Daily Recap, Monday, October 16

Monday at UEG Week 2023!

Browse our Daily Recap and get a taste of the action from Monday at UEG Week, featuring state-of-the-art scientific presentations, top abstracts and more congress awards.

Top Abstract: Surgery may not be the answer to reducing risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus

A multinational and population-based cohort study reveals that anti-reflux surgery is not superior to anti-reflux medication in the prevention of oesophageal adenocarcinoma among patients with Barrett's oesophagus (BO).

Since anti-reflux surgery has been found to be at least as effective as anti-reflux medication in controlling some of the key risk factors of oesophageal adenocarcinoma, it has been hypothesised as a potential preventative for tumour progression. To explore this, a comprehensive study was conducted comparing anti-reflux medication with anti-reflux surgery in patients with BO, who are high risk for oesophageal adenocarcinoma.

Patients (N=33,939) recorded in national patient registries as diagnosed with BO were included from Denmark (2012–2020), Finland (1987–1996 and 2010–2020), Norway (2008–2020) and Sweden (2006–2020).

Patients who underwent anti-reflux surgery (n=542) were compared with non-operated patients using anti-reflux medication, with a follow-up period of 32 years. During this extended period, multivariate Cox regression showed that patients who underwent anti-reflux surgery did not experience a reduction in the overall hazard ratio (HR) compared with those who used anti-reflux medication without surgery; instead, the HR increased (adjusted HR: 1.9; 95% CI [confidence interval]: 1.1–3.5). Furthermore, as the follow-up duration extended, HRs did not exhibit a decline, but an upward trend, rising from 1.8 (95% CI: 0.6–5.0) within 1 to 4 years of follow-up to 4.4 (95% CI: 1.4–13.5) after 10 to 32 years of follow-up.

The findings from this study indicate that among patients with BO, there is no observed reduction in the risk of oesophageal adenocarcinoma following anti-reflux surgery when compared with anti-reflux medication. In fact, the risk was observed to increase over the course of the follow-up period among those who had undergone anti-reflux surgery.

Top abstract: Oncogenic GNAS and KRAS signalling collectively drive dysplasia in an iPSC-derived organoid model for cystic pancreatic neoplasia

A new study has found that the GNS^R201C mutation promotes the early formation of dyplasia and amplifies the effects of the KRAS^G12D mutation.

Intraductal papillary mucinous neoplasia (IPMN) are cystic pancreatic duct neoplasms that can advance to invasive adenocarcinomas. These neoplasms frequently contain activating mutations in guanine nucleotide binding protein, alpha stimulating (GNAS) and/or Kirsten rat sarcoma viral oncogene homolog (KRAS), but the interactions and signalling crosstalk between these mutations are poorly understood.

Using a patient-derived induced pluripotent stem cell (iPSC) containing either wild-type GNAS or mutant GNAS along with an inducible oncogenic KRAS^G12D cassette, researchers investigated both mutations using a porcine urinary bladder (PUB) model to monitor neoplasia formation.

2 weeks following transplantation, all grafts exhibited a substantial presence of cytokeratin 7- and 19-positive pancreatic ductal structures, showcasing a robust cystic phenotype primarily attributed to GNAS^R201C, and that remained for 8 weeks. The induction of KRAS^G12D over a period of 6 weeks led to an enlargement of the ductal lumen, an effect that was more prominent when GNAS^R201C was present. Moreover, a pronounced GNAS^R201C-dependent expression of mucin 2, associated with the intestinal IPMN subtype, was found.

Quantitative analysis of dysplastic ductal structures revealed an increase in low-grade dysplasia driven by either KRAS^G12D or GNAS^R201C. However, the combination of both mutations was associated with a substantial rise in the number of high-grade dysplastic ductal structures. Within these ductal structures, a pro-proliferative phenotype was observed, primarily driven by GNAS^R201C. KRAS^G12D significantly increased the number of p21-positive nuclei, indicative of enhanced proliferation, while a dual mutation background of both KRAS^G12D and GNAS^R201C reduced this effect, indicating a decrease in oncogene-induced senescence.

The key finding is that GNAS^R201C influences early dysplasia formation and amplifies KRAS^G12D-driven dysplasia, particularly in high-grade cases. Additionally, the increased proliferation and reduced senescence in this context suggest GNAS^R201C may bypass oncogene-induced senescence. This unique patient-derived iPSC model offers valuable insights into the mechanisms underlying IPMN formation and its progression towards invasiveness.

Scientific highlight: Babies with a low birthweight are four times more likely to develop fatty liver disease in later life

A study presented today has discovered a significant connection between birthweight and the onset of nonalcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD), in young people.

To investigate this link, a team of researchers from Sweden used the nationwide ESPRESSO cohort and conducted a population-based case-control study of all people aged 25 years and younger, who had been diagnosed with biopsy-proven MASLD between January 1992 and April 2017, totalling 165 cases. To minimise confounding factors, each individual with MASLD was matched with up to five controls from the general population based on age, sex, calendar year and county of residence.

Individuals born with a low birthweight (<2500 g/5 lbs 8 oz) were four times more likely to develop MASLD in childhood, adolescence or young adulthood when compared with those born with normal birthweight. Those born as small for gestational age (SGA), falling below the 10th percentile, were also over three times more likely to develop MASLD early in life compared with those with an adequate (10th–90th) birthweight. In addition, the researchers found that individuals with a low birthweight, or those born as SGA, had an up to ~6-fold higher relative risk of developing more severe stages of MASLD in the form of liver fibrosis or cirrhosis.

Amidst escalating rates of obesity, MASLD has become the most common cause of chronic liver disease worldwide. In Europe alone, it is estimated to affect over 25% of adults, and its prevalence is increasing among obese or overweight young people. It has also emerged as one of the fastest growing causes of end-stage liver disease, primary liver cancer and liver transplantation.

UEG Rising Star Awards

Each year, the most promising and emerging scientists from across the digestive health field are granted the UEG Rising Star awards.

The award provides recipients with a durable platform in basic, translational and clinical science to build and grow their professional career. The awardees are jointly selected by the UEG National Societies Committee and the Scientific Committee based on a track record of international quality research and developing scientific independence.

Congratulations to this year’s ten Rising Stars!

Pilar Acedo, UK

Timon Adolph, Austria

Krisztina Barbara Gecse, Netherlands

Chris Lamb, UK

Mattias Mandorfer, Austria

Anna Saborowski, Germany

Kai Markus Schneider, Germany

Lena Seifert, Germany

Joana Torres, Portugal

Johann von Felden, Germany

Scientific highlight: Rectal microbiome at hospital admission can predict the course of acute pancreatitis

Pancreatitis – Microbiome As Predictor of Severity (P-MAPS) is a prospective, international, multicentre translational study revealing rectal microbiome as an early biomarker of acute pancreatitis severity.

At present, approximately 20–25% of patients with the inflammatory disorder, acute pancreatitis, progress to moderately severe disease and 10% to severe disease. The major local and systemic complications that often accompany these levels of disease activity can result in long hospital stays and subsequent economic health burden.

To address the lack of early biomarkers for predicting disease severity, the P-MAPS study examined the predictive potential of the microbiome when buccal (oral) and rectal swabs were collected within the first 72 hours of hospital admission. After samples from 16 European centres were sequenced with Oxford Nanopore Technologies and microbial data was normalised, 391 rectal and 409 buccal samples were available for analysis.

Results from the rectal samples revealed significant differences in beta diversities (Bray-Curtis) for the revised Atlanta classification (P<0.01), severity (P<0.01), mortality (P<0.01) and length of hospital stay (P<0.05). Importantly, results remained significant after factoring for 74 potential confounding variables, including alcohol consumption, antibiotics and smoking status. No beta diversities were observed from the buccal samples, nor were any differences found for alpha diversity.

Using different abundant taxa from the study, investigators developed a classifier for severity that achieved good discriminatory ability of 80% area under the receiver operating curve. Therefore, rectal microbiome offers promising accuracy for predicting the course of acute pancreatitis.

Scientific highlight: Gut microbiome variations could predict colorectal cancer risk

Researchers have identified significant variations in the gut microbiome of individuals who developed pre-cancerous colonic lesions, suggesting a potential connection between gut bacteria and the onset of colorectal lesions and cancers. These findings open promising new avenues for enhancing the detection and prevention of colorectal cancer.

The large-scale prospective study, involving 8208 participants, linked data from the Dutch Microbiome Project with the Dutch nationwide pathology database to identify all record cases of colonic biopsies from the last five decades. Researchers analysed the function and composition of the gut microbiomes of individuals who developed pre-cancerous colorectal lesions before faecal sampling between 2000 and 2015 (n=214), as well as those who developed lesions after faecal sampling between 2015 and 2022 (n=305). These groups were then compared with individuals with normal colonoscopy findings (n=202) and the general population. To gain a deeper insight into the gut microbiome’s role, researchers are also examining specific bacterial strains and their functions within the gut by reconstructing their genomes from metagenomic data.

The results revealed that individuals who developed colonic lesions after faecal sampling exhibited increased diversity in their gut microbiome compared with those who did not develop lesions. Moreover, the composition and function of the microbiome differed among individuals with pre-existing or future lesions and varied based on the type of lesion.

Notably, bacterial species from the family of Lachnospiraceae and the genera Roseburia and Eubacterium were linked with the future development of lesions.

Discussing the implications of the study’s findings, Dr Ranko Gacesa, the lead author, said, “The connection between the gut microbiome and pre-cancerous lesions has been underexplored, leaving uncertainty about whether gut bacteria can predict the future onset of colorectal cancer. Our findings suggest that the microbiome could act as a valuable tool to improve existing tests, advancing early detection methods for pre-cancerous lesions and colorectal cancer.”

That's all for today's recap! Tune in tomorrow for the final day of UEG Week 2023!