Introduction

Recurrence of Crohn’s disease (CD) after ileocolic resection is common. However, reliable non-invasive monitoring methods are lacking, for instance, the use of faecal calprotectin (FC) has showed inconsistent results in this subgroup of patients.

Aims & Methods

The aim of this study was to evaluate clinical and biochemical factors associated with post-operative endoscopic recurrence in CD patients.
Retrospective single-center study including patients with CD who underwent ileocolonoscopy for CD surveillance, after ileocolic resection. The patients’ clinical status was evaluated through Harvey-Bradshaw index (HBI), with clinical remission considered as ≤ 4 points. Biochemical parameters included erythrocyte sedimentation rate (ESR), c-reactive protein (CRP) and FC. Clinical and biochemical parameters were evaluated in the 6 months prior to ileocolonoscopy. Post-operative endoscopic recurrence was defined as a Rutgeerts score ≥ i2b.

Results

A total of 81 patients and 121 ileocolonoscopies were included. Most patients were female (55.6%), with a mean age of 48±13 years. Regarding the Montreal classification, 37 patients had ileal disease (45.7%) and 44 ileocolonic disease (54.3%); 9 patients had nonstricturing, nonpenetrating disease (11.1%), 35 stricturing (43.2%) and 37 penetrating disease (45.7%). Nineteen patients had perianal disease (23.5%). The mean time between the surgery and the endoscopic evaluation was 135±79 months. Post-operative endoscopic recurrence was observed in 52 ileocolonoscopies (43.0%).
Symptomatic patients (HBI > 4 points) were 11 times more likely to have post-operative endoscopic recurrence (OR 10.686, 95%CI 2.930-38.974, p<0.001). Those with post-operative endoscopic recurrence had a significantly higher FC values (median 189 vs 69 µg/g, p<0.001) and higher ESR values (median 14 vs 9 mm, p=0.002). In fact, patients with FC values ≥ 150 µg/g and those with ESR values > 12 mm were 4 and 3 times more likely to have post-operative endoscopic recurrence (OR 3.654, 95%CI 1.605-8.316, p=0.002 and OR 3.059, 95%CI 1.397-6.696, p=0.005, respectively). The presence of post-operative endoscopic recurrence was not associated with CRP values (median 2.9 vs 2.9 mg/L, p=0.466), and neither with mean time between the surgery and the endoscopic evaluation (mean 126±83 vs 142±75 months, p=0.263).

Conclusion

The presence of symptoms (HBI > 4 points), FC values ≥ 150 µg/g and ESR values > 12 mm was associated with post-operative endoscopic recurrence in CD. Therefore, the HBI, FC and ESR values can be used to monitor CD patients after ileocolic resection, and prompt endoscopic evaluation should be performed in those with HBI > 4 points, FC values ≥ 150 µg/g and/or ESR values > 12 mm.

Introduction

The emergence of antimicrobial resistant Helicobacter pylori (H. pylori) has impacted treatment success rates. Local audits of prescription patterns and eradication rates are necessary to assess treatment efficacy and compliance with clinical guidelines. The first Irish consensus guidelines on the management of H. pylori were published in 2017. Clarithromycin-amoxicillin triple therapy (CTT) or bismuth quadruple therapy (BQT) were the recommended first-line options. Other key recommendations included extending treatment durations to 14 days and the use of high-dose proton pump inhibitors (PPIs).

Aims & Methods

This study aimed to (i) investigate first-line H. pylori prescription patterns and cure rates over a 10-year period in Ireland, and (ii) evaluate the impact of the first Irish consensus guidelines on these trends. Data were collected at e-CRF AEG-REDCap from the European Registry on Helicobacter pylori Management (Hp-EuReg) and quality reviewed from 2013 to 2022. All treatment-naïve cases were assessed for effectiveness by modified intention-to-treat (mITT) analysis. Multivariate analysis was performed using a logistic regression model to evaluate the relationship between mITT rates and age, sex, indication, compliance, PPI dose and treatment duration.

Results

In all, data from 1,000 patients (mean age 50±15 years; 54% (n=536) female) were included in the analysis, from those 78% (n=784) were from Tallaght University Hospital, Dublin and 22% (n=216) were from Beacon Hospital, Dublin. The most common indication was dyspepsia (92%; n=920), followed by duodenal ulcer and gastric ulcer (2%; n=20 and 1%; n=10, respectively). CTT was the most common first-line treatment (88%; n=880). BQT represented 1.7% (n=17) of prescriptions. Of the reported treatment durations (n=998), 87% (n=868) were for 14 days, 4.5% (n=45) were for 10 days and 8.5% (n=85) were for 7 days. Of the reported PPI dose prescribed (n=999), 86% (n=860) were high (i.e., 80 mg omeprazole equivalent twice daily), 0.9% (n=9) were standard (i.e., 40 mg omeprazole equivalent twice daily), and 13% (n=130) were low (i.e., 20 mg omeprazole equivalent twice daily).

The eradication rate was 80.1% (95% confidence interval (CI) 77.5-82.5%) overall and 81.4% (95% CI 78.9-83.7%) for CTT. Multivariate analysis revealed that good compliance and the use of high dose PPI were significantly associated with higher overall mITT rates (odds ratio (OR) 4.5, 95% CI 1.4-14.2, p<0.05 and OR 1.9, 95% CI 1.2-2.8, p< 0.005, respectively) and CTT mITT rates (OR 4.2, 95% CI 1.2-14.2, p<0.05 and OR 1.9, 95% CI 1.1-3.2, p<0.05, respectively).

Following publication of the Irish consensus guidelines in 2017, prescriptions for 14 days therapy increased from 39% (n=82/208) pre-2017 to 99% (n=786/790; p<0.0001) and the use of high dose PPI increased from 37% (n=77/207) pre-2017 to 99% (n=783/792; p<0.0001). In line with this, overall eradication rates significantly increased from 74.5% (95% CI 68.2-80.0%) pre-2017 to 81.6% (95% CI 78.7-84.1%; p<0.05). CTT eradication rates significantly increased from 75.7% (95% CI 68.2-81.8%) pre-2017 to 82.6% (95% CI 79.6-85.1%; p<0.05).

Conclusion

CTT was the most frequently prescribed first-line therapy between 2013-2022. BQT was rarely prescribed, reflecting difficulty accessing bismuth in Ireland. While treatment success increased following publication of the Irish consensus guidelines, cure rates remain below 90%. Alternative first-line treatment strategies are required in the Irish healthcare setting.

Introduction

Endoscopic ultrasound (EUS) is an important tool for the evaluation of patients with common bile duct (CBD) dilation without obvious identified aetiology after ultrasonography (US), computed tomography (CT) and/or magnetic resonance cholangiopancreatography (MRCP).

Aims & Methods

The aim of this study was to evaluate the diagnostic performance of EUS for CBD dilation in patients with a negative initial study.
Retrospective, unicentric and cohort study including patients who underwent EUS for CBD dilation (diameter ≥7mm if intact anatomy or ≥10mm if prior cholecystectomy) in the absence of obvious pathology on prior imaging, including US, CT and/or MRCP, from January 2016 until June 2022. All EUS procedures were performed with a linear echoendoscope.

Results

Totally, 109 patients were included, 50 patients without symptoms or altered liver biochemistry (45.9%). Among the 41 patients with positive EUS, 33 patients had choledocholithiasis (30.3%), 6 chronic pancreatitis (5.5%) and 2 had ampullary cancer (1.8%). Older age was associated with positive EUS (median 79 vs 71 years, p=0.030). Patients with jaundice, cholelithiasis and altered liver biochemistry were 16.2 (p=0.002), 3.1 (p=0.024) and 2.9 (p=0.009) times more likely to have positive EUS, respectively.
A total of 53 patients underwent MRCP with a negative result (48.6%). In this group, 12 patients had a positive EUS, 10 had choledocholithiasis (18.9%) and 2 had chronic pancreatitis (3.8%). Of those, patients with abdominal pain and jaundice were 15.4 (p<0.001) and 20.0 (p=0.007) times more likely to have positive EUS, respectively. CBD diameter in MRCP was not associated with finding a causative lesion (p=0.473).
Considering only asymptomatic patients without altered liver biochemistry, CBD diameter ≥8.5mm, evaluated by CT, had a sensibility of 100% and specificity of 75% in predicting a positive EUS (AUC 0.734, p=0.048).

Conclusion

EUS is a useful diagnostic method for patients with unexplained CBD dilation, with a higher yield, even in patients with negative MRCP, and especially in patients with older age, symptoms such as abdominal pain and jaundice, cholelithiasis and/or altered liver biochemistry. CBD diameter evaluated by CT had a moderate discriminative ability in predicting a positive EUS in asymptomatic patients without altered liver biochemistry.

Introduction

The use of 3D cell culture models, including spheroids and organoids, has proven to be a valuable method to approximate in vivo conditions in basic research. Our recent work on the pathogenesis of spontaneous bacterial peritonitis (SBP) – a life-threatening complication of liver cirrhosis with a 1-year-mortality of 66% – shows that bacteria induce the degradation of important cell-cell contact proteins upon direct contact via various processes. The resulting destabilization of the epithelial barrier enables bacterial translocation and thus represents a mechanism in the development of SBP (Haderer et al., Gut 2022). To evaluate these processes under more physiological conditions, we investigate bacterial-induced effects on cell-cell contact proteins in a 3D spheroid model and subsequently in a patient-based organoid model.

Aims & Methods

To establish the method and create a reference, spheroids were generated from colon carcinoma cell line HCT116 with a concentration of 70,000 cells/ml. Spheroid development and formation of cell-cell contacts were assessed by fluorescence microscopy. Subsequently, bacterial-induced effects on the tight junction proteins Occludin, Claudin4 and Zonulin1 as well as on the adherens junction protein E-Cadherin were investigated after up to 12 hours of bacterial co-culture using qPCR, fluorescence microscopy and Western blot analysis. Bacterial co-culture was performed with the reference strain Escherichia coli (E.coli) O6:Hnt and the E. coli strain Ont:H41, which was isolated from the ascites of a patient with SBP.
In addition, organoids were generated from intestinal biopsies of patients with liver cirrhosis and co-cultured with both bacterial strains. Bacterial-induced effects on cell-cell-contact proteins were investigated using Western blot analysis.

Results

HCT116 cells formed formed spheroids composed of viable cells with well-defined cell-cell contacts. Co-culture with E. coli for up to 12 hours led to a significant degradation of Occludin (up to 60% reduction), E-Cadherin (up to 85% reduction) and Zonulin1 (up to 95% reduction), whereas Claudin4 levels remained mostly constant. Co-culture with heat-inactivated bacteria did not affect cell-cell contacts. The intensity of these effects was dependent on the respective protein, the bacterial strain used, as well as the multiplicity of infection (MOI) and the duration of the co-culture. Degradation of Occludin could also be visualized by fluorescence microscopy.
We were then able to transfer this experimental approach to an organoid setting. Bacterial-induced degradation of the epithelial barrier was confirmed in organoids, showing a clearly visible reduction of E-Cadherin, Occludin and Zonulin1 after 8 hours of bacterial co-culture. The intensity of the effects varied depending on the bacterial strain, with the patient strain showing a slightly higher level of aggressiveness.

Conclusion

Understanding the pathophysiological changes of the intestinal epithelial barrier in patients with liver cirrhosis is essential for advancing therapeutic strategies for SBP. In this context, a representative ex vivo model is crucial to draw reliable conclusions. Our work shows that relevant mechanisms of SBP, such as bacterial-induced degradation of cell-cell contacts, can be successfully modeled in spheroids and organoids. Thus, our study provides an approach for further approximation to in vivo conditions – bridging the gap between basic research and clinical utility.

References

Haderer M, Neubert P, Rinner E, Scholtis A, Broncy L, Gschwendtner H, Kandulski A, Pavel V, Mehrl A, Brochhausen C, Schlosser S, Gülow K, Kunst C, Müller M. Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases. Gut. 2022 Mar;71(3):580-592. doi: 10.1136/gutjnl-2020-321663 . Epub 2021 Mar 11. PMID: 33707230 ; PMCID: PMC8862089.

Introduction

Small bowel adenocarcinoma (SBA) are rare, but their incidence is increasing. Early diagnosis of SBA remains elusive, so that about one-third of patients are initially diagnosed with distant metastases. In clinical practice, regimens used for SBA parallel those commonly administered in the adjuvant setting for colorectal cancer, owing to its anatomic proximity. However, genomic profiling of SBA has been shown to be distinct from colorectal cancer through comprehensive analysis of genomic alterations. Therefore, it is vital to establish a distinct chemotherapy regimen for SBA based on its molecular pathological characteristics. Claudin-18 plays a key role in constructing tight junctions and altered claudin-18 expression has been documented in various human malignancies. On the basis of this, both monoclonal antibodies and claudin-18.2-specific chimeric antigen receptor engineered T-cells have been recently developed and employed in several clinical trials, showing promising results in the treatment of advanced gastroesophageal and pancreatobiliary tract cancers. However, little is known about the clinicopathological significance of claudin-18 expression in SBA.

Aims & Methods

To explore the localization of claudin-18 in human SBA tissue and draw comparisons and determine the relationship between their expression and clinicopathological factors, and genomic alterations.
We examined 50 surgical resections from patients with primary SBA for immunohistochemical analyses of claudin-18, CK7, CK20, CD10, CDX2, MUC2, MUC5AC, and MUC6 expression. DNA mismatch repair (MMR) status was defined by immunostaining for all MMR proteins; MLH1, MSH2, MLH6, and PMS2. Both MUC 2 and CD10 are markers of intestinal type tumors, whereas MUC5AC and MUC6 are markers of gastric type tumors. Tissue samples showing both gastric and intestinal phenotypes were classified as gastrointestinal type tumors, whereas those showing neither gastric nor intestinal phenotype expression were classified as null type tumors. In addition, genomic profiling was performed on 31 patients using targeted next-generation sequencing.

Results

Claudin-18 expression was observed in 46% of SBA patients. Claudin-18 expression was positively associated with cytokeratin 7 (P=0.003) and MUC5AC (P=0.020) expression, whereas it was negatively associated with MUC2 (P=0.010), CD10 (P=0.014), and CDX2 (P=0.003) expression. Tumor mucin phenotypes included gastric type (n=9), intestinal type (n=20), gastrointestinal type (n=17) and null type (n=4). Claudin-18 was more frequently expressed in gastric type (100%) than in intestinal type (30%) phenotypes (P=0.001). GNAS mutations (N=4) were found in only claudin-18 positive SBA patients, although the difference was not significant. Claudin-18 expression did not correlate with patient age at diagnosis, patient gender, site, histological type, depth of invasion, lymph node metastasis, distal metastasis, TNM stage, and MMR status. However, claudin-18 expression correlated with worse progression free survival.

Conclusion

Claudin-18 expression is associated with gastric immunophenotype and with worse progression free survival. These findings suggest that claudin-18 may be a potential therapeutic target in certain SBA cases.

Introduction

Alterations in body composition and metabolic factors may serve as a potential biomarker for early-detection of pancreatic ductal adenocarcinoma (PDAC).

Aims & Methods

This study aimed to capture the longitudinal changes occurring in body composition and metabolic factors preceding a diagnosis of PDAC. All patients (≥18 years) diagnosed with PDAC between 2000 and 2021 were identified. We collected data on demographics, comorbidities, PDAC characteristics, all abdominal CT scans and blood-based markers up to 3 years prior to date of diagnosis (index date). We applied a fully-automated abdominal segmentation algorithm previously developed by our group (Weston et al. Radiology 2019 [1]) for three-dimensional quantification of body composition on CT scans. Longitudinal trends of body composition and laboratory markers prior to a diagnosis of PDAC were estimated by linear mixed models and visualized using spline regression.

Results

We included 1,825 PDAC patients in body composition analysis, of which 581 (31.8%) had ≥2 pre-diagnostic CT exams. For analysis of longitudinal trends of blood-based markers, 4,846 patients were included. Mean age at diagnosis was 68.4 (SD 11.3) years, 43.6% were female and the mean BMI was 27.0 (SD 5.5). The distribution of PDAC stage was as follows: 12.5% stage I, 32.6% stage II, 19.7% stage III, and 35.2% stage IV. Prior to a PDAC diagnosis, we observed significant decreases in visceral fat volume, subcutaneous fat volume, bone volume, and a variety of blood markers including low-density lipoprotein and hemoglobin (Table 1). Concurrently, patients developed significant increases in HbA1c, fasting blood glucose, high-density lipoprotein and white blood cells prior to a clinical PDAC diagnosis. Most body composition and metabolic markers showed a linear decreasing or increasing trend over time to diagnosis of PDAC.

Table 1. Trends of body composition and laboratory markers over time prior to a diagnosis of PDAC estimated by linear mixed models.

Conclusion

This study identified significant alterations in a variety of soft tissue and metabolic markers that occur in the development of PDAC. These metabolic changes may become apparent several years before diagnosis, which may serve as a significant window of opportunity for early detection.

References

1. Weston AD, Korfiatis P, Kline TL, Philbrick KA, Kostandy P, Sakinis T, Sugimoto M, Takahashi N, Erickson BJ. Automated Abdominal Segmentation of CT Scans for Body Composition Analysis Using Deep Learning. Radiology. 2019 Mar;290(3):669-679. doi: 10.1148/radiol.2018181432. Epub 2018 Dec 11. PMID: 30526356.

Disclosure

On behalf of all authors, I declare no conflicts of interest.