Introduction

Patients with Inflammatory Bowel Disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC) are at high risk of developing malignancies, so prevention and adherence to cancer screening may improve its detection.
The aim of this study was to assess the compliance with medical recommendations, especially primary and secondary prevention of cancer.

Aims & Methods

The aim of this study was to assess the compliance with medical recommendations, especially primary and secondary prevention of cancer.
This one-center cross-sectional study was carried out between June and December 2021r. amongst patients from the Department of Internal Medicine and Gastroenterology with IBD Division, National Health Institute of Ministry of Interior Affairs and Administrations or outpatient clinic. Patients were asked to complete anonymous questionnaire which included 42 questions concerning lifestyle, cancer risk factors, cancer history and checkups in patients with IBD. The results of the qualitative variables were expresses as frequencies and percentage. We used Fisher exact test, chi-squares test. p<0.05 was considered significant. Statistical analyses were performed with the SPSS statistical package.

Results

A total of 313 patients were enrolled into the study: 145 women and 168 men. In the group, 182 had Crohn’s disease (CD), 120 had ulcerative colitis (UC) and 11 with IBDU (unclassified IBD). Most participants had disease duration over 8 years, received biological treatment, corticoids or/and immunosuppressive therapy. Amongst respondents 17% (31) of patients with CD, 25.8% (31) with UC were overweight and 10.5% (19) with CD and 15.8% (19) with UC were obese (p= 0.017). We found that 16.3% of all respondents were smokers (79.6% (144) CD, 90.8% (109) UC and 72.7%(8); p 0.053) and 33.9% declared to consume alcohol (39.4%(71) CD, 26.9%(32) UC and 18.2%(2) IBDU; p 0.045). 25.4% were exposed to UV radiation, only 18.8% of them used sunblock. 58.8% (67) of patients with CD, 35.8% (19) and UC receiving immunosuppressants did regular laboratory tests regularly (p= 0.02). 41.4% (46) of UC, 27.1% (49) of CD and 70.0%(7) IBDU declared not to do any dermatological control (p =0.013). 77% of patients had abdominal ultrasound done. Out of 52.9% of patients who had colonoscopy recommended, only 27.3% had it performed (16.9%(30) with CD vs . 43.1%(50) with UC p< 0 .001). Most of examinations were ordered by gastroenterologists. Female patients had regular breast control (CD 78.6% (66), UC 91.2%(52) and 50% (2) IBDU p 0.034) and 93.8% (76) had gynaecological examination. 80.2% of patients knew about HPV but most declared not to be vaccinated. 17.9% of patients had urological control, but most had no important pathology detected.

Conclusion

According to our study, many patients are still exposed to risk factors, such as obesity, smoking or little physical activity, which are modifiable. Systematic control especially dermatological check-ups should be recommended. Additionally, not only gastrologists but also other specialists and GPs should remind patients about regular checkups. Primary prevention, such as HPV vaccinations, should be reminded to all patients.

References

1. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies [published correction appears in Lancet. 2020 Oct 3;396(10256):e56]. Lancet. 2017;390(10114):2769-2778
2. Eder P, Łodyga M, Gawron-Kiszka M, et al. Guidelines for the management of ulcerative colitis. Recommendations of the Polish Society of Gastroenterology and the Polish National Consultant in Gastroenterology. Gastroenterology Review/Przegląd Gastroenterologiczny. 2023;18(1):1-42. doi:10.5114/pg.2023.125882.
3. Łodyga M, Eder P, Gawron-Kiszka M, et al. Guidelines for the management of patients with Crohn's disease. Recommendations of the Polish Society of Gastroenterology and the Polish National Consultant in Gastroenterology. Prz Gastroenterol. 2021;16(4):257-296
4. Gordon H, Biancone L, Fiorino G, et al. ECCO Guidelines on Inflammatory Bowel Disease and Malignancies [published online ahead of print, 2022 Dec 18]. J Crohns Colitis. 2022Rozich JJ, Holmer A, Singh S. Effect of Lifestyle Factors on Outcomes in Patients With Inflammatory Bowel Diseases. Am J Gastroenterol. 2020;115(6):832-840.

Introduction

Mirikizumab (miri), a p19-directed IL-23 antibody, showed efficacy in ulcerative colitis (UC)¹. Miri modulates transcripts associated with disease activity and anti-TNF resistance in UC and increases expression of transcripts associated with healthy mucosa². Here, we evaluate the transcription profile of patients with UC who respond to placebo (PBO, 20.6%) or miri 200mg treatment (59.7%) versus non-responders and build a model that can predict response in patients with UC.

Aims & Methods

In the phase 2 AMAC trial (NCT02589665), patients were randomized 1:1:1:1 to receive intravenous PBO (N=63), 50mg miri (N=63), or 200mg miri (n=62) with possible exposure-based dose increases or fixed 600mg miri (n=61) at Week (W)0, 4 and 8. Colonic biopsies were collected at baseline, W12, and W52. An Affymetrix HTA2.0 microarray measured gene expression. Limma comparing values at baseline and W12 determined differentially expressed genes (DEGs). DEGs maintaining their W12 expression level through W52 among responders in either the PBO and miri 200mg arms were designated as similarly expressed genes (DEGSEGs).
XGBoost models³ were trained to predict clinical response (decrease in 9-point Mayo subscore [rectal bleeding, stool frequency, endoscopy] of ≥2 points and ≥35% from baseline [BL] with either a decrease of RB subscore of ≥1 or an RB subscore of 0 or 1) using baseline levels of DEGSEGs and TNF biomarkers. Leave-one-out cross validation of the models using AMAC data and validation experiments by training on the PROTECT data⁴ then predicting in AMAC were used to evaluate our models.

Results

Miri 200mg responders were associated with 84 DEGSEGs, PBO responders were associated with 26 DEGSEGs, and 21 DEGSEGs were common to both. When using the PROTECT data as the training data and AMAC data as the validation cohort, we were able to achieve high ROC-AUC and PR-AUCs using the top 36 (FC > 1.5) miri DEGSEGs (PR-AUC=0.78), or combined (PR-AUC=0.93) gene sets as the features and found that the response prediction was significantly higher in AMAC responders vs. non-responders.

Conclusion

Baseline transcript features were predictive of clinical response in patients with UC treated with miri 200mg and our model distinguished responders from non-responders. Future studies are underway to validate this model.

References

1. Sandborn WJ, et al. Gastroenterology. 2020;158(3):537-549.e10.
2. Steere B, et al. J Crohns Colitis. 2020;S103-S104.
3. Chen T, et al. Proceedings of the 22^nd ACM SIGKDD International Conference. 2016;7285-794.
4. Hyams JS, et al. Lancet Gastroenterol Hepatol. 2017;2(12):855-868.

Disclosure

TJ and KH report no conflicts of interest. WR reports grant support and personal fees from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, and Merck Sharp & Dohme, and personal fees from Aptalis, Celltrion, Danone Austria, Elan, Ferring, Mitsubishi Tanabe Pharma Corporation, Otsuka, PDL BioPharma, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Bioclinica, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Covance, Galapagos, Genentech, Gilead Sciences, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Nestle, Novartis, Ocera, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Second Genome, SetPoint Medical, TiGenix, UCB, Zyngenia, and 4SC. BS, CH, NM, and VK are employees and shareholders of Eli Lilly and Company. CM is a former employee of Eli Lilly and Company. GD has served as an advisor for: AbbVie, Ablynx, Active Biotech, AgomAb Therapeutics, Allergan, AlphaBiomics, Amakem, Amgen, AM-Pharma, Applied Molecular Therapeutics, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Cosmo Pharmaceuticals, Dr. Falk Pharma, DSM Pharmaceuticals, Echo Pharmaceuticals, Eli Lilly and Company, enGene, Exeliom Biosciences, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic Therapeutics, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Medtronic, Merck Sharp & Dohme, Mitsubishi Pharma, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer, PhotoPills, ProciseDx, ProDigest, Progenity, Prometheus Laboratories/Nestlé, Protagonist Therapeutics, RedHill Biopharma, Robarts Clinical Trials, Salix Pharmaceuticals, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Setpoint, Shire, Takeda, Teva, TiGenix, Tillotts Pharma AG, Topivert, Versant, and Vifor Pharma; and received speaker fees from: AbbVie, Biogen, Ferring Pharmaceuticals, Galapagos NV/Gilead Sciences, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts Pharma AG, and Vifor Pharma.

Introduction

Epstein-Barr virus (EBV) associated gastric cancer (GC) has been reported to be about 5-16% of all gastric cancers with good prognosis compared to EBV-negative GC. The aim of this study was to evaluate the clinicopathological characteristics of EBV-positive GC including survival analysis in the prospective observational cohort study in a tertiary hospital in South Korea.

Aims & Methods

Total 4,586 patients who underwent EBV in situ hybridization (EBV-ISH) testing among 14,613 patients diagnosed with GC were prospectively enrolled at Seoul National University Bundang Hospital from 2003 to 2023. Data including age, sex, smoking, cancer type and stage, tumor size and location, histologic type, molecular features (p53 expression and MSI), and survival information including causes of death were collected and analyzed.

Results

EBV-positive cancer group showed significant differences compared to EBV-negative cancer group. That is, they showed higher proportion of males (p<0.001), predominant presence in the proximal stomach (p<0.001), higher proportion of undifferentiated cancer (p<0.001), and lower cancer stage (p=0.004) (Table). In Cox multivariate analyses, age (HR 1.022, p<0.001), tumor size (HR 1.118, p<0.001) along with cancer stage (stage 2 HR 5.843, p<0.001; stage3 HR 15.570, p<0.001; stage4 HR 50.075, p<0.001, respectively) were significant risk factors for GC-specific mortality, while EBV positivity was inversely correlated (HR 0.537, p=0.023). In the survival analyses, EBV-positive cancer group showed statistically significant survival advantages over EBV-negative cancer group in both overall (p=0.016) and gastric cancer-specific survival (p=0.005)

Conclusion

EBV-positive GC group was associated with male sex, proximal location, poorly differentiated histology and lower cancer stage, and showed significantly better prognosis than EBV-negative gastric cancer. EBV might play a role in the gastric carcinogenesis to make less metastasis resulting in better survival.

Introduction

Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial aetiology, which is still not completely understood. OCTN1, an organic cation transporter could have a role in modulating the inflammatory response, whose genetic polymorphisms were associated to increased risk of inflammatory bowel diseases. Up to now, limited information exists on its role in predicting/modulating response to therapies.

Aims & Methods

The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and immune composition to Infliximab therapy in murine colitis. Dextran sodium sulphate model of colitis on C57BL/6 mice and ocnt1 gene knockout mice was used to assess clinical efficacy of infliximab administered intravenously. Stool, colon and mesenteric lymph node samples were collected to assess differences in gut microbiota composition, histology for Rachmilewitz score and T cell populations respectively.

Results

Octn1^-/-influences microbiota profile and is associated with a worse dysbiosis in colitis mice. Infliximab treatment attenuates colitis-associated dysbiosis with increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1^-/- mice have a higher baseline percentage of Treg, Tmemory, Th2 and Th17.

Conclusion

Our data support murine model to study OCTN1 genetic asset in inflammatory bowel diseases. This could be the first step to consider this membrane transporter as a biomarker in inflammatory conditions and as a predictor of response to therapies.

Introduction

Inflammatory bowel disease (IBD) is characterized by chronic inflammation due to an uncontrolled immune response orchestrated through, i.e. neutrophils. The basement membrane acts as a front-line defense promoting tissue integrity, where the α-3 chain of type IV collagen is solely expressed on the outermost layer of the mucosa. Detection of subclinical ulceration is crucial since early-stage IBD presents a unique window of opportunity for intervention, as the disease might become a self-sustaining process once deep inflammation becomes established. We therefore, wanted to develop a biomarker reflecting early tissue injury, aiding in the implementation of prompt treatment.

Aims & Methods

A competitive enzyme-linked immunosorbent assay quantifying a human neutrophil elastase (HNE) degraded fragment of type IV collagen α-3 chain was developed (C4A3-HNE). Dilution- and spiking recovery, inter- and intra-variability, and interference were evaluated. Acceptance criteria for technical validation were a recovery of 100% ±25 and an inter-intra variability of <15%. Commercial serum samples were purchased from ProteoGenex. Biological relevance was validated in an observational study from Odense University Hospital (OUH) and healthy controls. Groups were compared using Kruskal Wallis (Dunn‘s corrected).

Results

The technical validation of the C4A3-HNE assay demonstrated acceptable results for recovery, variation, and interference. Biological relevance was assessed in commercial IBD samples and healthy donors. C4A3-HNE was elevated in both CD and UC compared to healthy (p=0.001 and <0.0001)(AUC [95% CI]: 0.820 [0.669-0.971]; 0.875 [0.775-1.000]). The results were validated in an independent cohort of IBD patients (both p<0.0001). For UC, analysis showed that compared to patients in endoscopic remission, C4A3-HNE is elevated in patients with mild endoscopic activity, decreasing dose-dependently for moderate and severe disease (T1). Fecal calprotectin and CRP levels were also lower in IBD patients with high levels of C4A3-HNE (T1). With a cut-off value of 54.1 ng/ml, C4A3-HNE could significantly discriminate between mild and severe endoscopic disease (T1).

Conclusion

Our study demonstrates the biological and possible clinical relevance of the novel C4A3-HNE biomarker. The biomarker is elevated in patients with IBD compared with healthy, and high levels may reflect early mucosal damage in patients with UC. Furthermore, inflammatory markers were lower in IBD patients with high levels of C4A3-HNE, pointing towards high levels being indicative of early disease. C4A3-HNE may provide early detection of mucosal damage or prediction of relapse; however, further studies are required to assess the clinical validity of this biomarker.

Disclosure

MA, MP, MK, and JM are employees of Nordic Bioscience A/S. MK owns stocks in Nordic Bioscience A/S.

Introduction

Carbohydrate sulfotransferase 15 (CHST15) is an enzyme biosynthesizing sulfated matrix glycosaminoglycan that modulates tissue remodeling.

Aims & Methods

We evaluated the efficacy of add-on submucosal injections of GUT-1, the RNA oligonucleotide inhibitor of CHST15, to ongoing tumor necrosis factor (TNF) antagonist treatment in patients with moderate-to-severe ulcerative colitis (UC) and insufficient response to TNF antagonists.
This was an open-label study of 250 nM of GUT-1, which was applied by endoscopic submucosal injections at weeks 0, 2 and 4 in five UC patients who lost response during maintenance treatment to TNF antagonists. The primary endpoint was the rate of endoscopic improvement at week 6 and secondary endpoints included the rates of clinical remission. All patients received follow-up observation with continuous maintenance treatment by the same TNF antagonists till the time of clinical recurrence, defined by rectal bleeding and endoscopic examination, or for overall 48 weeks (Clinical trial Registration Number: UMIN000020900).

Results

At baseline, all included patients showed insufficient clinical and endoscopic response to ongoing TNF antagonist treatment (3 for infliximab and 2 for adalimumab), as measured by modified Mayo Score (mMS) of 7.8 (95%CI: 6.2 to 9.4), Endoscopic Subscore of 2.4 (95%CI: 1.7 to 3.1), Stool Frequency Subscore of 2.8 (95%CI: 2.2 to 3.4) and Rectal Bleeding Subscore of 2.6 (95%CI: 1.9 to 3.3). At week 6, Endoscopic Subscore reduced to 1.0 (95%CI: 0.1 to 1.9) and rate of endoscopic improvement was 80% (n=4/5). mMS reduced to 1.3 (95%CI: 0.4 to 3.2) and rate of clinical remission was 60% (n=3/5). Exploratory, Nancy histological index reduced to 1.8 (95%CI: 0.2 to 3.4) at week 6 from 3.6 (95%CI: 2.9 to 4.3) at baseline. Three patients did not show any signals of clinical recurrence for 48 weeks. All three corticosteroid-dependent patients showed no corticosteroid exposure for at least 20 weeks after achieving clinical remission. During the follow-up period, clinical recurrence was observed in one patient at week 36 and another at week 44.

Conclusion

Add-on multiple injections of GUT-1 to ongoing TNF antagonist treatment was able to induce rapid and durable clinical responses in patients with TNF antagonist-refractory UC. GUT-1 was well tolerated by the patients.

Introduction

Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders characterised by alterations of acute relapses and remission. The past decades have brought substantial advances in the pharmacological management of IBD by the introduction of immunosuppressive agents, biologics and lately small molecules. Although, the sustained efficacy of the currently available anti-inflammatory therapies is still far from optimal. Therefore, the development of novel therapies represents a major unmet clinical need in this field. Recently the enrichment of the coagulation pathway genes and among these, plasminogen activator inhibitor 1 (PAI-1) was described in IBD, whereas PAI-1 emerged as a link between the epithelium and inflammation. Moreover, the genetic deletion of PAI-1 impaired the severity of experimental colitis in mice.

Aims & Methods

Based on these, our aim was to develop and test novel PAI-1 inhibitors for the treatment of IBD. Novel, peptide-based PAI-1 inhibitors were designed and screened in silico, then the selected ones were synthetized using the ixPeptide® platform. The inhibitory potential of the peptides was determined by an in vitro PAI-1 activity assay. Cytotoxicity was monitored in vitro in Hela cells with the CellTiter Glo assay. Based on the in vitro results LDN-071 was selected for further analysis. Experimental colitis was induced in mice with 3% DSS and after the induction of colitis 10 mg/bwkg LDN-071 was administrated per os for four consecutive days. The changes of body weight, spleen weight and colon length were measured. Haematoxylin eosin (HE) and Periodic acid-Schiff (PAS) staining were performed for histology. ELISA and qRT-PCR measurements were applied to analyse the mucosal cytokine expressions. In vivo toxicity of LDN-071 was determined in mice.

Results

LDN-071 significantly inhibited PAI-1 in vitro without decreasing the cell viability in a concentration range of 1µM-1mM. The administration of 10 mg/bwkg LDN-071 in the DSS-treated mice prevented the body weight loss, the development of bloody diarrhoea, the decrease of colon length and increase of the spleen weight, which were displayed by the DSS+vehicle-treated animals. The histological analysis of the colon revealed that DSS treatment induced a severe transmural inflammation, ulceration, loss of crypt structures and goblet cell depletion. Importantly, all of these parameters were significantly impaired by the administration of 10 mg/bwkg LDN-071. Additionally, mucosal gene and protein expressions of TNF-α, IL-1β and IL-6 were significantly impaired by PAI-1 inhibition. Importantly, no signs of toxicity were LDN-071 observed in mice exposed to 100 mg/bwkg LDN-071 for 7 days.

Conclusion

Our results showed that LDN-071, a novel peptide-based inhibitor of PAI-1. It significantly reduces the severity of experimental colitis in mice. We propose that the inhibition of PAI-1 could be a potential novel therapeutic strategy in IBD.

Disclosure

LDN-071 PAI-1 inhibitor is owned by Ladon Therapeutics Ltd.