Abstract Background In the randomized controlled LADI trial, a subset of patients with Crohn’s disease (CD) maintained clinical remission following extension of the adalimumab dose interval (1). The aim of this study was to assess long-term clinical outcomes for trial participants who extended the adalimumab interval to 3 or 4 weeks compared to conventional dosing. Methods At baseline, we enrolled CD patients in biochemical and corticosteroid-free clinical remission (CFCR) on adalimumab 40 mg/2 weeks. The intervention group started on a 3-week interval and increased to 4 weeks at week 24, if in clinical and biochemical remission. Controls remained on adalimumab 40 mg/2 weeks. Data >48 weeks was collected between 2017 and 2023. The primary endpoint of the current study was the proportion of patients in CFCR (HBI ≤4 or remission per physician global assessment) at year 3 while maintaining the assigned baseline adalimumab interval (intervention: 40 mg/3-4 weeks, control: 40 mg/2 weeks). Secondary endpoints included biochemical remission (CRP ≤10 mg/L and/or FC ≤250 µg/g), proportion of patients who discontinued adalimumab for stable remission, and adverse events (AEs). Patients without sufficient long-term data were excluded. Results Data was extracted for 143/174 initially randomized subjects (intervention: 95; control: 48). Figure 1 is a Sankey diagram for visualization of patient flow during follow-up. In the intervention group, 30/95 (31.6%) patients maintained de-escalation at 3 years (7 on a 3-week interval, 23 on a 4-week interval) while 4 patients stopped for stable remission. The primary endpoint of CFCR was achieved in 28/95 (29.5%) at year 3, and 23/95 (24.2%) were in biochemical remission. Twenty-eight patients re-escalated to 40 mg/2 weeks, 24/28 were in CFCR at year 3. In the control group, 30/48 (62.5%) patients maintained the 2-week interval after 3 years with 27/48 (56.3%) in CFCR, and 20/48 (41.7%) in biochemical remission. In addition to 4 subjects in each group that stopped adalimumab for stable remission, another 19 patients (13.3%) discontinued adalimumab by year 3 (intervention: n=17/95 (17.9%); control: n=2/48 (4.2%)). Discontinuation reasons were loss of response (n=9, 50.0% (8 in intervention group)), AEs (n=5, 27.8%), adalimumab antibodies (n=4, 22.2%, 3 in intervention group), and 1 missing. AEs are shown in Table 1. Conclusion Long-term follow-up showed that one-third of patients in the intervention group was in remission after continued de-escalation of adalimumab therapy at year 3, while another 25% recaptured remission after dose re-escalation. In the control group, over half of patients maintained remission on adalimumab every 2 weeks. References 1.van Linschoten RCA, Jansen FM, Pauwels RWM, Smits LJT, Atsma F, Kievit W, et al. Increased versus conventional adalimumab dose interval for patients with Crohn’s disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023;8(4):343-55.

A subset of pancreatic cystic neoplasms are regarded as precursor lesions of pancreatic cancer, but only a minority of all pancreatic cystic neoplasms will undergo malignant transformation. MicroRNAs are increasingly recognized as molecular targets in carcinogenesis. Previously, a 9-microRNA (miR) signature was suggested to discriminate between high risk and low risk pancreatic cystic neoplasm. In this study, we aimed to validate this 9-miR panel in a prospective cohort. Total miR was isolated from pancreatic cyst fluid and expression of miR18a, miR24, miR30a-3p, miR92a, miR99b, miR106b, miR142-3p, miR342-3p, and miR532-3p was analyzed by singleplex Taqman MicroRNA Assay. A total of 62 patient samples were analyzed. During follow-up, 24 (38.7%) patients underwent resection, of which 6 (9.7%) patients showed at least high grade dysplasia. A logistic regression model presented a “predicted risk” score which significantly differed between low and high risk cysts, either including all patients or only those with histological confirmation of diagnosis. Using a set cut-off of 50%, the sensitivity of the model for the total cohort was 10.0%, specificity 100.0%, positive predicted value 100.0%, negative predicted value 85.2%, and diagnostic accuracy of 85.5%. Thus, while observing a significant difference between low and high risk cysts, clinical implementation of this biomarker panel is as yet unlikely to be beneficial in the management of pancreatic cysts.

The authors regret that the sentence beginning on line 12 of first column on page 516, relating to Reference 43 is misleading.The sentence reads:“At the same time however, Gal-1 is found overexpressed on the stromal tissues of long term pancreatic cancer survivors [43], indicating that the prognostic significance of Gal-1 expression is not entirely clear”.However, the authors would like to correct this as:“At the same time, Gal-1 is found underexpressed on the stromal tissues of long term pancreatic cancer survivors [43], indicating that the prognostic significance of Gal-1 expression is promising”.The authors would like to apologise for any inconvenience caused. The authors regret that the sentence beginning on line 12 of first column on page 516, relating to Reference 43 is misleading. The sentence reads:“At the same time however, Gal-1 is found overexpressed on the stromal tissues of long term pancreatic cancer survivors [43], indicating that the prognostic significance of Gal-1 expression is not entirely clear”. However, the authors would like to correct this as:“At the same time, Gal-1 is found underexpressed on the stromal tissues of long term pancreatic cancer survivors [43], indicating that the prognostic significance of Gal-1 expression is promising”. The authors would like to apologise for any inconvenience caused. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategiesCancer Treatment ReviewsVol. 40Issue 4PreviewTraditional chemotherapeutics have largely failed to date to produce significant improvements in pancreatic cancer survival. One of the reasons for the resilience of pancreatic cancer towards intensive treatment is that the cancer is capable of high jacking the immune system: during disease progression the immune system is converted from a system that attacks tumor cells into a support structure for the cancer, exerting trophic actions on the cancer cells. This turn-around of immune system action is achieved through mobilization and activation of regulatory T cells, myeloid derived suppressor cells, tumor-associated macrophages and fibroblasts, all of which suppress CD8 T cells and NK cells. Full-Text PDF

Traditional chemotherapeutics have largely failed to date to produce significant improvements in pancreatic cancer survival. One of the reasons for the resilience of pancreatic cancer towards intensive treatment is that the cancer is capable of high jacking the immune system: during disease progression the immune system is converted from a system that attacks tumor cells into a support structure for the cancer, exerting trophic actions on the cancer cells. This turn-around of immune system action is achieved through mobilization and activation of regulatory T cells, myeloid derived suppressor cells, tumor-associated macrophages and fibroblasts, all of which suppress CD8 T cells and NK cells. This immune suppression occurs both through the expression of tolerance-inducing cell surface molecules, such as PD-L1, as well as through the production of “tolerogenic” cytokines, such as IL-10 and TGF-β. Based on the accumulating insight into the importance of the immune system for the outcome of pancreatic cancer patients multiple new immunotherapeutic approaches against pancreatic cancer are being currently tested in clinical trials. In this review we give an overview of both the immune escaping mechanisms of pancreatic cancer as well as the new immune related therapeutic strategies currently being tested in pancreatic cancer clinical trials.

. Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn’s disease for example. Recent developments in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role in the pathophysiology of Crohn’s disease. In our review, we summarize the recent studies to discuss the dual function of monocytes - on the one hand the impaired monocyte function initiating Crohn’s disease, and on the other hand the overactivation of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte functions need to be taken into account.

Braat, H1; Steidler, L2; Neirynck, S2; Kapsenberg, ML3; van Deventer, SJH1; de Jong, EC3; Hommes, DW1 Author Information

Braat, H1; Rottiers, P2; Huyghebaert, N3; Remaut, E2; Remon, J-P3; van Deventer, S1; Neirynck, S2 4; Peppelenbosch, MP5; Steidler, LS2 4; Hommes, DW3 Author Information

BACKGROUND Although it is widely recognized that the intake of so-called probiotic microorganisms is beneficial in chronic mucosal inflammation and topical allergic disease, the immunologic details explaining how such bacteria can exert these effects remain obscure. OBJECTIVE We determined whether Lactobacillus rhamnosus can modulate T cell responses in vitro and in vivo. DESIGN In vitro, human monocyte-derived dendritic cells (DCs) matured in the presence of L. rhamnosus were used to instruct naive CD4+ T cells; subsequently, the T cell response was assessed with the use of CD3/CD28 and interleukin (IL) 2. Cytokine production by ex vivo-stimulated naive cells and memory T cells was measured before and after oral supplementation with L. rhamnosus in 6 healthy volunteers and 6 patients with Crohn disease. RESULTS A decreased T cell proliferation and cytokine production, especially of IL-2, IL-4, and IL-10, was observed in CD3/CD28-stimulated T cells derived from L. rhamnosus-matured DCs. This T cell hyporesponsiveness was associated with enhanced DC-T cell interaction and normal responsiveness of T cells for IL-2. In vivo oral supplementation of L. rhamnosus for 2 wk induced a similar T cell hyporesponsiveness, including impaired ex vivo T helper subsets 1 and 2 responses without up-regulation of immunoregulatory cytokines in cohorts of both healthy volunteers and patients with Crohn disease. CONCLUSIONS We propose that L. rhamnosus modulates DC function to induce a novel form of T cell hyporesponsiveness; this mechanism might be an explanation for the observed beneficial effects of probiotic treatment in clinical disease.

Background and aims: Multiple rodent models implicate resident intestinal bacteria in the pathogenesis of chronic immune mediated intestinal inflammation. Specific pathogen free (SPF) interleukin 10 gene deficient (IL-10−/−) mice develop colitis, which does not occur in the germ free (GF) state. We investigated whether broad or narrow spectrum antibiotics affect onset and progression of disease in various regions of IL-10−/− mice. Methods: Metronidazole, ciprofloxacin, vancomycin-imipenem (50 mg/kg/day), or water (control) was administered orally before (prevention) or two weeks after (treatment) colonisation of GF IL-10−/− mice with SPF bacteria. After four weeks, colonic histology scores and cytokine production by colonic explants were determined. Caecal and colonic contents were collected for quantitative bacterial analysis. Results: In the prevention study, all antibiotics decreased inflammation in the caecum and colon. However, in the treatment study, ciprofloxacin and vancomycin-imipenem decreased caecal inflammation, and reduced Escherichia coli and Enterococcus faecalis concentrations, whereas only vancomycin-imipenem lowered direct microscopic bacterial counts. In contrast, metronidazole and vancomycin-imipenem reduced colonic injury and eliminated anaerobic bacteria, including Bacteroides spp. Conclusions: Both narrow and broad spectrum antibiotics can prevent disease but treatment of established colitis is more selective. Ciprofloxacin is most effective in the treatment of caecal inflammation, metronidazole preferentially treats the colon, whereas vancomycin-imipenem definitively treats both regions. These results suggest that subsets of aerobic or anaerobic bacteria show regional differences in their capacity to mediate experimental colitis in IL-10−/− mice.

spleen of the severely diseased mice.FACS analysis of T cell numbers showed that ASM981 was not preventing the activated T cells from proliferating as the numbers were not reduced in the ASM981-relative to vehicle-treated mice Conclusions:ASM981 is highly effective in a dlerapeutic setting.ASM981 has strong effects on some of the downstream systemic inthmmatory reactions in this model.The data from th~s severe chronic model of IBD together with the already impressive findings in chronic inflammatory skin disorders lead as to expect ASM981 to be effective in IBD in man T1143

In recent years it has become clear that chronic inflammatory bowel disease (IBD), especially Crohn's disease (CD), is caused by a loss of tolerance against the autologous bacterial flora of the intestine. Tolerance against the indigenous flora requires optimal recognition of antigens by pattern recognition receptors and the presence of important regulatory cells and cytokines. Interleukin-10 (IL-10) has a major role in the regulatory network of cytokines controlling mucosal tolerance, and it is, therefore, not surprising that this cytokine is proposed as a potent anti-inflammatory biological therapy in chronic IBD. This review will discuss the characteristics of IL-10, its immunoregulatory properties in mice and humans, and the use of IL-10 as a treatment for CD. The review will summarise the clinical studies that have taken place and discuss the lessons learned from these trials. Finally, the advantages and disadvantages of promising new strategies of IL-10 treatment, including gene therapy and the use of genetically modified bacteria, will be discussed. Both novel therapies have been shown to be successful in animal models of disease, and clinical testing is currently underway. The future goal of IL-10 treatment should be focused on mucosal delivery and remission maintenance instead of remission induction. In conclusion, it can be said that despite the disappointing results of IL-10 therapy so far, there is still enough rationale for the use of IL-10 as an anti-inflammatory biological treatment in chronic IBD.

was also quantified by Western blotting in primary human colon cancers and colon cancerderived cell hnes.Annexin-1 mRNA abundance was measured by real time PCR in AOM tumors.Results: In AOM tumors (N=8) and human colon cancers (N =4), annexin-1 was significantly overexpressed compared to normal colonic crypts with staining of malignant epithelium greater than stroma.The pattern was predominantly cytoplasmic and granular.Annexm-1 mRNA was significantly increased 10-fold in AOM tumors (p<0.05).Western blotting confirmed a sigmficant 6-fold up-regulation of annexin-1 protein in human tumors (p<0.05).Annexin-1 expression was also 2-3 fold up-regulated in several human colon cancer cell hnes, including RKO and LS 174T cells.Conclusions: Annemn-1 is overexpressed in AOM and human colon cancers.In AOM tumors this up-regulation involved increases in both mRNA and protein.Since derangements in EGFR signaling contribute to colonic carcinogenesis, and annexin-1 is the major substrate for this growth factor receptor, further studies to elucidate the mechanisms and biological consequences of dysregulated annexin-1 will be important.

Background: Stressful events are known to produce various effects on the gastro-intestmal tract, but pathways involved are not clearly defined.Mast cells (MC) contain chemotactic factors for T ceils, released upon activation, and IFN3, produced by stress-induced T calls is involved in the increase of gut epithelial cell permeability.This study aimed to characterize long-term (four days) changes in permeability triggered by stress and the possible implication of mast cells and IFN3t.Methods: Twelve groups of Swiss mice and two groups, B6 iafg ~-(IFN'y-deficient) and their control C57BL6/J mice were used in this study.Swiss mice (two groups) pretreated by the mast cell membrane stabilizer, doxantrazole (10 mg/kg) or its vehicle, were submitted during two hours to an acute stress session consisting of contention plus acoustic stimuli.Five of the groups of Swiss mice and the B6 infg 4 mice and their control C57BL6/J received one injection of the mast cell degranulator, Brx-537A (bromofasalocid ; 2 mg/kg IF).Colonic paracellular permeability was assessed by intracolonic infusion of 500 ~il ~Cr-EDTA (0.7 ~tCi) for two hours daily (14:00 to 16:00) from day one to day four, after a single stress session or MC stimulation.Colons were collected and permeability expressed as the ratio between body and total (body plus colon) radioactivities.Results: In Swiss mice, the two-hour permeability increased significantly only at day 4 after a single stress session (3.9% -+ 0.4 vs 1.7% _+ 0.3), while no significant change was observed at days 1, 2 and 3 (2.3%_+ 0.3, 0.8% -+ 0.3 and 1.7% _-4" 0.6 respectively).The same effect was obtained at day 4 after mast cell degranulatiun with Brx-537A (3.9% -+ 0.8 vs 0.9% + 0.1).Previous treatment with doxantrazole prevented the effects of stress on permeability seen at day 4 (1.5% -+ 0.3 vs 3.9% + 0.4).In B6 infg ~, we did not observe the increased permeability seen at day 4 in C57BL6/J mice (0.9% -+ 0.2 vs 4.1% _+ 0.3).Conclusion: An increase of colonic paraceUular permeability is observed at day 4 after acute stress or mast cell degranulation, and IFN7 is required in the genesis of this delayed effect.These data support that mast cells are implicated in the increase of paracellufar permeability observed after an acute stress.