Introduction

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory disease that affects the esophagus. In Chile and Latin America, its epidemiology is unknown.

Aims & Methods

The aim of this study is to describe the clinical, endoscopic, and histological characteristics of adult patients diagnosed with EoE. Prospective cohort of patients seen at the Digestive Diseases Center, diagnosed with eosinophilic esophagitis and undergoing one follow-up endoscopy. Endoscopic classification was performed using the Eosinophilic Esophagitis Endoscopic Reference Score (EEERS), and histological response was defined as fewer than 15 eosinophils (Eos) per high-power field. Descriptive statistics (median and interquartile range) were used for sample characterization, considering the non-normal distribution of the sample evaluated by the Kolmogorov-Smirnov test. The Chi-square test was used for the analysis of nominal (categorical) or ordinal data. The Wilcoxon test was used for the comparison of histological and endoscopic results, while the Mann-Whitney U test was used for the analysis of medical treatment. Statistical software SPSS® v.29 and GraphPad Prism 8.3.0 were used. Values of p < 0.05 were considered statistically significant.

Results

Eighty-five patients aged between 17 and 77 years old (Median=36 years) were included, with 75.3% being male. The median age at symptom onset was 31 years and at diagnosis was 34 years. The most frequent reason for consultation was dysphagia (54%), and the most common concomitant immune-allergic diseases were allergic rhinitis (38%) and asthma (29%). Women had more frequent autoimmune comorbidity, peripheral eosinophilia, and food allergies but had a lower eosinophil count and endoscopic score. Regarding treatment, 55% were on PPI therapy and 40% on mixed treatment. In terms of clinical outcomes, patients at admission had a median score of 4 for EREFS and 30 eosinophils/field on biopsy eosinophil count. At follow-up, a significant decrease was observed in both endoscopic and histological (biopsy) parameters (p < 0.001), with medians of 0 for each indicator, respectively. Moreover, regarding the influence of treatment type (PPI or mixed) on endoscopic or histological response, it was observed that both treatments are equally effective: patients on PPI therapy showed a 72% histological improvement and an 89% endoscopic response, while patients on mixed treatment showed a 77% and 85% improvement, respectively (p=ns).

Conclusion

This is the first patient cohort in Latin America to our knowledge with EoE. Characteristics are similar to those described in international groups. Women exhibited more frecuent autoimmune comorbidity, peripheral eosinophilia, and food allergies but had a lower eosinophil count and endoscopic score. We did not observe differences among the various therapeutic regimens.

Disclosure

None

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

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

With the advent of EUS guided biliary interventions, there is a lot of hype created that ERCP will cease to be performed. The most important and limiting factor for ERCP is successful bile duct cannulation. We have studied a large series of our cases and tried to study the impact of properly performed precut on success of bile duct cannulation.

Aims & Methods

Aim: To analyze the efficacy of freehand precut for selective cannulation in difficult ERCP and its role in improving technical success rate, obviating need for EUS guided / other rendezvous techniques.
Methods: Retrospective analysis of 3000 patients undergoing ERCP from 2017 till date for varied etiologies. No. of patients required precut accessotomy were noted and technical success rate was measured.

Results

No. of patients analyzed- 3000. Selective biliary cannulation- 2452 (81.74%). Difficult cannulations requiring freehand precut accessotomy- 548 (18.26%). Technical success after precut achieving biliary access- 539 (98.36%). Failure of biliary cannulation even after precut- 09 (1.64%). Most common etiology in precut casesstone disease 360 (65.70%) followed by malignant lesions 118 (21.53%), benign strictures 28 (5.11%), post cholecystectomy biliary leak 28 (5.11%), post traumatic biliary leak 10 (1.82%), post hydatid surgery biliary leak 02 (0.36%), post central hepatectomy biliary leak 02 (0.36%). Most common cause for failure in precut cases was extensive edema and deformed anatomy. Of all failed cases 3 were large stones who were subjected to surgery and 6 were malignant lesions who were subjected to EUS guided biliary drainage.

Conclusion

Free hand precut technique, done correctly, is a savior in difficult cannulation cases and it increases the success rate of selective biliary cannulation significantly avoiding the need for other costlier techniques such as EUS guided / Rendezvous techniques.

References

Mariani A, Di Leo M, Giardullo N, Giussani A, Marini M, Buffoli F, Cipolletta L, Radaelli F, Ravelli P, Lombardi G, D'Onofrio V, Macchiarelli R,
Iiritano E, Le Grazie M, Pantaleo G, Testoni PA. Early precut sphincterotomy for difficult biliary access to reduce post-ERCP pancreatitis: a randomized trial. Endoscopy. 2016 Jun;48(6):530-5. doi: 10.1055/s-0042-102250. Epub 2016 Mar 18. PMID: 26990509.
Davee T, Garcia JA, Baron TH. Precut sphincterotomy for selective biliary duct cannulation during endoscopic retrograde cholangiopancreatography. Ann Gastroenterol. 2012;25(4):291-302. ​PMID: 24714256; PMCID: PMC3959408.

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.

Introduction

Esophageal squamous cell carcinoma (ESCC) is the most common histological type of esophageal cancer in eastern Asia and Africa. Diagnosis at early stage is crucial to reduce the mortality of ESCC. Currently, esophagogastroduodenoscopy (EGD) is the golden standard for screening ESCC, however, the patient compliance rate has been low due to the invasiveness and high cost of EGD. Thus, there is an unmet need for the development of diagnostic modality that enables non-invasive early detection of ESCC.

Aims & Methods

The purpose of this study is to construct a urinary exosomal miRNA panel as a least invasive test that can detect ESCC with high accuracy and validate its performance in a prospective cohort enriched with early ESCC. We prospectively collected urine samples from 161 ESCC patients and 180 healthy controls (HC) at five institutions from September 2019 to March 2023. Exosomes were extracted from urine specimens by polymer precipitation method, and exosomal miRNAs were subjected for comprehensive expression analysis by small RNA seq. Of the 341 total samples, 309 samples (90.6%) that passed the QC check were selected for subsequent data-analysis. In the training cohort (100 samples of ESCC and 98 samples of HC), we measured the expression of 328 miRNAs to identify candidate biomarker miRNAs. A miRNA diagnostic panel was constructed using machine learning analysis, and diagnostic performance was evaluated using a 5-fold cross-validation method. In the validation cohort (50 samples of ESCC and 61 samples of HC), the diagnostic performance of the urinary miRNA diagnostic panel was verified with blind to clinical information.

Results

In the RNAseq analysis of the training cohort (ESCC; mean age 68.2 years, 77.9% male; HC; mean age 58.1 years, 76.3% male), 33 out of 328 miRNAs were differentially expressed between ESCC and HC. Out of the 33 dysregulated miRNAs, 21 were upregulated and 12 were down-regulated. A multi-miRNA biomarker panel composed of miRNAs that were individually significant and non-significant between ESCC and HC had a diagnostic performance of AUC 0.89 (95% CI 0.84 to 0.94) by 5-fold cross-validation. In the validation cohort (ESCC; mean age 63.0 years, 78.0% male, median size 32mm, Stage I/II/III/IV 54/10/26/10%, HC; mean age 51.0 years, 52.5% male), The diagnostic performance of the miRNA diagnostic panel was AUC 0.85(95% CI 0.80 to 0.90), with a sensitivity of 84%, specificity of 73.8%, and accuracy of 78.4% at a pre-defined cutoff value. There was no confounding of diagnostic performance by age, gender, BMI, history of alcohol consumption or smoking. The sensitivity by clinical stage of ESCC was 88.9/80.0/77.8/80% for Stage I/II/III/IV.

Conclusion

We developed and validated a urinary exosomal miRNA diagnostic panel, which may be a new non-invasive diagnostic method that contributes to the early detection of ESCC.

Disclosure

Tomonori Yano received research funding from Craif Inc.

Introduction

Colorectal cancer, with an estimated two million new cases each year worldwide, poses a significant socioeconomic burden on modern society. It is the second leading cause of cancer-related deaths, accounting for nearly one million premature deaths annually.

Aims & Methods

The role of Signal Transducer and Activator of Transcription 2 (STAT2) in this context is not yet understood, and no therapies targeting this transcription factor are currently being pursued. We explored the function of STAT2 in colorectal cancer by employing experimental mouse models, as well as conducting functional assays with three-dimensional tumoroids in the context of anticancer therapy.

Results

In vivo studies showed that Stat2KO mice were more resistant to developing tumors in both inflammation-driven and inflammation-independent models of experimental colorectal cancer. This unexpected outcome could not be reconciled with the known role of STAT2 in inducing cell death downstream of type I interferon signaling. We consequently performed ex vivo experiments with tumoroids derived from Stat2KO mice carrying the multiple intestinal neoplasia (Min) mutant allele of the adenomatous polyposis coli (Apc) gene. These tumoroids exhibited slower growth, were generally smaller in size, and showed a higher degree of differentiation compared to those derived from ApcMin/+ wildtype mice. Remarkably, when treated with anti-tumor agents that induce cell death through various mechanisms, tumoroids derived from ApcMin/+ Stat2KO mice were found to be highly sensitive. Additional functional studies indicated that the underlying mechanism might involve a STAT2-dependent disruption of innate immune DNA sensing.

Conclusion

Our results establish STAT2 as a promoter of colorectal cancer and a contributor to resistance against anti-tumor therapy. These findings suggest that targeting STAT2-dependent signaling could be a promising therapeutic strategy for patients with colorectal cancer.