Animal models are standard for safety evaluation, yet physiological differences limit human translation. Doxorubicin, a chemotherapeutic agent, can cause off-target gastrointestinal toxicity and treatment discontinuation. This study evaluated human colonoids as a controlled human-derived epithelial model for doxorubicin-induced gastrointestinal toxicity by comparing transcriptomic responses across human colonoids, mouse colonoids, and male C57BL/6J mouse colon tissue. Within each dataset, doxorubicin-treated conditions were pooled across model-specific exposure levels and time points to estimate broad doxorubicin-associated transcriptional signatures. Using a parallelogram approach, differential expression, co-expression, pathway mapping, and Comparative Toxicogenomics Database benchmarking were applied to compare model concordance and identify doxorubicin-responsive mechanisms. Shared responses converged on cell-cycle regulation, DNA damage response, DNA repair, and apoptosis. Concordance in differentially expressed genes was highest between mouse colonoids and mouse colon, while pathway mapping showed similarities between colonoid systems. A core set of p53-associated genes, including BAX, INKA2, and ZMAT3, was shared across datasets, with additional apoptotic and DNA damage response features observed in colonoids. Comparative Toxicogenomics Database benchmarking supported doxorubicin biology and highlighted underrepresented gastrointestinal toxicity-relevant signals, indicating gaps in intestinal toxicogenomic annotations. Colonoid-based transcriptomics supports human colonoids as controlled epithelial models for mechanistic gastrointestinal toxicity assessment, although missing vascular, immune, and systemic context means clinical validation remains necessary.

OBJECTIVES:Type 1 gastric neuroendocrine tumors (T1g-NETs) are well-differentiated lesions with excellent survival but frequent recurrence. Tumor size is the main prognostic factor, yet optimal management for tumors >1cm remains uncertain. This study aimed to evaluate treatment strategies and outcomes in patients with T1g-NETs>1 cm. METHODS:We conducted a retrospective multicenter study including 106 adults with T1g-NETs>1 cm. Clinicopathologic and management data were collected. The primary outcome event was a composite unfavorable outcome (UO), defined as recurrence or progression, used to analyze progression-free survival as the main time-to-event outcome. Analyses included multinomial logistic regression, Cox models, and Kaplan-Meier curves (p<0.05). RESULTS:Among 106 patients (58.5% female; median age 59), median tumor size was 15mm. Most tumors were Grade 1 (61.4%) or Grade 2 (37.7%), with median Ki-67 of 2%. Endoscopic resection was performed in 76 patients (71.7%), surgery in 33 (31.1%, including 13 initially treated endoscopically), and 10 (9.4%) were surveilled. Over a median 61-month follow-up, 24 patients (22.6%) recurred, 8 (7.5%) progressed; only 2 deaths (1.9%) were tumor-related. Larger tumors were associated with UO (p=0.005), with lesions ≥24mm predicting shorter progression-free survival (HR 3.93;p<0.001). Endoscopic submucosal dissection (ESD) and modified-endoscopic mucosal resection (m-EMR) were associated with a significantly longer progression-free survival (p=0.004). R0 resection showed a borderline protective effect. Five-year overall survival approached 95%. CONCLUSIONS:T1g-NETs>1cm frequently recur and may exhibit aggressive potential, particularly when lesions are larger. When endoscopic resection is feasible, ESD or m-EMR should be preferred to optimize outcomes.

INTRODUCTION:Local excision can be a definitive treatment for T1 SM1 N0 rectal adenocarcinomas, but post-excision histology may reveal adverse features or more advanced tumour stage, requiring adjuvant treatment. For patients who are unfit or unwilling to undergo invasive surgery, Contact X-ray Brachytherapy (CXB) boost and external beam (chemo)radiotherapy [EB(C)RT] can be used as an alternative option to reduce recurrence risk. METHODS:This study reports on patients who received post excision CXB with EB(C)RT between 2003 and 2020. It reports on lesion characteristics, excision techniques, and adjuvant treatment characteristics. Survival outcomes were compared across local excision techniques and radiotherapy schedules. Regression analysis was conducted to identify factors predictive of (local and distant) recurrence. RESULTS:In this cohort of 323 patients 5-year overall survival (OS) was 84.2 %, 3-year recurrence free survival (RFS) was 91.6 %, with 94.7 % disease-free and 95 % stoma-free. No significant differences were observed for 5-year OS and 3-year RFS between excision types (p = 0.10, p = 0.56) or radiotherapy schedules (p = 0.90, p = 0.13) respectively. Resection margin involvement tripled recurrence risk compared to R0 resections (OR = 3.67, 95 % CI: 1.13-16.42, p = 0.048). CONCLUSION:For high-risk pT1 tumours, post-excision treatment with EB(C)RT and CXB boost resulted in survival outcomes comparable to those reported with conversion to radical surgery. There were no significant differences in survival outcomes between radiotherapy schedules and local excision techniques. Involved resection margins were associated with a significantly increased recurrence risk. The clinical benefit of CXB should be formally evaluated in large, prospective studies.

Background: Transanal endoscopic microsurgery (TEMS) is an organ-preserving approach for treatment of early rectal cancer (ERC). However, adverse histopathological features identified post-TEMS often necessitate adjuvant therapy. This study aims to compare the long-term oncological outcomes of patients who underwent TEMS and were offered adjuvant treatments with total mesorectal excision (TME), chemoradiotherapy (CRT), radiotherapy (RT), active surveillance, or dose escalation with contact X-ray brachytherapy (CXB). Methods: This study included patients treated with TEMS for ERC between September 2012 and December 2022, with follow-up until December 2023. Patients with adverse histopathological features (extra-mural venous invasion, lympho-vascular invasion, R1 margins, tumour budding) were assigned to adjuvant treatments. Inverse probability of treatment weighting (IPTW) was applied to mitigate selection bias. Results: Of the 117 patients, 24 underwent TME, 17 received CRT, 25 received RT, 14 underwent active surveillance, and 37 patients received CXB boost along with CRT. The median follow-up was 60 months (IQR 52-73). During this time, 29 patients developed recurrence, and 15 died. The 5-year overall survival (OS) was 78.6%, and disease-free survival (DFS) was 70.9%. Compared to CXB, the mortality risk for CRT (HR = 0.81; 95% CI: 0.20-3.28; p = 0.77) and TME (HR = 3.68; 95% CI: 0.46-29.79; p = 0.22) was not significantly different. However, TME was associated with a significantly higher recurrence risk compared to CXB (HR = 7.57; 95% CI: 1.23-46.84; p = 0.029). Conclusions: An organ-preserving strategy with CRT or CRT combined with a CXB boost may offer comparable long-term outcomes and reduced recurrence risks for patients undergoing TEMS for ERC with poor prognostic features. Further research with larger cohorts is needed to validate these results.

Background/Objectives: With recent advancements in rectal cancer management leading to longer patient survival, the impact of various treatment approaches on patients’ quality of life (QOL) becomes an important focus of attention. While QOL studies exist for watch-and-wait after (chemo)radiation with/without local excision, data on health-related QOL (HRQOL) outcomes after contact X-ray brachytherapy (CXB) remain limited. This study evaluated functional and HRQOL outcomes in rectal cancer patients undergoing CXB and (chemo)radiation over one year. Methods: This prospective observational study (enrolment January–October 2023) with one-year follow-up assessed functional and HRQOL outcomes after CXB and (chemo)radiation using EORTC-QLQ-CR29, HADS, and EQ-5D-3L questionnaires. Longitudinal analyses were conducted using linear mixed-effects models, incorporating both fixed and random effects, following data processing based on relevant scoring manuals. Results: QOL was assessed in 53 patients who attended our centre for CXB for various clinical indications, with 51, 47, and 42 remaining at the end of treatment, 6-month, and 12-month follow-ups, respectively. Overall, symptom and functional scores from EORTC-QLQ-CR29 remained stable throughout the follow-up period. Significant improvements were observed in abdominal pain, flatulence, urinary frequency, and body weight at 12 months. HADS and EQ-5D-3L scores remained stable, while EQ-VAS scores showed improvement, indicating a good overall quality of life following CXB treatment. Conclusions: CXB treatment combined with (chemo)radiation maintained stable HRQOL, with some improvements in symptoms and QOL noted during the subsequent year. These findings will help rectal cancer patients understand the benefits and limitations of CXB as a treatment option.

BACKGROUND:Currently, there are no clinically predictive models that can prognosticate the response of rectal cancers to Contact X-ray brachytherapy (CXB). This review aims to critically evaluate existing models that have attempted to predict the response of rectal cancer to external beam radiotherapy, with the objective of laying the foundation for the development of a CXB-specific prediction model. METHODS:A random-effects meta-analysis was employed to calculate pooled estimates of the discriminative ability of published models. Using the Prediction Model Risk Of Bias Assessment Tool (PROBAST), each model was evaluated for its risk of bias and applicability. Additionally, the frequency of commonly utilised predictive factors was documented. RESULTS:Twelve papers discussed fifteen models based on pre-treatment factors. Models predicting response based on the Tumour regression grade (TRG) classified responders as patients who achieved a complete response or near complete response and achieved a pooled AUC of 0.82 (95% CI 0.74-0.89). Models that predicted pathologic complete response (pCR) had a pooled AUC of 0.76 (95% CI 0.71-0.82). The most utilised predictive parameters were age, tumour grade and T stage. However, these models were prone to significant risk of bias and had limited applicability to the general population. CONCLUSIONS:Although the existing models were statistically robust, they lacked broad applicability. This was primarily due to a lack of external validation, which limits their clinical utility. A future CXB-specific model should prioritise dedicated data collection based on pre-calculated sample size and include the predictive factors identified in this review.

Reliable prediction and prevention of adverse drug reactions (ADRs) remains a key challenge in the development of new medicines. Advanced mathematical and computational modelling approaches, which incorporate cutting-edge mechanistic understanding of ADRs in concert with systematically collected data addressing knowledge gaps, are integral components of model-informed drug discovery and development (MID3). These approaches provide a precise, quantitative framework for predicting and mitigating safety risks in the earliest phases of drug development. Here, we highlight recent developments in the burgeoning field of quantitative systems toxicology (QST), including insights into the current state-of-the-art, as well as outcomes from the Innovative Medicines Initiative (IMI) 2 TransQST project. QST models that describe the disruption of cardiovascular, gastrointestinal, hepatic and renal physiological functions following drug exposure are presented, along with recommendations for their application in drug discovery and development.

BACKGROUND:Survival rates after a diagnosis of cancer are improving. Poorly managed gastrointestinal (GI) side effects can interfere with delivery of curative cancer treatment. Long-term physical side effects of cancer therapy impinge on quality of life in up to 25% of those treated for cancer, and GI side effects are the most common and troublesome. AIM:To provide comprehensive, practical guidance on the management of acute and chronic luminal gastrointestinal symptoms arising during and after treatment for cancer METHODS: A multidisciplinary expert group including patients treated for cancer, divided into working parties to identify, and synthesise recommendations for the optimal assessment, diagnosis and appropriate interventions for luminal GI side effects of systemic and local cancer therapies. Recommendations were developed using the principles of the BMJ AGREE II reporting. RESULTS:103 recommendations were agreed. The importance of the patient perspective and what can be done to support patients are emphasised. Key physiological principles underlying the development of GI toxicity arising from cancer therapy are outlined. Individual symptoms or symptom clusters are poor at distinguishing the underlying cause(s), and investigations are required if empirical therapy does not lead rapidly to significant benefits. Patients frequently have multiple GI causes for symptoms; all need to be diagnosed and optimally treated to achieve resolution. Investigations and management approaches now known to be ineffective or of questionable benefit are highlighted. CONCLUSIONS:The physical, emotional and financial costs to individuals, their families and society from cancer therapy can be considerable. Identifying and signposting affected patients who require specialist services is the role of all clinicians. Progress in the treatment of cancer increasingly means that patients require expert, multidisciplinary supportive care providing effective and safe treatment at every stage of the cancer journey. Development of such expertise should be prioritised as should the education of health professionals and the public in what, when and how acute and chronic gastrointestinal symptoms and complications should be managed.

AIMS:Atherosclerosis initiation at sites of disturbed blood flow involves heightened inflammation coupled to excessive endothelial cell (EC) proliferation. Here, we unveil the pivotal role of c-REL, a member of the NF-κB transcription factor family, in orchestrating these processes by driving dual pathological inflammatory and cell cycle pathways. METHODS AND RESULTS:Analysis of cultured EC and murine models revealed enrichment and activation of c-REL at atherosusceptible sites experiencing disturbed flow. Transcriptome analysis, extensively validated in vitro and in vivo, demonstrates that endothelial c-REL drives inflammation via a TXNIP-p38 MAP kinase signalling pathway and enhances proliferation through a non-canonical NFKB2-p21 pathway. Consistent with its pivotal role in EC pathology, genetic deletion of c-Rel in EC significantly reduces plaque burden in hypercholesterolaemic mice. CONCLUSION:These findings underscore the fundamental role of c-REL in endothelial responses to disturbed flow and highlight therapeutic targeting of endothelial c-REL as a potential strategy for atherosclerosis treatment.

Neuroendocrine neoplasms (NENs) comprise well differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). NENs can develop at various anatomical sites, the most common being in the gastrointestinal tract and their incidence is increasing. Although uncommon, they are no longer considered to be rare. Comprehensive biochemical, histopathological and imaging investigations are required to assess an NEN's site, grade and stage and to determine whether it is producing hormones and resulting in a hormonal syndrome. Localised NENs are typically managed with surgery, while metastatic NENs are often treated initially with systemic therapy, such as somatostatin analogue injections. There are multiple options for NEN management, so these patients need to be discussed and managed by a multidisciplinary team of clinicians who have expertise in this tumour type. This article is intended to provide an introduction and summary for clinicians who have little prior experience of NENs.

People with neuroendocrine neoplasms (NENs) face a multitude of challenges, including delayed diagnosis, low awareness of the cancer among healthcare professionals and limited access to multidisciplinary care and expert centres. We have developed the first patient care pathway for people living with NENs in England to guide disease management and help overcome these barriers. The pathway was developed in two phases. First, a pragmatic review of the literature was conducted, which was used to develop a draft patient care pathway. Second, the draft pathway was then updated following semi-structured interviews with carefully selected expert stakeholders. After each phase, the pathway was discussed among a multidisciplinary, expert advisory group (which comprised the authors and the Deputy Chief Operating Officer, West Suffolk NHS Foundation Trust), who reached a consensus on the ideal care pathway. This article presents the outputs of this research. The pathway identified key barriers to care and highlighted how these may be addressed, with many of the findings relevant to the rest of the UK and international audiences. NENs are increasing in incidence and prevalence in England, compounding pre-existing inequities in diagnosis and disease management. Effective integration of this pathway within NHS England will help achieve optimal, equitable care provision for all people with NENs, and should be feasible within the existing expert multidisciplinary teams across the country.

Background and purpose Radical surgery is the standard of care for early rectal cancer. However, alternative organ-preserving approaches are attractive, especially in frail or elderly patients as these avoid surgical complications. We have assessed the efficacy of sole Contact X-ray Brachytherapy (CXB) treatment in stage-1 rectal cancer patients who were unsuitable for or declined surgery. Materials and methods This retrospective multi-centre study (2009–2021) evaluated 76 patients with T1/2-N0-M0 rectal adenocarcinomas who were treated with CXB alone. Outcomes were assessed for the entire cohort and sub-groups based on the T-stage and the criteria for receiving CXB alone; Group A: patients who were fit enough for surgery but declined, Group B: patients who were high-risk for surgery and Group C: patients who had received prior pelvic radiation for a different cancer. Results With a median follow-up of 26(IQR:12–49) months, initial clinical Complete Response (cCR) was 82(70–93)% with rates of local regrowth 18(8–29)%, 3-year actuarial local control (LC) 84(75–95)%, distant relapse 3 %, and no nodal relapse. 5-year disease-free survival (DFS) and overall survival (OS) were 66(48–78)% and 58(44–75)%. Lower OS was observed in Groups B [HR:2.54(95 %CI:1.17, 5.59), p = 0.02] and C [HR:2.75(95 %CI:1.15, 6.58), p = 0.03]. Previous pelvic radiation predicted lower cCR and OS. The main toxicity was G1-2 rectal bleeding (26 %) and symptoms of impaired anal sphincter function were not reported in any patients. Conclusion CXB treatment alone achieved a high cCR rate with satisfactory LC and DFS. Inferior oncological outcomes were observed in patients who had received prior pelvic radiotherapy. CXB alone, with its favourable toxicity profile and avoidance of general anaesthesia and surgery risks, therefore, can be considered for patients who are unsuitable for or refuse surgery.

Background Irritable bowel syndrome (IBS) is a common and debilitating disorder manifesting with abdominal pain and bowel dysfunction. A mainstay of treatment is dietary modification, fi cation, including restriction of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols). A greater response to a low FODMAP diet has been reported in those with a distinct IBS microbiome termed IBS-P. We investigated whether this is linked to specific fi c changes in the metabolome in IBS-P. Methods Solid phase microextraction gas chromatography-mass spectrometry was used to examine the faecal headspace of 56 IBS cases (each paired with a non-IBS household control) at baseline, and after four-weeks of a low FODMAP diet (39 pairs). 50% cases had the IBS-P microbial subtype, while the others had a microbiome that more resembled healthy controls (termed IBS-H). Clinical response to restriction of FODMAPs was measured with the IBS-symptom severity scale, from which a pain sub score was calculated. Findings Two distinct metabotypes were identified fi ed and mapped onto the microbial subtypes. IBS-P was characterised by a fermentative metabolic profile fi le rich in short chain fatty acids (SCFAs). After FODMAP restriction significant fi cant reductions in SCFAs were observed in IBS-P. SCFA levels did not change significantly fi cantly in the IBS-H group. The magnitude of pain and overall symptom improvement were significantly fi cantly greater in IBS-P compared to IBS-H (p p = 0.016 and p = 0.026, respectively). Using just fi ve metabolites, a biomarker model could predict microbial subtype with accuracy (AUROC 0.797, sensitivity 78.6% (95% CI: 0.78-0.94), - 0.94), specificity fi city 71.4% (95% CI: 0.55-0.88). - 0.88). Interpretation A metabotype high in SCFAs can be manipulated by restricting fermentable carbohydrate, and is associated with an enhanced clinical response to this dietary restriction. This implies that SCFAs harbour pronociceptive potential when produced in a specific fi c IBS niche. By ascertaining metabotype, microbial subtype can be predicted with accuracy. This could allow targeted FODMAP restriction in those seemingly primed to respond best. Funding This research was co-funded by Addenbrooke's ' s Charitable Trust, Cambridge University Hospitals and the Wellcome Sanger Institute, and supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

We have read with interest several recent papers in Gut that have reported novel insights about the potential consequences of reduced gastric acid secretion. These include reports that proton pump inhibitor (PPI) use increases the risks of developing diverse diseases including gastric adenocarcinoma 2 and severe COVID19 infection. An intriguing recent paper has also shown that pathological suppression of gastric acid secretion in people with autoimmune atrophic gastritis does not predispose to gastric adenocarcinoma development unless they are also infected with Helicobacter pylori. These patients are, however, more prone to developing type 1 gastric neuroendocrine (carcinoid) tumours (NETs). Interestingly, gastric NETs do not develop in people who have H. pylori induced atrophic gastritis or following long term druginduced acid inhibition. These observations highlight the complexity of the regulation of gastric acid secretion and suggest that the underlying cause of hypochlorhydria is a major determinant of its consequences. We have previously reported that different conditions that reduce gastric acid secretion have different consequences on the gastric microbiome and this may be one contributory mechanism. The extent and type of the hypergastrinaemia that is associated with hypochlorhydric conditions also varies considerably and may play a role. None of these recent advances in gastroenterology would have been possible without the seminal discovery of the presence of hydrochloric acid in gastric juice by William Prout FRS in 1823. As the current secretary (RL) and treasurer (DMP) of the ‘Prout club’, we thought it was important to acknowledge and remember the 200year anniversary of this important event. The Prout club was formed by the late Dr Hugh Baron (Consultant Gastroenterologist at St Mary’s Hospital, London) in 1972 to commemorate Prout’s discovery. The club meets annually during the British Society of Gastroenterology conference for dinner and a debate on a topic relevant to gastric acid secretion. Coincidentally, our 2022 meeting in Birmingham marked the 50th anniversary of the Prout club’s formation. Prout (1785–1850) completed his MD at the University of Edinburgh in 1811 and made several important contributions to science and medicine. In addition to his discoveries about the composition of gastric juice, he is probably best known within the field of chemistry for ‘Prout’s hypothesis’ concerning the structure of the atom. The legacies of his discoveries have been enormous. Our modern capacity to potently inhibit gastric acid secretion first with H2 receptor antagonists, subsequently with PPIs and most recently with potassiumcompetitive acid blockers has revolutionised the treatment of peptic ulcers and gastrooesophageal reflux disease over the 50 years since the Prout club was founded. These drugs, along with a recognition of the importance of H. pylori infection, have meant that surgery for benign diseases of the upper gastrointestinal tract is largely an extinct discipline. Such a statement would have been unimaginable to a general surgeon practising before the launch of cimetidine in 1976. However, it is important to remember that the normal physiological state of the human stomach is to produce concentrated hydrochloric acid. Although altering normal gastric acid secretion can be useful to treat certain diseases, it is not surprising that disturbing the physiological state, either as a result of pathology or pharmacology, may have unintended consequences. We are sure that Gut will publish many more important papers in this field before the Prout club celebrates its centenary in another 50 years’ time and we speculate that many of these will involve studies of the microbiome. There is still much to learn about gastric acid and its role in the pathogenesis of various human diseases. The legacy of Prout’s important discovery lives on.

Due to their increasing incidence, neuroendocrine neoplasms (NENs) are being detected more frequently by endoscopists while they are performing diagnostic upper or lower gastrointestinal (GI) endoscopies. These procedures are usually performed for unrelated indications or for screening, with the tumours often being detected incidentally. The most common scenario is of an endoscopist being surprised by receiving a histology report of a well-differentiated neuroendocrine tumour (NET) after biopsying a small polyp that was initially thought to be benign. This article aims to provide some guidance about what to do next in that situation. All patients with NET should, however, be referred to a fully constituted NEN multidisciplinary team for definitive investigations and management.In general, the site, size and number of any possible NENs should be fully assessed during the initial endoscopy and representative endoscopic images should be captured. If the initial endoscopic assessment was inadequate, the procedure may need to be repeated. Possible NENs should be sampled using biopsy forceps. Endoscopic resection should only be attempted following histological confirmation of the diagnosis and tumour grade and after additional investigations have been performed to fully stage the tumour and determine its hormone production status. This is essential so that patients do not undergo either unnecessary or inadequate endoscopic resections.This article discusses the endoscopic features and subsequent assessment of NENs that arise in the stomach, duodenum, terminal ileum and rectum, as these are the common tumour sites within the GI tract.