Trends in incidence, mortality rates, and survival of colorectal cancer in Western Australia from 1990 to 2014: a retrospective whole-population longitudinal study.

PURPOSE: This study aimed to investigate the trends in colorectal cancer (CRC) incidence and mortality rates among the Western Australian (WA) population. This study further compared the trends with the timing of the implementation and rollout of the National Bowel Cancer Screening Program (NBCSP) and examined the survival predictors in CRC cases. METHODS: This study was a whole-population, retrospective longitudinal study and included all individuals with a confirmed histological diagnosis of primary invasive CRC diagnosed in WA from 1990 to 2014 (n = 25,932). The temporal trends were assessed by Joinpoint regression models and Kaplan-Meier survival curves were used to asses 5-year survival. Predictors of survival were examined using multivariable Cox proportional hazard regression models, adjusting for age of diagnosis. RESULTS: The overall CRC incidence showed an upward trend between 1990 and 2010 (annual percent change (APC) = 1.1%); then, there was a downward trend from 2010 to 2014 (APC = - 5.0%). In younger people (< 50 years), the incidence rate increased steadily (APC = 0.9%) over the study period. The overall CRC mortality trend increased from 1990 to 1999 (APC = 1.6%), decreasing after that (APC = - 2.1%). Younger people had better CRC-related 5-year survival than older people (HR = 0.81, 95%CI 0.75-0.87, p = < 0.001). CONCLUSION: This study found that CRC incidence and mortality rates decreased among older people over the last 10 years in Western Australia. However, incidence continues to rise for younger people. Hence, more widespread adoption of the screening program, and potential preventive and early diagnostic strategies should become key priorities for the CRC control in WA.

Familial and non-familial risk factors associated with colorectal cancer survival in young and middle-aged patients.

BACKGROUND: Survival following colorectal cancer (CRC) survival may be influenced by a number of factors including family history, individual medical history, and comorbidities. The impact of these factors may vary based on the patient's age. METHODS: The study cohort consisted of individuals born in Western Australia between 1945 and 1996, who had been diagnosed with CRC prior to 2015 (n = 3220). Hospital, cancer, and mortality data were extracted for each patient from state health records and were used to identify potential risk factors associated with CRC survival. Family linkage data, in combination with cancer registry data, were used to identify first-degree family members with a history of CRC. The association between survival following CRC diagnosis and identified risk factors was examined using Cox proportional hazard models. RESULTS: Age and sex were not significantly associated with survival in young patients. However, in middle-aged patients increasing age (HR 1.03, 95% CI 1.01-1.05, p = 0.003) and being male (HR 0.72, 95% CI 0.60-0.87, p < 0.001) were associated with reduced survival. Being diagnosed with polyps and having a colonoscopy prior to CRC diagnosis were associated with improved survival in both young and middle-aged patients, while a history of non-CRC and liver disease was associated with reduced survival. In middle-aged patients, having diabetes-related hospital admissions (HR 1.53, 95% CI 1.15-2.03, p = 0.004) was associated with reduced survival. CONCLUSIONS: In both young and middle-aged patients with CRC, factors associated with early screening and detection were associated with increased CRC survival while a history of liver disease and non-CRC was associated with decreased CRC survival.

Evaluation of the benefits, harms and cost-effectiveness of potential alternatives to iFOBT testing for colorectal cancer screening in Australia.

The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll-out 2-yearly screening using the immunochemical Faecal Occult Blood Testing (iFOBT) in people aged 50 to 74 years by 2020. In this study, we aimed to estimate the comparative health benefits, harms, and cost-effectiveness of screening with iFOBT, versus other potential alternative or adjunctive technologies. A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate a total of 13 screening approaches involving use of iFOBT, colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC), faecal DNA (fDNA) and plasma DNA (pDNA), in people aged 50 to 74 years. All strategies were evaluated in three scenarios: (i) perfect adherence, (ii) high (but imperfect) adherence, and (iii) low adherence. When assuming perfect adherence, the most effective strategies involved using iFOBT (annually, or biennially with/without adjunct sigmoidoscopy either at 50, or at 54, 64 and 74 years for individuals with negative iFOBT), or colonoscopy (10-yearly, or once-off at 50 years combined with biennial iFOBT). Colorectal cancer incidence (mortality) reductions for these strategies were 51-67(74-80)% in comparison with no screening; 2-yearly iFOBT screening (i.e. the NBCSP) would be associated with reductions of 51(74)%. Only 2-yearly iFOBT screening was found to be cost-effective in all scenarios in context of an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS); this strategy was associated with an incremental cost-effectiveness ratio of A$2,984/LYS-A$5,981/LYS (depending on adherence). The fully rolled-out NBCSP is highly cost-effective, and is also one of the most effective approaches for bowel cancer screening in Australia.

Revised Australian national guidelines for colorectal cancer screening: family history.

INTRODUCTION: Screening is an effective means for colorectal cancer prevention and early detection. Family history is strongly associated with colorectal cancer risk. We describe the rationale, evidence and recommendations for colorectal cancer screening by family history for people without a genetic syndrome, as reported in the 2017 revised Australian guidelines. Main recommendations: Based on 10-year risks of colorectal cancer, people at near average risk due to no or weak family history (category 1) are recommended screening by immunochemical faecal occult blood test (iFOBT) every 2 years from age 50 to 74 years. Individuals with moderate risk due to their family history (category 2) are recommended biennial iFOBT from age 40 to 49 years, then colonoscopy every 5 years from age 50 to 74 years. People with a high risk due to their family history (category 3) are recommended biennial iFOBT from age 35 to 44 years, then colonoscopy every 5 years from age 45 to 74 years. Changes in management as a result of the guidelines: By 2019, the National Bowel Cancer Screening Program will offer all Australians free biennial iFOBT screening from age 50 to 74 years, consistent with the recommendations in these guidelines for category 1. Compared with the 2005 guidelines, there are some minor changes in the family history inclusion criteria for categories 1 and 2; the genetic syndromes have been removed from category 3 and, as a consequence, colonoscopy screening is now every 5 years; and for categories 2 and 3, screening begins with iFOBT for people aged 40 and 35 years, respectively, before transitioning to colonoscopy after 10 years.

Costs and outcomes of Lynch syndrome screening in the Australian colorectal cancer population.

BACKGROUND AND AIM: Individuals with Lynch syndrome (LS) are at increased risk of LS-related cancers including colorectal cancer (CRC). CRC tumor screening for mismatch repair (MMR) deficiency is recommended in Australia to identify LS, although its cost-effectiveness has not been assessed. We aim to determine the cost-effectiveness of screening individuals with CRC for LS at different age-at-diagnosis thresholds. METHODS: We developed a decision analysis model to estimate yield and costs of LS screening. Age-specific probabilities of LS diagnosis were based on Australian data. Two CRC tumor screening pathways were assessed (MMR immunohistochemistry followed by MLH1 methylation (MLH1-Pathway) or BRAF V600E testing (BRAF-Pathway) if MLH1 expression was lost) for four age-at-diagnosis thresholds-screening < 50, screening < 60, screening < 70, and universal screening. RESULTS: Per 1000 CRC cases, screening < 50 identified 5.2 LS cases and cost $A7041 per case detected in the MLH1-Pathway. Screening < 60 increased detection by 1.5 cases for an incremental cost of $A25 177 per additional case detected. Screening < 70 detected 1.6 additional cases at an incremental cost of $A40 278 per additional case detected. Compared with screening < 70, universal screening detected no additional LS cases but cost $A158 724 extra. The BRAF-Pathway identified the same number of LS cases for higher costs. CONCLUSIONS: The MLH1-Pathway is more cost-effective than BRAF-Pathway for all age-at-diagnosis thresholds. MMR immunohistochemistry tumor screening in individuals diagnosed with CRC aged < 70 years resulted in higher LS case detection at a reasonable cost. Further research into the yield of LS screening in CRC patients ≥ 70 years is needed to determine if universal screening is justified.

Population-based screening for Lynch syndrome in Western Australia.

We showed earlier that routine screening for microsatellite instability (MSI) and loss of mismatch repair (MMR) protein expression in colorectal cancer (CRC) led to the identification of previously unrecognized cases of Lynch syndrome (LS). We report here the results of screening for LS in Western Australia (WA) during 1994-2012. Immunohistochemistry (IHC) for loss of MMR protein expression was performed in routine pathology laboratories, while MSI was detected in a reference molecular pathology laboratory. Information on germline mutations in MMR genes was obtained from the state's single familial cancer registry. Prior to the introduction of routine laboratory-based screening, an average of 2-3 cases of LS were diagnosed each year amongst WA CRC patients. Following the implementation of IHC and/or MSI screening for all younger (<60 years) CRC patients, this has increased to an average of 8 LS cases diagnosed annually. Based on our experience in WA, we propose three key elements for successful population-based screening of LS. First, for all younger CRC patients, reflex IHC testing should be carried out in accredited pathology services with ongoing quality control. Second, a state- or region-wide reference laboratory for MSI testing should be established to confirm abnormal or suspicious IHC test results and to exclude sporadic cases by carrying out BRAF mutation or MLH1 methylation testing. Finally, a state or regional LS coordinator is essential to ensure that all appropriate cases identified by laboratory testing are referred to and attend a Familial Cancer Clinic for follow-up and germline testing.

Endoscopic clips allow for accurate pre-operative localisation of colorectal cancer.

BACKGROUND: Colorectal cancer is a major cause of morbidity and mortality worldwide. Optimal management of this disease relies upon accurate pre-operative localisation to allow multidisciplinary discussion and treatment planning. Current pre-operative localisation methods consist of colonoscopy and computed tomography (CT), which are only 79%-85% accurate. To minimise this error, colonoscopy tattooing is a routine practice to facilitate operative localisation. The aim of this study is to investigate if endoscopic radiopaque clips can more accurately localise the lesions pre-operatively. METHODS: A retrospective case-control study was conducted of patients diagnosed with colorectal cancer at a tertiary hospital between 2017 and 2019. Visualisation rates and accurate localisation rates were compared between patients receiving radiopaque clips and those who had colonoscopy alone. All patients received a tattoo distal to the tumour and a staging CT. Data on patient demographics, tumour demographics, post-procedure complications and changes to surgical management were collected. RESULTS: Of 285 patients, 245 had tumour localisation with colonoscopy alone and 40 had additional clip localisation. Groups had comparable patient demographics. For patients receiving clips and follow-up CTs within 14 days, 92% of lesions were visualised and 100% of these lesions were accurately localised. In contrast, colonoscopy only accurately localised 77% of lesions (p < 0.01). This resulted in 1.2% of patients requiring an altered operation due to incorrect localisation. No clip-related complications were reported. CONCLUSION: Radiopaque clips are a highly accurate and cost-effective method for localising colorectal cancer with a pre-operative accuracy rate over 92%.

A cohort study of missed and new cancers after esophagogastroduodenoscopy.

OBJECTIVES: Little is known about missed rates of upper gastrointestinal cancer (UGC) in Western populations, with most data originating from Japanese centers quoting high missed rates of 23.5-25.8%. The objective of this study was to better define missed rates of esophagogastroduodenoscopy (EGD) and the natural history of UGC in a Western population that underwent an initial EGD without cancer, but were subsequently diagnosed with a UGC. Our hypothesis was that a normal EGD rarely misses the detection of UGC. METHODS: This is a retrospective cohort study. A prospectively maintained electronic database was used to identify all patients who underwent EGD between 1990 and 2004 at the study institution. Patients in this cohort who were diagnosed with UGC before 2006 were identified through the Western Australian Cancer Registry. We defined missed cancers as those diagnosed within 1 year of EGD, possible missed cancers as those diagnosed 1-3 years after EGD, and new cancers as those diagnosed more than 3 years after EGD. This study had no interventions and was conducted at a tertiary referral center. The main outcome measurement included UGC. RESULTS: Of the 28,064 EGDs performed, UGC was diagnosed subsequent to the procedure in 116 cases (0.41%). There were 29 missed cancers, 26 possible missed cancers, and 75 new cancers. Of the missed cancers, 11 were esophageal, 15 were gastric, and 3 were duodenal. In 69% (n=20) of the missed cancers, an abnormality was described at the site of malignancy. In 59% (n=17) of the missed cancers, the indication for EGD was an alarm symptom of dysphagia or suspected blood loss. In an univariate analysis, the presence of an alarm symptom was related to missed cancers, whereas operator experience, trainee participation, and usage of newer equipment were not. One of the main limitations of this study is that it was a retrospective review. CONCLUSIONS: UGC is rare after normal EGD, confirming the high accuracy of EGD. Institutional approval was granted for the conduct of this study.

Outcomes of endoscopic resection of large colorectal neoplasms: an Australian experience.

BACKGROUND AND AIMS: Endoscopic resection of large colorectal neoplasms is increasingly being used as an alternative to surgery. However data on failure rates, safety and long-term outcomes remain limited. The aim of the study was to report short- and long-term outcomes from endoscopic resection of large colorectal neoplasms from a single centre and use a model to predict mortality had surgery been performed. METHODS: Consecutive patients referred for endoscopic resection of large (> or = 20 mm) colorectal neoplasms from January 2001 to February 2008 were included. Resection details were recorded in a prospectively maintained database. Data was collected on 30-day complication rates, and follow-up colonoscopy findings. The Colorectal-POSSUM score was used to estimate mortality from open surgery. RESULTS: There were 154 large neoplasms in 140 patients. Mean age was 68 years (range 22-94). Mean neoplasm size was 26 mm (range 20-80 mm, 24 > or = 40 mm). Complete endoscopic removal was achieved in 95% of cases. Twenty patients were referred for surgery (14%). In the endoscopy group, there were no deaths within 30 days. Twelve patients had a complication including two perforations. Endoscopic follow-up data was available in 90% of cases and five patients (4%) were found to have residual adenoma that was treated endoscopically with subsequent clearance. If surgery had been performed, the mean predicted mortality was 2.2% (range 0.5-10%). There were two deaths (10%) in patients who underwent elective surgery within 30 days. CONCLUSION: Endoscopic resection of large colorectal neoplasms is safe and effective even for very large benign neoplasms. When the lesion is endoscopically resectable this should be the preferred treatment.

Cost-Effectiveness of Personalized Screening for Colorectal Cancer Based on Polygenic Risk and Family History.

BACKGROUND: There is growing evidence for personalizing colorectal cancer screening based on risk factors. We compared the cost-effectiveness of personalized colorectal cancer screening based on polygenic risk and family history to uniform screening. METHODS: Using the MISCAN-Colon model, we simulated a cohort of 100 million 40-year-olds, offering them uniform or personalized screening. Individuals were categorized based on polygenic risk and family history of colorectal cancer. We varied screening strategies by start age, interval and test and estimated costs, and quality-adjusted life years (QALY). In our analysis, we (i) assessed the cost-effectiveness of uniform screening; (ii) developed personalized screening scenarios based on optimal screening strategies by risk group; and (iii) compared the cost-effectiveness of both. RESULTS: At a willingness-to-pay threshold of $50,000/QALY, the optimal uniform screening scenario was annual fecal immunochemical testing (FIT) from ages 50 to 74 years, whereas for personalized screening the optimal screening scenario consisted of annual and biennial FIT screening except for those at highest risk who were offered 5-yearly colonoscopy from age 50 years. Although these scenarios gained the same number of QALYs (17,887), personalized screening was not cost-effective, costing an additional $428,953 due to costs associated with determining risk (assumed to be $240 per person). Personalized screening was cost-effective when these costs were less than ∼$48. CONCLUSIONS: Uniform colorectal cancer screening currently appears more cost-effective than personalized screening based on polygenic risk and family history. However, cost-effectiveness is highly dependent on the cost of determining risk. IMPACT: Personalized screening could become increasingly viable as costs for determining risk decrease.

Pathways to a cancer-free future: a protocol for modelled evaluations to minimise the future burden of colorectal cancer in Australia.

INTRODUCTION: With almost 50% of cases preventable and the Australian National Bowel Cancer Screening Program in place, colorectal cancer (CRC) is a prime candidate for investment to reduce the cancer burden. The challenge is determining effective ways to reduce morbidity and mortality and their implementation through policy and practice. Pathways-Bowel is a multistage programme that aims to identify best-value investment in CRC control by integrating expert and end-user engagement; relevant evidence; modelled interventions to guide future investment; and policy-driven implementation of interventions using evidence-based methods. METHODS AND ANALYSIS: Pathways-Bowel is an iterative work programme incorporating a calibrated and validated CRC natural history model for Australia (Policy1-Bowel) and assessing the health and cost outcomes and resource use of targeted interventions. Experts help identify and prioritise modelled evaluations of changing trends and interventions and critically assess results to advise on their real-world applicability. Where appropriate the results are used to support public policy change and make the case for optimal investment in specific CRC control interventions. Fourteen high-priority evaluations have been modelled or planned, including evaluations of CRC outcomes from the changing prevalence of modifiable exposures, including smoking and body fatness; potential benefits of daily aspirin intake as chemoprevention; increasing CRC incidence in people aged <50 years; increasing screening participation in the general and Aboriginal and Torres Strait Islander populations; alternative screening technologies and modalities; and changes to follow-up surveillance protocols. Pathways-Bowel is a unique, comprehensive approach to evaluating CRC control; no prior body of work has assessed the relative benefits of a variety of interventions across CRC development and progression to produce a list of best-value investments. ETHICS AND DISSEMINATION: Ethics approval was not required as human participants were not involved. Findings are reported in a series of papers in peer-reviewed journals and presented at fora to engage the community and policymakers.

Reducing the cost of proton pump inhibitors by adopting best practice.

OBJECTIVES: To evaluate the appropriateness of proton pump inhibitor (PPI) use by assessing the level of compliance of PPI prescribing practices with published guidelines and to assess the potential cost avoidance through inappropriate prescribing. METHOD: A six-week observational study of PPI prescriptions was undertaken between April and June 2005, involving hospital inpatients who were taking a PPI prior to admission. The patients were evaluated using a standardised questionnaire to obtain information regarding their PPI use and efficacy. RESULTS: Among the 679 patients admitted during the study period, 133 were receiving a PPI, and of these 97 (50 men and 47 women) were enrolled into the study. The commonest indication for PPI use was gastro-oesophageal reflux disease (GORD, n = 71; 73.2%). In this cohort, more than one-quarter of patients (26.6%) were using greater than the standard PPI dose. Over half of the patients had at least one risk factor known to exacerbate GORD (51.5% were overweight, 46.4% alcohol consumers and 14% current smokers), and 71.1% were receiving medications known to cause or worsen reflux symptoms. Of those patients who reported alarm symptoms, 84% had undergone endoscopy. The overall compliance with the Pharmaceutical Benefits Scheme (PBS) prescribing guidelines was 78.4%, with the major reason for non-compliance being use for non-PBS indications. Estimated cost savings through adoption of recommended prescribing practices and the implementation of step-down therapy for GORD patients were up to AUD 90,866 and AUD 118,456 per 100 patient-treatment-years, respectively. CONCLUSION: PPIs continue to be prescribed outside the treatment guidelines. As a result, opportunities exist to reduce the cost of PPI use through management of contributing factors, adherence to recommended dosage schedules and use of step-down therapy in asymptomatic patients where appropriate.

What is the importance of the referral letter in the patient journey? A pilot survey in Western Australia.

BACKGROUND: Access to specialists is mediated by general practitioners in many countries. In these settings, specialists rely on information in referral letters when deciding which cases to schedule for their clinics. METHOD: Two-hundred and seven consecutive referral letters to gastroenterologists were scored for the amount of information relayed to the specialist, using a published schedule. The 'quality' scores for these referral letters were compared for four groups of patients: patients diagnosed with histological lesion, those with no histological lesion, those who failed to attend clinic, or those who had a diagnosis unknown. Forty-two referral letters were generated with a range of quality scores. Four gastroenterologists were asked to identify which letters described patients 'likely' to have a significant or benign colorectal condition, and whether they could triage the cases for their clinic given only the information in the letters. RESULTS: It was not possible to differentiate which letters related to patients in each of the four categories (P = 0.6). Patients who failed to attend were more symptomatic than those with a histological lesion (35.4 versus 28.2, mean difference 7.14, 95% confidence interval (CI) 14.1 to 0.15, P = 0.045). Patients referred 'urgently' were not, on the basis of the referral letters, the most symptomatic group (29.7 versus 27, mean difference 2.7, 95% CI -3.4 to 8.8, P = 0.38). The specialists failed to agree on the proportion of cases that could be triaged for their clinics. The cases that could be triaged contained more information (mean 66.38 versus 49.86, mean difference 16, 95% CI 1.3-31.7, P < 0.001). CONCLUSION: There was no evidence for an association between the amount of information relayed and the diagnosis of a histological lesion. However, more information was helpful when deciding which patients to schedule first. By corollary, patients referred with lesser documentation of their clinical presentation may be denied 'urgent' access to the gastroenterology clinic.

The National Bowel Cancer Screening Program: time to achieve its potential to save lives.

OBJECTIVES: Bowel cancer is the second most common cause of cancer deaths in Australia, affecting both men and women. The National Bowel Cancer Screening Program (NBCSP) began in 2006 with the aim of reducing the morbidity and mortality from bowel cancer in Australia. It is based on level I evidence of mortality reduction with screening using the faecal occult blood test (FOBT). Type of program or service: The NBCSP is a world-first national program using the immunochemical FOBT (iFOBT), beginning as a staged rollout limited to people aged 55 and 65 years. By 2020, rollout will be complete, with biennial screening for people aged between 50 and 74 years. The program is managed by the Australian Government Department of Health, in partnership with the states and territories. METHODS: Mailing of iFOBT kits is organised through a national register and participants with a positive test are recommended for colonoscopy by the usual care pathway. Outcomes are reported to a national register, with the Australian Institute of Health and Welfare providing crucial support with data monitoring and analyses. This paper analyses the program's implementation and outcomes to date, and looks at whether it is on track to reach its full potential. RESULTS: Program participants have been shown to have earlier cancer diagnoses and a 15% mortality reduction after accounting for lead-time bias. Modelling analyses predict that increasing participation from the current 41% will result in further reductions in mortality and improvements in cost-effectiveness, which should eventually deliver net savings to the Australian Government. LESSONS LEARNT: The initiation and success of the NBCSP has been founded on strong evidence, but there remain areas for improvement, including capture of outcomes data and timely colonoscopy access. On current evidence, increasing participation among the established 50-74-year-old cohort will yield the strongest investment in improved outcomes. Future technological change could present opportunities in risk-based, personalised prevention and screening. Expanding the age range, for example, by starting screening at 45 years, is currently under review. Importantly, maintenance and development of the program should be driven by strong evidence to ensure its ongoing success as a major Australian health initiative.

Randomised clinical trial: a placebo-controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease.

BACKGROUND: Nexvax2 contains three gluten-derived peptides, intended to tolerize coeliac disease patients to gluten. Sequences cover six epitopes that trigger immune activation in human leucocyte antigen-DQ2.5-positive patients, most notably after an initial dose. Patients experience gastrointestinal symptoms with increases in serum interleukin-2. Consistent with Nexvax2's induction of non-responsiveness, reactivity disappears after repeated doses, or is avoided with gradual dose escalation. Early clinical trials used intradermal dosing, but pharmacokinetics and rapid onset of effect suggest that subcutaneous delivery may also be effective. AIMS: To document the relative bioavailability of Nevax2 peptides after subcutaneous and intradermal dosing, and the tolerability and ability of subcutaneous dosing to induce non-responsiveness to Nexvax2 peptides. METHODS: A randomised, double-blind, placebo-controlled study was conducted to assess plasma pharmacokinetics after subcutaneous and intradermal Nexvax2 dosing in HLA DQ2.5-positive patients, who had symptoms after an oral gluten challenge. Randomisation was to semi-weekly Nexvax2 (n = 12) or placebo (n = 2) injections, over a 5-week subcutaneous dose escalation and 2-week maintenance period, the latter with four doses of 900 µg, two subcutaneous and two intradermal. Post-dose circulating peptide and interleukin-2 levels were assessed. Investigators recorded adverse events experienced by patients. RESULTS: Subcutaneous dosing resulted in slightly greater exposure. Interleukin-2 responses were seen with the gluten challenge but not after subcutaneous or intradermal dosing of 900 µg. Adverse events were generally mild and self-limited. CONCLUSIONS: Subcutaneous and intradermal dosing of Nexvax2 yield similar bioavailability of constituent peptides; subcutaneous dose escalation avoids an immune response to dominant gluten epitopes.

Familial and non-familial risk factors associated with incidence of colorectal cancer in young and middle-aged persons in Western Australia.

AIMS: The aim of this study was to examine factors including family history, medical history and comorbidities associated with the risk of colorectal cancer (CRC) in young (18-49 years) and middle-age (50-69 years) individuals. METHODS: State records were used to identify individuals born in Western Australia between 1945 and 1996, and their first-degree relatives. Individuals in the cohort and their relatives were linked to State cancer registry, hospital and mortality data to identify diagnoses of CRC and other risk factors. The associations between CRC and identified risk factors were examined using multivariable logistic regression. RESULTS: For both young and middle-aged patients, family history of CRC, and a history of smoking, inflammatory bowel disease, liver disease and non-CRC cancer were associated with a significant increase in odds of CRC. In middle-aged patients, having a colonoscopy in the previous 10 years was associated with a reduced odds of CRC regardless of the detection of polyps. However, in young patients only the absence of polyps as confirmed by colonoscopy was associated with a decreased risk of CRC (OR: 0.38, 95%CI: 0.26 - 0.54, p < 0.001). CONCLUSIONS: Many of the risk factors associated with CRC were similar in young and middle-aged persons, and should be used to identify high risk young patients for screening. The association between colonoscopy and polyps with CRC was modified by age, likely as the result of routine screening in middle-aged patients.

Elevated serum interleukin-2 after gluten correlates with symptoms and is a potential diagnostic biomarker for coeliac disease.

BACKGROUND: Coeliac disease patients on a gluten-free diet experience reactions to gluten, but these are not well characterised or understood. Systemic cytokine release was recently linked to reactivation of gluten immunity in coeliac disease. AIM: To define the nature and time-course of symptoms and interleukin-2 changes specific for coeliac disease patients. METHODS: 25 coeliac disease patients on a gluten-free diet and 25 healthy volunteers consumed a standardised 6 gram gluten challenge. Coeliac Disease Patient-Reported Outcome survey and global digestive symptom assessment were completed hourly up to 6 hours after gluten. Adverse events over 48 hours were recorded. Serum interleukin-2 was measured at baseline, and 2, 4 and 6 hours. RESULTS: Serum interleukin-2 was always undetectable in healthy controls, whereas it was undetectable at baseline and elevated >0.5 pg/ml at 4 hours in 92% of coeliac disease patients. All patient-reported outcome severity scores increased significantly after gluten in coeliac disease patients (P < .001 Wilcoxon signed rank test), but not in controls. Symptoms began after 1 hour, and peaked in the third. Nausea and vomiting characterised severe reactions, but mild reactions were limited to headache and tiredness. Peak interleukin-2 correlated with symptom severity, particularly for nausea and vomiting. CONCLUSIONS: Serum interleukin-2 elevations correlate with timing and severity of symptoms after gluten in coeliac disease. Standardised bolus gluten food challenge and interleukin-2 assessment could provide a valuable clinical test to monitor and diagnose coeliac disease in patients established on a gluten-free diet.

Immune-mediated ECM depletion improves tumour perfusion and payload delivery.

High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.

Referring patients to specialists: a structured vignette survey of Australian and British GPs.

BACKGROUND: In Australia and in the United Kingdom (UK) access to specialists is sanctioned by General Practitioners (GPs). It is important to understand how practitioners determine which patients warrant referral. METHODS: A self-administered structured vignette postal survey of General Practitioners in Western Australia and the United Kingdom. Sixty-four vignettes describing patients with colorectal symptoms were constructed encompassing six clinical details. Nine vignettes, chosen at random, were presented to each individual. Respondents were asked if they would refer the patient to a specialist and how urgently. Logistic regression and parametric tests were used to analyse the data RESULTS: We received 260 completed questionnaires. 58% of 'cancer vignettes' were selected for 'urgent' referral. 1632/2367 or 69% of all vignettes were selected for referral. After adjusting for clustering the model suggests that 38.4% of the variability is explained by all the clinical variables as well as the age and experience of the respondents. 1012 or 42.8 % of vignettes were referred 'urgently'. After adjusting for clustering the data suggests that 31.3 % of the variability is explained by the model. The age of the respondents, the location of the practice and all the clinical variables were significant in the decision to refer urgently. CONCLUSION: GPs' referral decisions for patients with lower bowel symptoms are similar in the two countries. We question the wisdom of streaming referrals from primary care without a strong evidence base and an effective intervention for implementing guidelines. We conclude that implementation must take into account the profile of patients but also the characteristics of GPs and referral policies.

Neoplastic Lesions of Gastric Adenocarcinoma and Proximal Polyposis Syndrome (GAPPS) Are Gastric Phenotype.

Neoplastic lesions of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) are gastric phenotype. GAPPS was reported in 2011 as a new autosomal dominant gastric polyposis syndrome characterized by involvement of the gastric body/fundus with sparing of the antrum by multiple polyps, reported to be primarily fundic gland polyps (FGPs), with progression to dysplasia and adenocarcinoma of intestinal type. Our series consists of 51 endoscopic biopsies and 5 gastrectomy specimens from 25 patients belonging to a previously defined GAPPS family. Slides were reviewed and further stains performed. Endoscopy was abnormal in 15 of the 25 patients: carpeting polyposis of the gastric body and fundus in 14 and a gastric mass without polyposis in one. The most common polypoid lesion (seen in 12 patients) was a disorganized proliferation of specialized/oxyntic glands high up in the mucosa involving the attenuated foveolar region around the gastric pits, which we have termed "hyperproliferative aberrant pits". Well developed FGP were seen in 10 patients. Established neoplastic lesions seen in 9 patients were: (1) discrete gastric adenomas, (2) multifocal "flat" dysplasia in the setting of hyperproliferative aberrant pits +/- FGPs, (3) adenomatous tissue associated with adenocarcinoma. All cases of dysplasia were of gastric phenotype based on morphology and mucin immunohistochemistry. IN CONCLUSION: (1) the spectrum of gastric pathology associated with GAPPS is wider than previously reported, (2) the earliest microscopic clue is the finding of hyperproliferative aberrant pits, and (3) the dysplasia is gastric phenotype and the subsequent adenocarcinoma may follow the gastric pathway of carcinogenesis.