and grade of disease, particularly in the endometrioid subtype (HR=2.86, 95% CI 1.25-6.51, p=0.012).These findings demonstrate the utility of serum HE4 as a prognostic biomarker in endometrial cancer in a large, population-based study. In particular they highlight the utility of HE4 for pre-operative risk stratification to identify high-risk patients within low-grade endometrioid endometrial cancer patients who might benefit from lymphadenectomy.

Although most women diagnosed with ovarian cancer initially respond to first-line chemotherapy, the vast majority eventually relapses and requires retreatment with second-line chemotherapy. Patient response is classified as either platinum sensitive or platinum resistant on the basis of the time of relapse after first-line treatment. A cancer with a progression-free interval of more than 6 months after completion of first-line chemotherapy is classified as “platinum-sensitive disease” and responds well to retreatment. A cancer with a progression-free interval of less than 6 months after completion of first-line chemotherapy is classified as “platinum-resistant disease” and responds poorly to second-line retreatment. Cure is not possible in patients with platinum-resistant recurrent ovarian cancer, and long-term progression-free survival is rare. The goal of care in these patients should be to maximize their quality of life. The aim of this population-based longitudinal study was to determine whether quality of life improves after second-line chemotherapy among women with platinum-resistant recurrent ovarian cancer. A secondary aim was to evaluate treatment response. Data for 172 women from 2 studies were combined. All participants were treated with chemotherapy for recurrent ovarian cancer and completed a validated quality of life questionnaire every 3 months. Change in quality of life during the first 6 months after second-line chemotherapy was analyzed using mixed effect models. A comparison group was composed of women with platinum-sensitive disease. Among the 172 patients, 44 (25%) were classified as having platinum-resistant disease. After the start of second-line chemotherapy, there was no significant increase or decrease in quality of life of women with platinum-resistant disease (least square mean scores at chemotherapy start, 3 months later, and 6 months later: 107, 105, and 103, respectively), although 26% reported a meaningful increase and 31% reported a meaningful decline. One third of the women with platinum-resistant cancer responded (11% complete and 21% partial response) to second-line chemotherapy; the response rate increased to 54% among the subset retreated with platinum-based agents with or without other agents. Preliminary subgroup analysis suggested that quality of life in women whose disease responded may be higher at the start of chemotherapy (median score, 121 vs 110). These findings show that the overall quality of life is maintained among women with recurrent platinum-resistant disease after retreatment with chemotherapy; however, some patients showed a meaningful increase whereas some showed a decline.

Objective To examine the association between gynecological conditions (including uterine fibroids, endometriosis, pelvic inflammatory disease and infections of the tubes/womb), and risk of endometrial cancer overall and by histological subtype. Methods Data came from a population-based, case-control study, which included 1399 women with endometrial cancer diagnosed between 2005 and 2007 and 1539 controls. Women provided detailed risk factor information via interview or self-completed questionnaire. Logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between gynecological conditions and cancer. Results A self-reported history of uterine fibroids was associated with an increased risk of endometrial cancer (OR=1.39; 95% CI: 1.10–1.74). This association was reduced for women with body-mass index≥35kg/m 2 (OR=0.71; 95% CI: 0.37–1.37), and increased in groups normally thought to be at low risk including women with normal BMI (OR=1.66; 95% CI: 1.14–2.41) and premenopausal women (OR=1.82; 95% CI: 0.99–3.32). After excluding conditions diagnosed in the previous year, we found no association between endometrial cancer and endometriosis, pelvic inflammatory disease, infections of the tubes/womb. There was no evidence that risk varied by tumor subtype. Conclusion Overall these results suggest that women with uterine fibroids are at increased risk of endometrial cancer, and that greater monitoring of premenopausal and normal weight women with fibroids may be important for the early detection of endometrial cancer.

Folate plays a key role in DNA synthesis and methylation. Limited evidence suggests high intake may reduce risks of esophageal cancer overall; however, associations with esophageal cancer subtypes and Barrett's esophagus (BE), a precancerous lesion, remain unexplored. We evaluated the relation between intake of folate, B vitamins, and methyl-group donors (methionine, choline, betaine) from foods and supplements, polymorphisms in key folate-metabolizing genes, and risk of BE, esophageal adenocarcinoma (EAC), and esophageal squamous cell carcinoma (ESCC) in 2 population-based case-control studies in Australia. BE patients without (n = 266) or with (n = 101) dysplasia were compared with population controls (n = 577); similarly, EAC (n = 636) or ESCC (n = 245) patients were compared with population controls (n = 1507) using multivariable adjusted logistic regression. Increasing intake of folate from foods was associated with reduced EAC risk (P-trend = 0.01) and mitigated the increased risks of ESCC associated with smoking and alcohol consumption. In contrast, high intake of folic acid from supplements was associated with a significantly elevated risk of BE with dysplasia. High intakes of riboflavin and methionine from food were associated with increased EAC risk, whereas increasing betaine intake was associated with reduced risks of BE without (P-trend = 0.004) or with dysplasia (P-trend = 0.02). Supplemental thiamin, riboflavin, niacin, and vitamin B-12 were associated with increased EAC risk. There were no consistent associations between genetic polymorphisms studied and BE or EAC risk. High intake of folate-containing foods may reduce risk of EAC, but our data raise the possibility that folic acid supplementation may increase risks of BE with dysplasia and EAC.

BACKGROUND: Variation in meat and fish intakes has been associated with a risk of some cancers, but evidence for ovarian cancer is limited and inconsistent. OBJECTIVE: We examined the association between intakes of total meat, red meat, processed meat, poultry, and fish and ovarian cancer risk. DESIGN: Data came from 2 Australian population-based case-control studies conducted 10 y apart. Analyses included a total of 2049 cases and 2191 control subjects. We obtained dietary information via a food-frequency questionnaire. We estimated multivariable-adjusted odds ratios (ORs) for each study by using logistic regression and combined results of the 2 studies by using random-effects models. We also assembled the published evidence in a systematic review and meta-analysis. RESULTS: Although there was no association between total or red meat intake and ovarian cancer risk, women with the highest intake of processed meat had a significantly increased risk of ovarian cancer in the 2 case-control studies (combined OR: 1.18; 95% CI: 1.15, 1.21) and the meta-analysis [7 studies; pooled relative risk (RR): 1.20; 95% CI: 1.07, 1.34]. In contrast, a frequent intake of poultry was associated with borderline significant reductions in risk in the 2 case-control studies (combined OR: 0.83; 95% CI: 0.67, 1.03) and the meta-analysis including 7 additional studies (pooled RR: 0.90; 95% CI: 0.79, 1.01). High fish intake was associated with a significantly reduced risk in the 2 case-control studies (combined OR: 0.76; 95% CI: 0.62, 0.94) and a smaller borderline significant reduction in the meta-analysis (6 additional studies; pooled RR: 0.84; 95% CI: 0.68, 1.03). CONCLUSION: Our results suggest that low consumption of processed meat and higher consumption of poultry and fish may reduce the risk of ovarian cancer.

OBJECTIVE: Participation rates have been declining in case-control studies, particularly among controls, raising concerns about possible bias. Formal assessments of the effect of low participation on odds ratios (OR) are seldom presented however. We sought to quantify possible bias using multiple imputation techniques. METHODS: Using data from two Australian case-control studies, we estimated the relative risks of oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC), and serous ovarian cancer (SOC) associated with smoking and body mass index (BMI). We compared ORs observed using self-reported data from participating controls with ORs derived using imputed exposures for non-participating controls. RESULTS: Participating controls were less likely than non-participants to smoke currently. Smoking remained significantly associated with oesophageal cancer even under the most extreme assumption of smoking prevalence among non-participants (OSCC: observed OR 6.54, 4.62-9.28, imputed OR 3.94, 2.83-5.49; OAC: observed OR 2.69, 1.87-3.85 imputed OR 1.58, 1.13-2.22). For SOC however, risks associated with smoking were attenuated to null under plausible smoking assumptions among non-participants. BMI distributions were similar among participating and non-participating controls, and risk estimates were essentially unchanged. CONCLUSION AND IMPLICATIONS: Bias is not an inevitable consequence of low control participation and depends on the association examined. Sensitivity analyses can assist in interpretation of results.

Endometrioid and clear cell subtypes of ovarian cancer are both known to be closely associated with endometriosis and endometrial pathology, and so have often been combined in studies of causation. We have examined these ovarian cancers separately for potentially distinct risk factors in our population-based, Australia-wide case control study of 142 women with incident invasive endometrioid, 90 with clear cell ovarian cancers and 1508 population controls. Multivariate logistic regression was used to calculated odds ratios (ORs) and 95% confidence intervals (CIs). Increasing parity, and hormonal contraceptive use for > or = 5 years, strongly decreased the risks of both subtypes. Breast feeding and tubal ligation were also inversely associated, but significantly so only for the endometrioid subtype. As expected endometriosis increased the risk of both subtypes (OR 2.2, 95% CI 1.2-3.9 for endometrioid and OR 3.0, 95% CI 1.5-5.9 for clear cell). Obesity was associated only with clear cell cancers, where we observed a two-fold increased risk (OR 2.2, 95% CI 1.2-4.1). Also a significant trend of decreasing risk with increasing intensity of smoking (p trend 0.02) and education beyond high school was associated with decreased development of clear cell cancers only. Endometrioid and clear cell ovarian cancers have some shared as well as some distinct risk factors, and therefore should be considered separately in studies of ovarian cancer.

Objective. We assessed the MnSOD Val9Ala polymorphism and its interaction with dietary antioxidant intake in ovarian cancer risk and survival. Methods. The MnSOD polymorphism was assessed in 543 ovarian cancer cases and 1130 controls. We used regression analysis to model the association between genotype and risk, case-only analyses to estimate risk modification by dietary variables, and proportional hazard models for survival analysis. Results. We found no association between this polymorphism and ovarian cancer risk or survival, nor was there evidence of any interaction with dietary antioxidant intake. Conclusion. The Val9Ala MnSOD polymorphism does not influence ovarian cancer risk or survival.

OBJECTIVE: Some molecular and histological evidence suggests that mucinous epithelial ovarian cancers develop via a sequence from benign tumor through borderline tumor to invasive cancer. Such a sequence would predict some shared risk factors between the different tumor types. To investigate this, we examined risk factors for benign, borderline and invasive mucinous ovarian tumors. METHODS: A population-based case-control study was conducted in Australia between 2002 and 2005. Women with benign (n=133), borderline (n=147) and invasive (n=43) mucinous tumors of the ovary and women from the general population (n=1487) completed comprehensive health and lifestyle questionnaires. RESULTS: Although parity was inversely related to risk of benign, borderline and invasive tumors, increasing numbers of births did not further decrease risk of any of the tumor types. Hormonal contraceptives and breast-feeding were unrelated to risk. However, 20 or more pack-years of smoking was associated with a more than twofold increase in risk of all three tumor types (OR=2.7, 95% CI 1.6-4.4 for benign tumors; OR=2.7, 95% CI 1.7-4.4 for borderline tumors; and OR=2.1, 95% CI 0.9-5.0 for invasive cancers) compared to never smoking. CONCLUSIONS: Overall, the risk factors for mucinous cancers appear to differ from other subtypes of ovarian cancer. Furthermore, patterns of risk factors across benign, borderline and invasive mucinous ovarian tumors are generally consistent with an adenoma-to-carcinoma sequence as the developmental pathway for this subtype of ovarian cancer. Our findings also suggest the potential preventability of borderline and invasive mucinous ovarian cancer by smoking cessation and by surgical excision of identifiable precursor lesions.

A survey of residents in an area subject to annual toxic cyanobacterial blooms was undertaken to examine potential health effects of cyanobacteria toxins. The survey assessed the health of marine recreational water users in Deception Bay/Bribie Island area in northern Moreton Bay, Queensland, which is exposed to blooms of the nuisance and potentially harmful cyanobacterium Lyngbya majuscula. A postal survey was mailed to 5000 residents with a response rate of 27%. High numbers of people (78%) responding to the survey reported recreational water activity in Moreton Bay. Of those having marine recreational water activity, 34% reported at least one symptom after exposure to marine waters, with skin itching the most reported (23%). Younger participants had greater water exposure and symptoms than older participants. Participants with greater exposures were more likely to have skin and eye symptoms than less exposed groups, suggesting agents in the marine environment may have contributed to these symptoms. Of those entering Moreton Bay waters 29 (2.7%) reported severe skin symptoms, 12 of whom attended a health professional. Six (0.6%) reported the classic symptoms of recreational water exposure to L. majuscula, severe skin symptoms in the inguinal region. Participants with knowledge of L. majuscula were less likely to report less skin, gastrointestinal and fever and headache symptoms. In conclusion, high numbers of participants reported symptoms after exposure to waters subject to L. majuscula blooms but only a small number appeared to be serious in nature suggesting limited exposure to toxins. Keywords: Cyanobacteria, Epidemiology, Toxin, Marine, Dermatitis, Marine recreation

Resistance to chemotherapy represents one of the most important causes of treatment failure in patients with ovarian cancer. Common polymorphisms in the glutathione- S -transferase ( GSTM1, GSTP1 and GSTT1 ) family have been implicated in chemoresistence and ovarian cancer survival. In this study, we have analysed Australian women diagnosed with primary invasive epithelial ovarian cancer between 1985 and 1997, using DNA extracted from peripheral blood and archival uninvolved (normal) tissues. GSTP1 genotypes were determined using ABI Prism 7700 Sequence Detection System methodology ( n = 448) and GSTT1 and GSTM1 genotypes using PCR-agarose methodology ( n = 239). We observed a significant survival advantage among carriers of GSTP1 Ile105Val GG/GA genotype (HR 0.77, 95% confidence interval (CI) 0.61–0.99, p = 0.04) and a non-significant survival advantage among women who were homozygous for the GSTM1 and GSTT1 deletion variants. There was also evidence of an additive effect, with a stronger survival benefit in women carrying three low function GST genotypes ( GSTM1 null, GSTT1 null and GSTP1 GA/GG ) (HR 0.47, 95% CI 0.22–1.02). The results of this study, the largest to date, are consistent with a number of previous smaller studies which have also observed that reduced GST function was associated with better survival outcomes in patients with ovarian cancer.

Objectives. Although early reports suggested that smoking was not associated with ovarian cancer risk, recent studies have reported positive associations for cancers of the mucinous subtype. We sought to clarify the relationship between smoking and ovarian cancer by histological subtype. Methods. We conducted a systematic literature review and meta-analysis of studies investigating the association between smoking and risk of the different histological subtypes of epithelial ovarian cancer. Eight population-based case–control studies, one pooled analysis of case–control studies, and one cohort study met the inclusion criteria. Summary relative risks (RR), 95% confidence intervals (CI), and tests for heterogeneity were generated from random effects models. Results. Combined, these studies included a total of 910 women with mucinous and 5564 with non-mucinous ovarian cancers. There was a significant doubling of risk of mucinous ovarian cancer in current smokers compared to never smokers (summary RR 2.1, 95%CI 1.7–2.7), but no increased risk of serous (1.0, 95%CI 0.8–1.2) or endometrioid (0.8, 95%CI 0.6–1.1) cancers and a significant risk reduction for clear cell cancers (0.6, 95%CI 0.3–0.9). The risk of mucinous cancer increased with increasing amount smoked but returned to that of never smokers within 20–30 years of stopping smoking. Conclusions. Meta-analysis suggests that current smoking doubles a woman's risk of developing mucinous ovarian cancer. Stopping smoking returns the risk to normal in the long term. Smoking may thus be one of the few modifiable factors offering potential for primary prevention of mucinous ovarian cancer.

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. (C) 2003 Elsevier Ltd. All rights reserved.

Background & Aims: CagA-positive Helicobacter pylori infection has been more closely associated with gastric disease than CagA-negative infection. This study evaluated whether geographic variation in the prevalence of CagA could explain variation in gastric cancer rates. Methods: The Eurogast study was conducted in 17 centers in 13 countries. Gastric cancer rates were calculated for each center, and serum samples from approximately 2850 subjects were assayed for immunoglobulin G antibodies to H. pylori and CagA and for pepsinogens A and C. Results: The proportion of CagA-positive H. pylori infections varied across the centers, but this variation did not explain any more of the variation in gastric cancer rates than H. pylori alone. Subjects with CagA-positive infection had, however, significantly higher pepsinogen levels and a lower pepsinogen A/C ratio than subjects with CagA-negative infection; this pattern was observed consistently across the study centers. Conclusions: Variation in the seroprevalence of CagA did not explain geographic variation in gastric cancer rates any better than H. pylori alone. However, the consistent variation in pepsinogen levels with CagA status across the study centers supports the importance of the role of CagA in the development of gastric disease.

In 1985, gastric cancer was the second most common cause of cancer death in the world. The rapid decline in gastric cancer rates over the last few decades has been attributed to a decline in the prevalence of environmental risk factors for gastric cancer and/or an increase in the prevalence of protective factors. One such risk factor could be the bacterium Helicobacter pylori. Epidemiological studies have shown that areas with high gastric cancer rates often have a correspondingly high prevalence of H. pylori and prospective studies have shown that subjects with serological evidence of H. pylori infection were significantly more likely to go on to develop gastric cancer than those who did not. Helicobacter pylori itself does not appear to be either genotoxic or mutagenic. Infection is, however, associated with increased cell turnover, a chronic immune response accompanied by increased levels of reactive oxygen metabolites and a reduction in gastric levels of ascorbic acid, all conditions that could favour the development of cancer. Nonetheless, the majority of those who are infected with H. pylori do not go on to develop gastric cancer and other factors, such as the strain of the infecting organism or consumption of dietary antioxidants including vitamin C, could also affect the risk of cancer. Finally, it has been estimated that more than one third, and possibly as many as 90% of gastric cancers might be attributable to infection with H. pylori. Prevention and treatment of infection are, therefore, possible approaches to reducing gastric cancer rates. It is, however, unclear what, if any, effect eradication of the infection would have on an individual's risk of gastric cancer and, to date, anti-Helicobacter therapy has only been shown to be of potential benefit in the treatment of low grade gastric MALT lymphomas.

Background/Aims: Low serum levels of pepsinogen A are indicative of chronic atrophy, a risk factor for gastric cancer. This study investigated the relationships between low pepsinogen A levels, Helicobacter pylori seropositivity, and gastric cancer rates in 17 populations worldwide. Methods: In each center, about 200 randomly selected subjects (50 male and 50 female, aged 25–34 and 55–64 years) provided serum samples for pepsinogen analysis and H. pylori serology. Results: Cumulative gastric cancer rates were associated with the prevalence of low pepsinogen A levels in men (coefficient, 0.15 [ P = 0.06] for mortality; coefficient, 0.36 [ P = 0.01] for incidence) but not women. The prevalence of low pepsinogen A levels was also correlated with H. pylori seropositivity in the older age group ( r = 0.55; P = 0.02). Low pepsinogen A levels were significantly more common in the older group (7.5% vs. 2.1% in the younger group; P P = 0.04), and among nonsmokers (5.8% vs. 2.9% in current smokers; P = 0.001). Conclusions: Low pepsinogen A levels are more common in areas with a high seroprevalence of H. pylori and in men in areas with high rates of gastric cancer. The prevalence of low pepsinogen A levels increases with age, but the excess in women and nonsmokers could reflect factors other than gastric pathology.

Alcohol has been declared a carcinogen for cancers of the esophagus, although the evidence relates largely to the squamous subtype. Evidence for an effect on adenocarcinomas is scant and inconsistent.We compared nationwide samples of patients with esophageal adenocarcinoma (EAC) (n=365) or esophagogastric junction adenocarcinoma (EGJAC) (n=426) or esophageal squamous cell carcinoma (ESCC) (n=303) with controls sampled from a population register (n=1580). We used generalized additive models to assess nonlinear effects of self-reported alcohol intake on cancer risk, and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariate logistic and piecewise regression.We observed no association between average weekly alcohol intake and EAC or EGJAC risk. For ESCC, the relationship with alcohol was nonlinear. At intakes of less than 170 g/wk there was no significant association; at greater than this level, there was a significant linear effect (OR, 1.03; 95% CI, 1.02-1.05 per 10 g alcohol/wk). For ESCC, but not EAC or EGJAC, a statistically significant multiplicative interaction between smoking and alcohol was observed (P=.02). In analyses by beverage type, ESCC risks, but not EAC or EGJAC, increased linearly with beer intake (OR, 1.05; 95% CI, 1.04-1.07). Those who drank modest levels of wine (50-90 g/wk) or port or spirits (10-20 g/wk) had significantly lower risks of all 3 cancers than nondrinkers; higher intakes were associated with increased risks of ESCC only.Alcohol intake above the recommended US dietary guidelines significantly increases the risk of ESCC, but not EAC or EGJAC. Smoking modifies the effect of alcohol intake on ESCC risk.