AGA Abstracts
fistula pathogenesis and trigger the expression of EMT-associated genes, including β6integrin, which might be involved in the activation of matrix metalloproteinases (MMP). Here, we investigated whether MMP-9, MMP-13, IL-22, IL-33, tryptase, chymase, and hypoxia-inducible-factor 1 alpha (HIF-1α), are involved in CD-associated fistula formation similar to other disease involving EMT. While MMPs are associated with tissue destruction, IL-22, IL-33 and HIF-1α are related to the onset of EMT. Methods: Protein expression of MMP-9, MMP-13, tryptase, chymase, IL-22, IL-33 and HIF-1 α were assessed in perianal fistula specimens of non-IBD and CD-patients (n=5) by immunohistochemistry (IHC). Results: Staining for MMP-9, which is activated by β6-integrin, was strongly detectable along fistula tracts, while only a few cell in deeper tissue layers revealed to be MMP-9 positive. Similar, also staining for MMP-13 was clearly visible around the fistula tracts. However, in contrast to MMP-9, MMP-13 staining was also considerably detectable in deeper tissue layers, likely representing inflammatory infiltrates. The mast cell markers chymase and tryptase appeared in layers slightly below the fistula surface, indicating mast cell aggregates. The epithelial cell protective cytokine IL-22 could be discovered exclusively in transitional cells (TC) covering the fistula tracts. A similar pattern was also observed for IL-33. Both cytokines were absent in deeper tissue areas. Of note, staining for HIF-1 α, an indicator for hypoxia, was very prominent in TC along the fistula tracts, indicating a pivotal role for this molecule in fistula pathogenesis. Conclusions: We demonstrate that MMP-9 and -13, HIF1α, IL-22, IL-33, tryptase and chymase are specifically expressed in cells lining the tract of perianal fistulae. While increased MMP expression is likely to be associated with tissue destruction, increased expression of IL-22, IL-33 and HIF-1 α might be connected with EMT that can be observed during fistula pathogenesis. Presence of mast cells, as indicated by tryptase and chymase staining, suggests ongoing inflammation around CD-associated fistulae. Taken together, our findings suggest an involvement of the indicated molecules in the pathogenesis of CD-associated intestinal fistulae.
and IBD associated adenocarcinima. However, epiregulin-positive cells displayed a distinct round-shaped morphology, different from the spindle-shaped palladin-positive cells. Moreover, they formed a cluster and were surrounded by the palladin-positive cells. Apparently, there was no overlap between the expression of palladin and epiregulin despite much more intense expression of αSMA in epiregulin-positive cells compared to the palladin-positive cells. Conclusion: We observed that both palladin and epiregulin were up-regulated in the αSMA positive cells in the stroma surrounding the cancerous cells in sporadic CRC and IBD associated adenocarcinoma. They were expressed in two distinct populations of stromal cells. This intriguing data suggest that epiregulin may also promote proliferation and growth of the spindle-like palladin-positive cells. Understanding the molecular mechanisms underlying the crosstalk between cancerous cells and stromal cells in IBD may allow us to identify novel targets for cancer prevention and intervention. Su1264 Re-Induction Regimen in Crohn's Disease Adalimumab Failure or Disease Relapse After a First Adalimumab Course. A Single Centre Experience Chiara Pratico', Paolo Gionchetti, Giulia Spuri Fornarini, Andrea Calafiore, Massimo Campieri, Carlo Calabrese, Fernando Rizzello BACKGROUND: Adalimumab (ADA) is a fully human monoclonal antibody targeting TNFalfa with proven efficacy in the treatment of Crohn's disease (CD). We evaluate the efficacy of a second new ADA induction regimen, in order to obtain clinical response. METHODS: Forty-six CD patients were treated with a second ADA induction regimen (40 patients with 160/80mg, 6 with 80/40mg) and maintenance with 40mg every other week (22 patients) or weekly (24 patients). Patients were divided into 3 groups: moderate CD relapses [HarveyBradshaw score (HBI) . 8] during ADA maintenance treatment after an initial response were defined as ‘secondary non responders' (SNR), failures at week 12 of the first induction regimen as ‘primary non responders' (PNR) and CD recurrences [HBI score . 5] within 6 months after the first successful ADA course as ‘early relapses' (ER). Three of them received azathioprine (AZA) plus ADA. Clinical response or remission were evaluated at week 12 [remission: HBI , 4; response: 3-point reduction in the HBI vs baseline]. RESULTS: Of 149 CD patients treated with ADA and followed prospectively, 46 patients [M|F:24|22;mean age 31,7 years (18-63years);median disease duration 7 years (0,3-18years);disease location:7 ileal,23 ileo-colonic,16 colonic;mean HBI at the baseline 11,9 (6-38)]were enrolled. Eighteen patients were SNR (mean first ADA treatment duration:50 weeks), 14 were PNR (mean first ADA treatment duration:14 weeks) and 14 had an ER (mean first ADA treatment duration:77 weeks). Considering the overall group of patients, at week 12 remission was observed in 24 patients (52,2%), 10 patients (21,7%) had partial response, while 12 patients (26,1%) had no improvement. In the subgroup of SNR, 5 patients (27,8%) regained remission, 5 regained (27,8%) response while 8 (44,4%) had no response. Seven patients (50,0%) out of the 14 PNR gained remission, 3 patients (21,4%) had a partial response and 4 patients (28,6%) had no response to the second ADA course. The 3 patients treated with ADA plus AZA achieved complete remission around week 24. At the same time, all of the 14 ER patients responded to the second ADA course: 12 (85,7%) showed new complete remission, 2 patients (14, 3%) had partial response. CONCLUSIONS: ADA re-induction regimen seems to be effective in patients that lost response during ADA maintenance treatment (SNR). Dose intensification with a new early induction regimen showed efficacy to gain response in PNR. A new induction regimen with ADA seems to be extremely effective to regain remission in patients with ER and previous ADA-response.
Su1262 Adalimumab Treatment for Post-Operative Recurrence of Crohn's Disease. A Single Centre Experience Chiara Pratico', Fernando Rizzello, Carlo Calabrese, Giulia Straforini, Ramona Brugnera, Gilberto Poggioli, Silvio Laureti, Paolo Gionchetti BACKGROUND: Crohn's disease commonly recurs after intestinal resection. Growing evidences suggest that infliximab and adalimumab are effective to prevent post operative Crohn's recurrence. We investigated the efficacy of adalimumab for inducing mucosal healing in patients with endoscopic recurrence of Crohn's disease after intestinal resection. METHODS: Twenty-four patients who had endoscopic early severe relapse (evaluated 12 months after an ileo-cecal or ileo-colic anastomotic "curative" resection) were treated with adalimumab. Severe endoscopic relapse was defined as a grade greater than i2 in the Rutgeerts postoperative score or as a presence of deep colonic mucosal lesions. Adalimumab treatment was started with induction regimen 160/80mg and followed by maintenance regimen with 40mg every other week. Mucosal healing was evaluated after 1 year of treatment and defined as i0, while improvement as 1-point reduction in the Rutgeerts score. Colonic mucosal lesions were classified as deep or superficial; mucosal healing was defined as absence of any mucosal lesions and improvement as reduction of the ulcers severity (from deep to superficial). RESULTS: Out of 24 patients with post-operative endoscopic recurrence [M|F: 10|14; mean age 35,7 years (16-58);median disease duration 11 years (2-21);disease location before surgery: 7 ileal, 15 ileo-colonic, 2 colonic;numbers of surgeries: 19 had 1 surgery, 3 had 2 surgeries, 2 had 3 surgeries] 19 had an ileal recurrence (median Rutgeerts Score 3; range 2-4) while 5 a colonic one. At week 52, in the subgroup of patients with ileal recurrence, mucosal healing was observed in 9 patients (47,4%), 3 patients (15,8%) had endoscopic improvement, 7 patients (36,8%) didn't have endoscopic improvement. Among the 5 patients with colonic recurrence, 3 (60%) achieved mucosal healing , 1 (20%) improved endoscopically and 1 (20%) didn't respond endoscopically. At the end of the study, 12 patients were in remission (Harvey Bradshaw Index -HBI- lower than 4), 7 patients had mild activity (mean HBI: 6) and 5 patients had a moderate-severe clinical relapse CONCLUSIONS: Adalimumab seems to be effective to induce mucosal healing in post operative endoscopic relapse. However one third of patients did not have any improvement. This may suggest that an early treatment with adalimumab could improve its efficacy.
Su1265 The Vitamin D Levels and Bone Metabolism in Adult Patients With Inflammatory Bowel Disease in China Jiaming Qian, Hong Lv Objective Explore the serum 25-hydroxyvitamin D3 (25 (OH) D3) levels and bone metabolism status of inflammatory bowel disease (IBD) patients in China, analyze their relationship to IBD disease severity, and identify risk factors. Methods The clinical data of 124 ulcerative colitis (UC) patients, 107 Crohn's disease (CD) patients and 122 normal controls, were collected. The serum 25 (OH) D3 levels, the bone mineral density of IBD patients were measured. Results 1. Serum 25 (OH) D3 levels from IBD patients decreased by 14.45% compared with the normal control group P ,0.001 with the UC group and the CD group decreasing by 19.81% and 10.10% respectively P= ,0.001 and 0.029 2. Within the UC group, serum 25 (OH) D3 levels of patients with severe active disease was significantly lower than those of remission, mildly active and moderate active UC patients P= 0.009,,0.001,0.039 . As well, serum 25 (OH) D3 levels of moderate active UC patients were significantly lower than that of mild active UC patients P=0.006 . Correlation analysis showed that the level of serum 25 (OH) D3 in patients with UC was negatively correlated with the IBD severity r= -0.371 P ,0.001 . 3. Within the CD group, serum 25 (OH) D3 levels of moderate active and severe active CD patients were significantly lower than that of remission CD patients P=0.033, 0.006 . Correlation analysis showed that serum 25 (OH) D3 levels were negatively correlated with CD severity r= -0.285 P=0.03 . 4. The prevalence of osteopenia and osteoporosis in UC patients are 37.2% and 5.1% respectively, and in CD patients are 36.8%, 3.5% respectively. 5. BMD does not differ significantly in UC and CD patients of differing disease severity P .0.05 . 6. In UC and CD patients with normal bone mineral density, osteopenia and osteoporosis, serum 25 (OH) D3 levels were no significantly different P.0.05 . 7. Cumulative amount of glucocorticoid was a risk factor for osteopenia/ osteoporosis in UC OR=1.219 95 percent CI 1.054-1.410 P=0.008 and CD OR=1.288 95 percent CI 1.033-1.606 P=0.025 patients. Conclusion IBD patients were found to have 25 (OH) D3 deficiencies that correlate with the IBD severity in IBD patients prone to osteopenia / osteoporosis, the cumulative amount of glucocorticoid was a risk factor.
Su1263 Up-Regulation of Palladin and Epiregulin Expression in Peritumor Stromal Cells in Sporadic and IBD-Associated Neoplasia Lori Brandt, Archana Patel, Jun Yang, David M. Jones, Catherine Bartholomew, Xinjun Zhu Introduction: Chronic inflammation and fibrosis have been linked to the development of several different types of cancers. Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Palladin is involved in cell motility and cytoskeleton organization and is upregulated in peritumoral fibroblasts in both pancreatic cancer and dysplasia. Epiregulin, an epidermal growth factor ligand, is upregulated in primary and metastatic CRC, gastric cancer, non-small cell lung cancer and breast cancer. In this study we compared the expression of palladin, epiregulin and a myofibroblast marker, alphasmooth muscle actin (αSMA) in adenoma polyps, sporadic CRC and IBD associated dysplasia and adenocarcinoma. Methods: A total of 443 patients with CRC or dysplasia with or without IBD were found at Albany Medical Center from 2000-2012. Parrafin-embedded surgical specimens from those 46 subjects were found. The specimens were analyzed using immunohistochemistry for palladin, epiregulin and αSMA. Staining intensity levels were compared across all specimens using confocal microscopy. Exclusion criteria included a genetic predisposition to cancer, cancer other than CRC, IBD with adenomatous polyps, or insufficient documentation. Results: Immunohistochemistry analysis revealed a strong palladin expression along with moderate expression of α-SMA which was restricted in the fibrotic spindleshaped cells in the stroma that surround the cancerous cells in sporadic CRC and IBD associated CRC, but not within the tumor cells. There was no significant increase in palladin expression in colon adenomatous polyps and IBD associated dysplasia. As anticipated, expression of epiregulin was also markedly increased in the stromal cells in sporadic CRC
AGA Abstracts
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