Clinical Case Summary

A 31-year-old woman presented to her physician with painful abdominal mass in the left hypochondrium since an episode of abdominal trauma. An abdominal computed tomography (CT) scan showed a voluminous cystic mass measuring 142 mm in its greatest axis, located between the left hepatic lobe and the stomach. She was referred to a General Surgery hospital consultation. An endoscopic ultrasound was performed, which revealed a cystic lesion measuring at least 12x10 cm, with an irregular hyperechoic wall, a lumen with multiple foci and hyperechoic sediment, without an evident solid component, in the pancreas area, consistent with a pancreatic pseudocyst. Endoscopic transgastric drainage was decided upon by a multidisciplinary group consultation. During the procedure, a puncture was performed with aspiration of transparent content and placement of a 10x15 mm Hot Axios stent under endoscopic and endoscopic ultrasound control, with immediate intra-cystic migration observed. A new 10x15 mm Axios stent was placed with appropriate final positioning. The stent was dilated with a TTS balloon up to 12 mm, and a 3 cm x 10 Fr. double pigtail plastic stent was placed. Biochemical analysis of the aspirated fluid showed CEA 24084 ng/mL; glucose <4 mg/dL; amylase <20 U/L, consistent with a mucinous cystic pancreatic neoplasm. The patient underwent distal pancreatectomy without immediate complications. The pathological analysis showed a histology consistent with a mucinous cystic pancreatic neoplasm with low-grade dysplasia. She remains under follow-up in an outpatient General Surgery consultation.
This is a case of a mucinous cystic pancreatic neoplasm with atypical presentation, mimicking a pseudocyst. Aspiration puncture and biochemical analysis of the aspirated fluid allowed for a directed approach, proving to be fundamental for differential diagnosis and treatment.

Introduction

The first international guideline for managing preneoplastic conditions of the stomach (MAPS I) was published in 2012, followed by an update (MAPS II) in 2019. As adherence to these guidelines remains uncertain, we evaluated adherence by comparing the management of preneoplastic gastric conditions before and after the introduction of MAPS I and II in selected European centers.

Aims & Methods

Patient data were retrieved from nine endoscopy units in seven European countries during three periods: pre-MAPS I (2010/2011), post-MAPS I (2017/2018), and post-MAPS II (2022/2023). Screening and dyspepsia-related endoscopies were included. Data on endoscopy, histopathology, Helicobacter pylori (H. pylori) treatment, and surveillance were collected using a standardized form. Adherence to nine MAPS recommendations was assessed, with improvement defined as a ≥10% increase in guideline-concordant management.

Results

A total of 2,426 patients were included. Most centers (57%) improved in at least seven of the nine recommendations over time. Virtal Chromoendoscopy use improved in six centers, with four reporting its use in >50% of cases. All centers improved in performing biopsies from the antrum and corpus, five conducted random biopsies in nearly all patients, and four performed these plus an incisura biopsy in >90% of cases. Endoscopic scores for patient stratification were rarely used, while five centers improved in histological scoring or intestinal metaplasia subtyping. H. pylori treatment recommendation remained high (71%-100%), and endoscopic surveillance adherence improved in four of seven centers

Conclusion

Adherence to MAPS guidelines improved in most centers. However, gaps in virtual chromoendoscopy, targeted biopsies, and endoscopic/histopathological scoring remain, potentially affecting surveillance recommendations. This underscores the need for a more tailored approach to enhance implementation.

References

1. Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, A. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 74(3), 229–263. https://doi.org/10.3322/caac.21834
2. Anderson, L. A., Tavilla, A., Brenner, H., Luttmann, S., Navarro, C., Gavin, A. T., Holleczek, B., Johnston, B. T., Cook, M. B., Bannon, F., Sant, M., & EUROCARE-5 Working Group: (2015). Survival for oesophageal, stomach and small intestine cancers in Europe 1999-2007: Results from EUROCARE-5. European journal of cancer (Oxford, England : 1990), 51(15), 2144–2157. https://doi.org/10.1016/j.ejca.2015.07.026
3. Pimentel-Nunes, P., & Dinis-Ribeiro, M. (2015). Endoscopic Submucosal Dissection in the Treatment of Gastrointestinal Superficial Lesions: Follow the Guidelines!. GE Portuguese journal of gastroenterology, 22(5), 184–186. https://doi.org/10.1016/j.jpge.2015.08.002
4. Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T, et al. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2015;47(9):829-854. doi:10.1055/s-0034-1392882
5. Latorre G, Vargas JI, Shah SC, et al. Implementation of the updated Sydney system biopsy protocol improves the diagnostic yield of gastric preneoplastic conditions: Results from a real-world study. Gastroenterol Hepatol. 2024;47(8):793-803. doi:10.1016/j.gastrohep.2023.08.005

Introduction

Eosinophilic Esophagitis (EoE) is an immune-mediated chronic inflammatory disease characterized by eosinophilic infiltration in the esophageal epithelium. Other histopathologic features such as epithelial barrier dysfunction, immune infiltration and inflammation lead to clinical symptoms such as dysphagia, vomiting, abdominal pain and food impaction. Dupilumab, which targets IL-4Ra to inhibit IL-4 and IL-13 signaling, leads to improved esophageal symptoms, reduced intraepithelial eosinophils and normalized gene expression in EoE biopsies. However, the effect of dupilumab in reducing cell infiltration beyond eosinophils and restoring the epithelial milieu is not well characterized. We evaluated the pharmacodynamic effect of dupilumab on immune cells and markers of barrier function in EoE esophageal biopsies.

Aims & Methods

Mucosal pinch biopsies were collected from the proximal, mid and distal esophagus of adult EoE patients treated with dupilumab or placebo as part of LIBERTY EoE TREET (NCT03633617). A subset of dupilumab 300mg QW (N=19) or placebo (N=9) were analyzed, including patients who continued dupilumab through 52 weeks or switched from placebo to dupilumab after 24 weeks. Gene expression was evaluated by transcriptome sequencing. Immune cell markers were evaluated by immunostaining with digital image analyses. Esophageal regions were analyzed separately and averaged for each patient at each timepoint. Percent changes were calculated using median fold change from baseline for each treatment group.

Results

Transcriptome analyses demonstrated dupilumab treatment modulated expression of genes including those associated with fibrosis and barrier function. Expression of desmoglein 1 (DSG1), a barrier function protein downregulated in EoE, was normalized at week 24 of dupilumab treatment (32-fold increase from baseline). The transcriptomic effects were sustained through 52 weeks of dupilumab treatment. Immunostaining of biopsies from dupilumab treated EoE patients at week 24 demonstrated median reductions across all immune cell types and markers examined, including mast cells (tryptase+, 73%), T cells (CD3+, 62%), myeloid cells (CD68+, 87%), proliferating T cells (CD3+Ki67+, 83%), Th2 (CD3+GATA3+Ki67+, 90%) and non-Th2 (CD3+GATA3-Ki67+, 82%) T cell lineages, as well as Ki67 (77%), compared to non-significant changes in the patients who received placebo. Sustained suppression was observed for all markers examined in patients with EoE treated with dupilumab for 52 weeks.

Conclusion

Dupilumab restored markers of barrier function, normalized overall gene expression, and reduced immune cell infiltration in the esophageal epithelium of EoE patients through 52 weeks of treatment. While dupilumab has been shown to affect the eosinophilic infiltrate characteristic of EoE, these data further demonstrate that the effects of dupilumab in reducing inflammation and healing the esophageal epithelium in EoE extend beyond eosinophils. Further study is needed to understand the relationship between the cell changes in restoring the epithelial integrity with endoscopic and symptomatic response in EoE.

Disclosure

Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.
Annamaria B. Farrell, Julie E. Horowitz, Wei Keat Lim, Madison Stoms, Sandra Coetzee, Shane E. McCarthy, Nathalie Fiaschi, Allen Radin, Sara Hamon, Bram P. Raphael, Kerry A. Casey, Seblewongel Asrat, Jamie M. Orengo, Andrea T. Hooper, Jennifer D. Hamilton: Regeneron Pharmaceuticals Inc. – employees and shareholders
Margaret H. Collins: Arena/Pfizer, AstraZeneca, Calypso Biotech, EsoCap Biotech, GSK, Receptos/Celgene/Bristol Myers Squibb, Regeneron Pharmaceuticals Inc., Robarts Clinical Trials Inc./Alimentiv, Inc., Sanofi, Shire – advisory board/consultancy fees
Kelley A. Wolfe: Sanofi – employee, may hold stock and/or stock options in the company

Clinical Case Summary

We report the case of a 54-year-old male with harmful alcohol consumption who presented to the emergency department for hematemesis with acute anaemisation. After stabilising the patient, an urgent gastroscopy was performed and large esophageal varices with red points were found, over which elastic bands (EVBL) were placed.
Hours after the endoscopic procedure, the patient presented a new episode of hematemesis and hemodynamic instability. After resucitation, he was transferred to the care unit for a new gastroscopy. In it, four small varicose cords with constant drooling of blood and clots were observed. Given the impossibility of EVBL, the patient was fitted with a fully covered self-expanding metal stent (SEMSs), achieving clinical stability for him.
Following this procedure, an etiological study was carried out, concluding that portal cavernomatosis secondary to chronic pancreatitis was the cause of the current clinical case. Given the etiology and what happened, five days after the endoscopic procedure, endovascular treatment was performed by Interventional Radiology with complete embolisation of oesophageal varices and subsequent recanalisation of the splenoportal axis by angioplasty and placement of a vascular stent. After that, the oesophageal stent was removed without complications. Six months later, the patient underwent clinical and endoscopic follow-ups, showing a lack of esophageal varices and other data of portal hypertension.
According to the latest consensus of Baveno VII and ESGE for the management of variceal hemorrhage, SEMSs implantation is considered the safest option as a bridge therapy to a more definitive treatment of refractory variceal bleeding; allowing time for etiological investigation and appropriate patient management^1-2.

References

1. ​de Franchis R, Bosch J, Garcia-Tsao G et al. Baveno VII – Renewing consensus in portal hypertension. J Hepatol 2022; 76: 959-74 https://doi.org/10.1016/j.jhep.2021.12.022
2. ​Gralnek IM, Camus-Duboc M, García-Pagán JC et al. Endoscopic diagnosis and managemet of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2022; 54 (11): 1094-1120 https://doi.org/10.1055/a-1939-4887

Introduction

Long-term maintenance treatment efficacy, safety and tolerability in eosinophilic esophagitis (EoE) is still partially understood. The aim of this study was to evaluate long-term outcomes of maintenance treatment for EoE with various drugs and dose regimens in real-world observational studies and randomized controlled trials (RCTs).

Aims & Methods

Systematic search was performed on Pubmed-MEDLINE, Embase and Cochrane Central Register of Controlled Trials from inception to October 2023. Studies reporting histologic success of maintenance therapy for EoE patients > 48 weeks, following 8-12 weeks of induction therapy with the same drug were included. Primary outcome was pooled histologic success (defined as < 15 eosinophils/HPF) at the end of follow-up for both study designs. Risk Difference (RD) or Odds Ratio (ORs) for histological success of maintenance therapy versus placebo (PBO) (for RCTs) and versus induction (for both study designs), pooled drug-related adverse events (AEs), endoscopic and clinical success rates were assessed as secondary outcomes. Random effects model metanalyses were performed. A-priori sub-group analyses were performed to address substantial inter-study heterogeneity (measured with I² statistic).

Results

From 3,916 full articles, 23 articles matched inclusion criteria (17 observational studies and 6 RCTs), 7 with pediatric patients only. Overall, 1,923 patients (M 70.1%; mean age 29.8±12.6 years). Mean follow-up time was 78.4 weeks. Budesonide (either oro-dispersible or viscous suspension) was administered in 7 studies (including 2 RCTs), PPI in 6 studies (all observational, 4 pediatric), Fluticasone in 5 studies (including 1 RCT with 4 cohorts), Dupilumab in 2 RCTs and Cendakimab in 1 RTC. Pooled rate of long-term histologic success for RCTs was 83% (95% CI, 77%-89%; I² 73.1%), while for observational studies attested at 53% (95% CI, 42%-65%; I² 93.5%) at a median follow-up of 97.8 weeks. Maintenance therapy in RCTs showed a RD of -0.71 (95% CI; -0.92-0.50; p<0.01; I² 88.9%) versus PBO, while a RD of -0.06 (95% CI; -0.11-0.01; p<0.016; I² 23.1%) compared with induction. Observational studies showed a non-significant (p=0.38) Odds Ratio (OR) of 1.37 (95% CI, 0.66-2.85; I² 81.3%) of losing histologic success during therapy de-escalation. Pooled clinical success among RCTs attested at 61% (95% CI, 51%-75%; I² 71.3%), comparable with observational studies (60% [95% CI, 42%-77%; I² 97.3%]). Biological therapy (either Dupilumab or Cendakimab at various regimens) ranked first for pooled histologic success rate among RCTs with 79% (95% CI; 71%-87%; I² 54.9%). In observational studies, PPI with histologic success of 64% (95% CI, 50%-78%; I² 88.7%) and clinical success of 79% (95% CI; 66%-93%; I² 85.2%) ranked first. Pooled rate of AEs among RCTs attested at 34% (95% CI; 22%-45%; I² 93.2%), with a pooled candidiasis infection rate of 6% (95% CI; 2%-10%; I² 61.9%), comparable with pooled AEs among observational studies (5% [95% CI, 2%-7%; I² 66.7%]). Pooled therapy discontinuation rate was 0.14 (95% CI, 0.073-0.210, I² 94.49%) in real-world data.

Conclusion

This is the first meta-analysis on efficacy and safety of long-term maintenance treatment (median 78 weeks) for EoE. All treatments showed good efficacy in maintaining long-term histological remission without clear disadvantage in de-escalating therapy during maintenance in real-word data. Biological therapies resulted the most effective in RCTs, while PPIs in observational studies. Low adverse events rates and low therapy discontinuation rates confirm long-term treatment is well tolerated.

References

1. Nistel M, Andrews R, Furuta GT, Atkins D. Elimination Diet or Swallowed Topical Steroid Treatment of Pediatric Eosinophilic Esophagitis: Five-Year Outcomes. J Allergy Clin Immunol Pract. 2023 Aug;11(8):2516-2523.e2. doi: 10.1016/j.jaip.2023.05.036. Epub 2023 May 30. PMID: 37263351; PMCID: PMC10525024.

Disclosure

ES has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapa-gos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, Mayoly Biohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, Uni-farco; has served as consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici.
Danese has served as a speaker, consultant and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Fer-ring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor.