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.

Post-colonoscopy colorectal cancers identified by probabilistic and deterministic linkage: results in an Australian prospective cohort.

OBJECTIVE: Post-colonoscopy colorectal cancers (PCCRCs) are recognised as a critical quality indicator. Benchmarking of PCCRC rate has been hampered by the strong influence of different definitions and methodologies. We adopted a rigorous methodology with high-detail individual data to determine PCCRC rates in a prospective cohort representing a single jurisdiction. SETTING: We performed a cohort study of individuals who underwent colonoscopy between 2001 and 2008 at a single centre serving Australian Capital Territory (ACT) and enclaving New South Wales (NSW) region. These individuals were linked to subsequent colorectal cancer (CRC) diagnosis, within 5 years of a negative colonoscopy, through regional cancer registries and hospital records using probabilistic and deterministic record linkage. All cases were verified by pathology review. Predictors of PCCRCs were extracted. PARTICIPANTS: 7818 individuals had a colonoscopy in the cohort. Linkage to cancer registries detected 384 and 98 CRCs for notification dates of 2001-2013 (ACT) and 2001-2010 (NSW). A further 55 CRCs were identified from a search of electronic medical records using International Classification of Diseases-10 diagnosis codes. After verification and exclusions, 385/537 CRCs (58% male) were included. PRIMARY OUTCOME MEASURE: PCCRC rates. RESULTS: There were 15 PCCRCs in our cohort. The PCCRC incidence rate was 0.384/1000 person-years and the 5-year PCCRC risk was estimated as 0.192% (95% CI 0.095 to 0.289). The index colonoscopy prior to PCCRC was more likely to show diverticulosis (p=0.017 for association, OR 3.56, p=0.014) and have poor bowel preparation (p=0.017 for association, OR 4.19, p=0.009). CONCLUSION: In this population-based cohort study, the PCCRC incidence rate was 0.384/1000 person-years and the 5-year PCCRC risk was 0.192%. These data show the 'real world' accuracy of colonoscopy for CRC exclusion.

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.

Perception of Colorectal Cancer Risk does not Enhance Participation in Screening.

High participation is a key requirement for effective cancer screening. Many strategies to improve participation hold that a person's knowledge and beliefs dictate screening behavior. We compared perception of colon cancer risk in participants and nonparticipants in a population-based study of screening colonoscopy, and also assessed past screening behavior. Surprisingly, while past screening behavior was a predictor of participation, we found that participants perceived their risk of colorectal cancer to be significantly and substantially lower than the real figure and that of nonparticipants. Our data suggest that health promotion strategies aimed at improving health knowledge may not be effective in improving population screening rates.

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.