Introduction

The melanocortin 1 receptor (MC1R)–specific agonist PL8177 and its main metabolite PL8435 have demonstrated MC1R binding affinity and functional activity that mirrors that of α-melanocyte–stimulating hormone, which has been shown to be effective in reducing inflammation in numerous experimental models. This study investigates the effects of PL8177 on inflammation, cell population composition, and gene and protein expression in colons from a dextran sulfate sodium (DSS)–induced rat model of colitis. The objective is to determine the effectiveness of PL8177 in this model and to characterize its underlying mechanism of action.

Aims & Methods

Male Wistar rats received 5% DSS in drinking water for 3 days to induce colitis (each group n=6). Rats in the sham group received drinking water only. The other groups received vehicle control (placebo)–filled capsules; PL8177-filled capsules at 20, 50, and 100 μg per animal (by oral gavage); or oral mesalazine (positive control). At termination on day 8, 24 hours after the last dose, colon tissues were harvested, dissected, and snap frozen with liquid nitrogen. Colon samples were analyzed for cytokine levels, single nuclei RNA-seq, and data-independent acquisition tandem mass spectrometry. Colitis was assessed by a disease activity index (diarrhea and rectal bleeding), colon length shortening, colon weight gain, and histopathological assessment. The total colitis index was used to assess inflammatory damage.

Results

Colitis was induced in rats treated with DSS. Treatment with oral PL8177 50 μg showed a significant (P<0.05) improvement in colon weight (53% reduction), stool consistency, and fecal occult blood score compared to vehicle. There was a significant (P<0.05) improvement in the total colitis index for the PL8177 100-μg group vs vehicle control group. All PL8177 cohorts showed greater improvement in the total colitis index compared to the mesalazine-treated cohort. PL8177 50 μg showed a significant (P<0.05) improvement in colon weight (53% reduction), whereas mesalazine treatment was associated with a marked reduction in colon length, but only moderate improvement (35%) in colon weight. Single nuclei RNA-seq analysis showed that after oral PL8177 100 µg treatment, relative cell populations and key gene expression levels were closer to those of healthy controls. A subclustering analysis revealed significant differences between the PL8177 100-µg and vehicle populations. Although both showed the presence of macrophages, those present in vehicle-treated colons were primarily M1 macrophages that are involved in inflammation. In the PL8177 100 µg–treated colons, macrophages were primarily M2, which are pro-resolution. Proteomic analysis showed that the colons of PL8177-treated rats are more similar to sham colons than to vehicle colons. Additionally, after treatment with PL8177, a protein known to promote intestinal homeostasis and a blood-based biomarker protein showed expression similar to that seen in the sham group, a result not seen in vehicle-treated colons.

Conclusion

In a rat model, oral PL8177 treatment of colonic inflammation showed significant improvement in anatomical markers of colitis vs the vehicle and mesalazine control groups, supporting the aim of treating inflammatory bowel disease (IBD) in humans. Transcriptomics and proteomics data show that oral PL8177 treatment causes diseased colons to move toward the healthy state and to resolve inflammation. Resolving inflammation—rather than blocking it—provides the possibility of efficacy coupled with safety in treating IBD.

Disclosure

Priyanka Dhingra, Alison Obr, Carl Spana, John H. Dodd, and Paul S. Kayne are employees of Palatin Technologies, Inc.

Introduction

Granulocyte–monocyte apheresis (GMA) is a non-pharmacological therapy approved for the treatment of ulcerative colitis (UC), mainly in steroid-dependent cases. Its mechanism of action is based on the removal of activated leukocytes, but its exact immunological changes have not been fully described yet.

Aims & Methods

Our aim was to characterize the response in the transcriptome at the single-cell resolution level and cell population effects of GMA device. We analysed scRNASeq data from peripheral blood mononuclear cells (PBMC) of two UC patients undergoing their first GMA session. Their gene expression profile was compared before (PRE) and one month after (POST) the GMA treatment, from the inflow and outflow lines, respectively. The analytical pipeline included quality control and filtering, cell-type annotation, differential gene expression and pathway enrichment analysis.

Results

Two patients with UC (mean age 59 years; both E2) were included. Overall, the cell populations that appear to have been affected by the GMA treatment were natural killer cells and monocytes with both populations being reduced after the treatment. The distribution of the annotated cell-types was 2,369 B cells (PRE:50%, POST:49%), 11,462 CD4+ (PRE:49%, POST:50%) and 8,845 CD8+ T-cells (PRE:51%, POST:48%), 47 dendritic cells (PRE:40%, POST:59%), 3,773 natural killer cells (PRE:54%, POST:45%) and 2,352 monocytes (PRE:59%, POST:40%). Annotation at higher resolution identified 27 cell-types with monocytes being subannotated as 1,972 CD14 (PRE:62%, POST:37%) and 380 CD16 (PRE:48%, POST:51%) monocytes. Differential gene expression analysis identified in total 86 significant genes across six cell-types (CD4+ naive and central memory T-cells, natural killer cells, B intermediate cells, double-negative T-cells and CD14 monocytes) with 63% of these genes being downregulated after the GMA treatment. Pathway enrichment analysis identified higher contribution of the double-negative T-cells to the enriching genes. More specifically, after the treatment the double-negative T-cells exhibited upregulation of the NEFL that is associated with the MAPK cascade and downregulation of genes related to immune response and signalling pathways. Regarding the CD14 monocytes, after the GMA treatment we observed significant downregulation of the genes LINC02315, IGHEP1 and IGHE, with the latter being linked to innate immune response pathways.

Conclusion

GMA induces a range of modifications in the gene expression profile across different cell types that change the immunological environment of UC patients.

Disclosure

Financial support from an unrestricted grant from Adacyte, who had no role in the study design, interpretation of data or drafting the abstract.

Introduction

Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking agent, was approved for the treatment of moderate-to-severe Crohn’s disease (CD) in Europe and the USA in 2014. We conducted a systematic literature review and meta-analysis of studies reporting real-world effectiveness of VDZ in patients with CD. Here we describe treatment persistence in biologic-naïve patients with CD treated with VDZ compared with anti-tumor necrosis factor-alpha (TNFα) treatment at 12 and 24 months to address the gap of long-term data available on patients with CD.

Aims & Methods

Systematic literature reviews were performed using MEDLINE, MEDLINE In-Process, Embase, Cochrane Library, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform to identify relevant studies published from May 2014 to July 2022. In addition, if the congress abstracts were not indexed in Embase, key congresses from 2015 to July 2022 were hand searched. Data from adults (aged ≥ 18 years) with CD treated with VDZ in observational/real-world studies were extracted for meta-analysis. The analysis was conducted using the DerSimonian-Laird random-effects method to obtain weighted mean rates (percentage of patients) and the corresponding 95% confidence interval (CI) for each treatment persistence or serious adverse event (SAE) as performed for a meta-analysis published in 2018.¹

Results

Overall, data from 78 studies of 30 158 patients with CD had at least one outcome of interest for analysis. Four and three studies of 7082 and 5040 patients with CD, respectively, reported the rate of treatment persistence in biologic-naïve patients treated with VDZ versus anti-TNFα treatment at 12 and 24 months. The rate of treatment persistence was higher with VDZ (83.8% [95% CI 71.4–96.1]) compared with anti-TNFα treatment (75.3% [69.9–80.7]) at 12 months. Similarly, the rate of treatment persistence was higher with VDZ (70.4% [95% CI 61.3–79.6]) compared with anti-TNFα treatment (64.5% [56.9–72.2]) at 24 months. Two studies of 491 and 86 biologic-naïve patients with CD treated with VDZ versus anti-TNFα treatment reported SAEs. In a retrospective study, safety outcomes were followed from treatment initiation up to five half-lives post-treatment discontinuation; 8.3% treated with VDZ experienced SAEs compared with 19.0% with anti-TNFα treatment.² In an additional retrospective study that reported SAEs within the first 12 months of treatment; the rate of SAEs was comparable between patients treated with VDZ (18.2%) and anti-TNFα treatment (17.0%).³ Among these patients, only those receiving anti-TNFα treatment experienced drug-induced SAEs (3.8%; pancreatitis and systemic lupus erythematosus).³

Conclusion

This meta-analysis of real-world studies demonstrated higher rates of long-term treatment persistence and suggests that VDZ may have a favorable safety profile compared with anti-TNFα treatment in biologic-naïve patients with CD.

References

1. Schreiber S et al. J Gastroenterol 2018;53:1048–64.
2. Bressler B et al. J Crohns Colitis 2021;15:1694–706.
3. Moens A et al. Inflamm Bowel Dis 2021;28:1135–42.

Disclosure

This study was funded by Takeda Pharmaceuticals International AG. Medical writing services were provided by Elena Sugrue, PhD, of Oxford PharmaGenesis, and funded by Takeda Pharmaceuticals International AG.
AA Advisory board/lecture fees from AbbVie, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda.
RJB is an employee of PHMR Ltd., who received funding for this study from Takeda Pharmaceuticals International AG.
PB is an employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
MN is an employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
SW is an employee and stockholder of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
SS has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, ProventionBio, Takeda and Theravance Biopharma.

Introduction

Screening for Barrett’s esophagus (BE) could lead to earlier detection (EAC) and improve survival of esophageal adenocarcinoma (EAC). The Cytosponge, a non-endoscopic cell collection device that is coupled with the biomarker Trefoil Factor 3 (TFF3), has been shown in the Barrett’s Esophagus Screening Trial 3 (BEST3) trial, to lead to a 10-fold increase in BE diagnosis in a reflux population. The aims of this study were to: 1) Estimate the proportion of missed BE or stage-1 EAC under the current primary care reflux referral pathway, 2) Define a target screening population and, 3) To estimate the trade-off between the target population to screen and the proportion of BE or stage-1 EAC diagnosed.

Aims & Methods

This was a retrospective analysis and modelling from the multicentre, pragmatic, randomised controlled BEST3 trial that took place across 109 general practices in England. The findings from the main study were previously reported.¹ For aim 1, we used the BEST3 intervention (n=6834) and control arm (n=6388) data to estimate the number of missed BE or stage-1 EAC under the current reflux referral pathway. For aim 2, we determined which clinical risk factors predict a diagnosis of BE or stage-1 EAC in individuals who swallowed the Cytosponge (n=1654) and then modelled the probability of a diagnosis of BE and stage-1 EAC. For aim 3, we used different probabilities of a diagnosis of BE and stage-1 EAC to estimate the starting age to screen, to estimate the trade-off of the number-needed-to-screen and the proportion of BE or stage-1 EAC that would be diagnosed.

Results

Among usual care (control), 0.2% (13/6388) of individuals had BE or stage-1 EAC whereas, the expected prevalence of BE or stage-1 EAC within the intervention (Cytosponge) arm was 10.6% (680/6388), leading to the estimation that the proportion of missed pre-symptomatic BE and stage-1 EAC cases under current care is ~98%. Using logistic regression, we showed that male gender (Odds Ratio, OR 2.46, 95% Confidence Interval, CI 1.67-3.64, p<0.001), age (OR 1.05, 95% CI 1.03-1.07, p<0.001) and family history (OR 1.81, 95% CI 1.04-3.15, p=0.036) were significant predictors of BE or stage-1 EAC diagnosis. Next we modelled and simulate the trade-off for the numbers-needed-to screen on a population level according to different probability thresholds for a diagnosis of BE or stage-1 EAC (≥3%, ≥5%, and ≥10% among individuals with reflux). For these models we set an upper age limit of 74 years for practical considerations (Table 1). These data suggest that a 5% threshold is likely the optimal strategy. This reduces the screening population by 45.2% (males age 55-74 and females 65-74) while still diagnosing 71.0% of cases with a number-needed-to-screen to detect one case of 10.7.

Conclusion

A targeted screening strategy has the potential to substantially improve detection rates for BE and stage-1 EAC compared with current care. The trial data can be used to inform the optimal age for screening in males versus females in order to maximise the yield of screening according to the resources available.

References

Fitzgerald RC, di Pietro M, O'Donovan M, et al. Cytosponge-trefoil factor 3 versus usual care to identify Barrett's oesophagus in a primary care setting: a multicentre, pragmatic, randomised controlled trial. The Lancet 2020;396(10247):333-44.

Disclosure

R.C.F. and M.O. are named inventors on patents pertaining to the Cytosponge and associated technology. R.C.F. and M.O are shareholders of Cyted Ltd., a company working on early detection technology. The other authors declare no conflict of interest.

Introduction

Capsule endoscopy (CE) is a minimally invasive exam suitable of panendoscopic evaluation of the gastrointestinal tract. Nevertheless, CE is time-consuming, with suboptimal diagnostic yield in the upper GI tract. Convolutional neural networks (CNN) are human brain architecture-based models suitable for image analysis. However, there is no study about their role in capsule panendoscopy.

Aims & Methods

Our aim was to develop an artificial intelligence (AI) model for panendoscopic automatic detection of pleomorphic lesions (namely vascular lesions, protuberant lesions, hematic residues, ulcers, and erosions). 355110 images (6977 esophageal, 12918 gastric, 258443 small bowel, 76772 colonic) from eight different CE and colon CE (CCE) devices were divided into a training and validation dataset in a patient split design. The model classification was compared to three CE experts’ classifications. The model’s performance was evaluated by its sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the precision-recall curve.

Results

The binary esophagus CNN had a diagnostic accuracy for pleomorphic lesions of 83.6%. The binary gastric CNN identified pleomorphic lesions with a 96.6% accuracy. The undenary small bowel CNN distinguished pleomorphic lesions with different hemorrhagic potential with 97.6% accuracy. The trinary colonic CNN (detection and differentiation of normal mucosa, pleomorphic lesions, and hematic residues) had 94.9% global accuracy.

Conclusion

Our group developed the first AI model for panendoscopic automatic detection of pleomorphic lesions in both CE and colon CE from multiple brands, solving a critical interoperability technological challenge. Deep learning-based tools may change the landscape of minimally invasive capsule panendoscopy.

References

1. Pennazio M, Rondonotti E, Despott EJ, Dray X, Keuchel M, Moreels T, et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2022. Endoscopy. 2023 Jan;55(1):58-95. PubMed PMID: 36423618. Epub 20221124.
2. Le Berre C, Trang-Poisson C, Bourreille A. Small bowel capsule endoscopy and treat-to-target in Crohn's disease: A systematic review. World J Gastroenterol. 2019 Aug 21;25(31):4534-54. PubMed PMID: 31496630. PMCID: PMC6710184.
3. Iddan G, Meron G, Glukhovsky A, Swain P. Wireless capsule endoscopy. Nature. 2000 May 25;405(6785):417. PubMed PMID: 10839527.
4. Rondonotti E, Pennazio M. Colon capsule for panendoscopy: a narrow window of opportunity. Endosc Int Open. 2021 Dec;9(12):E1860-E2. PubMed PMID: 34917450. PMCID: PMC8670997. Epub 20211214.
5. Vuik FER, Moen S, Spaander MCW. Colon capsule endoscopy as panendoscopy: Using current knowledge to enhance possibilities. Endosc Int Open. 2022 May;10(5):E584. PubMed PMID: 35571484. PMCID: PMC9106432. Epub 20220513.

Introduction

Accurate distinction between benign and malignant biliary strictures (BS) is challenging. The use of bile duct biopsies and brush cytology via endoscopic retrograde cholangiopancreatography (ERCP) remains suboptimal. Single-operator cholangioscopy increases the diagnostic yield in BS but has limited availability and high costs. Convolutional neural network (CNN)-based systems have the potential to assist in the diagnostic process and improve reproducibility. Thus, we assessed the feasibility of using deep learning to differentiate BS out of fluoroscopy images during ERCP.

Aims & Methods

We conducted a retrospective review of adult patients (n=251) from three university centers in Germany (Leipzig, Dresden, Halle) who underwent an ERCP. We developed and evaluated a deep learning-based model (DenseNet) by means of fluoroscopy images. We measured the area under the receiver operating characteristic curve (AUROC) to evaluate the performance of the classifier and used saliency maps analyses to understand the decision-making process of the model.

Results

In cross-validation (Leipzig cohort), malignant BS were detected with a mean AUROC of 0.88 ± 0.02. On two independent external validation cohorts (Dresden, Halle), the of the deep learned based classifier reached a mean AUROC of 0.71 ± 0.04 and 0.74 ± 0.07, respectively. The artificial intelligence model's predictions identify plausible characteristics within the fluoroscopy images.

Conclusion

By using a deep learning model, we were able to discriminate malignant BS from benign biliary conditions. Artificial intelligence improves the diagnostic yield of malignant BS and needs to be validated in prospective design.

Introduction

Infection related morbidity and mortality is still a major hazard associated with the standard re-usable duodenoscopes used for endoscopic retrograde cholangiopancreatography (ERCP). The single use duodenoscope (SUD) has been developed as a potential disposable instrument for preventing cross-transmission of infections via contaminated devices in high-risk patients. However, data for the use of SUD in real-world practice is very scarce.

Aims & Methods

In this study we aimed to assess our single centre experience with SUDs in patients underwent ERCPs, in terms of performance and safety. We included all the patients who underwent ERCP with the use SUD (Boston Scientific designed EXALT Model D) between October 2020 and February 2023 at Cambridge University Hospitals. Based on the retrospective review of procedure notes, outcomes were analysed with regards to procedure indication, success rate for the intended clinical indication, interventions performed, and adverse events. The SUD was used when prespecified institutional criteria (immunocompromised patient, multi drug resistant infection or failed procedure with standard re-usable duodenoscopes) were met or when there was no reusable duodenoscopes available at the time of procedure.

Results

The SUD was used in total of 34 patients during the study period. Baseline patient characteristics and procedure details are shown in Table 1. 59% of the patients were females. The median age was 64.5 years. Nineteen patients (56%) had a native papilla. The most common indication for the ERCP was choledocholithiasis (12, 35%) followed by benign biliary stricture (11,32%), head of pancreas tumor (6, 18%) and cholangiocarcinoma (4,12%).
28 out of 34 (82%) procedures achieved technical success. 20 procedures (59%) had the SUD used as the primary endoscope and 19 were successful (95%). In the other 14 cases (41%) SUD was used after the standard re-usable duodenoscopes due to anatomical problems encountered preventing progression of the procedure and of these 9 (64%) were completed successfully. In 5 of these (83%), failure occurred due to distorted duodenal anatomy which did not allow the scope to reach a favorable position.
Regarding the post procedure adverse events, 5 patients (15%) developed post procedure pancreatitis, two (5%) developed cholangitis and one patient (2%) had post sphincterotomy bleeding .

Conclusion

The SUD may be an effective tool in patients with distorted gastro-duodenal anatomy with failure when using a re-usable duodenoscopes. The reason for this may be due to the diameter and stiffness of the SUD. It was observed that SUDs are associated with comparably higher rates of adverse events in this study group due to the technical difficulty of the procedures. In addition to the fact that SUD eliminates the risk of device-related infection transmission, it appears to represent a reliable and effective alternative to standard re-usable duodenoscopes for a variety of indications and levels of difficulty.

Disclosure

Dr Corbett received honorarium from Boston Scientific previously.