Introduction

ERCP in patients with surgically altered anatomy (SAA) is one of the most challenging endoscopic procedures. For patients in whom cannulation cannot be achieved with a colonoscope, we placed a tube with the tip near the papilla/anastomosis, and the end out of patient’s mouth; a duodenoscope was then inserted following tube placement to finish ERCP in the same session.

Aims & Methods

The aim of the current study was the evaluation of feasibility and safety of two-step ERCP (Figure 1) for biliopancreatic interventions in patients with SAA. Patients with SAA receiving two-step ERCP at a single endoscopic reference center were retrospectively enrolled between January 2016 and June 2023.

Results

58 patients (20 female, 38 male), median age 58 years (range 43-88) and biliary (n=45) and pancreatic (n=13) indications for two-step-ERCP were enrolled. Types of surgical reconstruction: Roux-enY n=47, Billroth II with Braun anastomosis n=11. Technical success rates for intubation, cannulation and interventions were 94.8%, 85.5% and 100%, respectively. Overall two-step-ERCP-success rate was 77.6%. One major complication occurred (1.7%; intestinal perforation during intubation).

Conclusion

The current study showed for the first-time feasibility and safety of two-step-ERCP with colonoscope and duodenoscope in SAA patients at an expert center. This data justifies further evaluation of this new technique preferably in a prospective multicenter trial.

Introduction

Pancreatic cancer (PC) presents as a highly aggressive malignancy characterized by limited treatment modalities and a poor prognosis. Its prevalence is steadily increasing, with projections indicating that it will rank as the second most common cause of cancer-related mortality by the year 2030, reflecting a substantial escalation in the global burden ^[1]. Due to the early metastasis of PC and the limited efficacy of current treatment for advanced stages, the overall five-year survival rate remains below 9% ^[2-3]. Therefore, the development of novel therapeutic approaches is crucial.
In recent years, there has been a surge of interest in natural products due to their perceived potential as anti-cancer agents. Our initial findings suggest that the co-administratin of Formononetin (FMN, a compound derived from Astragalus mongholicus) combined with Salvianolic Acid B (SalB, one of the major water-soluble components of Salvia miltiorrhiza), referred to as "FcS" in subsequent sections of this study, effectively suppresses the proliferation, metastasis, and promotes apoptosis of Panc-1 cells in a zebrafish embryo xenograft model. While FMN and SalB individually inhibited the PC cell viability, their combined treatment exhibited a stronger and significant suppressive effect. However, the mechanism of this combined treatment suppressing the malignant progression of PC remains unclear.

Aims & Methods

This study aims to assess the potential therapeutic effectiveness of FcS therapy for PC, with a focus on investigating the impact of this treatment strategy on PC cell survival, proliferation, and migration capabilities through a series of experiments conducted in vitro and in vivo. Additionally, our study investigated the expression of MBOAT2 in PC and its correlation with prognosis and tumor invasion.
The proliferation of PC cells was evaluated through the utilization of CCK-8 and EdU assay in vitro experiments to investigate the effects of FcS. Wound healing assay and transwell assay were conducted to assess the impact of FcS on the migration and invasion of PC cells. Through molecular docking and analysis of the Cancer Genome Atlas (TCGA) database, the potential regulatory factor MBOAT2 was identified. A Mboat2 knockdown cell line was established and treated with FcS to investigate the interaction between MBOAT2 and FcS. In vivo experiments were conducted using the LSL-Kras (G12D/+), LSL-Trp53 (R172H/+), and Pdx-1-Cre (KPC) transgenic mouse model, with tumor weight serving as a measure of the effects of FcS. Immunohistochemistry was utilized to assess protein expression levels from mice tumor tissues.

Results

Experiments conducted on three PC cell lines revealed that treatment with FcS resulted in reduced cell viability, inhibited proliferation, and decreased cell migration and invasion. Furthermore, analysis of TCGA data was utilized to investigate the impact of FcS on MBOAT2 expression in pancreatic cancer cells, demonstrating a down-regulation of MBOAT2 and subsequent reductions in viability, proliferation, and invasion. Additionally, the study identified the JAK/STAT signaling pathway as a potential regulatory mechanism. In vivo administration of FcS also exhibited tumor growth suppression in a KPC transgenic mouse model.

Conclusion

FcS treatment may be effective in suppressing the growth and invasion of PC cells through the downregulation of MBOAT2. The unique contribution of this research lies in the therapeutic impact of combining natural compounds and identifying MBOAT2 as a potential target, along with the involvement of the JAK/STAT signaling pathway.

References

1. Wungki, Park,Akhil, Chawla,Eileen M, O'Reilly,Pancreatic Cancer: A Review [J]. JAMA, 2021, 851-862. https://doi.org/10.1001/jama.2021.13027
2. Rebecca L, Siegel,Kimberly D, Miller,Ahmedin, Jemal,Cancer statistics [J]. CA Cancer J Clin. 2020, 7-30. https://doi.org/10.3322/caac.21590
3. Ahmedin, Jemal,Rebecca, Siegel,Elizabeth, Ward et al. Cancer statistics [J]. CA Cancer J Clin, 2006,106-130. https://doi.org/10.3322/canjclin.56.2.106

Introduction

Previously,our investigations have underscored the potential of hyperthermia to improve the therapeutic efficacy of gemcitabine(GEM) in pancreatic cancer(PC). Nonetheless,the precise underlying mechanisms remain elusive.

Aims & Methods

We aimed to explored the underlying mechanisms of how hyperthermia enhances GEM sensitivity of PC cells. We engineered two GEM-resistant PC cell lines(BxPC-3/GEM and PANC-1/GEM) and treated them with GEM alongside hyperthermia. The impact of hyperthermia on the therapeutic potency of GEM was ascertained through 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, assessment of the concentration of its active metabolite difluorodeoxycytidine triphosphate(dFdCTP), and evaluation of deoxycytidine kinase (dCK) activity. Lentivirus-mediated dCK silencing was further employed to validate its involvement in mediating the GEM-sensitizing effect of hyperthermia. The mechanism underlying hyperthermia-mediated dCK activation was explored using bioinformatics analyses. The interplay between hyperthermia and the ephrin A4 (EFNA4)/β-catenin/dCK axis was investigated, and their roles in GEM resistance was further explored via the establishment of xenograft tumor models in nude mice.

Results

Hyperthermia restored dCK expression in GEM-resistant cell lines, concurrently enhancing GEM sensitivity and fostering DNA damage and cell death. These observed effects were negated by dCK silencing. Regarding the mechanism, hyperthermia activated dCK by downregulating EFNA4 expression and mitigating β-catenin activation. Overexpression of EFNA4 activated the β-catenin
while suppressing dCK, thus diminishing cellular GEM sensitivity—a phenomenon remediated by the β-catenin antagonist MSAB. Consistently, in vivo, hyperthermia augmented the therapeutic
efficacy of GEM on xenograft tumors through modulation of the ephrin A4/β-catenin/dCK axis.

Conclusion

This study delineates the role of hyperthermia in enhancing GEM sensitivity of PC cells, primarily mediated through the suppression of the EFNA4/β-catenin axis and activation of dCK.

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Introduction

Ulcerative colitis (UC) is a chronic, relapsing, nonspecific inflammatory bowel disease (IBD). Cucurbitacin B (CuB) is a naturally occurring compound primarily found in plants of the Cucurbitaceae and Cruciferae families. CuB has been shown to have a wide range of pharmacological activities, including anti-inflammatory, antioxidant, antiviral, hypoglycemic, hepatoprotective, neuroprotective, and anti-cancer effects. However, there is a paucity of reports providing direct evidence of the efficacy of CuB in ameliorating colitis in mice.

Aims & Methods

This study aimed to explore the therapeutic effect and underlying molecular mechanisms of CuB on dextran sulfate sodium (DSS)-induced UC mice and lipopolysaccharide (LPS)-induced RAW264.7 cells. The protective effect of CuB on DSS-induced UC was evaluated by assessing weight loss, disease activity index (DAI) score, spleen index, colon length shortening, myeloperoxidase (MPO) activity, and pathological changes. The levels of inflammatory cytokines were detected by ELISA and RT-PCR analysis. The expressions of tight junction (TJ) proteins like ZO-1, Occludin, and the target proteins in the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) were determined by western blotting analysis.

Results

CuB significantly attenuated the symptoms of UC and suppressed colon MPO activity. In addition, CuB could significantly increase the expression of TJs in UC mice. Meanwhile, CuB treatment reduced the levels of inflammatory cytokines and inhibited the phosphorylation of MAPK and NF-κB signaling pathways in UC mice and in LPS-induced RAW264.7 cells.

Conclusion

In summary, our study demonstrated that CuB ameliorated DSS-induced UC by inhibiting the inflammatory response and maintaining the intestinal barrier function via modulation of the MAPK/NF-κB pathways. These results suggest that CuB could be a promising candidate for UC therapy.

Disclosure

The authors hereby declare to have no conflict of interest regarding this article.

Clinical Case Summary

Intragastric balloons (IGBs) have emerged as a treatment option for obesity, bridging the gap between lifestyle modification/pharmacotherapy and bariatric surgery. The Allurion IGB is a swallowable balloon that spontaneously degrades after residing in the stomach for 4 months, allowing the balloon to be naturally excreted. Here we present a novel strategy for removing an Allurion intragastric balloon at a non-specialist centre using standard endoscopic accessories.

A 57-year-old female presented 4 weeks following insertion of an Allurion IGB abroad with severe abdominal pain and emesis after every meal since balloon placement. Contrast CT showed the IGB inflated within the fundus but no evidence of intestinal obstruction or perforation. Following consultation with other centres, we proceeded with endoscopic removal under general anaesthetic and with surgical support. On gastroscopy, 1L of food residue was aspirated and the IGB was seen in the stomach. An endoscopic ultrasound (EUS) 19Fr aspiration needle was used to puncture the balloon. 200ml was aspirated with a 50ml syringe. The remaining fluid was released with a further puncture performed using grasper forceps. The balloon was then successfully retrieved with grasper forceps. The patient’s symptoms resolved and she was discharged two days later.

The technique described here allows for safe retrieval of an Allurion IGB using endoscopic accessories available at hospitals without a dedicated bariatric service. Nausea and pain are often encountered following IGB insertion and occasionally necessitate endoscopic balloon retrieval. Although general anaesthetic for IGB removal remains contentious, we felt this represented the safest strategy given the documented risks of aspiration as well as the lack of prior experience at our centre. With increasing numbers of patients undergoing weight-loss interventions, familiarity with strategies for addressing their complications is crucial, even at non-specialist centres.

References

Bazerbachi F, Vargas EJ, Abu Dayyeh BK. Endoscopic Bariatric Therapy: A Guide to the Intragastric Balloon. American Journal of Gastroenterology. 2019;114(9):1421-1431. doi:10.14309/ajg.0000000000000239

National Institute for Health and Care Excellence. Swallowable gastric balloon capsule for weight loss: interventional procedures guidance [IPG684]. Published 18 November 2020.

Introduction

According to the ROME IV criteria, functional dyspepsia (FD) can be subdivided into PDS (postprandial distress syndrome) with meal-related symptoms such as early satiation and postprandial fullness and EPS (epigastric pain syndrome) with meal-unrelated complaints such as epigastric pain or burning. Nausea can also co-exist in FD but the literature is poor in reporting whether this symptom is mainly triggered by meal ingestion. A recent global epidemiology study of gastroparesis-like symptoms showed that the prevalence of nausea or vomiting, in combination with postprandial fullness or early satiation varies between continents.¹

Aims & Methods

This study aims to compare the difference in prevalence rates of nausea within each FD subgroup between western and eastern secondary and tertiary care centers. Adult patients with disorders of gut-brain interaction (DGBI) recruited in 9 western and 7 eastern secondary and tertiary care facilities between the ages of 18 and 70 years completed the Enhanced Asian Rome IV questionnaire (Asian European Gastrointestinal Symptoms cohort or AEGIS). The western centers were located in Belgium, Bulgaria, France, Israel, Italy (2x), Slovakia, Sweden and The United Kingdom while the eastern centers were located in Australia, China, Iran, Japan, Malaysia and Singapore (2x). FD patients were divided into PDS, EPS and PDS-EPS overlap (OVP) subgroups. Patients were furthermore classified as having nausea when this symptom was reported at least once per week. The questionnaire EARQ4 questionnaire was also used to address the relationship between nausea and food intake. Patients were asked how often they experienced nausea, whether nausea was triggered or worsened by meal intake, how often nausea occurred after a meal and if so, how soon after a meal nausea started. A comparison of the prevalence of nausea and meal-related nausea was made between eastern and western patients and among FD subgroups. Continuous variables are reported as median (IQR) and compared with a Kruskal-Wallis test. Categorical variables were compared using a Pearson Chi-square test.

Results

Of the 1074 DGBI patients that completed the survey, 483 were classified as having FD (59.4% PDS, 27.5% EPS, 13.0% PDS-EPS overlap). FD patients from eastern (N=202) and western sites (N=281) had a similar body mass index (22.5 (19.6-25.7) vs. 21.3 (19.7-25.4)kg/m²) and age (39.0 (29.0-55.0) vs. 38.0 (26.0-54.0) years). Eastern sites included significantly more female patients than western sites (43 % vs. 17.5%, p<0.001). PDS and EPS patients from eastern sites had significantly less nausea than PDS and EPS patients from western sites (17.9% vs. 46.3% and 6.8% vs. vs 40.5% respectively, both p<0.001). The majority of FD patients with nausea experienced meal-related nausea with no difference between eastern and western sites (63.9% vs. 73.7%). In PDS patients with nausea, nausea was significantly more triggered or worsened by a meal (72.4%) than in PDS-EPS overlap and EPS (48.6% and 35.3% respectively; p<0.001). All groups reported that meal-related nausea started mostly (> 85%) within 60 minutes after the meal.

Conclusion

In contrast to previous literature, we found that western PDS and EPS patients report nausea more frequently than eastern PDS and EPS patients. In both eastern and western patients nausea was mostly meal-related. Meal-related nausea is more common in PDS than in PDS-EPS overlap and EPS patients. Further research is needed to investigate the role of ethnic factors in the pathophysiology of nausea in functional dyspepsia.

References

Huang IH, Schol J, Khatun R, et al. Worldwide prevalence and burden of gastroparesis-like symptoms as defined by the United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis. United Eur Gastroenterol J. 2022;10(8):888-897.

Disclosure

Bert Broeders received lecture fees from the Rome Foundation.