Upper GI Tract

Introduction Eosinophilic esophagitis (EoE) is a chronic immune-mediated oesophagal disease in children that causes feeding difficulty, vomiting, abdominal pain, dysphagia, and poor quality of life. Standard therapy often includes proton-pump inhibitors and swallowed topical corticosteroids (STCs). However, many children either do not respond adequately, cannot tolerate STCs, or have contraindications to their use. This creates an important therapeutic gap, especially in younger children with persistent inflammation and risk of long-term oesophagal remodelling. Problem statement The key clinical question is whether dupilumab remains effective in children with EoE who have already used STCs, particularly those with inadequate response, intolerance, or contraindication (IRIC) to steroid therapy. Summary This subgroup analysis from the phase 3 EoE KIDS study evaluated children aged 1–11 years with EoE not responsive to proton-pump inhibitors. Among 102 patients, 80% had prior STC use and 58% had prior IRIC to STCs. At week 16, higher-exposure dupilumab achieved histologic remission in about 61% of children with prior STC exposure and in a similar proportion of those with prior IRIC, compared with 0% on placebo. Improvements in endoscopic and histologic secondary outcomes paralleled these findings. Benefits were maintained through week 52, and children switched from placebo to dupilumab also improved. Lower-exposure dupilumab showed similar but generally smaller responses. Safety was consistent with the known dupilumab profile. Overall, this study supports dupilumab as an effective steroid-sparing option for children with difficult-to-treat EoE.

What Are MEK Inhibitors? MEK inhibitors are targeted drugs that block the MAPK/ERK signalling pathway, specifically the MEK (mitogen-activated protein kinase kinase) enzyme. This pathway regulates cell proliferation, survival, and differentiation, and its abnormal activation contributes to several cancers. Drugs such as trametinib are already used in oncology (e.g., melanoma and BRAF-mutant cancers) and are now being explored for reversing early precancerous changes in tissues before cancer develops. What Are Gastric Precancerous Lesions? Gastric precancerous lesions are pathological changes in the stomach lining that increase the risk of gastric cancer. The most important include:

1. Chronic atrophic gastritis
2. Intestinal metaplasia (IM)
3. Dysplasia These lesions often arise after long-term Helicobacter pylori infection and may progress to gastric cancer over many years. Summary In a phase 1 clinical trial evaluating trametinib, a MEK inhibitor, for reversing gastric precancerous lesions such as intestinal metaplasia and parietal cell atrophy. The trial suggested that short-term, low-dose MEK inhibition may improve gastric mucosal histology, indicating a potential preventive strategy against gastric cancer. However, the authors highlight important limitations. The study included only 15 patients, lacked a randomised placebo-controlled group, and focused exclusively on patients with previously resected stage I gastric cancer and prior H. pylori eradication, limiting generalizability. Additionally, histologic improvements are intermediate markers and do not prove reduced cancer risk, particularly with only 1 year of follow-up. Statistical concerns, such as a lack of adjustment for multiple comparisons, were also noted. Despite these limitations, the study represents the first human investigation of MEK inhibitors for gastric cancer prevention, providing early proof-of-concept and laying the groundwork for larger, long-term trials assessing cancer incidence as the ultimate outcome.

Introduction Eosinophilic gastrointestinal diseases (EGIDs) are chronic, immune-mediated disorders defined by eosinophil-predominant inflammation in the GI tract. Over the past 30 years, EGIDs—especially eosinophilic esophagitis (EoE)—have risen sharply without a clear plateau. This review summarises what has changed most in epidemiology, natural history, diagnosis, and treatment, and where the biggest gaps remain. 20 Key Takeaways (Clinician-focused) Two big buckets: EGIDs are now classified as EoE (oesophagus only) and non-EoE EGIDs (stomach, small bowel, colon ± overlap). New nomenclature matters: “Eosinophilic gastroenteritis” is being de-emphasised in favour of site-specific labels (EoG, EoN, EoC), improving clarity for care and research. EoE is no longer rare: Incidence and prevalence have continued to climb globally, often faster than endoscopy/biopsy rates. “Tip of the iceberg” problem: Many patients likely remain undiagnosed due to under-biopsying, missed follow-up after food bolus impaction, and diagnostic delay (often years). High-yield clinical settings for EoE: EoE is common in dysphagia, extremely common in food impaction, and should be excluded before antireflux surgery or when strictures are present. Atopy linkage is strong: Food allergy, asthma, eczema, and allergic rhinitis markedly increase EoE probability; risk rises with more atopic comorbidities. Diagnosis of EoE is straightforward: Symptoms of oesophageal dysfunction + ≥15 eos/hpf on oesophageal biopsy + exclusion of competing causes. Severity tracking is evolving: Tools like I-SEE help frame symptoms/complications, inflammatory activity, and fibrostenotic features over time. Non-EoE EGIDs remain uncommon—but likely underrecognized: Prevalence is low in many datasets, but symptom nonspecificity and biopsy/reading variability may miss cases. Non-EoE diagnosis is harder because eosinophils are “normal” distally: Unlike the oesophagus, eosinophils are normal residents in stomach/small bowel/colon—so thresholds and context matter. Proposed histologic thresholds vary by segment: Practical cutoffs (approximate) increase from stomach/duodenum toward ileum/right colon and then decline leftward. Non-EoE EGIDs can be mucosal, muscular, or serosal: Symptoms and complications reflect depth—muscular disease can obstruct; serosal disease can present with eosinophilic ascites. Natural history of EoE is chronic and often progressive: Untreated inflammation can move toward fibrosis/stricture (fibrostenosis); risk increases with time and gaps in care. EoE relapse is the rule when therapy stops: Multiple RCTs show high recurrence rates after withdrawing effective treatment. EoE treatment pillars are now established: PPI, swallowed topical corticosteroids (STCs), food elimination diets (FEDs), and dupilumab are central options. PPI is a legitimate anti-inflammatory strategy in EoE: About half achieve histologic remission; twice-daily dosing tends to perform better than once daily; maintenance can work for many responders. STCs are highly effective and now disease-specific: Budesonide formulations (e.g., oral suspension/orodispersible tablet) have strong induction and maintenance data; candidiasis is the most common AE. Dupilumab is the first approved biologic for EoE: It targets IL-4/IL-13 signaling and achieves meaningful histologic and symptom benefits, with a generally favourable safety profile. Diet therapy is effective but should start simply: Empiric elimination is recommended, often beginning with the least restrictive (commonly milk elimination) and escalating stepwise if needed; allergy tests do not reliably identify triggers. Non-EoE EGIDs: steroids still dominate; biologics are emerging: Evidence is mostly observational; systemic/topical steroids and elemental/elimination diets are used, while newer agents (e.g., IL-13 pathway drugs, dupilumab in EoG/EoN trials) are promising, but the field still lacks approved therapies and robust endpoints.