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.

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.

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.

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.

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.

Benefits, Harms, and Cost-Effectiveness of Potential Age Extensions to the National Bowel Cancer Screening Program in Australia.

BACKGROUND: The Australian National Bowel Cancer Screening Program (NBCSP) is rolling out 2-yearly immunochemical fecal occult blood test screening in people aged 50 to 74 years. This study aimed to evaluate the benefits, harms, and cost-effectiveness of extending the NBCSP to younger and/or older ages. METHODS: A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate the fully rolled-out NBCSP and alternative strategies assuming screening starts at 40 or 45 years and/or ceases at 79 or 84 years given three scenarios: (i) perfect adherence (100%), (ii) high adherence (60%), and (ii) low adherence (40%, as currently achieved). RESULTS: The current NBCSP will reduce colorectal cancer incidence (mortality) by 23% to 51% (36% to 74%) compared with no screening (range reflects participation); extending screening to younger or older ages would result in additional reductions of 2 to 6 (2 to 9) or 1 to 3 (3 to 7) percentage points, respectively. With an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS), only screening from 50 to 74 years [incremental cost-effective ratio (ICER): A$2,984-5,981/LYS) or from 45 to 74 years (ICER: A$17,053-29,512/LYS) remained cost-effective in all participation scenarios. The number-needed-to-colonoscope to prevent a death over the lifetime of a cohort in the current NBCSP is 35 to 49. Starting screening at 45 years would increase colonoscopy demand for program-related colonoscopies by 3% to 14% and be associated with 55 to 170 additional colonoscopies per additional death prevented. CONCLUSIONS: Starting screening at 45 years could be cost-effective, but it would increase colonoscopy demand and would be associated with a less favorable incremental benefits-to-harms trade-off than screening from 50 to 74 years. IMPACT: The study underpins recently updated Australian colorectal cancer management guidelines that recommend that the NBCSP continues to offer bowel screening from 50 to 74 years.

Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

BACKGROUND: Nexvax2® is a novel, peptide-based, epitope-specific immunotherapy intended to be administered by regular injections at dose levels that increase the threshold for clinical reactivity to natural exposure to gluten and ultimately restore tolerance to gluten in patients with celiac disease. Celiac disease patients administered fixed intradermal doses of Nexvax2 become unresponsive to the HLA-DQ2·5-restricted gluten epitopes in Nexvax2, but gastrointestinal symptoms and cytokine release mimicking gluten exposure, that accompany the first dose, limit the maximum tolerated dose to 150µg. Our aim was to test whether stepwise dose escalation attenuated the first dose effect of Nexvax2 in celiac disease patients. METHODS: We conducted a randomized, double-blind, placebo-controlled trial at four community sites in Australia (3) and New Zealand (1) in HLA-DQ2·5 genotype positive adults with celiac disease who were on a gluten-free diet. Participants were assigned to cohort 1 if they were HLA-DQ2·5 homozygotes; other participants were assigned to cohort 2, or to cohort 3 subsequent to completion of cohort 2. Manual central randomization without blocking was used to assign treatment for each cohort. Initially, Nexvax2-treated participants in cohorts 1 and 2 received an intradermal dose of 30µg (consisting of 10µg of each constituent peptide), followed by 60µg, 90µg, 150µg, and then eight doses of 300µg over six weeks, but this was amended to include doses of 3µg and 9µg and extended over a total of seven weeks. Nexvax2-treated participants in cohort 3 received doses of 3µg, 9µg, 30µg, 60µg, 90µg, 150µg, 300µg, 450µg, 600µg, 750µg, and then eight of 900µg over nine weeks. The dose interval was 3 or 4days. Participants, care providers, data managers, sponsor personnel, and study site personnel were blinded to treatment assignment. The primary outcome was the number of adverse events and percentage of participants with adverse events during the treatment period. This completed trial is registered with ClinicalTrials.gov, number NCT02528799. FINDINGS: From the 73 participants who we screened from 19 August 2015 to 31 October 2016, 24 did not meet eligibility criteria, and 36 were ultimately randomized and received study drug. For cohort 1, seven participants received Nexvax2 (two with the starting dose of 30µg and then five at 3µg) and three received placebo. For cohort 2, 10 participants received Nexvax2 (four with starting dose of 30µg and then six at 3µg) and four received placebo. For cohort 3, 10 participants received Nexvax2 and two received placebo. All 36 participants were included in safety and immune analyses, and 33 participants completed treatment and follow-up; in cohort 3, 11 participants were assessed and included in pharmacokinetics and duodenal histology analyses. Whereas the maximum dose of Nexvax2 had previously been limited by adverse events and cytokine release, no such effect was observed when dosing escalated from 3µg up to 300µg in HLA-DQ2·5 homozygotes or to 900µg in HLA-DQ2.5 non-homozygotes. Adverse events with Nexvax2 treatment were less common in cohorts 1 and 2 with the starting dose of 3µg (72 for 11 participants) than with the starting dose of 30µg (91 for six participants). Adverse events during the treatment period in placebo-treated participants (46 for nine participants) were similar to those in Nexvax2-treated participants when the starting dose was 3µg in cohort 1 (16 for five participants), cohort 2 (56 for six participants), and cohort 3 (44 for 10 participants). Two participants in cohort 2 and one in cohort 3 who received Nexvax2 starting at 3µg did not report any adverse event, while the other 33 participants experienced at least one adverse event. One participant, who was in cohort 1, withdrew from the study due to adverse events, which included abdominal pain graded moderate or severe and associated with nausea after receiving the starting dose of 30µg and one 60µg dose. The most common treatment-emergent adverse events in the Nexvax2 participants were headache (52%), diarrhoea (48%), nausea (37%), abdominal pain (26%), and abdominal discomfort (19%). Administration of Nexvax2 at dose levels from 150µg to 900µg preceded by dose escalation was not associated with elevations in plasma cytokines at 4h. Nexvax2 treatment was associated with trends towards improved duodenal histology. Plasma concentrations of Nexvax2 peptides were dose-dependent. INTERPRETATION: We show that antigenic peptides recognized by CD4-positive T cells in an autoimmune disease can be safely administered to patients at high maintenance dose levels without immune activation if preceded by gradual dose escalation. These findings facilitate efficacy studies that test high-dose epitope-specific immunotherapy in celiac disease.

Helicobacter pylori overcomes natural immunity in repeated infections.

Repeated experimental reinfection of two subjects indicates that Helicobacter pylori infection does not promote an immune response protective against future reinfection. Our results highlight the importance of preventing reinfection after eradication, through public health initiatives, and possibly treatment of family members. They indicate difficulties for vaccine development, especially therapeutic vaccines.

Colonoscopic surveillance after surgery for colorectal cancer.

BACKGROUND: Intensive colonoscopic surveillance after resection of colorectal cancer (CRC) has been shown not to improve outcome. The National Health and Medical Research Council of Australia (NHMRC) has recently published guidelines recommending appropriate surveillance intervals after CRC resection. The aims of the present study were to assess current and past patterns of postoperative CRC surveillance and to determine the yield of neoplasia from such surveillance. METHODS: An audit was performed of all patients who underwent colonoscopy following surgical resection of CRC from 1989 to 2001. Two groups were assessed: (i) all patients undergoing surveillance colonoscopies; and (ii) all patients diagnosed with CRC at Sir Charles Gairdner Hospital (SCGH) who subsequently had postoperative colonoscopies. Patients who had their index colonoscopy at the study centre and who subsequently underwent surveillance colonoscopies were studied in detail. Yield for neoplasia, patterns of surveillance and concordance with NHMRC recommendations were determined. RESULTS: There were 990 surveillance examinations performed and colorectal adenomas were identified in 184. However, only one case of recurrent cancer was detected. There were a total of 161 patients who had CRC diagnosed and underwent surveillance at SCGH. Of these patients, 75% underwent colonoscopy at 12 months after resection and 48% of these cases underwent a further examination within 12 months. Only 23% of examinations concurred with NHMRC recommendations and practice has not changed with release of these guidelines. CONCLUSIONS: Resectable CRC recurrences are rarely detected at colonoscopic surveillance. Surveillance colonoscopies are -performed too frequently and release of NHMRC guidelines has failed to change practice.

Gastric intraepithelial neoplasia in a Western population.

BACKGROUND AND STUDY AIMS: Descriptions of the natural history and endoscopic appearances of gastric dysplasia/intraepithelial neoplasia (IEN) that originate mainly from Europe. Currently, there are no Australian data available. We aimed to document endoscopic appearances and progression rates of gastric IEN and to determine the significance of indefinite for IEN. PATIENTS AND METHODS: This is a retrospective study, in which cases diagnosed with gastric IEN were identified between 2000 and 2009. Endoscopic appearances, progression rates to more advanced IEN or cancer, and long-term outcomes were recorded. RESULTS: A total of 160 cases with IEN (26.9% high grade, 57.5% low grade, 15.6% indefinite) were identified. The mean age was 67.8 years and 53.8% were men. Endoscopic lesions were polypoid in 29.4% and nonpolypoid in 70.6%. The most common location was the antrum (58.7%). Forty patients had an intervention and 76 underwent endoscopic follow-up only. Twenty-two cancers were diagnosed; three who had an intervention were diagnosed within 12 months, one with low-grade intraepithelial neoplasia developing a cancer after 9.9 years, and 13 undergoing surveillance only, were diagnosed with cancer within 12 months of index endoscopy. Five cases had cancer after a mean of 2.6 years. Forty-seven cases initially labelled as indefinite; following rereview 25 remained unchanged, 11 reclassified as negative for IEN, 10 as low grade, and one as high grade. Three of these cases developed cancer over the study period. CONCLUSION: We concluded that (a) majority of gastric IEN are associated with endoscopic lesions, (b) high rate of early cancer diagnosis was observed (c) rates of progression to cancer were lower than reported rates, and (d) indefinite for IEN is not innocuous requiring an expert pathologist's review.