David Mark Pritchard

INTRODUCTION: 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 >1 cm 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, defined as recurrence or progression, used to analyze progression-free survival (PFS) 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 15 mm. 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 unfavorable outcome ( P = 0.005), with lesions ≥24 mm predicting shorter PFS (hazard ratio 3.93; P < 0.001). Endoscopic submucosal dissection and modified-endoscopic mucosal resection were associated with a significantly longer PFS ( P = 0.004). R0 resection showed a borderline protective effect. Five-year overall survival approached 95%. DISCUSSION: T1g-NETs > 1 cm frequently recur and may exhibit aggressive potential, particularly when lesions are larger. When endoscopic resection is feasible, endoscopic submucosal dissection or modified-endoscopic mucosal resection should be preferred to optimize outcomes.

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.

Animal models are standard for safety evaluation, yet physiological differences limit human translation. Doxorubicin (DOX), a chemotherapeutic, can cause off-target gastrointestinal (GI) toxicity and treatment discontinuation. This study evaluated human colonoids as a potential human-relevant epithelial model for DOX-induced GI toxicity by comparing transcriptomic responses across human colonoids, mouse colonoids, and male C57BL/6J mouse colon tissue. Within each dataset, DOX-treated conditions were pooled across model-specific exposure levels and time points to prioritize robust DOX-associated transcriptional signatures. Using a parallelogram approach, differential expression, co-expression, pathway mapping, and Comparative Toxicogenomics Database (CTD) benchmarking were applied to compare model concordance and identify DOX-responsive mechanisms. Shared responses converged on cell-cycle regulation, DNA damage response, DNA repair, and apoptosis. DEG-level concordance 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. CTD benchmarking supported DOX biology and highlighted underrepresented GI-relevant signals, indicating gaps in intestinal toxicogenomic annotations. Colonoid-based transcriptomics supports human colonoids as controlled epithelial models for mechanistic GI toxicity assessment, although missing vascular, immune, and systemic context means clinical validation remains necessary.

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.

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.

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.

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.