Introduction

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated oesophageal disease that is showing a skyrocketing increase of new diagnoses in last two decades. Although tons of papers have been published clarifying several aspects of this disease, most of the evidences come from high volume – referral centres that may be not representative of the whole EoE population. In fact, little is known about demographic and clinical features as well as treatment outcomes of patients managed in community hospitals.

Aims & Methods

Between January 2021 and June 2023, we prospectively enrolled all EoE patients evaluated for the first time at two different centres: 1) a high-volume tertiary-care centre, the University Hospital of Padua (PH), that represent a national referral centre; 2) a low-volume community hospital, the hospital of Feltre (FH), with a catchment area of about 25,000 people, both located in the North-East of Italy. The diagnosis of EoE was made according to the latest international guidelines. Endoscopic features were assessed according to EREFS score (0-8 points). Histological remission was considered for eosinophilic peak <15 eos/HPF.
The main goals of our study were to compare the cohorts of EoE patients from a community and a tertiary care centre in terms of demographic and clinical features as well as to assess differences in the rate of histological response to medical treatments.

Results

Overall, 210 patients were consecutively enrolled, 177 (84.3%) in the tertiary centre (PH) and 33 (15.7%) in the community one (FH). We did not find any significant difference between PH cohort and FH patients regarding age (34.80 vs 38.24 years, p=0.193), male prevalence (79.1% vs 72.7%, p=0.491), body mass index (22.55 vs 22.63, p=0.906), prevalence of non-atopic comorbidities (35.6% vs 21.2%, p=0.158), diagnostic delay (3.35 vs 2.62 years, p=0.682). A not significant trend in higher EREFS score values was found in PH (3.3 vs 2.7, p=0.062). There was a significant difference regarding the number of patients that were evaluated for a second opinion (77% vs 15%, p<0.001) and the prevalence of atopic comorbidities (68.9% vs 42.4%, p=0.008), both higher in PH court.
Regarding medical treatments 184 patients were treated with PPI (157, 88.7% at PH and 27, 81.8% at FH, p=0.219). There was a significant difference in the rate of PPI response comparing PH and FH patients (29.94% vs. 51.85%, p=0.044). No differences in terms of rate of responsiveness regarding swallowed flixotide puffer (44% vs 36%, p=0.295) and orodispersibile budesonide (50.9% vs 61.5%, p=0.564).

Conclusion

This study elucidated several significant aspects regarding EoE. Firstly, it revealed that EoE patients treated in peripheral hospitals may exhibit a milder phenotype, characterized by less severe endoscopic features and fewer atopic comorbidities. Conversely, more complex cases tend to be referred to specialised centres, often seeking for a second opinion. Accordingly, the rate of PPIs responsiveness was found to be higher in community hospitals and, indeed, they still hold a significant as effective therapeutic option for EoE patients. Given that most of the evidence come from high-volume referral centres, it is crucial to keep in mind these differences when assessing the wide spectrum of EoE patients. Although the need for new therapies is still a fact, the increasing prevalence of EoE also necessitates a thorough evaluation of the financial implications of these drugs.

Introduction

With the recent rise in the occurrence of esophageal adenocarcinoma (EAC) in Western nations, there is an escalating worry regarding Barrett’s esophagus (BE). In contrast, Asian countries exhibit a lower prevalence of BE compared to their Western counterparts. Given the annual increase in chronic gastroesophageal reflux disease (GERD) cases, there is an expectation of a concurrent rise in the prevalence of BE. Consequently, we are embarking on a multicenter prospective study to assess the current prevalence of BE and pinpoint its risk factors in Taiwan.

Aims & Methods

Aim: to evaluate current prevalence and risk factors of Barrett's esophagus in Taiwan.
Methods: We carried out a prospective multicenter study involving consecutive outpatients who underwent upper gastrointestinal endoscopy for various upper gastrointestinal symptoms. Biopsies were taken from endoscopically suspected esophageal metaplasia (ESEM), clearly visible at least 1 cm above the gastroesophageal junction during endoscopy. The biopsy procedure involved obtaining standardized random samples, with four pieces taken every 2 cm from the four quarters of the esophagus exhibiting the ESEM lesion. BE was defined based on the histological confirmation of specialized intestinal metaplasia in the metaplastic esophageal epithelium.

Results

A total of 8925 subjects were enrolled in this study. The prevalence of BE was 2.6%. A total of 228 subjects with BE were detected among 751 ESEM subjects. Short segment BE (78.1 % , n = 178) was more prevalent than long segment BE (22.9 % , n = 50). The prevalence of GERD symptoms, erosive esophagitis (EE), and hiatal hernia (HH) was 52.5%, 27.3% and 7.85%, respectively. Multivariate analysis disclosed that old age [odds ratio (OR) = 1.59; 95% CI, 1.20-2.11; P <0.01], male gender (OR = 2.27; 95%CI, 1.65-3.11; P < 0.01),alcohol consumption (OR = 1.70, 95%CI, 1.19-2.44; P< 0.01), GERD symptoms (OR = 1.45, 95%CI, 1.10-1.92; P< 0.01), EE (OR = 1.94, 95%CI, 1.47-2.56; P< 0.01) and presence of hiatal hernia (OR = 2.49; 95%CI, 1.78-3.47; P < 0.001) were significant risk factors predicting BE.
Risk factors for Barrett esophagus: multivariable analysis.

Conclusion

The prevalence of BE was identified as 2.6%. Notably, advanced age (>50), male gender, alcohol consumption, symptoms of gastroesophageal reflux disease (GERD), erosive esophagitis, and the presence of hiatal hernia emerged as independently significant risk factors for Barrett's esophagus.

References

1. Sharma P. Barrett Esophagus: A Review. Jama. 2022;328(7):663-71.
2. Marques de Sá I, et al. The global prevalence of Barrett's esophagus: A systematic review of the published literature. United European Gastroenterol J. 2020;8(9):1086-105.
3. Chang CY, et al. Current status of Barrett's esophagus research in Asia. J Gastroenterol Hepatol. 2011;26(2):240-6.
4. Shiota S, et al. Prevalence of Barrett's Esophagus in Asian Countries: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2015;13(11):1907-18.
5. Chang CY, et al. The application of Prague C and M criteria in the diagnosis of Barrett's esophagus in an ethnic Chinese population. Am J Gastroenterol. 2009;104(1):13-20.
6. Fock KM, et al. Asia-Pacific consensus on the management of gastro-oesophageal reflux disease: an update focusing on refractory reflux disease and Barrett's oesophagus. Gut. 2016;65(9):1402-15.
7. Eusebi LH, et al. Global prevalence of Barrett's oesophagus and oesophageal cancer in individuals with gastro-oesophageal reflux: a systematic review and meta-analysis. Gut. 2021;70(3):456-63.
8. Akiyama T, et al. Alcohol consumption is associated with an increased risk of erosive esophagitis and Barrett's epithelium in Japanese men. BMC Gastroenterol. 2008;8:58.
9. Andrici J,et al. Hiatal hernia and the risk of Barrett's esophagus. J Gastroenterol Hepatol. 2013;28(3):415-31.

Introduction

Persulfidation of proteins (PSSH) appears functionally significant, e.g. in aging, preventing cellular oxidation, but its role in GI diseases remains clinically elusive. This posttranslational proteins modification relies on endogenous hydrogen sulfide (H₂S) signaling. GERD induces oxidation in esophageal squamous cells. However, the contribution of persulfidation and H₂S bioavailability in etiology, diagnosis or treatment of Barrett’s esophagus (BE) is unknown. We hypothesized that GERD-induced pathway-specific PSSH impairments underlie BE pathogenesis. We explored whether restoration/depletion of esophageal H₂S impacts persulfidation-sensitive, BE-associated targets and BE development.

Aims & Methods

We clinically performed a wide-scale analysis of persulfidated proteins (normalized to total proteins levels) in three-sets of endoscopic biopsies representing BE or squamous segments +/- GERD (n=4-5 each), using the recent chemoproteomic method. We used the microsurgical rat model of GERD/BE (esophago-gastroduodenal anastomosis) +/- i.g. pharmacological treatments to up-/downregulate esophageal H₂S levels over 10 weeks. In parallel, we employed in vitro model of chronic GERD +/- H₂S donors using human esophageal squamous cell lines with (NES-G2T) or without (EPC2) clinical GERD and a Barrett’s cells (BAR-T). CRISPR-Cas9 was used to knockout H2S-producing enzymes.

Results

Global persulfidation level (reflecting H₂S bioavailability) was decreased in clinical BE vs GERD-exposed squamous biopsies. GERD induced statistically significant pathway-specific PSSH changes of ≈90 proteins in squamous segments compared to patients w/o GERD. These persulfidomic alterations further increased in BE where >900 targets were deregulated. IL-1b, prostaglandin (PG)E2 pathways or mTOR-associated proteins, but not exclusively, showed persulfidation shift (e.g. PSSH fall of IL-1b-receptor antagonist (IL-1RA)). H2S-decrease was noted in vitro or in vivo after long-term GERD in rats with chronic esophageal lesions and in human squamous, but not BAR-T cells. In cells and/or rats, treatment with NaSH or GYY4137 to restore H2S induced IL-1RA and inhibited IL-1b/PGE2/mTOR signaling, RNA oxidation, limiting molecular or morphological BE development. H₂S-enzymes inactivation promoted BE-related events in both models.

Conclusion

BE is preceded by GERD-induced, pathway-specific persulfidation shifts, initiated early in squamous epithelium and enhanced in metaplasia. Decreased but stable biosynthesis of H2S reflects the adaptative resistance of the metaplastic cells to GERD. Restored H2S signaling counteracts BE development by interfering in oxidative balance and BE-associated IL-1β, PGE2 and mTOR pathways activation. These findings suggest that BE is a mechanistic outcome of reduced esophageal H₂S caused by GERD. [Funding: National Science Centre (Poland): 2016/23/D/NZ4/01913, 2019/33/B/NZ4/00616, 2023/07/X/NZ4/01052]

Introduction

Distinguishing T1a and T1b oesophageal adenocarcinoma is imperative under current treatment paradigms. Piecemeal EMR is suggested to be acceptable for T1a oesophageal adenocarcinoma whereas enbloc R0 excision is required for in T1b disease, offering a potential cure and mitigate recurrence. Thus, we sought to ascertain whether internationally renowned expert Barrett’s endoscopists were able to make this distinction based on optical evaluation.

Aims & Methods

A set of 60 endoscopic images of histologically confirmed high grade dysplasia (HGD), T1a and T1b disease (n=20 for each) were compiled from consecutive patients at a single institution. Each set contained four images, and were standardized to include an overview, a close-up in high-definition white light, a near-focus magnification image, and a narrow-band image. Experts were blind to histology and invited to predict it for each set of images – HGD vs T1a vs T1b.

Results

19 experts from 8 countries (Australia, USA, Italy, Netherlands, Germany, Canada, Belgium, and Portugal) participated. The majority have been practicing for >20 years, with a median annual case volume for Barrett’s EMR of 50 (IQR 18-75), and Barrett’s ESD of 25 (IQR 10-45). Oesophageal adenocarcinoma (T1a/b) could be distinguished from HGD, with a pooled sensitivity of 89.1% (95% CI: 86.7-91.2). When predicting the T-stage for T1b adenocarcinoma cases, the pooled sensitivity was 43.8% (95% CI: 38.5-49.2). Fleiss’ kappa was 0.421 (95% CI: 0.399-0.442, P<0.001).

Conclusion

Expert Barrett’s endoscopists can reliably differentiate T1a/T1b oesophageal adenocarcinoma from HGD. Although there is fair-to-moderate agreement for T-staging, T1a disease cannot be reliably distinguished from T1b disease. This may have implications on clinical decision making and selection of endoscopic treatment methods.

Disclosure

Michael J. Bourke: Research Support: Olympus, Cook Medical, Boston Scientific.

Introduction

Lifestyle factors are significant contributors to fatigue, which affects approximately 45% of patients with Inflammatory Bowel Disease (IBD) in remission.

Aims & Methods

In this study, we evaluated the effect of a digital multimodal lifestyle intervention on fatigue in patients with IBD. Patients with IBD in biochemical remission (fecal calprotectin <150 mg/kg) were enrolled in a multicenter, non-randomized, controlled interventional study. The intervention group participated in a 12-month lifestyle program—provided by the non-profit organization Voeding Leeft—that included digital group meetings with a nutritionist and a lifestyle coach focusing on gradual and sustainable behavior change regarding nutrition, physical activity, sleep, and stress management. In addition, the program encouraged patients to exercise more self-control over their personal health. Following the initial six months, attendance at online sessions was not mandatory; however, patients could attend online sessions every six to 12 weeks to stay motivated and foster the lifestyle habits they acquired throughout the course. Patients in the control group received standard care that included an informational leaflet about the potential causes of fatigue in IBD, the leaflet also included basic lifestyle information and advice to exercise more, eat a healthier diet, stop smoking, reduce alcohol intake, improve sleeping habits, and manage stress. The allocation to a study group was determined by the availability within the group and participant’s ability to attend the scheduled intervention. Clinical data and patient-reported outcomes were collected. Fatigue was measured with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); any increase in FACIT-F after six months was considered a positive response to the intervention. The Minimal Clinically Important Difference (MCID) for fatigue was at least a four-point increase in the FACIT-F score¹. Inverse probability treatment weighting was used to correct confounding by indication.

Results

Thirty-six patients in the intervention group and 32 in the control group were compared. After six months, more patients in the intervention group (82.1% of patients) than in the control group (54.2% of patients) experienced improvement in fatigue, P = 0.029. Likewise, significantly more patients in the intervention group (71.4% of patients) than the control group (33.3% of patients) achieved a MCID regarding fatigue; P = 0.006. The improvements in fatigue were sustained throughout the study period in the intervention group. Acceptance of the health status was a significant factor for improvement in fatigue (β 7.813, SE 1.908, P < 0.001). Compared to the control group, quality of life improved in the intervention group; these patients gained 0.05 more quality-adjusted life years throughout the study. Last but not least, significant improvements in dietary quality were observed as early as three months after the baseline in the intervention but not the control group; these improvements in the intervention group were sustained throughout the study period.

Conclusion

Multimodal lifestyle intervention improves fatigue, quality of life, and dietary quality in patients with IBD who are in remission. Acceptance of the health status appears essential for fatigue improvement; instruments evaluating acceptance could help to personalize treatment and maximize its effectiveness.

References

1. Cella D, Yount S, Sorensen M, et al. Validation of the Functional Assessment of Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol 2005;32:811-9.

Disclosure

AEvdMdJ received unrestricted research grants from Galapagos, Norgine, Vedanta, Nestle, including speaker’s fees from Galapagos, Tramedico, Takeda, Ferring, and Janssen Pharmaceuticals. PWV has received speaker fee from Galapagos and Takeda and served on the advisory board of Lilly, Galapagos, Janssen, BMS, Takeda, and Abbvie. RL has received travel expenses from Galapagos and Cablon Medical and served on the advisory board at Cablon Medical. NW and MJHB are employed by the non-profit organization Voeding Leeft and were a part of the team that guided participants in the intervention group. All other authors have no conflicts of interest to declare.

Introduction

Pancreatic Cancer (PC), a highly lethal malignancy of the digestive system, is associated with a poor prognosis, as evidenced by a less than 7% 5-year survival rate ^[1]. Projections suggest that by 2030, PC will rank as the second leading cause of cancer-related deaths ^[2-3]. A crucial aspect of the progression of pancreatic cancer involves its crosstalk with endothelial cells (ECs), particularly in the regulation of vascular homeostasis ^[4]. Numerous studies have demonstrated the significant involvement of Vascular Endothelial Growth Factor (VEGF) in the process of ECs functional remodeling ^[5-6]. Activation of the PI3K/AKT signaling pathway has been shown to enhance VEGF-mediated vascular formation, thereby contributing to the normal development and repair of the vascular system ^[7-8]. Considering the aberrant vascular features observed in tumors, targeting specific pathways to revert immature and unstable vessels to a normal vasculature state appears to be a promising therapeutic strategy for the treatment of the disease. Previous studies have indicated that the combination of Formononetin and Salvianolic acid B (FcS) significantly inhibits pancreatic xenograft tumors in vitro. However, it remains unclear whether this combination can inhibit the abnormal vascularization of pancreatic tumors to achieve its anti-cancer effect.

Aims & Methods

This study aimed to investigate the efficacy of FcS in modulating the effects of pancreatic cancer on endothelial cells, explore the alterations in molecular mechanisms within these cells, and elucidate the intricate molecular mechanisms underlying this interaction.
To elucidate the interaction between endothelial cells and pancreatic cancer cells, a co-culture system using Human Umbilical Vein Endothelial Cells (HUVECs) and PANC-1 cells was established to investigate the potential of targeting abnormal vasculature as a promising avenue for anti-tumor therapy. The proliferation, migration, invasion, and lumen formation of HUVEC were compared in mono-culture (HUVECs) and co-culture with PANC-1 (H-P), followed by treatment of H-P with FcS to assess its anti-angiogenic properties. Then, molecular docking was utilized to predict the interactions between Formononetin and Salvianolic acid B with RhoA, and the expression of RhoA in HUVECs post-FcS treatment was assessed. Furthermore, the role of RhoA in the effects of FcS on HUVECs was explored using shRhoA lentivirus. In vivo investigations were conducted using a zebrafish xenograft tumor model to assess the anti-tumor effects of FcS, focusing on cancer cell proliferation, migration, apoptosis, and vascular sprouting.

Results

The treatment with FcS showed a dose-dependent inhibition of PANC-1-induced alterations in HUVECs, including proliferation, migration, invasion, and tube formation. Molecular docking analysis indicated potential interactions between FcS and RhoA. FcS downregulated the expression of RhoA and modulated the PI3K/AKT pathway in PANC-1-induced HUVECs. Furthermore, the inhibitory effects of FcS on HUVEC phenotypic changes were attenuated by RhoA knockdown. In vivo experiments using a zebrafish xenograft model demonstrated the anti-tumor effects of FcS, including the inhibition of proliferation, metastasis, and vascular sprouting, and promotion of tumor cell apoptosis.

Conclusion

This study illuminates the potential of FcS in inhibiting pancreatic cancer-induced changes in endothelial cells. FcS exhibits pronounced anti-abnormal vasculature effects, potentially achieved by downregulating RhoA expression, inhibiting the PI3K/Akt signaling pathway.

References

1. Siegel, R. L., Giaquinto, A. N., Jemal, A., 2024. Cancer statistics, 2024. CA Cancer J Clin. Jan-Feb. 74, 12-49.
2. The Lancet Gastroenterology Hepatology, 2023. Cause for concern: the rising incidence of early-onset pancreatic cancer. Lancet Gastroenterol Hepatol. Apr. 8, 287.
3. Neoptolemos, J. P., Kleeff, J., Michl, P., Costello, E., Greenhalf, W., Palmer, D. H., 2018. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol. Jun. 15, 333-348.
4. Kishimoto, T., Saito, K., Ishikura, H., 1995. Mechanism of blood-borne metastasis in relation to the interaction between pancreatic carcinoma and endothelial cells. Nihon Rinsho. Jul. 53, 1765-9.
5. Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., Jain, R.K., 2011. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. Jul. 91, 1071-121.
6. Jain, R.K., 2001. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. Sep. 7, 987-9.
7. Brazil, D. P., Hemmings, B. A., 2001. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci. Nov. 26, 657-64.
8. Sarbassov, D. D., Guertin, D. A., Ali, S. M., Sabatini, D. M., 2005. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. Feb. 18, 1098-101.

Introduction

Acute pancreatitis (AP) often has unpredictable and complicated clinical course. Numerous biochemical predictors may aid in the risk stratification of AP (including interleukin 6 (IL-6)), but none of them are accurate. YKL-40 is glycoprotein playing mayor role in inflammation and angiogenesis, with reported average serum concentrations of ≥ 190 ng/mL in inflammatory diseases. It has been shown that IL-6 stimulates the production of YKL-40 and, in reverse, YKL-40 (at least in some tissues) induces the production of IL-6.

Aims & Methods

The aim of our study is to assess whether combined concentrations of both YKL-40 and IL-6 could be more informative in risk stratification of developing more severe form of AP than concentrations of either biomarker alone.
We included 150 consecutive consenting adults with AP admitted to Sestre milosrdnice UHC, Zagreb (June 2020-June 2023). Patients with any acute/chronic diseases known to be associated with dysregulated expression of YKL-40 were excluded. Alongside routine laboratory studies (including C-reactive protein (CRP)), 7 mLs of blood were withdrawn for determining YKL-40 and IL-6 concentrations on admission and 48h after. Severity of disease was defined using revised Atlanta classification. Blood samples for YKL-40 and IL-6 quantification in 30 consenting non-AP adults consistent with previously mentioned exclusion criteria were withdrawn. They were matched 1:1 by age and sex to randomly selected 10 patients from each of AP severity categories. Analysis were performed using enzyme-linked immunosorbent assays. AP patients were classified into 2 categories for each biomarker (based on YKL-40 and IL-6 concentrations on admission and 48h after): 1. for YKL-40: low (<190 ng/mL) and high (≥190 ng/mL); 2. for IL-6: low (<42 pg/mL) and high (≥42 pg/mL). Cumulative multimodal logit models were fitted to ordinal outcome “AP severity” – using raw data, and data after entropy balancing undertaken to balance the two categories of YKL-40 and IL-6 concentrations on age, sex, time between symptom onset and admission, and CRP concentrations.

Results

The results showed lower YKL-40 (<50 ng/mL) and IL-6 (<20 pg/mL) concentrations in 30 non-AP adults compared to AP patients. At both time points (on admission and 48h after), odds of more severe AP were clearly higher with YKL-40 and IL-6 concentrations above vs. below the cut-off values (190 ng/mL and 42 pg/mL, respectively), and were particulary higher in patients with both cytokines above the cut-off vs. patients with both cytokines below the cut-off. The same relationship was maintained with adjustments for age, body mass index, days elapsed since symptom onset and admission, and for CRP concentrations – however, the strength of association was lower. This is in line with the fact that high CRP concentration predicts more strongly severe AP forms when taken 48h after compared to admission. This phenomenon was apparent also when the interaction term was included in the model: at CRP concentrations 45 mg/L, neither YKL-40, or IL-6 or their combination above the cut-off values were associated with the outcome; at CRP concentrations 90 mg/L, odds were higher, and were particularly high for a combination of high YKL-40 and high IL-6. The same was observed at CRP concentrations 180 mg/L.

Conclusion

Overall, data suggest that combined YKL-40 and IL-6 concentrations in acute AP, taken either on admission or 48h after, predict more strongly moderate and/or severe (vs. mild) AP than either cytokine alone, and do so 'on-top' of the CRP concentrations.

References

1. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG et al. Classification of acute pancreatitis - 2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102–111.
2. van den Berg FF, de Bruijn AC, van Santvoort HC, Issa Y, Boermeester MA. Early laboratory biomarkers for severity in acute pancreatitis; A systematic review and meta-analysis. Pancreatology. 2020;20(7):1302-1311.
3. Tizaoui K, Yang JW, Lee KH, Kim JH, Kim M, Yoon S et al. The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review. Int J Biol Sci. 2022;18(9):3731-3746. doi: 10.7150/ijbs.67587.
4. Blazevic N, Rogic D, Pelajic S, Miler M, Glavcic G, Ratkajec V et al. YKL-40 as a biomarker in various inflammatory diseases: A review. Biochem Med. 2023;34(1):010502.