Introduction

Polycystic liver diseases (PLDs) are a group of genetically heterogeneous conditions characterised by the presence of multiple fluid-filled cysts within the liver. Cyst growth results in hepatomegaly (liver enlargement), leading to abdominal pain, shortness of breath and malnutrition, and consequently, patients suffer from an extremely poor quality of life. Additionally, cysts are at risk of rupture and infection, which leads to sepsis if left untreated. There are currently no widely approved pharmaceutical treatments for PLD patients and despite several dysregulated molecular targets having been previously identified within cyst cells, none of these have been translated for clinical practice.
Cyst epithelial cells are surrounded by a complex cyst microenvironment (CME), which is instructed by the cyst epithelia. Very little work, however, has focused on how non-epithelial cells within the CME contribute to cyst growth within the liver, particularly in human disease, nor whether modulation of the CME represents a therapeutic strategy to target the formation of cysts in patients.
In cancer, therapies that target the microenvironment, namely immunotherapy, have revolutionised patient care; could taking a similar approach and targeting the CME in PLD yield similar clinical successes?

Aims & Methods

We hypothesise that the formation of a unique CME in PLD offers a number of candidate targets for therapeutic intervention and aim to 1. Spatially map the CME in PLD patients; 2. Generate a novel mouse model of PLD to map the evolution of the CME over time; and 3. Identify targetable processes across the swaddwhich could reduce cystic growth.
Using patient PLD tissue, we have used GeoMx spatial transcriptomics and Akoya fusion high-plex immunophenotyping to spatially map the formation and composition of the CME in PLD. We have then used a combination of human ductular organoid cultures and mouse models of PLD to characterise how and which immune cells infiltrate the CME with disease progression.

Results

By combining single cell RNA sequencing from PLD tissue with a forward-phase cytokine arrays from human PLD organoids, we have found that cystic cells significantly increase the expression of a range of cytokines, including Ccl20, Tgfb and Tnf. These data indicate that cystic cells actively recruit an immune infiltrate to cystic lesions thereby promoting cystogenesis. Using spatial mapping technologies enables us to define where within the PLD CME different cells are found and we can show that T cells are the most abundant immune cell type within the cyst microenvironment in human PLD, while other immune cells like neutrophils are reduced from the human CME. Furthermore, T cells within the PLD CME express PD-1, suggesting that these T cells are in an exhausted state and susceptible to anti-PD-1 therapeutics.

Conclusion

Cyst cells recruit and pattern immune cells within the CME. These immune cells are largely made up of exhausted, PD-1⁺ T cells, which represent an immunotherapy candidate for pharmaceutical intervention in human PLD.

References

Waddell SH, Yao Y, Olaizola P, Walker A, Jarman EJ, Gournopanos K, Gradinaru A, Christodoulou E, Gautier P, Boerrigter MM, Cadamuro M, Fabris L, Drenth JP, Kendall TJ, Banales JM, Khamseh A, Mill P, Boulter L. A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease. Sci Transl Med. 2023 Sep 13;15(713):eabq5930. doi: 10.1126/scitranslmed.abq5930. Epub 2023 Sep 13. PMID: 37703354; PMCID: PMC7615241.
Olaizola P, Rodrigues PM, Caballero-Camino FJ, Izquierdo-Sanchez L, Aspichueta P, Bujanda L, Larusso NF, Drenth JPH, Perugorria MJ, Banales JM. Genetics, pathobiology and therapeutic opportunities of polycystic liver disease. Nat Rev Gastroenterol Hepatol. 2022 Sep;19(9):585-604. doi: 10.1038/s41575-022-00617-7. Epub 2022 May 13. PMID: 35562534.

Introduction

In addition to gluten and a genetic predisposition, other external factors dictate the onset of coeliac disease (CeD). These, including the microbiota, have not yet been well characterised, but could explain why the disease occurs later in life in a large proportion of patients. Microbiota-associated barrier defects may contribute to this process.

Aims & Methods

Our aim was to investigate the potential of microorganisms to alter small intestinal epithelial polarity as well as epithelial barrier function - in particular with regard to epithelial gluten peptide uptake.
The study was designed in two phases. In the screening phase, the cell lines Caco2-Bbe and Caco2-PIP2 were exposed to different microorganisms. Caco2-PIP2 was stably transfected with a GFP-labelled PIP2 binding unit, which allowed for analysis of cell polarity. Read-outs in the screening phase included transepithelial resistance (TER), tight junction (TJ) integrity and epithelial polarity (IF and confocal imaging) and paracellular permeability by sandwich assay. In experimental phase II, the microorganisms (including a invasio-defective ALS3-mutant) were selected for a detailed analysis using human duodenal organoid 2D monolayers (isolated from healthy individuals and CeD patients). Read-outs included: TER, TJ integrity, epithelial polarity, 33mer-gliadin translocation and differential transcriptome analysis of bulk-RNA isolated from microbiota-exposed duodenal organoids.

Results

​Pseudomonas aeruginosa and Candida albicans were selected in phase I. They caused a decrease in TER by 90% and 95% of the original TER, respectively. Escherichia coli K12 and Saccharomyces cerevisiae were used as controls for P. aeruginosa and C. albicans, respectively. In phase II, both candidates revealed a reduced TER, an abolition of epithelial polarity and disrupted TJs as well as an increased epithelial 33mer uptake in CeD and control 2D organoids. Candida invaded – in an ALS3-dependent manner – the 2D organoid duodenal epithelia and thereby interacted with epithelial dynamin. On the other hand, differential gene expression of P. aeruginosa-exposed epithelia revealed altered apoptosis, barrier function and ion transport.

Conclusion

Our results suggest that distinct microorganisms can cause an epithelial barrier defect and increase 33mer transport in epithelial monolayers, thereby contributing to CeD immune pathology.

Introduction

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. A remarkable increase in early onset colorectal cancer (EOCRC), defined as diagnosis before the age of 50 years, has been observed globally over the past decades. Recent data indicate that EOCRC presents distinct clinicopathological features, such as advanced stage at diagnosis and unique molecular signatures. Interestingly, EOCRC has been reported to be more likely to occur in the left sided colon, commonly called early onset left sided colorectal cancer (EOLCC). However, the underlying molecular mechanisms of EOLCC carcinogenesis and progression have still not been fully explored.
Concurrently, the prevalence of metabolic syndrome (MetS), including central obesity, insulin resistance, hypertension, and dyslipidemia, has increased in younger populations. As reported, MetS promotes carcinogenesis through chronic inflammation, hyperinsulinemia, and oxidative stress. Importantly, MetS is more common in patients with EOLCC. Although a hypothesis has been proposed regarding the possible link between MetS and EOLCC, the genetic and molecular mechanisms involved remain largely unexplored. Moreover, possible targeted treatment strategies for patients with both conditions remain limited.

Aims & Methods

This study aimed to investigate and elucidate key biomarkers associated with MetS-related EOLCC progression and treatment response.
The in-hospital cohort was employed to evaluate the clinical implications of the original tumor location in early-onset colorectal cancer (EOCRC). By utilizing differentially expressed genes (DEGs) and weighted gene coexpression network analysis (WGCNA), we identified potential genes associated with MetS-related EOLCC. The potential mechanisms of MetS-related EOLCC were analyzed using functional pathway enrichment. Random forest (RF) and support vector machine recursive feature elimination (SVM-RFE) algorithms were used to screen candidate biomarkers. The analyses of survival implications, expression patterns, and diagnostic performance were conducted to identify the key biomarkers. The responses to treatment were evaluated. Potential candidate compounds were screened, and molecular docking was performed. The expression and functional signatures were validated in single-cell RNA sequencing (scRNA-seq) datasets and experiments in vitro.

Results

The in-hospital cohort revealed the EOCRC patients had the greater proportion of EOLCC. Through the use of the edgdR package and WGCNA, we identified co-expressed genes common to both EOLCC and MetS, which are notably enriched in pathways related to stromal remodeling and metabolic regulation. By utilizing machine learning, 3 candidate biomarkers were highlighted. Moreover, only CD151 was associated to the prognosis of EOLCC and advanced stage. CD151 were found closely linked to stromal reconstruction and chemoresistance. Meanwhile, the potential compounds targeted to MetS-related EOLCC were identified by molecular docking. Subsequent scRNA-seq analysis confirmed the expression and function patterns of CD151, with especially prominent expression in tumor cells. Ultimately, the bioinformatics findings were validated by quantitative real-time PCR (qRT-PCR) and Immunohistochemical (IHC) staining of clinical samples.

Conclusion

This study investigated CD151 as the key biomarker in MetS-related EOLCC, leading to insights into prognosis, tumor biological status, and personalized treatment strategies. This key biomarker serves as a valuable reference for further exploring the development of clinical applications.

References

1. Wolf AMD, Fontham ETH, Church TR, et al. (2018) Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin 68: 250–281.
2. Frostberg E, Rahr HB (2020) Clinical characteristics and a rising incidence of early-onset colorectal cancer in a nationwide cohort of 521 patients aged 18-40 years. Cancer Epidemiol 66: 101704.
3. Soto J, Gutiérrez Alonso N, Bringas Beranek M, et al. (2022) Analysis of survival trends, clinical, and molecular characteristics of patients with early-onset colorectal cancer (EOCRC). J Clin Oncol 40: 59–59.
4. Dharwadkar P, Greenan G, Singal AG, et al. (2021) Is Colorectal Cancer in Patients Younger Than 50 Years of Age the Same Disease as in Older Patients? Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 19: 192-194.e3.
5. Ushula TW, Mamun A, Darssan D, et al. (2022) Dietary patterns and the risks of metabolic syndrome and insulin resistance among young adults: Evidence from a longitudinal study. Clin Nutr Edinb Scotl 41: 1523–1531.
6. Bitzur R, Brenner R, Maor E, et al. (2016) Metabolic syndrome, obesity, and the risk of cancer development. Eur J Intern Med 34: 89–93.

Introduction

Gastric cancer is a major cause of cancer-related mortality, and early detection improves outcomes. However, organized gastric cancer screening programs are largely absent in Europe, and vulnerable groups often have low awareness of preventive services. Roma communities face pronounced health disparities and barriers to healthcare, including social exclusion and low literacy, which may limit their use of preventive services [1].

Aims & Methods

We aimed to explore the knowledge, attitudes, and preferences regarding gastric cancer screening among Roma adults with low health literacy in Cluj-Napoca, Romania, to inform culturally tailored outreach strategies, as part of the TOGAS project. Approximately 40 Roma adults (18–72 years) were recruited via community centers for three focus groups (two urban, one rural) in Cluj-Napoca. All participants first attended a brief educational session on digestive health and gastric cancer to ensure baseline understanding. Guided by trained moderators, groups discussed their awareness of gastric cancer and perceptions of screening methods (endoscopy, blood tests, stool tests). All discussions were audio-recorded, transcribed, and thematically analyzed.

Results

Baseline awareness of gastric cancer screening was minimal. Most participants had never heard of any screening test or program for gastric cancer, indicating a major knowledge gap. Nevertheless, after receiving information, many expressed interest in screening for early detection. A prominent theme was communication preferences: nearly all participants preferred to receive health information via mobile phone or social media (e.g., messaging) and also through traditional channels like primary care providers. Overall, participants were open to screening if it was offered conveniently and respectfully.

Conclusion

Outreach is needed to improve engagement in cancer prevention among underserved populations. The lack of awareness in this Roma community echoes reports of poor knowledge of cancer prevention in other Roma groups and signals the need for targeted health promotion to reduce inequalities. As European health authorities consider implementing gastric cancer screening, input from vulnerable communities will be vital for equitable uptake.

References

1. Leja M. Where are we with gastric cancer screening in Europe in 2024? Gut. 2024 Nov 11;73(12):2074-2082.

Introduction

Optical diagnosis (OD) with a “resect and discard” strategy involves diagnosing diminutive polyps with high confidence, photodocumenting and resecting these without sending to histology. This greener, more efficient and cost-effective process underwent a comprehensive evaluation in the DISCARD3 study which showed, in a single screening centre, this meets the threshold for implementation and is feasible and safe with a quality assurance (QA) process in place. The NHS Bowel Cancer Screening Programme (NHSBCSP) in England approved implementation in 2023. Early learning from translating this research into a population based programme is presented.

Aims & Methods

All 506 screening colonoscopists in England have been invited to undertake accreditation in OD. Part 1 of the process involves attendance at a training day including a pre- and post-training test where 120 polyps are optically diagnosed. Pass criteria is ≥85% accuracy for high confidence optical diagnoses and overall ≥50% high confidence calls. Part 2 involves supervised OD at each endoscopists’ base hospital of 20 consecutive high confidence, optical polyp diagnoses with assessment of photodocumentation quality and diagnostic accuracy. To pass part 2 photodocumentation quality is required to be adequate in ≥90% of cases using the “3C photo quality score” and diagnosis accuracy ≥85%. Once achieved, individuals are fully accredited to perform OD with a resect and discard strategy for screening cases and must undertake re-accreditation with online assessment of a further 120 polyp images every 2 years to demonstrate competency. Those accredited are supported by “Optical Diagnosis Champions” at each screening centre who monitor performance and support QA. Once in place “Optical Diagnosis Champions” will support those becoming accredited in OD.

Results

65 screening colonoscopists attended part 1 of the accreditation in March 2024. 85% (55/65) passed the post-test on the first attempt with a further 7 individuals passing on repeat attempts. Overall 62/65 (95%) have completed part 1. Of these, 55/62 (89%) have successfully completed part 2 and are fully accredited.
As of 31 March 2025, 9618 polyps have been resected and discarded with a cost saving equivalent to £355866 (assuming a cost of £37 per polyp). An estimated 3206 hours of histopathology time has been saved (assuming 20 minutes per polyp).
Further training days have been held in September 2024, February 2025 and March 2025 increasing the total number of screening participants to over half of all screeners in England (310/506). The results from these will be reported in due course.

Conclusion

The NHSBSCP is the first population based screening programme in the world to implement OD with a resect and discard strategy. Quality assurance and monitoring is ongoing. In this early stage there have already been cost and time savings for the NHS which are expected to increase substantially once roll out completes in 2027.

References

Ahmad A et al. Implementation of optical diagnosis with a “resect and discard” strategy in clinical practice: DISCARD3 study. Gastrointestinal Endoscopy 2022; 96(6): 1021-1032.e2.

Disclosure

BPS has done consultancy and speaker work for Olympus. There are no other relevant current conflicts of interest to declare.

Introduction

Endoscopic sleeve gastroplasty (ESG) is a minimally invasive and effective treatment for obesity. However, concerns remain regarding gastric mucosal folding and the resulting reduced visibility of the gastric lining. To address these limitations, we developed a novel peroral endoscopic myo-neurotomy (POEM-N) technique (1), adapted from peroral endoscopic myotomy (POEM), as a weight-loss procedure. Although promising, the original POEM-N was time-consuming. This study aims to evaluate the safety and efficacy of a revised POEM-N (R-POEM-N) technique using a submucosal approach as a less invasive bariatric option in a porcine model.

Aims & Methods

Twelve pigs were assigned to either the R-POEM-N group (n = 8) or a sham endoscopic control group (n = 4). Myo-neurotomy was performed at four gastric sites in the R-POEM-N group: two on the greater curvature of the gastric body and two in the antrum. All pigs were fed a hypercaloric diet (twice the standard weight-based intake) and monitored for eight weeks post-procedure. The primary outcome was the proportional change in body weight at 8 weeks, calculated as the ratio of weight change to baseline weight. Secondary outcomes included food intake, changes in serum glucolipid levels, and assessments of safety and procedural duration.

Results

R-POEM-N was successfully completed in all pigs without major adverse events. The mean procedure time was 171.3 ± 3.0 minutes. At 8 weeks, the proportional change in body weight was significantly lower in the R-POEM-N group compared to controls (P = 0.017). Food intake was also significantly reduced in the R-POEM-N group (P < 0.05). No significant differences were observed in serum glucolipid levels between groups.

Conclusion

R-POEM-N effectively limited weight gain in a porcine model and demonstrated a favorable safety profile. These findings suggest that R-POEM-N may serve as a promising, minimally invasive bariatric intervention.

References

(1) Hamada K, Yamasaki Y, Takaki A, et al. Gastric peroral endoscopic myo-neurotomy as less-invasive bariatric surgery in porcine models: an experimental study. iGIE. 2024; 3: 358–65 doi: 10.1016/j.igie.2024.06.002.

Introduction

Recent insights in polyp molecular biology have suggested that hyperplastic polyps (HP) are closely related to sessile serrated lesions (SSL). Their hallmark serrated crypts closely resemble those found in SSL. Furthermore, similar to SSL, specific subtypes of HP can harbor BRAFV600E-mutations. These findings, amongst others, have raised the hypothesis that some HP may have an intrinsic malignant potential through the serrated neoplasia pathway. However, in everyday clinical practice, no routine HP subdifferentiation is performed. Therefore, we aimed to develop a deep learning algorithm to classify molecular subclasses of HP, namely microvesicular hyperplastic polyps (MVHP) and goblet cell-rich hyperplastic polyps (GCHP), based on their endoscopic features.

Aims & Methods

In this single-center trial 238 hyperplastic polyps from 159 patients were retrospectively selected. All polyps had high quality endoscopic video in white light endoscopy and virtual chromoendoscopy (i-scan) using Pentax EC38-i20c and EC34-i10 endoscopes. All histological slides were reviewed by an expert pathologist, updating diagnoses to MVHP, GCHP or mixed HP. We selected the polyps without mixed constitution for development of a deep learning algorithm. These polyps were randomly split into 70% for training, 10% for validation and 20% for testing. Sequences of still images of the polyps were manually annotated and subsequently used to train a deep learning algorithm, with dataset imbalance addressed by randomly oversampling the MVHP.

Results

The 238 HPs were reclassified as 152 GCHP, 59 MVHP and 27 mixed HPs after expert histological review. We subsequently trained a convolutional neural network on the 211 HPs without mixed constitution. This resulted in a model with an AUC of 0.817, corresponding to a sensitivity of 80.0% for predicting MVHP and 78.4% for predicting GCHP. However, due to the low prevalence of MVHP (28%) the positive predictive value for MVHP is only 33.3%, whilst the positive predictive value for GCHP is 96.7%.

Conclusion

We successfully developed a deep learning algorithm capable of differentiating between molecular subclasses of hyperplastic polyps (MVHP vs GCHP) based on their endoscopic features. This model demonstrated a robust AUC of 81.7% with a sensitivity of 80.0% and 78.4% for predicting MVHP and GCHP respectively. However, the low prevalence of MVHP (28%) limited its positive predictive value (33.3%) for predicting MVHP. Despite these challenges, this pilot study serves as a proof of concept that artificial intelligence is capable of predicting hyperplastic polyp subclasses based on endoscopic appearance. Furthermore, it highlights the potential of artificial intelligence to enhance the diagnostic precision, which could contribute to more tailored surveillance and management strategies in the future.

Disclosure

The authors declare no conflicts of interest.