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Background and Aims: Intestinal ultrasound [IUS] is widely accepted as a reliable tool to monitor Crohn's disease [CD]. Several IUS scores have been proposed, but none has been formally accepted by international organizations. Our aim here was to compare the available scores regarding their correlation with endoscopic activity., Methods: Consenting CD patients undergoing ileocolonoscopy at our Unit between September 2021 and February 2023 were included. Endoscopic activity was defined as SES-CD ≥ 3 or Rutgeerts score ≥ i2b for operated patients. IUS was performed within 6 weeks of endoscopy and scored with IBUS-SAS, BUSS, Simple-US and SUS-CD scores. All correlations were performed using Spearman's rank coefficient [rho = ρ]. Receiver operating characteristic [ROC] curves were compared with the Hanley and McNeil method., Results: Of 73 CD patients, 45 [61.6%] presented endoscopic activity, of whom 22 were severe [30.1%]. All IUS scores showed a significant positive correlation with endoscopy [p < 0.0001], with IBUS-SAS ranking the highest [ρ = 0.87]. Similarly, IBUS-SAS was the most highly correlated with clinical activity [ρ = 0.58]. ROC analysis of IBUS-SAS for any endoscopic activity showed the highest area under the curve (0.95 [95% confidence interval 0.87-0.99]), with sensitivity of 82.2% and specificity of 100% for a cut-off value of 25.2. IBUS-SAS was statistically superior to all the other scores in detecting severe endoscopic activity [SES-CD ≥ 9 or Rutgeerts i4]., Conclusions: All IUS scores provided solid correlation with endoscopy and clinical symptoms. IBUS-SAS outperformed the others due to a more granular description that might help in stratifying different levels of disease activity. Therefore, the use of IBUS-SAS in centres with well-founded expertise in IUS can be suggested., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The tight junctions (TJ) responsible for the integrity of the intestinal barrier are altered in patients with inflammatory bowel disease (IBD), but the physiopathological mechanisms that lead to this alteration are not yet clear. The aim of this study was to determine whether vitamin D, which regulates the integrity of the epithelial barrier by expressing TJ proteins, reduces claudin-2 (Cl-2) levels by inhibiting Stat-6 phosphorylation and whether it increases claudin-4 (Cl-4) levels by blocking Smad-7 activity., Methods: Biopsies were obtained from inflamed and non-inflamed tracts of the right side colon (caecum or ascending colon) from the same patient with active UC. All the patients were affected by a recent flare-up of ulcerative rectocolitis (RCU), with no previous biologic or immunosuppressive therapy, and all the biopsies were obtained before any treatments. The biopsies were cultured in the presence or not of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ). We also used T84 cells as an in vitro model to perform transfection experiments with Stat-6 and Smad-7., Results: Our results indicate that 1,25(OH) 2 D 3 is able to regulate CL-2 and CL-4 protein levels, which are increased and reduced in the intestinal mucosa of UC patients, respectively. In the biopsies obtained from UC patients 1,25(OH) 2 D 3 reduces Cl-2 levels by blocking Stat-6 phosphorylation and increases Cl-4 levels by blocking Smad-7 activity. T84 cells, transfected with siRNA of Stat-6 and Smad-7, showed reduced Cl-2 levels and increased Cl-4 levels, confirming that 1,25(OH) 2 D 3 regulates Cl-2 and Cl-4 by decreasing p-Stat-6 and Smad-7 levels., Conclusions: Our results indicate that the effects of vitamin D on Cl-2 and Cl-4 are mediated by p-Stat-6 and Smad-7 signal, respectively. The study suggests that vitamin D administration to UC patients could be a useful therapeutic intervention, given that vitamin D deficiency is found in these patients.

Up-regulation of intercellular adhesion molecule-1 (ICAM-1) and its soluble form are involved in the chronic inflammation. For the first time, we demonstrated that resveratrol (RE), a natural polyphenol with antioxidant and anti-inflammatory properties, reduces the increase of expression and release of ICAM-1, due to TNFα-induced oxidative stress, in a myofibroblast cell line derived from human colonic (18Co cells). RE is scavenger of radical oxygen species (ROS) and modulates signaling pathways in which Sirt-1 and NF-κB are involved. Effectively, in TNFα-stimulated 18Co cells RE decreases ROS production and increases Sirt-1 expression and activity, but it reduces TNFα-induced ICAM-1 up-regulation by a Sirt-1-independent mechanism, as demonstrated by EX527 and Sirt-1 siRNA treatments. RE inhibits TNFα-induced activation of NF-κB by reducing both ROS and the degradation of IκB-α, an endogenous inhibitor of NF-κB, with consequent decrease of NF-κB nuclear translocation. This study also shows that NF-κB is not the only factor involved in the TNFα-induced ICAM-1 up-regulation and confirms our previous evidence according to which TNFα increases ICAM-1 levels by redox- and non-redox-regulated mechanisms. RE can represent good and useful support in therapies for intestinal inflammatory diseases in which TNFα plays a crucial role in the increase of adhesion molecule expression., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Aims: Endoscopic outcomes are increasingly used in clinical trials and in routine practice for inflammatory bowel disease [IBD] in order to reach more objective patient evaluations than possible using only clinical features. However, reproducibility of endoscopic scoring systems used to categorize endoscopic activity has been reported to be suboptimal. The aim of this study was to analyse the inter-rated agreement of non-dedicated gastroenterologists on IBD endoscopic scoring systems, and to explore the effects of a dedicated training programme on agreement., Methods: A total of 237 physicians attended training courses on IBD endoscopic scoring systems, and they independently scored a set of IBD endoscopic videos for ulcerative colitis [with Mayo endoscopic subscore], post-operative Crohn's disease [with Rutgeerts score] and luminal Crohn's disease (with the Simple Endoscopic Score for Crohn's Disease [SESCD] and Crohn's Endoscopic Index of Severity [CDEIS]). A second round of scoring was collected after discussion about determinants of discrepancy. Interobserver agreement was measured by means of the Fleiss' kappa [kappa] or intraclass correlation coefficient [ICC] as appropriate., Results: The inter-rater agreement increased from kappa 0.51 (95% confidence interval [95% CI] 0.48-0.55) to 0.76 [95% CI 0.72-0.79] for the Mayo endoscopic subscore, and from 0.45 [95% CI 0.40-0.50] to 0.79 [0.74-0.83] for the Rutgeerts score before and after the training programme, respectively, and both differences were significant [P < 0.0001]. The ICC was 0.77 [95% CI 0.56-0.96] for SESCD and 0.76 [0.54- 0.96] for CDEIS, respectively, with only one measurement., Discussion: The basal inter-rater agreement of inexperienced gastroenterologists focused on IBD management is moderate; however, a dedicated training programme can significantly impact on inter-rater agreement, increasing it to levels expected among expert central reviewers., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Objective: Epithelial barrier function is primarily regulated by the tight-junction proteins. Ulcerative colitis (UC) is characterized by Th2 immune response with inflammation and epithelial barrier dysfunction, including an elevation of claudin-2 protein function. Recent studies support an important role of vitamin D in the pathogenesis as well as potential therapy of IBD. Vitamin D deficiency is in fact common in patients with IBD. The aim of the study was to determine whether vitamin D could affect IL-13 and IL-6 levels, and regulate the activity of tight-junction proteins. Claudin-1, -2, -4, and -7 in the inflamed and non-inflamed colonic mucosa of UC patients., Material and Methods: Biopsies from inflamed and non-inflamed tract of colon and rectum from the same active UC patients were cultured with1,25(OH)2D3. IL-13, IL-6 and the tight-junction proteins level were determined., Results: Claudin-1 and claudin-2 proteins were up-regulated in active UC. The treatment with 1,25(OH)2D3 decreases the claudin-1 and claudin-2 protein levels in both inflamed and non-inflamed tract. Claudin-4 and claudin-7 proteins were down-regulated and their levels increase after incubation with the 1,25(OH)2D3. When the biopsies were incubated with 1,25(OH)2D3, a decrease in IL-13 and IL-6 levels was registered., Conclusions: Our results, indicating the inhibition of cytokine levels and the regulation of claudin-2, claudin-4, and claudin-7 by 1,25(OH)2D3, suggest that vitamin D may represent a potential therapeutic agent for the treatment of active UC.

Background: The disease course and colectomy rate of ulcerative colitis (UC) vary largely in population-based and referral center cohorts. We retrospectively evaluated our cohort to determine the disease course and risk factors for colectomy., Methods: A cohort of 1723 ulcerative colitis patients (986 males; mean age, 34.8 ± 15.4 yrs) were identified and followed since 1960s for a mean of 11 ± 9 years (range, 1-49 yrs)., Results: The disease extension was classified as E1, E2, and E3 on diagnosis at 19.7%, 54.2%, and 26.1% of patients, respectively. At the final follow-up, the disease extension increased in 20% of the cases. Extraintestinal manifestations (EIMs) were reported by 11% of the patients, whereas systemic corticosteroids (CS), IM or anti-TNFα agents were used by 68.6%, 20.4%, and 6.4% of patients, respectively. The crude colectomy rate was 7% (120 pts), with a 1.2% rate (n = 21) at 1 year from diagnosis (95% CI, 0.7-1.7) and a Kaplan-Meyer estimation of up to 18.2% after 30 years of follow-up. The 1-year colectomy rate showed no significant difference through the decades, whereas the 5-year and 10-year absolute value of colectomy was halved in the last 2 decades compared with the period from 1960 to 1990 (P = 0.01), with a general trend of a reduced colectomy rate at survival curves (P = 0.056)., Conclusions: The colectomy rate was low in our cohort and further reduced in the last 2 decades. However, despite the availability of anti-TNFα agents, no further significant reduction of colectomies was observed in the last decade.

Endoscopy plays a crucial role in the management of inflammatory bowel disease (IBD). Advances imaging techniques allow visualization of mucosal details, tissue characteristics and cellular alteration. In particular chromoendoscopy, magnification endoscopy, confocal laser endomicroscopy and endocytoscopy seem to have the possibility to radically modify the approach to surveillance and decision making. Dye-based chromoendoscopy (DBC) and magnification chromoendoscopy improve detection of dysplasia, and evaluation of inflammatory activity and extension of ulcerative colitis and are thus considered the standard of care. Dye-less chromoendoscopy could probably replace conventional DBC for surveillance. Narrow band imaging and i-scan have shown to improve activity and extent assessment in comparison to white-light endoscopy. Confocal laser endomicroscopy (CLE) can detect more dysplastic lesions in surveillance colonoscopy and predict neoplastic and inflammatory changes with high accuracy compared to histology. This technology is best used in conjunction with chromoendoscopy, narrow-band imaging, or autofluorescence because of its minute scanning area. This combination is useful for appropriate tissue classification of mucosal lesions already detected by standard or optically enhanced endoscopy. The best combination for IBD surveillance appear to be chromoendoscopy for identification of areas of suspicion, with further examination with CLE to detect intraepithelial neoplasia. However cost, availability, and experience are still an issue.

Background: Endoscopic activity has become a therapeutic endpoint in inflammatory bowel disease. Aim of this study was to evaluate inter-observer agreement for endoscopic scores in a real-life setting., Methods: 14 gastroenterologists with experience in inflammatory bowel disease care and endoscopic scoring reviewed videos of ulcerative colitis (n=13) and postoperative (n=10) and luminal (n=8) Crohn's disease. The Mayo subscore for ulcerative colitis, Rutgeerts score for postoperative Crohn's disease, Crohn's disease endoscopic index of severity (CDEIS), and the simple endoscopic score-Crohn's disease (SES-CD) for luminal Crohn's disease were calculated. A subset of five endoscopic clips were assessed by 30 general gastroenterologists without specific experience in endoscopic scores. Kappa statistics and intraclass correlation coefficients were used to measure agreement., Results: Mayo subscore agreement was suboptimal: kappas were 0.53 (95% confidence interval 0.47-0.56) and 0.71 (0.67-0.76) for the two groups. Rutgeerts score agreement was fair: kappas were 0.57 (0.51-0.65) and 0.67 (0.60-0.72). Agreements for CDEIS and SES-CD were good: intraclass correlation coefficients for the two groups were 0.83 (0.54-1.00) and 0.67 (0.36-0.97) for CDEIS and 0.93 (0.76-1.00) and 0.68 (0.35-0.97) for SES-CD, respectively., Conclusion: The reproducibility of endoscopic scores in inflammatory bowel disease remains suboptimal, which could potentially have major effects on therapeutic choices., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aim: The adhesion molecule expression and matrix metalloproteinases (MMPs) are proposed to be major factors for intestinal injury mediated by T cells in (IBD) and are up-regulated in intestinal mucosa of IBD patients. To investigate the effect of vitamin D derivatives on adhesion molecules and MMPs in colonic biopsies of IBD patients., Methods: Biopsies from inflamed and non-inflamed tract of terminal ileum and colon and PBMC from the same IBD patients were cultured with or without vitamin D derivatives. MMP activity and adhesion molecule levels were determined., Results: 1,25(OH)2D3 and ZK 191784 significantly decrease ICAM-1 protein levels in the biopsies obtained only from the inflamed region of intestine of UC patients, while MAdCAM-1 levels decrease in the presence of 1,25(OH)2D3 in the non-inflamed region, and, in the presence of ZK, in the inflamed one. In CD patients 1,25(OH)2D3 and ZK decrease ICAM-1 and MAdCAM-1 in the biopsies obtained from the non-inflamed and inflamed regions, with the exception of ICAM-1 in the inflamed region in the presence of 1,25(OH)2D3. The expression of MMP-9, MMP-2, and MMP-3 decreases in the presence of vitamin D derivatives in UC and CD with the exception of 1,25(OH)2D3 that does not affect the levels of MMP-9 and MMP-2 in CD. Vitamin D derivatives always affect MMP-9, MMP-2 and ICAM-1 in PBMC of UC and CD patients., Conclusions: Based on the increased expression of ICAM-1, MAdCAM-1 and MMP-2,-9,-3 in IBD, our study suggests that vitamin D derivatives may be effective in the management of these diseases., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Purpose: We report a preliminary evaluation of the performance of computed tomography colonography (CTC) systematically obtained before optical colonoscopy (OC) in subjects with positive faecal occult blood test (FOBT) within a population-based screening programme for colorectal cancer (CRC)., Materials and Methods: Seventy-nine subjects with positive FOBT from a regional screening programme were invited to perform same day CTC and OC. CTC was performed with standard bowel preparation. OC with segmental unblinding was the reference standard. A per-patient per-adenoma analysis was performed., Results: Forty-nine of 79 subjects (62%) with positive FOBT adhered to the study and completed both examinations. Twenty-two (44.9%) of the 49 had a cancer or an adenoma ≥6 mm. Per-patient sensitivity, specificity, negative predictive value and positive predictive value for cancer or adenoma ≥6 mm were 95.5% (95%CI:77.2%-99.9%), 51.9% (95%CI:32.0%-71.3%), 93.3% (95%CI:68.1%-99.8%) and 61.8% (95%CI:43.6%-77.8%)., Conclusions: In the setting of a FOBT-based screening programme for CRC, CTC showed a high sensitivity, but relatively low specificity and positive predictive value, for cancer and adenoma ≥6 mm. Probably performing CTC without faecal tagging as second line test after a positive FOBT is not a cost-effective strategy.

Intracellular adhesion molecules and matrix metalloproteinases (MMPs) are up-regulated in intestinal mucosa of patients with inflammatory bowel diseases (IBD), i.e. ulcerative colitis (UC) or Crohn's disease (CD). Our aim was to verify whether the vitamin D analogue ZK 156979 (ZK) down-regulates adhesion molecules, and decreases MMPs production by PBMC of IBD patients. ICAM-1 and LFA-1 levels increase, when PBMC were incubated with PHA or LPS or TNF-alpha, and decrease when these substances were used in combination with ZK. MMPs activity increases incubating the cells with PHA or LPS or TNF-alpha. MMP-9 decreases when ZK was used in association, while MMP-2 decreases only when ZK was used in combination with anti-TNF-alpha. Our results suggest that the down-regulation of ICAM-1 and LFA-1 on PBMC and the inhibition of MMP-9 activity by ZK could provide a potential role of this low calcemic vitamin D derivative in future strategies in IBD therapy., ((c) 2010 Elsevier Inc. All rights reserved.)

Immunochemical faecal occult blood tests have shown a greater sensitivity than guaiac test in colorectal cancer screening, but optimal number of samples and cutoff have still to be defined. The aim of this multicentric study was to evaluate the performance of immunochemical-based screening strategies according to different positivity thresholds (80, 100, 120 ng ml(-1)) and single vs double sampling (one, at least one, or both positive samples) using 1-day sample with cutoff at 100 ng ml(-1) as the reference strategy. A total of 20 596 subjects aged 50-69 years were enrolled from Italian population-based screening programmes. Positivity rate was 4.5% for reference strategy and 8.0 and 2.0% for the most sensitive and the most specific strategy, respectively. Cancer detection rate of reference strategy was 2.8 per thousand, and ranged between 2.1 and 3.4 per thousand in other strategies; reference strategy detected 15.6 per thousand advanced adenomas (range=10.0-22.5 per thousand). The number needed to scope to find a cancer or an advanced adenoma was lower than 2 (1.5-1.7) for the most specific strategies, whereas it was 2.4-2.7, according to different thresholds, for the most sensitive ones. Different strategies seem to have a greater impact on adenomas rather than on cancer detection rate. The study provides information when deciding screening protocols and to adapt them to local resources.

Aim: To report our experience with computed tomography colonography (CTC) systematically performed in subjects with positive faecal occult blood test (FOBT) and an incomplete colonoscopy in the setting of a population-based screening for colorectal cancer (CRC)., Methods: From April 2006 to April 2007, 43290 individuals (age range 50-70) who adhered to the regional screening program for the prevention of CRC underwent immunochemical FOBT. FOBT was positive in 1882 subjects (4.3%). 1463 (77.7%) of these subjects underwent colonoscopy, 903 performed in a single center. Of 903 colonoscopies 65 (7.2%) were incomplete. Forty-two of these subjects underwent CTC. CTC was performed with a 16-MDCT scanner after standard bowel prep (polyethyleneglycole) in both supine and prone position. Subjects whose CTC showed polyps or masses were referred to the endoscopist for repeat colonoscopy under sedation or underwent surgery. Per-lesion and per-segment positive predictive values (PPV) were calculated., Results: Twenty-one (50%) of 42 CTCs showed polyps or masses. Fifty-five of these subjects underwent a repeat colonoscopy, whereas 2 subjects underwent surgery for colonic masses of indeterminate nature. Four subjects refused further examinations. CTC correctly identified 2 colonic masses and 20 polyps. PPV for masses or polyps greater than 9 mm was of 87.5%. Per-lesion and per-segment PPV were, respectively, 83.3% and 83.3% for polyps greater or equal to 10 mm, and 77.8% and 85.7% for polyps of 6-9 mm., Conclusion: In the context of a screening program for CRC based on FOBT, CTC shows high per-segment and per-lesion PPV for colonic masses and polyps greater than 9 mm. Therefore, CTC has the potential to become a useful technique for evaluation of the non visualized part of the colon after incomplete colonoscopy.

Background: Lymphocytes are crucial in the pathogenesis of inflammatory bowel disease (IBD) and are an important target for drug development. Our aim was to verify whether 2 vitamin D derivatives, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and EB 1089, could induce cell apoptosis and affect cell-cell interaction by regulating adhesion molecule levels., Methods: Peripheral blood mononuclear cell (PBMC) proliferation was studied by [3H]thymidine incorporation and apoptosis was determined using an enzyme-linked immunosorbent assay (ELISA) kit. (Poly(ADP-ribose)polymerase (PARP) cleavage, caspase-3, and ICAM-1 protein levels were determined by Western blot analysis., Results: Our results indicate that 1,25(OH)2D3 or EB 1089 or anti-TNF-alpha (infliximab) induce apoptosis in PBMC obtained from healthy subjects. In IBD patients apoptosis is induced by vitamin D derivatives and by anti-TNF-alpha only in CD patients. Caspase-3 activation and PARP cleavage are registered when PBMC were treated with vitamin D derivatives. ICAM-1 levels remarkably increase when PBMC was incubated with lipopolysaccharide (LPS) or TNF-alpha. The treatment with the vitamin D derivatives, alone or in combination with LPS or TNF-alpha, significantly decreases ICAM-1 levels both in healthy subjects and IBD patients. In HUVEC cocultured with PBMC, previously incubated with LPS or TNF-alpha associated with 1,25(OH)2D3, ICAM-1 levels decrease both in healthy subjects and IBD patients., Conclusions: 1,25(OH)2D3 and EB 1089 inhibit PBMC proliferation, induce apoptosis in PBMC of healthy subjects and IBD patients, and affect ICAM-1 expression on PBMC and on HUVEC cocultured with PBMC, suggesting that the ICAM-1 downregulation could provide a new target for controlling the recruitment of leukocytes at the sites of inflammation in IBD.

We evaluated the sensitivity for colorectal cancer (CRC) of the latex agglutination test (LAT), an immunochemical test routinely used in the Florence District screening programme since 2000. Sensitivity was calculated by the proportional interval cancer incidence method in a population of 27,503 consecutive subjects screened in 2000-2002, interval cancers being identified by linkage to the Tuscany Cancer Registry files. Sensitivity was calculated overall and by gender, age, time since last negative LAT, CRC site, and rank of screening. Overall 1- and 2-year sensitivity estimates were 80.7 and 71.5%, respectively, suggesting that faecal occult blood testing screening sensitivity may be suboptimal due to testing or programme quality problems. Increasing screening sensitivity might be achieved if the detection rate of advanced adenomas could be increased without unacceptable loss in specificity.

Background: Gastric cancer may be suspected with otherwise unexplained positive faecal occult blood testing., Aims: To assess the frequency of gastric cancer following positive faecal occult blood testing and negative colonoscopy., Subjects: Age 40-74 cohort at first screening (1985-2001) with (a) faecal occult blood testing- (83,489), (b) faecal occult blood testing +/colonoscopy+ (2025), or faecal occult blood testing+/colonoscopy- (3555)., Methods: Gastric cancer incidence in faecal occult blood testing subsets, compared with expected standardized incidence rates., Results: Gastric cancer risk was increased (standardized incidence rate=146.7; 95% confidence interval: 105.8-203.4) in faecal occult blood testing+/colonoscopy- subjects. A four-fold excess incidence occurred during first year (observed cases=10, standardized incidence rate=408.3; 95% confidence interval: 219.7-758.8), irrespective of faecal occult blood testing type (guaiac, immunological). No excess risk occurred in faecal occult blood testing- (observed cases=53, standardized incidence rate=91.2; 95% confidence interval: 84.1-98.8) or in faecal occult blood testing+/colonoscopy+ subjects (observed cases=2, standardized incidence rate=101.9; 95% confidence interval: 25.5-407.4). Assuming a 100% 3-year study sensitivity for gastric cancer, faecal occult blood testing positive predictive value would be 0.4% (40-74 years) or 0.7% (> or =60 years) in faecal occult blood testing+/colonoscopy- subjects., Conclusions: Data suggest an association of faecal occult blood testing+/colonoscopy- and excess gastric cancer incidence in the following year. Due to low faecal occult blood testing+ positive predictive value, routine upper digestive tract endoscopy in these subjects is questionable.

We assessed the correlation between quantitative results of immunological faecal occult blood testing (I-FOBT) and colonic lesions (191 colorectal cancers, 890 adenomas) detected at colonoscopy in 2597 FOBT+ (cutoff 100 ng ml(-1) Hb) subjects. At univariate analysis, a higher average faecal Hb content was significantly associated with male gender (P=0.003), age (P=0.02), and colonoscopy findings (P=0.000). Among adenomas, higher faecal Hb content was significantly associated with size (P=0.0000), presence of severe dysplasia (P=0.0001), presence of villous component (P=0.0002), and location in the left colon (P=0.003). At multivariate analysis adjusting for potential confounders, age (P=0.03), size (P=0.0000), and location in the left colon (P=0.0005) were confirmed as having an independent association with higher faecal Hb content. Immunological FOBT is confirmed to be a specific screening test to detect cancer and adenoma, with a low positivity rate (3.7%) and a high positive predictive value (41.5%). Faecal Hb content is significantly higher for those lesions (cancer and high-risk adenomas) screening is aimed at detecting.

Crohn's disease (CD) is an inflammatory disease characterized by the activation of the immune system in the gut. Since tumor necrosis factor (TNF-alpha) plays an important role in the initiation and perpetuation of intestinal inflammation in CD, we investigated whether TX 527 [19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)], a Vitamin D analogue, could affect peripheral blood mononuclear cells (PBMC) proliferation and exert an immunosuppressive effect on TNF-alpha production in CD patients, and whether this immunosuppressive action could be mediated by NF-kappaB down-regulation. TX 527 significantly decreased cell proliferation and TNF-alpha levels. On activation, NF-kappaB, rapidly released from its cytoplasmatic inhibitor (IKB-alpha), transmigrates into the nucleus and binds to DNA response elements in gene promoter regions. The activation of NF-kappaB, stimulated by TNF-alpha, and its nuclear translocation together with the degradation of IKB-alpha were blocked by TX 527. At the same time, NF-kappaB protein levels present in cytoplasmic extracts decreased in the presence of TNF-alpha and increased when PBMC were incubated with TX 527. The results of our studies indicate that TX 527 inhibits TNF-alpha mediated effects on PBMC and the activation of NF-kappaB and that its action is mediated by Vitamin D receptor (VDR), which is activated when the cells are stimulated with TX 527.

Background: The active form of vitamin D, 1,25(OH)(2)D(3), exerts important effects on proliferation and differentiation of many cell types, and immunoregulatory activities in particular on T cell-mediated immunity., Aim: The aim of this study was to investigate whether KH 1060, a vitamin D analogue, could decrease tumor necrosis factor-alpha (TNF-alpha) levels in patients with inflammatory bowel disease (IBD)., Methods: PBMC proliferation was determined by [(3)H]thymidine incorporation. TNF-alpha levels were measured by ELISA kit; VDR, Bcl-2 and Bax protein levels with Western blot analysis., Results: KH 1060 inhibited PBMC proliferation and decreased TNF-alpha levels in IBD patients and this effect was synergistic with anti-TNF-alpha. VDR protein levels were significantly increased by PBMC treatment with KH 1060 or anti-TNF-alpha or their combination in ulcerative colitis (UC) patients, and decreased in Crohn's disease (CD) patients, treating the cells with KH 1060. In UC patients an increase in Bcl-2 and Bax levels was observed incubating, PBMC with KH 1060 or anti-TNF-alpha or their combination. In CD patients a slight decrease in Bcl-2 levels was registered when anti-TNF alone or in association with KH 1060 was used. Bax protein levels were slightly increased in the presence of KH 1060 alone or in combination with anti-TNF., Conclusion: This study shows that KH 1060 acts as an immunomodulator on PBMC, acting as TNF-alpha inhibitor. This finding provides strong evidence that vitamin D status could be an important regulator of immunity IBD.

The aim of this study was to investigate whether the vitamin D analogue KH 1060 could exert a suppressive action on Tumor necrosis factor-alpha (TNF-alpha). The chimeric anti-TNF-alpha monoclonal antibody (anti-TNF), alone or in combination with KH 1060, was also used. KH 1060 (0.01, 0.1, 1 nM) significantly inhibited cell proliferation, determined after 5 days by [3H]thymidine incorporation, when peripheral blood mononuclear cells (PBMC), obtained from healthy subjects, were stimulated with phytohaemagglutinin (PHA) and incubated for 24 h in the absence and in the presence of lipopolysaccharide (LPS). In the same experimental conditions, anti-TNF exerted a significant inhibition on PBMC proliferation, at the lowest doses (0.001, 0.01 microg/ml) in the absence of LPS, and at 0.001, 1, 10 microg/ml in its presence. A synergistic inhibition was registered combining KH 1060 and anti-TNF, at well-defined concentrations. 0.1 nM KH 1060 produced a significant decrease in TNF-alpha levels, determined by ELISA, although less remarkable than in the presence of anti-TNF. This decrease was synergistic, associating 0.1 nM KH 1060 and 0.1 microg/ml anti-TNF. VDR protein levels were increased by 0.1 nM KH 1060, 0.1 microg/ml anti-TNF or their combination. The protein levels of two oncogenes, Bax and Bcl-2, remained unchanged, when PBMC were incubated with KH 1060, anti-TNF or their combination in the absence of LPS, while, in its presence, an increase was registered. The demonstrated anti-TNF-alpha effect of KH 1060 may suggest for this compound an immunosuppressive action and the possibility to synergistically act with other drugs.

Infliximab treatment demonstrated clinical and endoscopic benefits in active refractory and fistulizing Crohn's disease. The aim of this research was to investigate the proliferative response of peripheral blood mononuclear cells (PBMC) obtained from patients with active and fistulizing Crohn's disease treated with infliximab therapy. PBMC proliferation and VDR protein levels were also studied when 1,25(OH)2D3 or its analogues (EB 1089, KH 1060) were added to cells cultures. At day 5 of culture, the proliferation of PBMC obtained from patients responsive to the therapy showed a remarkable decrease (about 60%) at T6 (after two infusions) with respect to T0 (before the first infusion). On the contrary, in the unresponsive patient, the proliferative response was four times higher at T6 in comparison with T0. Vitamin D derivatives induced a decrease in cell proliferation higher in responsive patients than in the unresponsive one. Increased VDR levels during therapy were registered only in the unresponsive patient. Our results indicate that PBMC proliferation and VDR expression may be useful indicators to predict the response of patients with Crohn's disease to the infliximab therapy.

Objective: 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the hormonal active form of vitamin D3, could represent a potentially therapeutic agent in autoimmune diseases. Cyclosporin A (CsA) shows immunoregulatory properties, which, in many respects, seem to be similar to those of 1,25(OH)2D3. Our aim was to investigate the possible synergistic effect exerted by CsA in combination with 1,25(OH)2D3 or its nonhypercalcemic analogues, EB 1089 and KH 1060, on the proliferative response of T lymphocytes obtained from active ulcerative colitis patients., Methods: The T lymphocyte-enriched population was treated with phytohemagglutinin and CsA (doses from 1 ng to 1000 ng/ml) alone or in association with 1,25(OH)2D3 or EB 1089 or KH 1060 (0.1, 1, 10 nM final concentration). Cell proliferation was determined by [3H]thymidine incorporation and analyzed on day 5 of culture., Results: After incubation with CsA, T lymphocyte proliferation was significantly inhibited in comparison with the vehicle-treated cultures. However, T lymphocytes from ulcerative colitis patients were significantly more sensitive to CsA than those from healthy controls. The inhibition in T lymphocyte proliferation, after treatment of the cultures with CsA associated with either 1,25(OH)2D3 or EB 1089 or KH 1060, was synergistic at well-defined concentrations., Conclusions: Taking into account the lowest CsA dose (1 ng/ml), the highest synergistic inhibition in the proliferation of T lymphocytes prepared from ulcerative colitis patients was found combining CsA and 10 nM of 1,25(OH)2D3 or 10 nM of EB 1089 or KH 1060 at the three concentrations. The results obtained, associating the lowest CsA dose and the lowest KH 1060 concentration, may suggest an alternative therapeutic approach in these patients, reducing the dose, and consequently the toxicity, of CsA.

This study examined the effect exerted by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and two vitamin D analogues, EB 1089 and KH 1060, on the proliferation of T lymphocytes obtained from ulcerative colitis (UC) patients and healthy controls. The proliferative response of T lymphocytes to phytohaemagglutinin treatment was first analyzed on days three, five, and seven of culture. Cell proliferation was significantly lower in UC patients than that observed in healthy controls. The highest proliferation value, in either controls or patients, was registered on day five of culture. On day seven, a decrease in proliferation occurred, less evident in patients with respect to controls, whereas on day three, controls and patients showed the same proliferation value. The response of T lymphocytes of either healthy controls or UC patients to 1,25(OH)2D3, EB 1089, or KH 1060 was then investigated, treating the cells for three, five, and seven days with 10 nM vitamin D derivatives. In the presence of these compounds, cell proliferation was significantly inhibited in both groups, but on day seven, the inhibition of lymphocyte proliferation was remarkable in controls, whereas in patients it was similar to that registered on day five. The highest inhibition values were always obtained in the presence of KH 1060, and the time dependence was continuous in controls, but in the presence of EB 1089 only in patients. T lymphocytes prepared from healthy controls and UC patients were then cultured for five days in the presence of vitamin D derivatives at three different concentrations (0.1, 1, and 10 nM). In the two groups, a dose-dependent inhibition was registered in the presence of 1,25(OH)2D3 or EB 1089, while the inhibition of proliferation exerted by KH 1060 was not dose-dependent. The results obtained suggest an option for the use of the two non-hypercalcemic vitamin D analogues in the therapy of UC patients, perhaps in association with other immunosuppressive drugs.

Aims: This large-scale study was aimed at evaluating the long-term history of Crohn's disease in a cohort of consecutive patients referred to the Careggi Hospital in Florence from January 1973 to June 1996., Patients: A total of 382 patients (187 females, 195 males; mean age of 47 years) were included in our study. The median follow-up was more than 11 years and only 46 patients (12%) had a follow-up of less than 1 year. The main endpoints evaluated in these patients included mortality for any cause, disease-specific mortality, recurrences, and need for surgery. Furthermore, in a subgroup of 130 patients observed during the last 6 months of our study, a more detailed assessment of the disease was carried out in which the distribution of inflammatory, fibrostenosing and fistulizing forms was determined., Results: Our results showed that the disease-specific mortality rate was extremely low (around 3% at 10 years and 5% at 20 years), but the rate of recurrence was approximately 50% at 3 years and more than 60% at 6 years. Surgery was needed in more than 50% of the patients over the 10 years following diagnosis, and the risk of a second operation was of a further 30% within 4 years of the first operation., Conclusions: These epidemiological data emerging from our study are interesting since a large patient population was evaluated and the duration of the follow-up is extremely long.

Background: Extraintestinal manifestations can complicate the course of ulcerative colitis and can influence the prognosis., Aims: Sixty-eight patients of the metropolitan area of Florence with ulcerative colitis in clinical and endoscopic remission were evaluated to establish the presence of spondyloarthritis., Patients and Methods: Each patient was studied through clinical and radiological evaluations to assess the presence of joint involvement., Results: We found signs of spondyloarthritis in 19 patients (27.9%). Four of them had a classic ankylosing spondylitis (5.8%) and in 3 of them the aplotype HLA B27 was present. Sacroileitis was found in 9 (13.2%) patients (monolateral in 5 cases and bilateral in 4). Six patients (8.8%) showed an unclassifiable form of arthritis, fulfilling the Amor criteria. In 13 of 19 patients with spondyloarthritis, we found a pancolic extension of disease (68.4%)., Conclusions: The results obtained from our series of ulcerative colitis patients reveal a lower proportion of cases of spondyloarthritis than that found in other Italian studies. We are planning further investigations on a larger population to better assess the prevalence of spondyloarthritis in ulcerative colitis patients.

Objectives: To assess the efficacy of a combination of oral and topical 5-aminosalicylic acid (5-ASA) for the maintenance treatment of ulcerative colitis, we undertook a double-blind randomized clinical trial., Methods: Patients aged 18 to 65 yr (with disease extent greater than proctitis only) were eligible for inclusion in the study if they met the following criteria: (a) history of two or more relapses in the last year; (b) achievement of remission in the last 3 months (with maintenance of remission for at least 1 month). Patients enrolled in the study were randomly assigned to one of the two following 1-yr treatments: (1) combined therapy with 5-ASA tablets 1.6 g/day and 5-ASA enemas 4 g/100 ml twice weekly; (2) oral therapy with 5-ASA tablets 1.6 g/day and placebo enemas/twice weekly. The main end point of the study was the maintenance of remission at 12 months., Results: Upon completion of the study, relapse occurred in 13 of 33 patients in the combined treatment group versus 23 of 36 patients in the oral treatment group (39 vs 69%; p = 0.036). No significant side effects related to treatment were observed in either group. A simplified pharmacoeconomic analysis shows that this form of combined treatment can have a favorable cost-effectiveness ratio., Conclusions: Our results indicate that 5-ASA given daily by oral route and intermittently by topical route can be more effective than oral therapy alone. This form of combination treatment can be appropriate for patients at high risk of relapse.

Background: In the group of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD) are considered to be more frequent in Western countries and in areas with a high socioeconomic development but relatively infrequent in southern Europe. Sporadic reports have indicated a lower incidence and a milder course of the disease in Mediterranean countries. Although conclusive data on this point are still lacking, recent reports suggest an increase in both incidence and prevalence rates., Methods: The incidence of UC and CD during the period January 1978 to December 1992 and their prevalence on 31 December 1992 were estimated in the 15-year-old population of the metropolitan area of Florence. Clinical, demographic, and follow-up information was collected for all identified IBD patients., Results: A total of 796 residents (345 females and 454 males) were newly diagnosed as having IBD during the study period. Of these 593 had UC and 203 CD. The age-standardized incidence rates, calculated for each of five 3-year consecutive periods, rose from 3.8 (in 1978-80) to 9.6 per 100,000 person-years (in 1990-92) for UC and from 1.9 (in 1978-80) to 3.4 (in 1990-92) for CD. Both trends were statistically significant. The prevalence estimated on 31 December 1992 was 121.0 and 40.0 per 100,000 inhabitants for UC and CD, respectively., Conclusions: Our results confirm that IBD incidence rates and prevalence in this area of central Italy are currently comparable with those reported in northern Europe. These data are necessary for planning adequate health care services for IBD patients.

We performed a 12-month clinical trial to compare the relative effectiveness of an intermittent 5-ASA regimen and a continuous 5-ASA regimen for the maintenance treatment of patients with ulcerative colitis in remission. Fifty patients with ulcerative colitis in remission for a minimum period of 1 month participated in the study. Twenty five patients received an intermittent treatment with 5-ASA tablets (2.4 g for the first week of each month) and 25 received a continuous treatment with tablets (1.6 g each day). Patients were assessed clinically every two months and endoscopically every 6 months. Our results show that the two treatments were equally effective. The relapse-free rates at 12 months were 71% in patients receiving the intermittent treatment and 66% in patients given the continuous treatment. This difference is not statically significant. Further studies are needed to assess whether the intermittent regimen can be an alternative to life-long treatment in patients who have maintained remission for a long period of time.

Ulcerative colitis (UC) is a disease condition which typically affects young people; pregnancy is therefore frequent in women with this disease. 5-aminosalicylic acid (5-ASA) is known to be efficacious in maintaining remission of UC, but its safety in pregnancy has not yet been established. In the present study, the safety of 5-ASA was assessed in 16 women with UC (mean age: 31 years, range 25-35) who had a total of 19 pregnancies over the period from 1988 to 1992. All the patients were in clinical remission of UC at the beginning of pregnancy and were receiving a regular maintenance therapy with 5-ASA (ASACOL tablets, 1.2 g/day). During pregnancy, 4 women had a clinical relapse requiring treatment with higher doses of 5-ASA and, in some cases, with steroids. Our observations confirm that the treatment with 5-ASA does not affect the course of pregnancy nor does it damage the fetus, but it can protect from recurrences of UC.