Medical Journal of Australia

ABSTRACT Objectives: To determine the response to colorectal cancer (CRC) screening by colonoscopy, through direct invitation or through invitation by general practitioners. Design and setting: Two-way comparison of randomised population sampling versus cluster sampling of a representative general practice population in the Australian Capital Territory, May 2002 to January 2004. Intervention: Invitation to screen, assessment for eligibility, interview, and colonoscopy. Subjects: 881 subjects aged 55-74 years were invited to screen: 520 from the electoral roll (ER) sample and 361 from the general practice (GP) cluster sample. Main outcome measures: Response rate, participation rate, and rate of adenomatous polyps in the screened group. Results: Participation was similar in the ER arm (35.1%; 95% CI, 30.2%-40.3%) and the GP arm (40.1%; 95% CI, 29.2%-51.0%) after correcting for ineligibility, which was higher in the ER arm. Superior eligibility in the GP arm was offset by the labour of manual record review. Response rates after two invitations were similar for the two groups (ER arm: 78.8%; 95% CI, 75.1%-82.1%; GP arm: 81.7%; 95% CI, 73.8%-89.6%). Overall, 53.4% ineligibility arose from having a colonoscopy in the past 10 years (ER arm, 98/178; GP arm, 42/84). Of 231 colonoscopies performed, 229 were complete, with 32% of subjects screened having adenomatous polyps. Conclusions: Colonoscopy-based CRC screening yields similar response and participation rates with either random population sampling or general practice cluster sampling, with population sampling through the electoral roll providing greater ease of MJA 2004; 181: 423-427 recruitment

Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis

BACKGROUND: MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis. METHODS AND FINDINGS: By murine N-ethyl-N-nitrosourea mutagenesis we identified two distinct noncomplementing missense mutations in Muc2 causing an ulcerative colitis-like phenotype. 100% of mice of both strains developed mild spontaneous distal intestinal inflammation by 6 wk (histological colitis scores versus wild-type mice, p , 0.01) and chronic diarrhoea. Monitoring over 300 mice of each strain demonstrated that 25% and 40% of each strain, respectively, developed severe clinical signs of colitis by age 1 y. Mutant mice showed aberrant Muc2 biosynthesis, less stored mucin in goblet cells, a diminished mucus barrier, and increased susceptibility to colitis induced by a luminal toxin. Enhanced local production of IL-1b, TNF-a, and IFN-c was seen in the distal colon, and intestinal permeability increased 2-fold. The number of leukocytes within mesenteric lymph nodes increased 5-fold and leukocytes cultured in vitro produced more Th1 and Th2 cytokines (IFN-c, TNF-a, and IL-13). This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis, and wound repair. Expression of mutated Muc2 oligomerisation domains in vitro demonstrated that aberrant Muc2 oligomerisation underlies the ER stress. In human ulcerative colitis we demonstrate similar accumulation of nonglycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in noninflamed intestinal tissue. Although our study demonstrates that mucin misfolding and ER stress initiate colitis in mice, it does not ascertain the genetic or environmental drivers of ER stress in human colitis. CONCLUSIONS: Characterisation of the mouse models we created and comparison with human disease suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stress-related pathology and relevant environmental epidemiology are warranted. The Editors’ Summary of this article follows the references

Colonoscopic screening for colorectal cancer improves quality of life measures: a population-based screening study

BACKGROUND: Screening asymptomatic individuals for neoplasia can have adverse consequences on quality of life. Colon cancer screening is widespread but the quality of life (QOL) consequences are unknown. This study determined the impact of screening colonoscopy on QOL measures in asymptomatic average-risk participants. METHODS: Asymptomatic male and female participants aged 55–74 years were randomly selected from the Australian Electoral Roll or six primary care physicians' databases. Participants completed the Short-Form (SF-36) Quality of Life Assessment at baseline and at a mean of 39 days after colonoscopy. Outcome measures were (i) significant changes in raw scores in any of the eight SF-36 domains assessed following colonoscopic screening and (ii) improvements or declines in previously validated categories, representing clinically significant changes, within any of the eight SF-36 domains. RESULTS: Baseline QOL measures were similar to those of a matched general population sample. Role Limitations due to Emotions, Mental Health and Vitality raw scores significantly improved following colonoscopy (P < 0.05, 2-tailed t-test). Health ratings according to Category were similar (same clinical status) in the majority of participants. However, 30% participants recorded clinically significant improvement in the Mental Health and Vitality domains (P < 0.05, Wilcoxon Signed-Ranks test). This improvement was not offset by declines in other domains or in other participants. Improvement in QOL was not related to colonoscopy results. CONCLUSION: Average-risk persons benefit significantly from colon cancer screening with colonoscopy, improving in Mental Health and Vitality domains of Quality of Life. This improvement is not offset by declines in other domains

Accurate identification of interval colorectal cancers: results from a single Australian jurisdiction

Introduction: Interval colorectal cancers (CRCs) are those diagnosed within 5 years of a negative colonoscopy. We investigated the proportion of interval CRCs that develop within 6–60 months of colonoscopy, and their clinical and molecular characteristics. Methods: We performed a cohort study of all individuals who underwent colonoscopy between 2001 and 2008 at a single large teaching hospital. These records were linked with (i) the regional cancer registry using probabilistic record linkage and (ii) the hospital medical record using deterministic linkage. Matches were verified, and pathology, tumor stage and mismatch repair status were extracted. Results: A total of 10 854 individuals had a colonoscopy at our centre in the period. Linkage to ACT and NSW Cancer Registries detected 384 and 98 CRCs for notification dates of 2001–2013 (ACT) and 2001–2010 (NSW). The second match process identified a further 55 CRCs from a search of the hospital electronic medical records using relevant ICD‐10 diagnosis codes. A total of 404/537 CRCs (58% male) were included in this study after excluding cases that did not have a colonoscopy between 2001–2008, diagnosis of carcinoid tumor, metastatic malignancy of unknown primary and cases that could not be verified by pathological or clinical records. There were seventeen (4.2%) interval cancers. Individuals with interval cancers were more likely to have diverticulosis at the index colonoscopy (p = 0.019), and the index colonoscopy was more likely to be performed by a trainee (p = 0.044). Interval cancers were somewhat more likely to have mucinous histology (p = 0.059). There were no differences with respect to CRC site, stage, mismatch repair or BRAF mutation status. Conclusions: In our population‐based cohort study in Australia, 4.2% of patients with CRC had interval cancers. The data show that improvement is possible in colonoscopy training and surveillance in diverticulosis. These data are comparable to rates of interval cancers from other population studies and establish a benchmark for Australian jurisdictions

Colonoscopy screening for colorectal cancer: the outcomes of two recruitment methods

Objectives: To determine the response to colorectal cancer (CRC) screening by colonoscopy, through direct invitation or through invitation by general practitioners. Design and setting: Two-way comparison of randomised population sampling versus cluster sampling of a representative general practice population in the Australian Capital Territory, May 2002 to January 2004. Intervention: Invitation to screen, assessment for eligibility, interview, and colonoscopy. Subjects: 881 subjects aged 55-74 years were invited to screen: 520 from the electoral roll (ER) sample and 361 from the general practice (GP) cluster sample. Main outcome measures: Response rate, participation rate, and rate of adenomatous polyps in the screened group. Results: Participation was similar in the ER arm (35.1%; 95% CI, 30.2%-40.3%) and the GP arm (40.1%; 95% CI, 29.2%-51.0%) after correcting for ineligibility, which was higher in the ER arm. Superior eligibility in the GP arm was offset by the labour of manual record review. Response rates after two invitations were similar for the two groups (ER arm: 78.8%; 95% CI, 75.1%-82.1%; GP arm: 81.7%; 95% CI, 73.8%-89.6%). Overall, 53.4% ineligibility arose from having a colonoscopy in the past 10 years (ER arm, 98/178; GP arm, 42/84). Of 231 colonoscopies performed, 229 were complete, with 32% of subjects screened having adenomatous polyps. Conclusions: Colonoscopy-based CRC screening yields similar response and participation rates with either random population sampling or general practice cluster sampling, with population sampling through the electoral roll providing greater ease of recruitment

The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner

Mucous metaplasia (MM) is an aberrant secretory phenotype that arises during Helicobacter-induced gastric carcinogenesis. HSPA5, a key modulator of the unfolded protein response (UPR) activated by endoplasmic reticulum (ER) stress is overexpressed in gastric cancer (GC). We studied activation of the UPR in MM and GC in humans and mice. We assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, and CHOP) in human GC, and correlated with Helicobacter pylori (H. pylori) status, then surveyed HSPA5 in normal gastric mucosa and gastric pre-neoplasia including gastritis and intestinal metaplasia (IM). The role of H. pylori infection in the UPR was assessed by co-culture with AGS GC cells. ER stress markers in metaplasia and dysplasia from transgenic K19-Wnt1/C2mE mice and C57Bl/6 mice with chronic Helicobacter felis (H. felis) infection were compared. HSPA5 was overexpressed in 24/73 (33%) of human GC. Induction of HSPA5 and XBP1 splicing was associated with H. pylori-associated GC (P=0.007 for XBP1 splicing). HSPA5 was overexpressed in MM but not gastritis in patients with H. pylori infection. Stimulation of AGS cells with CagA-positive H. pylori suppressed HSPA5 expression and XBP1 splicing. In the normal gastric mucosa of human and mouse, HSPA5 was constitutively expressed in MIST1-positive chief cells. Increased Hspa5 and Chop expression were found in dysplasia of C57Bl/6 mice with chronic H. felis infection but was absent in spontaneous gastric dysplasia in K19-Wnt1/C2mE mice with concomitant loss of Mist1 expression, similar to that observed in H. pylori-associated human GC. Induction of the UPR in the milieu of Helicobacter-induced chronic inflammation and MM may promote neoplastic transformation of Helicobacter-infected gastric mucosa.This work was supported by grants from the National Health and Medical Research Council (DT), the Canberra Hospital Radiation Oncology Trust Fund (DT), the Canberra Region Medical Foundation (DT), and ESA International (DT)