Introduction

Current risk stratification of Barrett's esophagus (BE) patients, based on histological identification of dysplasia, lacks reliability due to poor interobserver agreement and the limited predictive value of low-grade dysplasia (LGD).

Aims & Methods

This study aims to identify genomic factors enhancing risk stratification for BE patients with a community diagnosis of LGD.
Progressors to early esophageal adenocarcinoma and non-progressors were identified in a randomized controlled trial screening cohort of community-based LGD patients. Sequencing used a targeted capture-based panel to detect mutations and copy number changes (CNV). Detected mutations, homozygous deletions, and high-level amplifications underwent filtering for likely pathogenic events. We performed logistic regression, covariate analysis, and penalized mixed-effect models. A joint model for survival and mixed effects was applied for spatiotemporal data analysis. The model's performance was compared with that of general and expert pathologists to evaluate its clinical relevance.

Results

220 samples, comprising 28 progressors with a median time to progression of 1.2 (IQR 0.4-2.2) years and 95 non-progressors with a median progression-free follow-up of 7.9 (IQR 5.9-10.6) years, all with a median C3M5 BE, were analyzed. Multiple factors were associated with progression, including TP53 (p < 0.0001, Hazard Ratio (HR) = 13.39, 95% confidence intervals (CI) 5.64-31.78), chromosomal arm 17p loss (p < 0.0001, HR = 10.24, 95% CI 4.82-21.76), mutational burden (p < 0.001, HR = 1.52, 95% CI 1.21-1.90), and total number of CNVs (p<0.0001, HR = 1.48, 95% CI 1.34-1.64). Several other alterations trended to be associated with progression, including APC mutation and presence of an oncogenic amplification. The combined influence of TP53 and 17p loss enhanced the accuracy of risk prediction. However, high correlation precluded their use as cumulative risk. Patients with samples containing >3 mutations had a very high risk of progression (HR = 10.33, 95% CI 2.22-48.01). Presence of any genetic variant—amplification, deletion, CNV, or mutation— indicated progression risk (p<0.0001, HR = 1.15, 95% CI 1.11-1.21). Samples lacking any genetic variants showed no progression. A combined TP53 and CNV model effectively identifies progression risk with a sensitivity of 64.3%, specificity of 94.7%, and an AUC of 0.837, distinguishing 89 out of 94 non-progressors. In contrast to traditional assessments, this model demonstrates substantial improvements (p=0.002) compared to the expert pathologist assessment (median sensitivity of 67.9 % [0.321, 0.821], median specificity of 80.4% [0.606, 0.957], k value: 0.47).

	Predicted non-Progressive	Predicted Progressive
True Non- Progressors	91	4
True Progressors	10	18

Conclusion

This study not only reinforces the well-established role of TP53 mutations but also introduces crucial novel genomic markers. The addition of 17p loss emerges as indispensable for enhanced risk assessment. Furthermore, distinct genetic variations, including CNVs and total mutations, individually and collectively signify a significantly higher risk. Intriguingly, patients without any distinctive genetic abnormalities did not progress. A combined genomic model could consistently accurately risk stratify BE patients with a community-based LGD diagnosis, highlighting its enhanced and reliable predictive accuracy.

Disclosure

NA

Clinical Case Summary

Introduction: Inflammatory bowel diseases gather several phenotypes of autoimmune affectation of the GI tract - sometimes they may frame into a polyautoimmune syndrome (PAS).
Case description: We present a 28-year-old man with nephrotic syndrome, autoimmune hepatitis/primary biliary cholangitis overlap syndrome and alopecia areata universalis, who was on cyclosporine and budesonide.
The patient was admitted with chronic bloody diarrhea and weight loss. He had anemia, hypoalbuminemia and increased CRP; fecal calprotectin (FC) was 4500ug/g. CT scan showed concentric colon thickening. Endoscopic studies showed deep, exudative ulcers in the colon and rectum - biopsies showed chronic active colitis.
Previous immunosuppressive therapies were stopped and prednisolone was begun. Biopsies tested positive for CMV and antivirals were started. The patient improved and was discharged home on steroids.
This was assumed to be a case of unclassified inflammatory colitis with concurrent CMV colitis. In the following months, the patient was re-hospitalized 5 times for severe exacerbations with partial response to steroids and new CMV reactivations. Infliximab was started but discontinued due to loss of response; azathioprine therapy was tried but stopped due to adverse reaction.
It was decided to start tofacitinib. After 6 months of therapy, he is asymptomatic, regaining weight and recovering body hair. FC is 1191ug/g, with no other analytical changes.
Genetic tests show a possible pathogenic variant in LRBA gene (linked to immunodeficiency type 8 with autoimmunity). The LRBA deficit study has been expanded.
Conclusion: This case highlights the complexity of patients with PAS and the need for a multidisciplinary approach. It also proves the efficacy of tofacitinib in this patient, having prevented new admissions so far, with important clinical/analytical improvements. If LRBA deficiency is proven, abatacept may be considered for treatment as it is effective in most of these patients.

Introduction

Inflammatory bowel disease (IBD) commonly affects female patients of reproductive age, making the interaction between fertility, pregnancy and IBD an important issue in disease management. The effect of disease activity on the outcome of pregnancy and its impact on neonatal growth is a field of intense research. Close follow-up of pregnant IBD patients by a multidisciplinary team improves maternal and neonatal outcomes.

Aims & Methods

Α national retrospective study of pregnancies in women with IBD between 2010-2020 was carried out in 22 IBD reference centers in Greece. Patient characteristics such as disease profile, type of treatment, and disease activity during gestation were analyzed in correlation to the method of delivery, pregnancy outcomes, as well as breastfeeding and offspring health.

Results

Two-hundred and twenty-three pregnancies in 175 IBD patients were registered in the study. 122 with Crohn’s disease (CD). Median age during diagnosis was 25.6 years (12-44) with median disease duration of 7.4 years (0-23). One-hundred and twenty-nine patients (58%) were recorded during their first pregnancy. Early pregnancy termination was reported by 48 patients (22%). Pregnancy as a result of in vitro fertilization (IVF) occurred in 15 cases (6.7%). At the beginning of gestation 165 patients (74%) were under treatment: 48 with anti-TNF agents (29%), 43 with azathioprine (26%), 101 with 5-aminosalicylic acid formulations (61%) and 12 with steroids (7%). We recorded 49 cases of IBD flares (22%) during pregnancy. Two-thirds of them (n=30) were in remission at the onset of the pregnancy. Almost half of them (n=22) required corticosteroid treatment. Patients with ulcerative colitis (UC) were in greater risk of disease flare during pregnancy (p<0.001). All but 3 pregnancies (99.1%) resulted in uncomplicated delivery. In 147 cases (67.1%) cesarean delivery was performed. Two late fetal deaths (0.9%) were reported, both in patients with continuously active disease since the beginning of pregnancy. After delivery, 75 patients (34%) presented with a disease flare, which was associated with active disease at the beginning of pregnancy (p <0.001).
Table 1. Demographics and characteristics of the cohort

Mean age of diagnosis (years)	25.6 (12-44)
Crohn’s Disease n (%) L1 L2 L3 B1 B2 B3 P	122 (54.7) 41 10 70 76 31 15 24
Ulcerative colitis n (%) E1 E2 E3	101 (45.3) 15 44 41
Smokers n (%) Smoking during pregnancy n (%)	104 (46.6) 31 (14)
Median disease duration (years)	7.4 (0-23)
History of surgery n (%) Right hemicolectomy n (%) Enterectomy n (%) ΙPAA n (%) Perianal surgery n (%)	41 (18.3) 19 (9.4) 6 (3) 2 (1) 14 (7)
Extraintestinal manifestations n (%) Arthritis n (%) Psoriasis n (%) Uveitis n (%)	85 (38.1) 58 (26) 19 (9) 7 (3)
Median age at conception (years)	33
In vitro fertilization n (%)	15 (6.7)
Use of contraceptives n (%)	39 (17.5)

Conclusion

The majority of female, Greek IBD patients, had a favorable pregnancy outcome. Active inflammation during gestation and UC diagnosis were associated with a negative impact on pregnancy outcomes. The results of this study are in favor of the continuation of IBD treatment during pregnancy.
This study was funded by a research grant 2020EOMIFNEmp1 from the Hellenic Group for the Study of IBD (EOMIFNE)

Introduction

Chronic pancreatitis is a progressive inflammatory disease characterized by irreversible damage to the pancreas. The etiology of the disease is heterogenous and includes alcohol abuse, smoking, genetic risk factors and autoimmune diseases. Several clinical classification and severity scoring systems have been proposed, but none have been globally accepted or reached broad clinical use. Identifying patients at a higher risk of death is crucial for improving patient care and management.

Aims & Methods

This study aimed to develop a prediction model based on promoter hypermethylation of specific genes and clinical factors to differentiate patients with chronic pancreatitis who are at a higher risk of mortality. Clinical variables such as age, sex, smoking status, alcohol consumption, exocrine insufficiency, and endocrine insufficiency, as well as the methylation status of 16 genes, were analyzed using a backward stepwise Cox regression model. The methylation status was determined by a specialized bisulfite based PCR technique. The final model's performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), and used to determine a risk score for each patients. The “cutpt” package in Stata was used to determine an optimal cut-off, in order to stratify patients into low and high-risk groups. Kaplan-Meier survival curves, and cox regression, and AUC were used to determine the accuracy of the risk groups.

Results

Ninety-seven patients with chronic pancreatitis were included in the study. The final prediction model included age, sex, exocrine insufficiency, endocrine insufficiency, and the methylation status of 5 genes: SFRP2, HIC1, MLH1, RASSF1A, and CDKN2B. The AUC of the model was 0.84, indicating high reliability. The model was superior to a model including only clinical variables (AUC = 0.76), indicating added value of the methylation markers. The optimal cut-off value for the risk score was 7.76. According to this, 67 patients were in the low-risk group, and 30 in the high-risk group. The 5-year survival in the high-risk group was 53% compared to 94% in the low-risk group. Being in the high-risk group was significantly associated with an increased HR of death of 10.2 (95% CI; 4.9-21.1), demonstrating the model's strong prognostic value.

Conclusion

The developed prediction model, which combines clinical factors and gene promoter hypermethylation status, could be a valuable tool for identifying patients with chronic pancreatitis who are at a higher risk of death. This study serves as proof-of-concept of the unexplored potential of methylation analysis in cell-free DNA in chronic pancreatitis. This model can potentially enhance patient care by enabling targeted interventions and monitoring for high-risk individuals, ultimately improving their prognosis and quality of life.

Disclosure

S.D.H., P.H.M., O.T.-U., and H.B.K. declare that they have a patent on a diagnostic panel including the promoter hypermethylation status of 8 genes. Application No. 16161073.8 – 1403 Pancreatic Cancer methylation Markers (18.03.2016)

Introduction

Mental health is an overlooked aspect of inflammatory bowel disease (IBD) patient care and the most common psychological conditions in patients with IBD are anxiety and depression¹. The objective of this study was to examine the possible factors that will impact mental health burden of CD patients in Europe.

Aims & Methods

A multi-centre online medical chart review study of patients with CD was conducted between Jul – Sep 2022 among UK, FR, DE, IT & ES gastroenterologists practicing across hospital and private practices. Physicians were screened for practice duration and patient volume. Charts of patients prescribed with advanced therapy were included in the analysis.

Results

206 sampled physicians collectively reported 1178 CD patients. From the reported CD patients, 190 suffered mental health burden (depression or anxiety) and 988 CD patients did not suffered any mental health burden. Among CD patients suffered mental health burden, a higher proportion of CD patients are female vs those who did not suffered any (55% vs 46%). ‘Family history of IBD’ was the co-morbidity more likely to experience in reported CD patients suffered mental health burden vs those who did not (11% vs 7%).
When looking at employment status between these two patient groups, reported CD patients suffer mental health burden was less likely to be in full-time employment vs those not suffered mental health burden. A higher proportion of reported CD patients suffered mental health burden were in part-time employment or housewife/househusband.

Table 1: Employment status in reported CD patients (% patients)

CD patients	Suffered mental health burden	NOT suffered mental health burden
% full-time employment	47%	62%
% part-time employment	22%	14%
% housewife/ husband	8%	4%

CD patients with mental health burden had greater CRP level than patients without mental health burden (CRP mean: 16 vs 12). This aligns with reported CD patients with mental health burden had frequent surgery times vs without mental health burden (Mean surgery times: 2 vs 1) and had greater steroid usage (% reported patients currently on steroids – 18% vs 13%).

Conclusion

Comparisons in this study cohort highlight there are other factors could impact CD patients’ mental health burden other than IBD itself. This coincided with low full-time employment rate that attributed to financial stress may increase CD patients’ mental health burden. Also, higher rate of surgery and steroid usage in CD patients experienced mental health burden might suggest they had more severe or complications with their disease that will impact overall mental health. Further investigation using comparator cohort is warranted.

References

1. Shurong Hu, Yiping Chen, Yan Chen & Caihua Wang (2021): Depression and Anxiety Disorders in Patients With Inflammatory Bowel Disease, NCBI, DOI: 10.3389/fpsyt.2021.714057

Clinical Case Summary

Approximately 20% of patients with Ulcerative Colitis (UC) develop Acute Severe UC (ASUC), for which intravenous systemic steroid therapy and possibly Infliximab-based rescue therapy is generally imposed. However, there are no significant guideline recommendations on ASUC regarding Vedolizumab as an alternative to Infliximab. A 56-year-old male, non-obese, past smoker, with steroid-dependent UC on therapy with mesalazine and therapeutic-targeted azathioprine developed ASUC induced by second-line chemotherapy (for development of colitis pembrolizumab-induced by immunotherapy set in the first line) with gemcitabine plus carboplatin for treatment of recurrence of right pleomorphic lung carcinoma with lower lobe involvement as well as lymph node to hilar and paratracheal sites (primary tumor, G3, arising on the left lung and treated with left pneumectomy). Treatment with intravenous methylprednisolone was imposed; however, there was no reduction in bowel movements in the days following admission. Rescue therapy with Infliximab was contraindicated because of the oncologic history. Surgical consultation contraindicated colectomy and abdomen computerized tomography showed no megacolon. Administration of Vedolizumab 300 mg was initiated. After infusion with Vedolizumab, there was a significant reduction in bowel movements starting the day after infusion until normalization of bowel movements within three days and the concomitant normalization of inflammatory indices. Enteral feeding was reintroduced since parenteral nutrition was set up in the previous days under clinical nutritionist consultation with customized nutritional bags. The patient is currently in clinical remission and on therapy with Vedolizumab 108 mg subcutaneously every two weeks and is in oncologic follow-up for pulmonary neoplasm. This case highlights a novel potential of Vedolizumab as a possible rescue therapy in ASUC, especially in special populations, where it may offer a better safety profile.

References

- Sedano R, Quera R, Simian D, et al. An approach to acute severe ulcerative colitis. Expert Rev Gastroenterol Hepatol. 2019;13:943–955.
- Spinelli A, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, Bachmann O, Bettenworth D, Chaparro M, Czuber-Dochan W, Eder P, Ellul P, Fidalgo C, Fiorino G, Gionchetti P, Gisbert JP, Gordon H, Hedin C, Holubar S, Iacucci M, Karmiris K, Katsanos K, Kopylov U, Lakatos PL, Lytras T, Lyutakov I, Noor N, Pellino G, Piovani D, Savarino E, Selvaggi F, Verstockt B, Doherty G, Raine T, Panis Y. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Surgical Treatment. J Crohns Colitis. 2022 Feb 23;16(2):179-189.
- Choy MC, Seah D, Faleck DM, et al. Systematic Review and Meta-analysis: Optimal Salvage Therapy in Acute Severe Ulcerative Colitis. Inflamm Bowel Dis. 2019;25:1169–1186.
- Bonovas S, Fiorino G, Allocca M, et al. Biologic Therapies and Risk of Infection and Malignancy in Patients With Inflammatory Bowel Disease: A Systematic Review and Network Meta-analysis. Clin Gastroenterol Hepatol. 2016;14:1385-1397.e10.

Introduction

Disorders of gut-brain interaction (DGBI) and obesity are common and overlap between these two conditions has been reported in patient samples (1). However, the prevalence of DGBI among obese subjects in the general population is unknown.

Aims & Methods

Our aim was to assess the prevalence of DGBI among obese subjects in the general population in comparison with non-obese subjects, as well as exploring factors associated with DGBI in obesity in Europe.
We included subjects who completed the internet-based survey of the Rome Foundation Global Epidemiology study (2) in 11 European countries (Belgium, United Kingdom, France, Germany, Italy, Poland, Romania, Russia, Spain, Sweden, and the Netherlands). Obesity was defined as a BMI>30 and categorized to 3 classes: 1: BMI 30 to <35, 2: BMI 35 to <40, and 3: BMI 40 or higher. In the non-obese population, we included participants with normal BMI (between 18.5 and <25) and overweight (between 25 and <30), but excluded underweight participants (BMI<18.5, n=744). The prevalence of DGBI was determined, and then compared between obese and non-obese participants. Factors potentially associated with DGBI and obesity including demographics, psychological distress (PHQ-4), somatization (PHQ-15) and quality of life (PROMIS) were assessed.

Results

We included 20,117 participants in our analysis, and 2,023 patients were excluded because of missing BMI information. The prevalence of obesity was 17.8% (95%CI 17.3, 18.4), with 12.6%, 3.7% and 1.6% in obesity classes 1, 2 and 3, respectively. The prevalence of any DGBI was 44.2% in the obese group vs. 39.6% in the non-obese group (OR=1.20 (1.12, 1.30)). Most DGBI were more prevalent in the obese vs. non-obese group (table), with the exception of functional constipation where the opposite was seen. Female sex, higher level of psychological distress and somatization were found in the group with DGBI associated with obesity, as well as lower quality of life.

Table: Prevalence of any DGBI, by anatomical region and individual DGBI in obese and non-obese subjects

Variable	Non-obese (N=15784)	Obese (N=3589)	OR (95%CI)
Any DGBI Esophageal DGBI Functional Heartburn Functional Chest Pain Reflux Hypersensitivity Globus Functional Dysphagia	39.6% (38.9-40.4) 6.1% (5.8-6.5) 1.0% (0.9-1.2) 1.5% (1.3-1.7) 0.8% (0.7-0.9) 0.9% (0.8-1.1) 3.1% (2.9-3.4)	44.2% (42.5-45.8) 7.3% (6.5-8.2) 1.3% (1.0-1.8) 1.8% (1.4-2.3) 1.1% (0.8-1.5) 0.9% (0.6-1.3) 3.6% (3.0-4.3)	1.20 (1.12, 1.30) 1.21 (1.05, 1.39) 1.28 (0.92, 1.76) 1.18 (0.88, 1.54) 1.38 (0.95, 1.96) 0.98 (0.66, 1.43) 1.17 (0.96, 1.42)
Gastroduodenal DGBI Postprandial Distress Syndrome Epigastric Pain Syndrome Functional Dyspepsia Excessive Belching Chronic Nausea and Vomiting Cyclic Vomiting Rumination Syndrome	9.9% (9.4-10.4) 5.8% (5.5-6.2) 2.6% (2.3-2.8) 7.0% (6.6-7.4) 0.7% (0.6-0.9) 0.9% (0.7-1.0) 1.1% (0.9-1.2) 2.4% (2.2-2.7)	12.3% (11.2-13.4) 6.7% (5.9-7.5) 2.8% (2.3-3.4) 8.2% (7.3-9.1) 1.1% (0.8-1.5) 0.9% (0.6-1.3) 1.3% (1.0-1.7) 3.6% (3.0-4.3)	1.28 (1.14, 1.43) 1.15 (0.99, 1.33) 1.10 (0.88, 1.37) 1.18 (1.03, 1.35) 1.54 (1.06, 2.18) 1.04 (0.70, 1.51) 1.24 (0.89, 1.70) 1.51 (1.23, 1.84)
Bowel DGBI Irritable Bowel Syndrome Functional Constipation Functional Diarrhea Functional Bloating Unspecified Functional Bowel Disorder Opioid-Induced Constipation	33.2% (32.4-33.9) 3.9% (3.6-4.2) 12.0% (11.5-12.6) 4.3% (4.0-4.6) 3.6% (3.3-3.9) 8.7% (8.2-9.1) 1.2% (1.1-1.4)	36.6% (35.0-38.2) 4.9% (4.2-5.7) 10.2% (9.2-11.2) 7.3% (6.5-8.2) 4.2% (3.5-4.9) 9.0% (8.1-10.0) 1.5% (1.1-2.0)	1.16 (1.08, 1.25) 1.27 (1.07, 1.51) 0.83 (0.73, 0.93) 1.77 (1.53, 2.05) 1.17 (0.97, 1.41) 1.04 (0.91, 1.18) 1.21 (0.88, 1.62)
Anorectal DGBI Fecal Incontinence Levator Ani Syndrome Proctalgia Fugax	7.5% (7.1-7.9) 1.2% (1.0-1.4) 1.1% (1.0-1.3) 5.6% (5.3-6.0)	8.7% (7.8-9.7) 2.1% (1.6-2.6) 1.2% (0.9-1.6) 5.8% (5.1-6.6)	1.18 (1.03, 1.34) 1.78 (1.35, 2.32) 1.11 (0.78, 1.53) 1.04 (0.89, 1.21)

Conclusion

DGBI are common among obese subjects in the general population and linked with certain demographic and disease-related factors. This should be acknowledged in the management of patients with obesity.

References

1. Aasbrenn M, Høgestøl I, Eribe I, Kristinsson J, Lydersen S, Mala T, et al. Prevalence and predictors of irritable bowel syndrome in patients with morbid obesity: a cross-sectional study. BMC Obes. 2017;4:22.
2. Sperber AD, Bangdiwala SI, Drossman DA, Ghoshal UC, Simren M, Tack J, et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology. 2021;160(1):99-114.e3.

Disclosure

C.M. has served as a consultant/advisory board member for Kyowa Kirin, Norgine, Biocodex, Mayoly Spindler, Tillots, Ipsen and Nestlé HealthScience.
OP has received salary support from Royal DSM and the Rome Foundation, consulting fees from iHealth, and royalties from MetaMe Health.
MS has received grants and personal fees from Glycom and Danone Nutricia Research; personal fees from Ironwood, Menarini, Biocodex, Adnovate, Arena, Tillotts, Kyowa Kirin, Takeda, Alimentary Health, AlfaSigma, and the Falk Foundation; and grants from Genetic Analysis.
J.T. has given scientific advice to Adare, AlfaWassermann, Allergan, Arena, Bayer, Christian Hansen, Clasado, Danone, Devintec, Falk, Grünenthal, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Neurogastrx, Neutec, Novartis, Noventure, Nutricia, Shionogi, Shire, Takeda, Theravance, Tramedico, Truvion, Tsumura, Zealand, and Zeria Pharmaceutical; received research support from Shire, Sofar, and Tsumura; and served on the Speakers Bureau for Abbott, Allergan, AstraZeneca, Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Truvion, and Zeria Pharmaceutical, all outside the submitted work.
J.M.S. report personal fees from Biocodex, Kyowa Kirin, Norgine, Mayoly Spindler, Arko Pharma, and Tillots Pharma outside the submitted work.
J.P.H., J.K., Q.A., S.I.B., and A.S. have no conflict of interest.