The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia.

This corrects the article DOI: 10.1038/bjc.2017.310.

The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia.

BACKGROUND: Rural Australians have poorer survival for most common cancers, due partially to later diagnosis. Internationally, several initiatives to improve cancer outcomes have focused on earlier presentation to healthcare and timely diagnosis. We aimed to measure the effect of community-based symptom awareness and general practice-based educational interventions on the time to diagnosis in rural patients presenting with breast, prostate, colorectal or lung cancer in Western Australia. METHODS: 2 × 2 factorial cluster randomised controlled trial. Community Intervention: cancer symptom awareness campaign tailored for rural Australians. GP intervention: resource card with symptom risk assessment charts and local cancer referral pathways implemented through multiple academic detailing visits. Trial Area A received the community symptom awareness and Trial Area B acted as the community campaign control region. Within both Trial Areas general practices were randomised to the GP intervention or control. PRIMARY OUTCOME: total diagnostic interval (TDI). RESULTS: 1358 people with incident breast, prostate, colorectal or lung cancer were recruited. There were no significant differences in the median or ln mean TDI at either intervention level (community intervention vs control: median TDI 107.5 vs 92 days; ln mean difference 0.08 95% CI -0.06-0.23 P=0.27; GP intervention vs control: median TDI 97 vs 96.5 days; ln mean difference 0.004 95% CI -0.18-0.19 P=0.99). There were no significant differences in the TDI when analysed by factorial design, tumour group or sub-intervals of the TDI. CONCLUSIONS: This is the largest trial to test the effect of community campaign or GP interventions on timeliness of cancer diagnosis. We found no effect of either intervention. This may reflect limited dose of the interventions, or the limited duration of follow-up. Alternatively, these interventions do not have a measurable effect on time to cancer diagnosis.

Public health advocacy in action: the case of unproven breast cancer screening in Australia.

In recent years, nonmammographic breast imaging devices, such as thermography, electrical impedance scanning and elastography, have been promoted directly to consumers, which has captured the attention of governments, researchers and health organisations. These devices are not supported by evidence and risk undermining existing mammographic breast cancer screening services. During a 5-year period, Cancer Council Western Australia (CCWA) used strategic research combined with legal, policy and media advocacy to contest claims that these devices were proven alternatives to mammography for breast cancer screening. The campaign was successful because it had input from people with public health, academic, clinical and legal backgrounds, and took advantage of existing legal and regulatory avenues. CCWA's experience provides a useful advocacy model for public health practitioners who are concerned about unsafe consumer products, unproven medical devices, and misleading health information and advertising.

The Improving Rural Cancer Outcomes (IRCO) Trial: a factorial cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural patients with cancer in Western Australia: a study protocol.

INTRODUCTION: While overall survival for most common cancers in Australia is improving, the rural-urban differential has been widening, with significant excess deaths due to lung, colorectal, breast and prostate cancer in regional Australia. Internationally a major focus on understanding variations in cancer outcomes has been later presentation to healthcare and later diagnosis. Approaches to reducing time to diagnosis of symptomatic cancer include public symptom awareness campaigns and interventions in primary care to improve early cancer detection. This paper reports the protocol of a factorial cluster-randomised trial of community and general practice (GP) level interventions to reduce the time to diagnosis of cancer in rural Western Australia (WA). METHODS AND ANALYSIS: The community intervention is a symptom awareness campaign tailored for rural Australians delivered through a community engagement model. The GP intervention includes a resource card with symptom risk assessment charts and local referral pathways implemented through multiple academic detailing visits and case studies. Participants are eligible if recently diagnosed with breast, colorectal, lung or prostate cancer who reside in specific regions of rural WA with a planned sample size of 1350. The primary outcome is the Total Diagnostic Interval, defined as the duration from first symptom (or date of cancer screening test) to cancer diagnosis. Secondary outcomes include cancer stage, healthcare utilisation, disease-free status, survival at 2 and 5 years and cost-effectiveness. ETHICS AND DISSEMINATION: Ethics approval has been granted by the University of Western Australia and from all relevant hospital recruitment sites in WA. RESULTS: Results of this trial will be reported in peer-reviewed publications and in conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12610000872033.

Alcohol and cancer: a position statement from Cancer Council Australia.

The Cancer Council Australia (CCA) Alcohol Working Group has prepared a position statement on alcohol use and cancer. The statement has been reviewed by external experts and endorsed by the CCA Board. Alcohol use is a cause of cancer. Any level of alcohol consumption increases the risk of developing an alcohol-related cancer; the level of risk increases in line with the level of consumption. It is estimated that 5070 cases of cancer (or 5% of all cancers) are attributable to long-term chronic use of alcohol each year in Australia. Together, smoking and alcohol have a synergistic effect on cancer risk, meaning the combined effects of use are significantly greater than the sum of individual risks. Alcohol use may contribute to weight (fat) gain, and greater body fatness is a convincing cause of cancers of the oesophagus, pancreas, bowel, endometrium, kidney and breast (in postmenopausal women). The existing evidence does not justify the promotion of alcohol use to prevent coronary heart disease, as the previously reported role of alcohol in reducing heart disease risk in light-to-moderate drinkers appears to have been overestimated. CCA recommends that to reduce their risk of cancer, people limit their consumption of alcohol, or better still avoid alcohol altogether. For individuals who choose to drink alcohol, CCA recommends that they drink only within the National Health and Medical Research Council guidelines for alcohol consumption.

Impact of a short, culturally relevant training course on cancer knowledge and confidence in Western Australia's Aboriginal Health Professionals.

OBJECTIVE: To develop, deliver and evaluate a cancer education course for Indigenous Health Professionals. METHOD: The cancer education course combines expert presentations, interactive sessions and visits to local cancer treatment centres. Three four-day courses have been run, in both metropolitan and regional Western Australia (WA). Cancer knowledge and confidence were measured at baseline, course completion and at follow-up (six to eight months). Data were analysed within subject. RESULTS: Thirty-five Aboriginal Health Professionals have completed the program, most from rural or remote WA. All confidence items significantly improved at course completion (p<0.005), but improvements for only two items, 'I know what cancer is' and 'I can describe the different common cancers', were sustained at follow-up (p<0.05). Knowledge of treatment (p<0.05), screening (p<0.05) and the most common cancers in women (p<0.005) were significantly greater after course completion, but increased knowledge was not sustained at follow-up. CONCLUSION: Demand for places suggests that Aboriginal Health Professionals are interested in developing knowledge, skills and confidence in cancer control. Attendance increased understanding of cancer and improved cancer knowledge however this was not maintained. IMPLICATIONS: A short, culturally relevant training course increases cancer knowledge and confidence, however, ongoing education is needed to maintain this.

Estimates of beneficial and harmful sun exposure times during the year for major Australian population centres.

OBJECTIVE: To examine the influence of geographical and seasonal factors on duration of solar ultraviolet (UV) radiation exposure of skin to produce recommended vitamin D levels without producing erythema. DESIGN AND SETTING: An ecological study using daily Ultraviolet Index (UVI) data collected in major population centres across Australia for 1 year (1 January - 31 December 2001) to calculate sun exposure times for recommended vitamin D production and erythema. MAIN OUTCOME MEASURES: Sun exposure times to produce either serum vitamin D concentrations equivalent to an oral intake of 200-600 IU/day or erythema for people aged 19-50 years with fair skin (Fitzpatrick type II skin) exposing 15% of the body. RESULTS: In January, across Australia, 2-14 minutes of sun three to four times per week at 12:00 is sufficient to ensure recommended vitamin D production in fair-skinned people with 15% of the body exposed. However, erythema can occur in as little as 8 minutes. By contrast, at 10:00 and 15:00, there is a greater difference between exposure time to produce erythema and that to produce recommended vitamin D levels, thereby reducing the risk of sunburn from overexposure. From October to March, around 10-15 minutes of sun exposure at around 10:00 or 15:00 three to four times per week should be enough for fair-skinned people across Australia to produce recommended vitamin D levels. Longer exposure times are needed from April to September, particularly in southern regions of Australia. CONCLUSION: Our study reinforces the importance of existing sun protection messages for the summer months throughout Australia. However, fair-skinned people should be able to obtain sufficient vitamin D from short periods of unprotected sun exposure of the face, arms and hands outside of the peak UV period (10:00-15:00) throughout Australia for most of the year. The greater variability in sun exposure times during winter, means that optimal sun exposure advice should be tailored to each location.

Liver inflammation and cytokine production, but not acute phase protein synthesis, accompany the adult liver progenitor (oval) cell response to chronic liver injury.

Oval cells are facultative liver progenitor cells, which are invoked during chronic liver injury in order to replenish damaged hepatocytes and bile duct cells. Previous studies have observed inflammation and cytokine production in the liver during chronic injury. Further, it has been proposed that inflammatory growth factors may mediate the proliferation of oval cells during disease progression. We have undertaken a detailed examination of inflammation and cytokine production during a time course of liver injury and repair, invoked by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. We show that immediately following initial liver injury, B220-expressing leucocytes transiently infiltrate the liver. This inflammatory response occurred immediately before oval cell numbers began to expand in the liver, suggesting that the two events may be linked. Two waves of liver cytokine production were observed during the CDE time course. The first occurred shortly following commencement of the diet, suggesting that it may represent a hepatic acute phase response. However, examination of acute phase marker expression in CDE-fed mice did not support this hypothesis. The second wave of cytokine expression correlated with the expansion of oval cell numbers in the liver, suggesting that these factors may mediate oval cell proliferation. No inflammatory signalling was detected following withdrawal of the injury stimulus. In summary, our results document a close correlation between inflammation, cytokine production and the expansion of oval cells in the liver during experimental chronic injury.

Establishment, characterization, and long-term maintenance of cultures of human fetal hepatocytes.

Cultured human hepatocytes have broad research and clinical applications; however, the difficulties in culturing rodent and human hepatocytes are well known. These problems include the rapid loss of the hepatocytic phenotype in primary culture and the limited replicating capacity of the cultured cells. We describe the establishment of serum-free primary cultures of human fetal hepatocytes (HFHs) that retain hepatocytic morphology and gene expression patterns for several months and maintain sufficient proliferative activity to permit subculturing for at least 2 passages. Initially, HFH cultures contained 2 main cell types that morphologically resembled large and small hepatocytes. The fetal hepatocytes expressed alpha-fetoprotein (AFP), cytokeratin (CK) 19, albumin, and other hepatic proteins. Treatment of the cultures with oncostatin M (OSM) increased cell size and enhanced cell differentiation and formation of bile canaliculi, probably through an effect on hepatocyte nuclear factor (HNF) 4alpha. Approximately 1 month after plating, multiple clusters of very small cells became apparent in the cultures. These cells had very few organelles and are referred to as blast-like cells. Flow cytometric analysis of these cells showed that they express oval cell/stem cell markers such as CD90 (Thy-1), CD34, and OV-6 but do not stain with antibodies to beta(2)-microglobulin. HFH cultures maintained for 9 to 12 months produced grossly visible organoids containing ductular structures that stained for CK18, CK19, and AFP. In conclusion, HFH cultures, which might contain a population of hepatic stem cells, constitute an excellent tool for a variety of studies with human hepatocytes, including the mechanisms of viral infection.

Oval cell-mediated liver regeneration: Role of cytokines and growth factors.

In experimental models, which induce liver damage and simultaneously block hepatocyte proliferation, the recruitment of a hepatic progenitor cell population comprised of oval cells is invariably observed. There is a substantial body of evidence to suggest that oval cells are involved in liver regeneration, as they differentiate into hepatocytes and biliary cells. Recently, bone marrow cells were shown to be a source of a stem cells with the capacity to repopulate the liver. Presently, the relationship between bone marrow cells and oval cells is unclear. Investigations will be greatly assisted by the availability of in vitro models based on a knowledge of cytokines that affect oval cells. While the cytokines, which regulate the different hematopoietic lineages, are well characterized, there is relatively little information regarding those that influence oval cells. This review outlines recent developments in the field of oval cell research and focuses on cytokines and growth factors that have been implicated in regulating oval cell proliferation and differentiation.

Ethanol interactions with a choline-deficient, ethionine-supplemented feeding regime potentiate pre-neoplastic cellular alterations in rat liver.

To examine the effect of ethanol on hepatocarcinogenesis induced by a choline-deficient, ethionine-supplemented (CDE) diet, rats were fed either an ethanol-supplemented diet or ethanol-free, isocaloric diet for 2 months, followed by a CDE diet or control diet for up to 8 months. Changes to cellular composition and pattern of gene expression in the liver were determined at 0 and 3 days, and 1, 2 and 3 weeks after commencing the CDE diet, using histological/immunochemical techniques and northern analysis. Oval cells in the liver were identified morphologically and by expression of pi-glutathione S-transferase (pi-GST), alpha-fetoprotein (AFP) and the embryonic isoform of pyruvate kinase (M2-PK). Oval cell numbers and changes in the pattern of gene expression induced by the CDE diet were accelerated by pre-treatment with ethanol. At all stages, the proportion of oval cells in the test group exceeded that in controls. After 1 week, oval cells had spread sufficiently from the periportal region to be observed pericentrally in test animals and by 3 weeks, extensive formation of ductal structures was apparent, which were absent in controls. Additionally, M2-PK and AFP mRNA were detected earlier, and in greater abundance in animals pre-treated with ethanol. After 8 months of CDE treatment, one or two small hepatic foci (<10 hepatocytes), strongly positive for pi-GST, were detected in the liver of ethanol-pre-treated animals. These foci were absent in CDE-treated animals; however, animals pre-treated with ethanol followed by chronic CDE treatment showed increased size (>40 hepatocytes) and numbers of foci, correlating with the extent of liver damage and varying from 5 to 50% of the liver section. Our data suggest that ethanol pre-treatment potentiates the short-term effects of the CDE diet by enhancing oval cell proliferation, while chronic CDE administration enhances the appearance of pre-malignant hepatic foci that are observed with ethanol pre-treatment alone.

Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma.

Oval cells are bipotential liver stem cells able to differentiate into hepatocytes and bile duct epithelia. In normal adult liver oval cells are quiescent, existing in low numbers around the periportal region, and proliferate following severe, prolonged liver trauma. There is evidence implicating oval cells in the development of hepatocellular carcinoma, and hence the availability of an immortalized oval cell line would be invaluable for the study of liver cell lineage differentiation and carcinogenesis. A novel approach in the generation of cell lines is the use of the p53 knockout mouse. Absence of p53 allows a cell to cycle past the normal Hayflick limit, rendering it immortalized, although subsequent genetic alterations are thought necessary for transformation. p53 knockout mice were fed a choline-deficient, ethionine-supplemented diet, previously shown to increase oval cell numbers in wild-type mice. The oval cells were isolated by centrifugal elutriation and maintained in culture. Colonies of hepatic cells were isolated and characterized with respect to phenotype, growth characteristics and tumorigenicity. Analysis of gene expression by Northern blotting and immunocytochemistry suggests they are oval-like cells by virtue of albumin and transferrin expression, as well as the oval cell markers alpha fetoprotein, M(2)-pyruvate kinase and A6. Injection into athymic nude mice shows the cell lines are capable of forming tumors which phenotypically resemble hepatocellular carcinoma. Thus, the use of p53 null hepatic cells successfully generated immortalized and tumorigenic hepatic stem cell lines. The results presented support the idea that deleting p53 allows immortalization and contributes to the transformation of the oval-like cell lines. Further, the tumorigenic status of the cell lines is direct evidence for the participation of oval cells in the formation of hepatocellular carcinoma.