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

Pancreatic steatosis (PS) has been increasingly recognized and associated with some relevant metabolic implications. However, data on its correlation with exocrine pancreatic function remain limited. We conducted a systematic review and meta-analysis to evaluate whether PS is associated with exocrine pancreatic insufficiency (EPI).

Aims & Methods

This study aimed to investigate whether imaging-detected PS is related to exocrine pancreatic dysfunction, assessed by fecal elastase-1 (FE-1) levels. We searched PubMed, EMBASE, and Cochrane Central for studies including adults with and without PS identified on imaging, and reporting FE-1 concentrations. Data were pooled using random-effects models.

Results

Three studies evaluating a total of 1,864 patients were included. Fecal elastase levels were significantly lower in patients with PS compared to controls, indicating worse exocrine pancreatic function in this group (MD -199.78; 95% CI -303.66 to -95.91; p < 0.05; I² = 97%). Moreover, PS was associated with a significantly increased risk of exocrine pancreatic insufficiency (RR 3.13; 95% CI 1.17–8.40; p = 0.023; I² = 81%), reinforcing the link between fat accumulation in the pancreas and impaired exocrine function.

Conclusion

This meta-analysis demonstrates a significant association between PS and impaired pancreatic exocrine function, compared to individuals without known pancreas disease. These findings underscore the importance of a comprehensive metabolic assessment in patients with PS, given its potential role in pancreatic dysfunction.

Introduction

Besides stage, age and CA19-9 there is limited knowledge on “patient-related factors” associated with chemotherapy response for Pancreatic Ductal Adenocarcinoma (PDAC) patients. Smoking worsens chemotherapy response in other tumours and seems to promote tumor progression in PDAC preclinical models, but data in human PDAC are scanty.

Aims & Methods

PDAC patients were prospectively enrolled at diagnosis with exposome and clinical data registered, and tumors sampled for research purpose during Endoscopic Ultrasound (EUS). Patients were then followed-up to register chemotherapy treatment [whether Folfirinox (F), Abraxane-gemcitabine (AG) or a combination of cisplatin, abraxane, capecitabine and gemcitabine (PAXG)] and evaluate disease control rate (DCR) at 6-months (DCR-6), Progression-Free-Survival (PFS) and Overall-Survival (OS). We also explored transcriptomic signatures associated with smoking on a subset of EUS-acquired PDAC samples undergoing RNA-sequencing, with differential gene expression (DGE) analysis and pathways analysis performed. Furthermore, in vitro analyses with PDAC cell lines CAPAN-1 were treated with Folfirinox or gemcitabine with/without the nicotine compound 4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone to evaluate in vitro effects.

Results

326 patients treated with chemotherapy of interest were analyzed. Median age was 65, with 51.5% being males. Disease’s resectability at diagnosis was 10.4% resectable, 37.7% borderline-resectable, 26.9.% locally-advanced, 24.8% metastatic. AG was used in 42.3% of patients, PAXG in 25.7%, Folfirinox in 31.9%. DCR-6 was 57.9% in current smokers vs 70.4% in never-/ex-smokers (p=0.05). Current smoking was associated with a lack of DCR-6 at adjusted multivariable analysis (OR=1.99; 95%CI:1.1-3.5; p=0.01). At subgroup analysis, this was confirmed only for Folfirinox patients, with DCR-6 being 46.2% for current smokers vs 75.6% for non-current smokers(p=0.007). Current smokers had a significantly shorter PFS (5 vs 13 months; HR:1.79; 95%CI:1.13-3.21; p=0.01) and OS (24 vs 34; HR 1.93; 95%CI: 1-3.67; p=0.04) compared to non-smokers at adjusted multivariable analysis.
At transcriptomic analysis on a subset of 84 patients, current smokers were more prevalent in patients developing the more aggressive basal-like subtype (50% vs 15%; p=0.03), had lower expression of the classical marker GATA6 (3.27 vs 3.92; p=0.03) as also different activated pathways such as activated MAPK signalling, Axon guidance, Hypoxia and epithelial-mesenchymal-transition signalling among the others.
At in vitro experiments, for cell survival analysis, CAPAN-1 PDAC cells showed a significant reduced response to Folfirinox treatment when treated in combination with nicotin compounds, which was not observed for gemcitabine alone or in combination.

Conclusion

Collectively, our results consistently point towards a deleterious effect of smoking on response to Folfirinox regimen. Clinical data show that current smoking is a predictive factor for lower DCR-6, shorter PFS and OS; transcriptomic analyses show different gene expressions between smokers and non-smokers, with a transition toward reduced expression of classical phenotype and activation of inflammatory and pro-mesenchimal pathways. In vitro experiments support the negative effect of smoking on the response to Folfirinox. Smoking should be considered as a covariate to be investigated when choosing chemotherapy regimens in patients with PDAC, and patients should be discouraged to continue smoking.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is frequently indicated in patients who underwent Roux-en-Y gastric bypass (RYGB) surgery. (1, 2) However, due to the altered anatomy, it is challenging to gain pancreatobiliary access in patients following a RYGB. Several strategies are currently available, but all have their disadvantages. Laparoscopy-assisted ERCP (LA-ERCP), the current golden standard, has higher success rates but also comes with logistical challenges of intraoperative ERCP, peri-operative complications and high costs. (3 - 5) Endoscopic ultrasound directed ERCP (EDGE) is a technique used to create a gastro-gastrostomy by placing a lumen apposing metal stent (LAMS) between the gastric pouch and the excluded stomach, facilitating subsequent ERCP.(6) Although EDGE gained more popularity over the last few years, prospective studies are lacking.

Aims & Methods

The aim of this study is to provide prospective evidence for the efficacy and safety of EDGE, including fistula closure.This multicentre prospective cohort study included all consecutive patients scheduled for elective ERCP after RYGB surgery. EDGE was performed as a two-step procedure. Primary endpoint was overall technical success. Secondary endpoints were technical success of LAMS placement and ERCP individually, persistent fistula and other procedure-related adverse events (AEs).

Results

Between January 2021 and August 2024, 26 patients were included in 4 Dutch hospitals. Overall technical success was achieved in 25/26 patients (96.2%). Median LAMS indwelling time was 14 days [IQR 11 – 28 days]. Two EDGE-related AEs occurred (7.7%); one perforation of the contralateral duodenal wall following scope insertion and one bleeding after LAMS placement. Two ERCP-related AEs occurred (7.7%): one CBD perforation and one post-ERCP pancreatitis. Two patients were lost to follow-up. None of the remaining patients had a persistent fistula, based on radiologic or endoscopic evidence (0/24). No mortality occurred.

Conclusion

This prospective study shows that two-step EDGE is relatively safe and associated with high technical success, without any cases of a persistent fistula. However, AEs occurred in 4 patients (15.4%), of which two were EDGE-related (7.7%).

References

1. Yang H, Petersen GM, Roth MP, Schoenfield LJ. Risk factors for gallstone formation during rapid loss of weight. Digestive diseases and sciences. 1992;37(6):912-8.
2. Haal S, Guman MSS, Boerlage TCC, Acherman YIZ, de Brauw LM, Bruin S, et al. Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery (UPGRADE): a multicentre, double-blind, randomised, placebo-controlled superiority trial. Lancet Gastroenterol Hepatol. 2021;6(12):993-1001.
3. Gangwani MK, Aziz M, Haghbin H, Iqbal A, Dillard J, Dahiya DS, et al. Comparing EUS-directed Transgastric ERCP (EDGE) Versus Laparoscopic-Assisted ERCP Versus Enteroscopic ERCP: A Network Meta-analysis. J Clin Gastroenterol. 2024;58(2):110-9.
4. da Ponte-Neto AM, Bernardo WM, de ACLM, Josino IR, Brunaldi VO, Moura DTH, et al. Comparison between Enteroscopy-Based and Laparoscopy-Assisted ERCP for Accessing the Biliary Tree in Patients with Roux-en-Y Gastric Bypass: Systematic Review and Meta-analysis. Obes Surg. 2018;28(12):4064-76.
5. Abbas AM, Strong AT, Diehl DL, Brauer BC, Lee IH, Burbridge R, et al. Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass. Gastrointestinal endoscopy. 2018;87(4):1031-9.
6. van Wanrooij RLJ, Bronswijk M, Kunda R, Everett SM, Lakhtakia S, Rimbas M, et al. Therapeutic endoscopic ultrasound: European Society of Gastrointestinal Endoscopy (ESGE) Technical Review. Endoscopy. 2022;54(3):310-32.

Clinical Case Summary

Immunotherapy with checkpoint inhibitors (CPI) has transformed oncology management, achieving durable remissions. However, its widespread has also led to significant immune-mediated side effects, whose treatment is a challenge in today's medicine.
We present the case of a 59-year-old man diagnosed with non-small-cell lung cancer who started treatment with Nivolumab(anti-PD1). After 6 months, the patient was admitted for 3 weeks diarrhoea(4 liquid stools/day).
A colonoscopy was done, identifying severe pancolitis with oedema, erythema, nodularity and superficial ulcers. PA revealed diffuse non-specific colitis with CMV IHC -. Given the suspicion of immune-mediated colitis vs de novo IBD, treatment was started with iv GCC, with no improvement.
Given the contraindication of long-term use of anti-TNF in IBD patients with active malignancies, induction with IV Ustekinumab (anti-IL12/23) was decided. Ustekinumab 390 mg iv was given, after which the patient showed clinical improvement until complete resolution. He continued with Ustekinumab 90 mg/8 weeks. A follow-up colonoscopy showed pancolic scarring with pseudopolyps and no inflammatory activity. Given these findings Ustekinumab was discontinued after 1 year, with the patient remaining asymptomatic and without oncologic progression.
Immune-mediated colitis is a common side effect, being mild in most cases. When severe cases occur, CPI should be discontinued indefinitely, and high-dose iv GCC (up to 2 mg/kg) should be initiated. Up to one-third of GCC-treated patients don't respond and are candidates for immunosuppressive therapy with biologic drugs.
Although clinical guidelines recommend Infliximab/Vedolizumab for induction as 2º line treatment, the therapeutic decision should be individualized, as they are contraindicated in IBD patients with active malignancies. Therefore, in this context of complex differential diagnosis, Ustekinumab (with lower rate of oncological side effects) appears to be an effective option.

References

Photo 1: Initial colonoscopy: severe pancolitis with erythema, oedema, superficial ulcers and mucosal nodularity.
Photo 2: Abdominal CT: Diffuse thickening of the colon with increased uptake of the wall.
Photo 3: Follow-up colonoscopy: Chronic scar changes without signs of acute activity.

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

The PAN-PROMISE symptom score is the first patient-reported outcome (PROM) in acute pancreatitis (AP), and it was developed and validated in a prospective cohort of patients to be used as an endpoint in research. The aim of this study was to assess the performance of the score in a large randomized controlled trial (RCT) and its association with well-established AP endpoints.

Aims & Methods

This is an ancillary study of the WATERFALL trial, where PAN-PROMISE was evaluated at baseline, 24, 48 and 72 hours. The study examined the association between PAN-PROMISE with stablished endpoints in AP: severity, pancreatic and/or peripancreatic fat necrosis (necrosis), infected necrosis, intensive care unit (ICU) admission, persistent organ failure (POF), prolonged hospital stay and mortality. Areas under the ROC curve (AUC) were calculated and used to compare baseline PAN-PROMISE and baseline Bedside Index for Severity in AP (BISAP) for the prediction of these endpoints.

Results

248 patients from the WATERFALL trial were included. A statistically significant association was found between PAN-PROMISE and severity, necrosis, POF, ICU admission, and prolonged hospital stay at all checkpoints (p<0.05). Higher scores were also significantly associated with infected pancreatic necrosis at 24, 48, and 72h and death at baseline and 24 hours. PAN-PROMISE baseline score had a higher AUC than BISAP for severity and necrosis, but the results were not statistically significant.

Conclusion

In the context of a RCT, the PAN-PROMISE score, a patient-centered measure, has been validated with established AP outcomes and as an endpoint for future clinical trials.