Introduction

Colorectal cancer (CRC) is the 3rd most common cancer worldwide. Approximately 85% of CRC develop on a background of Wnt/β-catenin signalling impairment. Familial adenomatous polyposis (FAP), caused by inherited APC gene mutations (part of the β-catenin destruction complex), is characterized by the development of hundreds to thousands adenomatous polyps. FAP patients have up to 100% risk of developing CRC during their lifetime. The Wnt/β-catenin together with the PI3K/mTOR signalling control the self-renewal and homeostasis of intestinal stem cells and are frequently deregulated in CRC therefore representing attractive targets for chemoprevention and treatment [1], [2]. It has been shown that each pathway may be deregulated by an altered composition of the gut microbiota [3], [4], which plays an important role in the onset, development and progression of CRC thus representing potential target for prevention and potentially biomarkers for the early detection of deranged Wnt/β-catenin-driven lesions [5].

Aims & Methods

The aim of the study was to identify potential targets for the prevention and early detection of CRC in the setting of Wnt/β-catenin disruption.
Transcriptional and translational levels of Wnt/β-catenin and PI3K/mTOR pathways were evaluated by RT-qPCR and immunohistochemical analysis, respectively, in FAP adenomas (n=17 patients) and in sporadic CRC tissues (tumor stages I-III; n=15 patients). In FAP adenomas germline and somatic APC mutations were confirmed by Sanger and Targeted Next Generation Sequencing. The composition of oral, fecal and mucosal-associated microbiota was sequenced by the bacterial 16S rRNA gene. Non-diseased Faecal Immunochemical Testing positive subjects (FIT+; n=17) were included as control group.

Results

We found increased expressions of AXIN2 and cMYC, downstream targets of Wnt/β-catenin, in FAP adenomas. The activation status of PI3K/mTOR was confirmed by an increase of RPS6 gene and pS6R protein expression, indicating that germline and somatic APC mutations of FAP adenomas induce an activation of both pathways. On the other hand, compared to FAP adenomas, a higher expression of AXIN2, cMYC and cytosolic and nuclear β-catenin was found in CRC, while no changes were detected in pS6R, suggesting that the hyperactivation of Wnt/β-catenin in sporadic CRC contributes to the impairment of mTOR signalling. Importantly, we analyzed the microbiome composition in FAP and CRC settings. The oral microbiota of FAP was significantly enriched of Proteobacteria (p<0.01), which decreased in FAP adenomatous mucosal samples compared to FIT+ and CRC. In contrast, Firmicutes showed an opposite trend in FAP patients, with a decrease in the oral composition (p<0.01) and an increase in the adenomatous mucosa (p<0.05). Interestingly, a significant decrease of the CRC-protective phylum Actinobacteria was found in oral and adenomas microbiota of FAP patients compared to FIT+. In contrast, CRC fecal microbiota was enriched of Proteobacteria and a higher abundance of the well-known cancer associated families Fusobacteriaceae, Clostridiaceae and Gemellaceae was found in CRC mucosal samples compared to FIT+.

Conclusion

These findings reveal new insights into the role of Wnt/β-catenin and PI3K/mTOR pathways in influencing the homeostasis of precancerous CRC lesions. Moreover, by defining different microbial signatures in FAP patients, these results will contribute to the enhancement of non-invasive screening tools for the early detection of WNT signalling-driven colorectal cancers.

References

[1] X. Cheng, X. Xu, D. Chen, F. Zhao, and W. Wang, “Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer,” Biomed. Pharmacother., vol. 110, pp. 473–481, 2019, doi: https://doi.org/10.1016/j.biopha.2018.11.082.
[2] J. Zhang, T. M. Roberts, and R. A. Shivdasani, “Targeting PI3K Signaling as a Therapeutic Approach for Colorectal Cancer,” Gastroenterology, vol. 141, no. 1, pp. 50–61, 2011, doi: https://doi.org/10.1053/j.gastro.2011.05.010.
[3] M. H. Noureldein and A. A. Eid, “Gut microbiota and mTOR signaling: Insight on a new pathophysiological interaction,” Microb. Pathog., vol. 118, no. March 2018, pp. 98–104, 2018, doi: 10.1016/j.micpath.2018.03.021.
[4] O. Silva-García, J. J. Valdez-Alarcón, and V. M. Baizabal-Aguirre, “Wnt/β-catenin signaling as a molecular target by pathogenic bacteria,” Front. Immunol., vol. 10, no. SEP, pp. 1–14, 2019, doi: 10.3389/fimmu.2019.02135.
[5] J. H. Kim, Y. J. Kim, G. M. Oh, W. Jung, and S. J. Park, “How is gut microbiome of patients with familial adenomatous polyposis different from healthy people?,” Medicine (Baltimore)., vol. 101, no. 49, p. e32194, Dec. 2022, doi: 10.1097/MD.0000000000032194.

Introduction

Endoscopic submucosal dissection (ESD) is one of the effective treatments for superficial non-ampullary duodenal epithelial tumors (SNADETs). To avoid postoperative perforation and bleeding, our hospital had introduced D-LECS with ESD for SNADETs. From 2021, D-LECS was divided into D-LECS with FTR, which is a full-thickness resection, and D-LECS with ESD, which is intended for post-ESD reinforcement (1). D-LECS with ESD is considered to be a therapeutic procedure that not only ensures safety but also contributes to the improvement of endoscopic skills.

Aims & Methods

The aim of this study is to evaluate the impact of D-LECS with ESD on the skill development of endoscopists. The subjects were 17 cases in which D-LECS was performed among 79cases diagnosed with SNADA by biopsy at our hospital between January 2000 and October 2023. 5 cases in which D-LECS with ESD was performed. The ESD assessment score was defined using a ladder chart based on muscle layer exposure, perforation, ESD time, and pathological examination results. The scoring for points each item is as follows. (Exposure of muscle layer none: 0, <3mm: 1pt, 3~10mm: 2pt, 10mm<: 3pt, Perforation of the muscle none: 0, <3mm: 1pt, 3~10mm: 5pt, 10mm<: 10pt, ESD time <60min.: 0pt, 60~120min.: 5pt, 120min.<: 10pt, Pathological examination result pR0: 0pt, cR0+pRX: 5pt, pR1:10pt) Images and videos were used in combination to evaluate the muscle layer.

Results

ESD assessment scores of cases undergoing D-LECS with ESD were presented. The state of exposure of the muscle layer had a median of 5 (1-7), a mean of 4.8, and a standard deviation (SD) of 2.3. The state of perforation of the muscle layer had a median of 0 (0-10), a mean of 2.6, and a SD of 4.3. The median ESD time was 170 minutes, the mean was 146 minutes (41-198). The state of pathological examination had a median of 0 (0-10), a mean of 2.0, and a SD of 4.5. The ESD assessment scores are presented as follows: (Exposure of muscle layer, Perforation of muscles layer, ESD, Pathological examination result). The results of each score are as shown on the right, Case1: (7, 0,10, 0), Case2: (5,10, 10, 0), Case3: (5, 0, 10, 0), Case4: (6, 3, 10, 10), Case5: (1, 0, 1, 0). Although the number of cases was small, the time required for ESD was shortened and the degree of perforation tended to improve with experience. 2 examples revealed some important points. Case 1: This case had many blood vessels, and the ST hood was needed because it is difficult to perform ESD. When the endoscope was extended, perforation occurred. Once the perforation was made, it was difficult to move the patient to other bed, so the muscle layer was sutured with OTSC, and a PGA sheet. Case 2: The endoscopic strategy and device were improved, and the lesion could be dissected within 1 hour. ESD was performed with Dual Knife J 1.5. Pulling the lesion with an S-O clip. The RDI function was used during hemostasis to avoid the burn effect on the muscle layer.

Conclusion

D-LECS with ESD will lead to improvements of duodenal ESD techniques. But to ensure safety, laparoscopic closure is preferable until reliable suturing via endoscope becomes possible.

References

(1) Souya Nunobe, Motonari Ri, Naoki Hiki et al: Safety and Feasibility of laparoscopic and endoscopic cooperative surgery for duodenal neoplasm: a retrospective multicenter study. Endoscopy 53: 1065-1068, 2021

Introduction

Upper gastrointestinal bleeding (UGIB) poses a significant threat in patients presenting to the emergency department, particularly in those with associated hemodynamic instability. Despite major advancements in medical and endoscopic therapeutic options, mortality rates have not shown a substantial decline over the years. This study aimed to assess clinical practice patterns in order to gain a clearer understanding of the pre-endoscopic assessment for patients with acute UGIB.

Aims & Methods

This study was an international online survey based on a prospective two-phase data collection approach, conducted between April 2023 and November 2023. The survey targeted practicing physicians actively involved in managing patients with UGIB. Data collection and management were performed through Research Electronic Data Capture (REDCap), an electronic data collection tool. The survey comprised four key domains: demographics and clinical practice, definitions of hemodynamic instability, pre-endoscopic assessment, and optimal timing of endoscopy, encompassing a total of 33 questions. The primary analysis provided a descriptive assessment of responses reported as proportions. Secondary analyses explored differences in responses based on years of clinical experience, practice setting, and the estimated annual number of UGIB cases encountered

Results

A total of 533 clinicians from 50 countries completed our survey. Among respondents, 54.6% work in university-based hospitals, and 67.7% reported managing over 100 UGIB patients annually. Regarding clinical experience, 55.7% have less than 10 years, with 44.3% with over 10 years of experience. Only 47.1% of respondents reported that their hospitals implement a triage system for UGIB patients. Additionally, 39.6% indicated that they do not use any risk stratification scores at the time of patient presentation. For initial fluid resuscitation, 0.9% saline (40.9%) and balanced crystalloid fluids (39.5%) were almost equally preferred. The rate of fluid resuscitation was reported to depend on the patient’s hemodynamic status by 40.2% of respondents. Most respondents indicated that hemodynamically unstable patients are primarily managed in the emergency department or intensive care unit. A total of 34.3% of respondents indicated that they do not routinely use prokinetics prior to endoscopy in UGIB patients, while 27.6% reported not commonly using them even in cases involving severe bleeding or known gastric emptying disorders. Proton pump inhibitors are administered prior to upper GI endoscopy in all cases by 70.4% of respondents, while vasoconstricting agents are used by 61% in cases of suspected variceal bleeding.

Conclusion

Our survey found considerable variability among respondents regarding the pre-endoscopic management of patients presenting with upper gastrointestinal hemorrhage. The overall adherence to international guidelines was low, which can potentially result in a significant negative impact on patient outcomes.