Addressing the puzzling role of amidated gastrin 17 (G17) and the gastrin/CCKB/CCK2 receptor in colorectal carcinogenesis, we analysed potential candidate genes involved in G17-dependent NF-jB inhibition and apoptosis. The colorectal carcinoma cell line Colo320 overexpressing the wild-type CCK2 receptor (Colo320wt) underwent G17-induced apoptosis along with suppressed NF-jB activation and decreased expression of the antiapoptotic NF-jB target genes cIAP1 and cIAP2, whereas G17 was without effect on Colo320 cells expressing a CCK2 receptor bearing a loss of function mutation (Colo320mut). Gene microarray analysis revealed an elevated expression of the stress response gene IEX-1 in G17-treated Colo320wt but not Colo320mut cells. Quantitative real-time PCR and conventional RT-PCR confirmed this G17-dependent increase of IEX-1 expression in Colo320wt cells. If these cells were subjected to IEX-1 knockdown by small interfering RNA transfection, the apoptosis-inducing effect of G17 was abolished. Moreover, tumor necrosis factor alpha (TNFa)-or 5-FUinduced apoptosis that is greatly enhanced by G17 treatment in Colo320wt cells was prevented if IEX-1 expression was repressed. Under these conditions of blocked IEX-1 expression, the NF-jB activity remained unaffected by G17, in particular in Colo320wt cells co-treated with TNFa and also the suppressive effect of G17 on cIAP1 and cIAP2 expression was not observed anymore if IEX-1 expression was blocked. Conversely, IEX-1 overexpression in Colo320mut cells caused an increase of basal and TNFa-or 5-FU-induced apoptosis, an effect not further triggered by G17 treatment. Using a xenograft tumor model in severe combined immune deficiency mice, we could show that experimental systemic hypergastrinemia induced by the administration of omeprazole led to enhanced apoptosis as well as to a marked increase of IEX-1 expression in Colo320wt tumors, but not in Colo320mut tumors. These observations indicate that the proapoptotic effect of G17 on human colon cancer cells expressing the wild-type CCK2 receptor is mediated by IEX-1, which modulates NF-jB-dependent antiapoptotic protection and thereby exerts tumor-suppressive potential.

Background The association between celiac disease and colorectal neoplasia has been previously studied, but the question whether recently diagnosed celiac patients show an increased colorectal adenoma prevalence remains unanswered. Aims To compare the prevalence of colorectal adenomas between adult patients with a recent diagnosis of celiac disease versus healthy controls. Materials and Methods A retrospective case-control study was undertaken. Patients with a diagnosis of celiac disease at an age of 45 years or more who undertook colonoscopy six months before or six months after the initiation of a gluten-free diet were enrolled as cases. Asymptomatic subjects undertaking screening colonoscopy were recruited as controls in a 2 : 1 fashion. The prevalence of colorectal adenomas and the prevalence of advanced adenomas were compared between groups. Results 57 celiac disease patients and 118 controls were enrolled. There was a greater prevalence of female patients among the celiac group, with no significant differences in terms of age. There were more obese patients among controls and a higher proportion of tabaquism among celiac patients. Adenoma prevalence was significantly higher among celiac patients (47.37% versus 27.97%, p = 0.01). Advanced adenoma detection was not different between groups. Conclusion Adult patients with a recent diagnosis of celiac disease have an increased prevalence of colorectal adenomas.

Background and Aim. Treatment adherence is a frequent problem in inflammatory bowel disease (IBD). No study has assessed adherence in Argentinian patients with IBD. The aim of this study was to determine inadequate adherence to oral and parenteral therapies in patients with IBD from Argentina and to identify factors associated with it. Methods. A multicenter cross-sectional study involving seven referral centers from three cities of Argentina was undertaken. Patients with a diagnosis of ulcerative colitis (UC), Crohn’s disease (CD), or indeterminate colitis (IBDU/IC) were invited to answer an anonymous survey, which included a 5-point Likert scale to evaluate adherence to therapies. Independent variables associated with inadequate adherence were evaluated. Results. Overall, 447 UC/IBDU and 135 CD patients were enrolled. Median age was 37 years (range 21-72); 39.8% were male; median time from diagnosis was 6 years (0.5-35). 91.4% were under treatment with at least one oral medication; 50.3% of patients reported inadequate adherence to oral medications. Patients with UC/IBDU had a lower risk of inadequate adherence when compared to patients with CD (OR 0.57 (0.37-0.87)). 21.8% reported inadequate adherence to biologics; subcutaneous administration was significantly associated with inadequate adherence to biologics (OR 4.8 (1.57-14.66)). Conclusion. Inadequate treatment adherence is common among patients with IBD, and potentially modifiable factors were identified.

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Background Risankizumab (RZB), a selective interleukin-23 inhibitor, demonstrated clinically meaningful improvements in endoscopic outcomes in patients with moderate to severe Crohn’s disease (CD) during two phase 3 induction trials (ADVANCE and MOTIVATE) and the maintenance study (FORTIFY). Here, we compared the efficacy of RZB in inducing and maintaining improvements in endoscopic outcomes in patients with CD who demonstrated intolerance and/or inadequate response (IR) to biologic therapies (with prior bio-failure) versus those who demonstrated IR to conventional therapies only (without prior bio-failure). Methods Data included in this subgroup analysis included pooled data from patients randomized to receive intravenous (IV) RZB 600mg (N=527) or placebo (PBO) IV (N=362) every 4 weeks (wks) for 12wks during induction (ADVANCE+MOTIVATE), and data from patients receiving subcutaneous (SC) RZB 360mg (N=141) or withdrawn from RZB IV to receive PBO SC (withdrawal [PBO SC], N=164) every 8wks for 52-wks during maintenance. At Wks 12 and 52, endoscopic response, endoscopic remission, ulcer-free endoscopy (absence of ulceration), and deep remission (Wk52 only) were evaluated both in the overall population and in subpopulations of patients with and without prior bio-failure. (Endpoints are defined in Table footnotes). Safety was assessed throughout the studies. Results Approximately three-quarters of randomized patients included in this subgroup analysis had prior bio-failure (ADVANCE+MOTIVATE: 75.4%; FORTIFY: 73.8%). Higher rates of endoscopic response, endoscopic remission, and ulcer-free endoscopy were observed at Wk12 among patients receiving induction with RZB IV versus PBO IV. Subgroup analysis demonstrated treatment effects with risankizumab in patient subpopulations with and without prior bio-failure, with greater adjusted differences versus PBO in patients without prior bio-failure (Figure). At Wk52, endoscopic response, endoscopic remission, ulcer-free endoscopy, and deep remission rates favored RZB SC compared to withdrawal (PBO SC). Again, treatment effects were observed in patients with and without prior bio-failure, with greater adjusted differences versus withdrawal (PBO SC) in patients without prior bio-failure. RZB maintenance treatment was well-tolerated and no new safety signals were observed. The safety profile of RZB has been reported previously.1,2 Conclusion Induction and maintenance therapy with risankizumab achieved higher rates for endoscopic endpoints in patients with moderate to severe Crohn’s disease versus placebo, regardless of prior bio-failure status. However, numerically higher efficacy rates were observed in patients without prior bio-failure. 1 D’Haens, G. et al. in DDW 2021 2 Ferrante, M. et al. in UEGW 2021