Introduction

Functional dyspepsia (FD) is a prevalent disorder that effects the proper function of the gastrointestinal (GI) system. One of the hallmarks of FD is the impaired ability of the stomach to accommodate after food intake, leading to epigastric pain, heartburn, bloating and nausea. However, the exact cause of this disorder is poorly understood. Studies have shown that combinations of herbal extracts known as phytotherapeutic preparations have demonstrated efficacy in improving dyspeptic symptoms in FD. Amara oral drops is traditionally used for the treatment of GI dysmotility and contains an herbal mixture of nine hydroethanolic herbal extracts (Artemisia abstinthium, Erythraea centaurium, Cichorium intybus, Gentiana lutea, Juniperus communis, Millefolium, Imperatoria ostruthium, Salvia officinalis and Taraxacum).

Aims & Methods

The study aim was to investigate the mechanisms of the Amara whole extract and its individual extracts on gastric motility ex vivo and in vitro. The whole extract and the individual extracts were prepared from the commercial medicinal product Amara oral drops or from the ethanolic tinctures, respectively. Muscle strips from guinea-pig (GP) gastric fundus were set up in organ baths in circular orientation and exposed to the whole extract or vehicle in a concentration-dependent manner (3.5 – 1,000 μg/mL). To assess the relaxation mechanism of the whole extract and its individual extracts on the stomach muscle strips, we studied different G-protein-coupled receptors known to play a central role in GI disorders: muscarinic M₃ and M₂, opioid μ (OP1) and several serotonin receptors (5-HT1B, 5-HT1D, 5-HT3, 5-HT7 and 5-HT1A). The whole and individual extracts were studied in vitro for antagonist activity on those motility receptors. All assays were performed in CHO-K1 cell line. To investigate M₂ antagonist activity ex vivo, muscle strips from GP gastric fundus were exposed to Carbachol (Cch), a well-known muscarinic agonist. Once the contraction was stabilized, vehicle or whole extract were added in increasing concentrations (94 – 1,000 μg/mL) to study their relaxation effect on the muscle contraction.

Results

Addition of the ethanol-free whole extract caused relaxation of guinea-pig fundus circular muscle strips which was found to be significantly different compared to the vehicle group at the highest concentrations tested (p-value < 0.001). In vitro studies revealed that the whole extract impaired the activity of OP1 and M₂ receptors, shown by inhibition of intracellular cAMP release (IC₅₀: 304 & 219 μg/mL, respectively). Furthermore, Juniperus, Salvia and Imperatoria extracts impaired M₂ receptors’ activity (IC₅₀: 32, 20 & 21 μg/mL, respectively), whereas Gentiana, Artemisia, Cichorium and Juniperus inhibited OP1 receptors’ activity (IC₅₀: 42, 22, 104 & 25 μg/mL, respectively). However, serotonin and M₃ receptors’ activities were not affected. After Cch-induced contraction, the whole extract showed a clear tendency on producing a concentration-dependent relaxation of the contracted muscle strips. Ongoing research is being conducted to strengthen the latter mentioned data.

Conclusion

This data demonstrates that the whole extract is capable of altering gastric motility by relaxing the fundus part of the stomach, most likely through the modulation of motility-related M₂ and OP1 receptors. Additionally, all individual extracts’ properties may act together, resulting in an increase of the overall preparation’s efficacy. These findings suggest that Amara oral drops could be an efficient treatment for FD patients suffering from impaired gastric accommodation.

Disclosure

All authors are employees of Weleda AG.

Introduction

Colorectal cancer’s (CRC) incidence above 50 years old has been decreasing globally in the last decades, but its incidence in patients below 50 years old (early-onset colorectal cancer, EO-CRC) has been increasing, for reasons not yet fully understood.

Aims & Methods

A unicentric cohort study was conducted in a tertiary centre, including all patients admitted for a first diagnosis of CRC and evaluated by the Multidisciplinary Colorectal Cancer Group from 01.01.2017 until 31.12.2018. Patients with a previous diagnosis of a Hereditary Colorectal Cancer Syndrome were excluded.

Results

A total of 438 patients were included, 58.2% males, with a mean age at diagnosis of 67.7±11.1 years old. Mean follow-up time was 41.49 months. There were 25 EO-CRC patients (5.7%), 17 males (68%), mean age 43.1±6.0 years old.
Globally, 32.4% of the patients were current or past smokers, 18.5% had previous non-colorectal cancer, 7.5% and 3.4% were previously exposed to immunosuppressive drugs or abdominal/pelvic radiotherapy, respectively. The majority presented with normal(29.7%) to high Body Max Index (39.7%), median 25.6 (IQR:22.6-28.4) Kg/m². The most common CRC location was the rectum (42.9%) and 56.1% were stage I or II (AJCC 8^th edition).
In the univariate analysis, a significant association was found between EO-CRC and: smoking status (past or current smokers 52% in EO-CRC vs. 31.2% in older cases p=0.009); lymphovascular invasion (40.0% in EO-CRC vs. 17.4% in over 50, p=0.018) No significant differences were found for histological subtype (p=0.447), perineural invasion (p=0.474), or tumor stage at diagnosis, although a relevant proportion of the younger patients had metastatic disease at diagnosis (28.0% vs. 12.8%, p=0.064).
Immunohistochemistry for mismatch-repair proteins showed loss of expression of at least one protein in 1/18 EO-CRC patients and 22/179 of older patients (p=0.728).
From the EO-CRC patients, 16 were evaluated in the Familial Cancer Clinic and 14 underwent germline mutation analysis: 13 patients had inconclusive results, one of them presented a MUTYH heterozygote mutation and another was diagnosed with MUTYH-associated Polyposis (composed heterozygote mutation).

Conclusion

Colorectal cancer showed distinctive features in the younger population, with a higher prevalence of lymphovascular invasion and, possibly, a higher incidence of metastatic disease at diagnosis. Smoking had a significant association with CRC, especially in this younger population. Whether this means there is a biological difference is not yet clear. More evidence is needed in order to clarify EO-CRC aetiology and to develop screening and improve management strategies.

References

Siegel RL, Jakubowski CD, Fedewa SA, Davis A, Azad NS. Colorectal Cancer in the Young: Epidemiology, Prevention, Management. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-14. doi: 10.1200/EDBK_279901. PMID: 32315236

Introduction

The effect of analgesic modalities on short term outcomes in acute pancreatitis (AP) is unknown. Opioids are frequently used in AP but there are concerns regarding safety from preclinical models of AP. The aim of this study was to assess the effect of different analgesic modalities, in particular opioids, on the severity, morbidity, and mortality in hospitalized patients with AP.

Aims & Methods

This prospective cohort study recruited consecutive patients admitted with a first episode of AP from 1 April to 31 June 2022 with 1-month follow up. Data on aetiology of AP, clinical course, and analgesic treatment were collected. The primary outcome was the association between analgesic type and severity of AP. Statistical analysis was performed using univariate comparisons, multivariable regression, and mediation analysis.

Results

A total of 2,119 patients were recruited from 118 centers in 27 countries. The patients were 53 % male sex with median age of 55 years (IQR, 41-71). The most common aetiology of AP was gallstones (58%), followed by alcohol (21%). Pain duration prior to admission was >24 hours in 978 (47%) patients and <12 hours in 530 (25 %) patients. As for the first analgesic modality simple analgesics were administered in 1,456 (70%) patients and opioids were given in 521 (25%) patients. There were 1,383 (69%) patients who had opioid use at any time during admission. On univariate analysis, moderately severe/severe AP was associated with male sex, younger age, alcohol aetiology, predicted severe AP, higher pain scores, and opioid treatment (all p≤0.01). Also, on univariate analysis patients who received opioid treatment were at increased risk of severe AP, organ failure, necrosis, and longer length of admission (all p≤0.01). On multivariate analysis alcohol aetiology, predicted severity of AP and opioid treatment showed increased risk for moderately severe/severe AP (all p<0.001). Mediation analysis showed a significant direct effect of opioid use on AP severity (p<0.001).

Conclusion

This prospective multicentre study suggests that opioids have a direct effect on the severity and morbidity of AP. Further randomized controlled trials should be designed to test the safety of opioids in AP.

Introduction

Acute pancreatitis (AP) is a common cause of acute hospital admissions, with the potential for severe acute complications, progression to chronic pancreatitis and recurrent episodes. A first presentation leads to investigations to identify a cause, including serum blood tests and transabdominal ultrasound. Following these investigations, a significant minority of patients have no clear cause for pancreatitis. Endoscopic ultrasonography (EUS) can identify aetiologies of AP, and direct intervention to reduce recurrence. The goal of this study was to determine the diagnostic yield of EUS and the impact of subsequent biliary intervention on recurrence of AP.

Aims & Methods

This was a retrospective service evaluation of EUS referrals to a regional referral centre in the UK from January 2015 to December 2019. Demographics, symptoms, liver blood tests, non-invasive imaging, EUS records and outcomes were reviewed. A EUS was labelled as diagnostic if findings were identified which explained the cause for pancreatitis that had not been explained with other investigations. Symptom resolution was defined as no further episodes of acute pancreatitis or abdominal pain requiring investigation, imaging, or presentation to secondary care during the follow-up period. Statistical significance for the difference between proportions was calculated using chi-squared tests.­­­­­­­­­­

Results

Ninety-seven patients were included in the study. The median age of the cohort was 58 (range 18-88) years. 55 (57%) patients were male. 22/97 (23%) patients had previously had a cholecystectomy. 41/97 (42%) had abnormal liver blood tests at the time of referral. Three patients had no non-invasive imaging. 27/97 (28%) had one of either transabdominal ultrasound, MRCP or CT, 63/97 (65%) had two tests and 4/97 (4%) had all three. 5 (5%) patients previously had a non-diagnostic EUS.
72/97 (74%) EUS were diagnostic. Findings included gallstones (n=15), gallbladder microlithiasis/sludge (n=51), bile duct stones (n=13), bile duct microlithiasis/sludge (n=11), chronic pancreatitis (n=7) and a pancreatic mass (n=1) which was later diagnosed as a pancreatic adenocarcinoma.
65 patients had a biliary aetiology for their pancreatitis which was amenable to treatment. Of these, 12 had subsequent ERCP, 7 had ERCP and cholecystectomy, 33 had a cholecystectomy and 13 were treated conservatively. Recurrent pancreatitis occurred in 12/52 (23%) patients who had treatment for a biliary aetiology of their pancreatitis compared with 8/13 (75%; p<0.01) of patients who were managed conservatively despite a biliary aetiology for pancreatitis, 8/32 (25%; p=0.84) of patients with a diagnostic EUS with a finding not amenable to treatment or a non-diagnostic EUS experienced further episodes. One patient died from complications related to acute pancreatitis and was not included in this analysis. Median duration of follow-up was 51 months (range 32-80 months).

Conclusion

In our cohort of patients referred for EUS for unexplained acute pancreatitis, EUS had a high diagnostic yield. A lower proportion of patients had a biliary aetiology for their pancreatitis that was amenable to intervention with either ERCP, cholecystectomy or both procedures; these patients experienced fewer episodes of recurrent acute pancreatitis than those managed conservatively. This supports the use of EUS in patients with acute pancreatitis with no cause identified with non-invasive imaging.

Introduction

Peri-pancreatic fluid collections (PFCs) are frequent complications of acute pancreatitis and their management, especially in the presence of necrosis, is often challenging. Invasive interventions are indicated in case of PFC infection or symptoms related to organ compression. Endoscopic ultrasound (EUS)-guided transluminal drainage rapidly developed over time and the introduction of new dedicated stents represented a game changer of PFC treatment. In particular Bi-Flanged Metal Stent (BFMS) and Lumen Apposing Metal Stent (LAMS), with their technical characteristics, facilitate to create a stable connection between the gastrointestinal wall and the target cavity, allowing the introduction of the endoscope through the stent for direct therapeutic intervention, reporting high rates of technical and clinical success. To date, only one retrospective study have compared Nagi and Hot-Axios for EUS-guided drainage of PFCs.

Aims & Methods

The present study aimed to retrospectively evaluate the safety, technical and clinical success of the two different dedicated metal stents for EUS-guided drainage of PFC. Data from a large multicenter series of patients with PFCs treated with Hot-Axios and Nagi stents were retrieved among 30 italian centers during a 5-year period (January 2016–July 2020). Technical and clinical success, rate of adverse events were taken into account as outcome measures. To overcome biases owing to the different distribution of covariates among patients who were treated with the two kinds of stent, a 1-to-1 match was created using propensity score analysis.

Results

Out of 476 patients underwent EUS-guided drainage of PFC, 386 were treated with Hot-Axios and 90 with Nagi stent, with a median follow-up of 290 days (95% CI 244 to 361). After 1:1 propensity score matching two groups were compared, 84 subjects who experienced Hot-Axios and 84 Nagi stent, resulting well comparable in terms of several variables. Median age was 62 (49.5-73) years in the Hot-Axios group and 63 (50-74) years in the Nagi group (p=0.40), male patients were 70% and 61% in the two groups, respectively (p=0.59). WON represented 39% of cases in the Hot-Axios and 32% in the Nagi group (p=0.70); 52% and 61% of PFCs were located in the body of pancreas in the two groups respectively (p=0.62) with a median width of 92 mm (61-120) in the Hot-Axios and 88 mm (56-110) in the Nagi group (p=0.25).
The two stents did not differ in terms of adverse events (AE) rate (13% versus 15%, p=0.29).
Overall, 11 AEs were observed in the Hot-Axios group, of which 3 (3.5%) mild, 4 (4.7%) moderate, 3 (3.5%) severe and 1 (1.1%) fatal, whereas 13 AEs were registered in the Nagi group, of which 3 (3.5%), 5 (5.9%), 3 (3.5%), and 2 (2.3%) mild, moderate, severe and fatal, respectively (p=0.63). Most common AE was bleeding (5.9% in both groups). Collection recurrence was observed in 4 cases after Hot-Axios (4.7%) and 3 cases (3.5%) after Nagi stent (p=1.0).
Technical and clinical success in the two groups were respectively 92% versus 95% (p=0.36) and 91% versus 94% (p=0.64).

Conclusion

Although literature is not univocal on which type of stent offers the best outcome for EUS-guided PFC drainage, our study demonstrates that, among dedicated metal stents, Hot-Axios and Nagi stent have similar technical and clinical success rate with comparable safety profile, suggesting that the choice of one stent over another should be multifactorial, based on clinical and technical aspects and/or personal expertise, rather than just efficacy rate.

Disclosure

Chiara Coluccio is lecturer for Steris.
Andrea Anderloni is consultant for Boston Scientific, Olympus and Medtronic.
Carlo Fabbri is consultant for Boston Scientific and lecturer for Steris and Q3 Medical.
All the other authors have no conflict of interest to declare