Introduction

Colon cancer is one of the most common malignant tumors in humans, with colon adenocarcinoma (COAD) being the predominant type. It typically arises from the transformation of colon adenomas. However, the cellular and molecular mechanisms driving the progression from adenoma to adenocarcinoma remain incompletely understood. Investigating this transformation process is crucial for the early intervention and treatment of colon cancer.

Aims & Methods

To elucidate the mechanisms driving the adenoma-carcinoma transition in COAD, we conducted single-cell sequencing on samples from adjacent normal tissue, adenomatous tissue, and colon adenocarcinoma tissue. We also integrated single-cell datasets from two GEO databases. Through cell communication analysis, differential gene expression analysis, and pseudotime analysis, we explored the role of the CD8⁺ Tex subset in the adenoma-carcinoma transition. Utilizing GEO transcriptome datasets, we constructed a disease risk prediction model based on nine genes (CEBPB, LEF1, ANXA2, SERPINE2, RUNX2, MLLT6, MAT2A, STAT1, NOTCH1). This model was validated using the TCGA transcriptome dataset and the IMvigor210 immunotherapy cohort. Combining the risk coefficients of the nine genes with survival analysis results, we identified RUNX2 as a potentially significant risk factor. The function of key molecules was further validated using an in vivo AOM/DSS colon cancer model and the HCT116 colon cancer cell line in vitro. Additionally, the interaction between CD8⁺ Tex cells and tumor cells was confirmed through multiplex immunofluorescence.

Results

The study found that the proportion of CD8⁺ Tex cells significantly increased in colon adenoma and carcinoma samples compared to adjacent normal tissue. These cells may promote the transition from adenoma to COAD through multiple mechanisms. Pseudotime analysis indicated that CD8⁺ Tex cells in COAD might differentiate from those in adenomas, and highly malignant COAD epithelial cells may originate from highly malignant adenoma cells. The risk score model based on nine genes identified RUNX2 as a potentially significant risk factor. Both in vivo and in vitro experiments confirmed that RUNX2 promotes the proliferation, invasion, and migration of the HCT116 colon cancer cell line, while the RUNX2 inhibitor CADD522 can suppress the adenoma-to-carcinoma transition. Additionally, TNF-α was found to enhance RUNX2 mRNA and protein expression, thereby promoting the malignant behavior of HCT116 cells and the expression of genes related to the adenoma-to-carcinoma transition.

Conclusion

This study identifies that CD8+ Tex cells may activate the transcription factor RUNX2 in colon cancer cells by binding the ligand TNF-α to the TNFR1 receptor on the membrane of malignant epithelial cells. This activation promotes the transition of malignant epithelial cells in colon adenomas to malignant cancer cells, leading to poor prognosis in COAD. This finding not only elucidates the key cellular and molecular mechanisms of the adenoma-to-carcinoma transition but also provides new potential targets for early intervention and treatment of colon cancer.

Introduction

Acute appendicitis is a widely encountered emergency across the globe, showcasing the resilience of modern medicine, as it is traditionally addressed through the transformative procedure of appendectomy. Endoscopic Retrograde Appendicitis Therapy (ERAT) has emerged as a minimally invasive alternative; however recurrence is a worry.

Aims & Methods

This multi-center retrospective study aimed to evaluate the long-term safety, efficacy, and recurrence-related risk factors of ERAT to guide clinical decision-making. A total of 435 patients who underwent ERAT for acute appendicitis between October 2017 and October 2024 at three Chinese medical centers were included. Appendicitis recurrence was defined as imaging-confirmed symptoms returning within one-month post-ERAT. Univariate and multivariate regression analysis identified independent recurrence risk variables.

Results

All ERAT procedures were technically successful and achieved a clinical success rate of 92.4%. Over a median follow-up period of 37 months, the overall recurrence rate was 16.1%, with the majority of recurrences (13%) observed within the first year. Independent risk factors for recurrence included recurrent appendicitis (HR=1.916), appendiceal lumen distortion (HR=7.996), absence of stent placement (HR=0.375, protective), and operator inexperience (HR=2.318). Stent implantation effectively minimizes recurrence risk, especially in complicated incidents. ERAT facilitated overseeing appendicolith elimination, which assisted in occurring appendicolith-associated appendicitis.

Conclusion

ERAT is deemed safe and effective for acute appendicitis, with the highest recurrence risk occurring within the first year. Effective stent placement and skilled operators are crucial for reducing recurrence in complex cases. The aforementioned findings put forward significant insights for enhancing ERAT and advancing therapeutic outcomes.

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, with potential progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revolutionized obesity treatment, but their role in MASH with fibrosis remains under investigation.

Aims & Methods

This study evaluates the efficacy and safety of GLP-1 RAs in MASH with fibrosis. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) from PubMed, Embase, and Cochrane. Primary outcomes included histologic improvement in fibrosis without worsening MASH, MASH resolution without worsening fibrosis, and improvement in disease activity score. Secondary outcomes included adverse events (AEs), laboratory, and anthropometric data.

Results

Six RCTs (1,000 patients, mean follow-up: 47 weeks) were included. GLP-1 RAs did not significantly improve fibrosis without worsening MASH (RR 1.35; 95% CI 0.91–2.01; p=0.141; I²=53.5%) or disease activity score (RR 1.33; 95% CI 0.93–1.89; p=0.114; I²=64%). However, they significantly increased MASH resolution without worsening fibrosis (RR 3.50; 95% CI 2.44–5.02; p<0.001; I²=0%). No significant differences were observed in serious AEs. GLP-1 RAs improved laboratory, imaging, glycemic, lipidic, blood pressure, and anthropometric parameters.

Conclusion

GLP-1 RAs appear effective and safe in MASH with fibrosis, particularly in resolving MASH without worsening fibrosis.

Clinical Case Summary

A 19-year-old man with a long-standing history of recurrent abdominal pain and a recent episode of melena of unknown origin. He presented to the emergency department (ED) with hematochezia and asthenia, with a drop in hemoglobin to 8.9 g/dL. Upper and lower endoscopy were inconclusive. Capsule enteroscopy revealed a double-lumen sign and mildly erythematous mucosa, raising suspicion of Meckel’s diverticulum. A technetium-99m pertechnetate (Tc-99m) scan confirmed the presence of ectopic gastric mucosa. The patient subsequently underwent enterectomy, and histological analysis confirmed gastric mucosal heterotopia.
A 13-year-old man with a history of iron-deficiency anaemia requiring transfusion at 7 years old, and previous episodes of abdominal pain due to ileo-ileal intussusception. He had
undergone an inconclusive exploratory laparoscopy. He was admitted to the ED with melena and hypogastric pain. Blood tests revealed hemoglobin of 12.9 g/dL. Abdominal ultrasound showed thickening of the distal ileum over 11 cm, without signs of intussusception. Capsule enteroscopy revealed a segment of circumferential edema and erythema in the ileum, with absence of a clear villous pattern and an appearance suggestive of gastric mucosa. A Tc-99m scan confirmed the presence of ectopic gastric mucosa. Exploratory laparoscopy identified a 10–15 cm segment with gastric fold-like appearance within otherwise normal small intestinal mucosa, in the absence of a diverticulum. Histological analysis confirmed gastric mucosal heterotopia.
Gastric heterotopia is an important differential diagnosis in patients with gastrointestinal bleeding and can occur independently of the presence of Meckel’s diverticulum. The authors highlight the role of capsule enteroscopy in the diagnostic algorithm.

Introduction

TAK-062 is an orally delivered glutenase computationally designed to degrade immunogenic gliadin peptides. A phase 2 trial of TAK-062 (NCT05353985) did not meet the primary or secondary endpoints; however, the results may still be used to inform endpoints for future clinical studies in celiac disease. This study assessed the trial data for multiple histologic endpoints and determined the outcomes and relative performance of each.

Aims & Methods

The efficacy of TAK-062 vs placebo was assessed over a 24-week treatment period. Eligible patients were aged ≥18 years and had biopsy-confirmed celiac disease defined as a villous height to crypt depth ratio (Vh:Cd) of <2.5 at screening endoscopy (Week –4). All patients received simulated inadvertent gluten exposure (SIGE), consisting of a bar containing 500 mg of gluten three times per week throughout the treatment period. Duodenal biopsies taken at baseline and Week 24 were fixed in formalin and stained with hematoxylin and eosin for Vh:Cd analysis. Vh:Cd measurements were made by multiple readers with a proprietary digital pathology platform and averaged. CD3- and CD8-stained biopsy samples were used to count intraepithelial lymphocytes (IELs) and CD8 T cells, respectively, using a proprietary semi-automated counting software. The above measures were used to calculate two composite endpoints: (i) Vh:Cd and IEL counts (VCIEL), and (ii) Quantitative-Mucosal Algorithmic Rules for Scoring Histology (Q-MARSH). Qualitative assessment of Marsh–Oberhuber classification was conducted by a single pathologist. The variability and effect size of each outcome was determined.

Results

Analysis of the source of variability in the Vh:Cd measurement showed that 52% of the variability was at the patient level and 23% at the biopsy level. Only 1% of the variability was due to reader effects. Most other histology endpoints showed a similar response trend as observed with Vh:Cd. Determination of Vh, Cd, IEL counts, VCIEL, Q-MARSH and Marsh–Oberhuber scoring all showed significant worsening relative to baseline with TAK-062 treatment. Comparison of effect sizes for each endpoint showed that no endpoint outperformed Vh:Cd. Use of a statistically meaningful target criterion for response (Vh:Cd change of 0.4) found that 13.3% of patients in the placebo arm and 3.4% of patients in the TAK-062 treatment arm achieved this target response. Using a stringent remission criterion (Vh:Cd ≥ 2.7), 8.3% of the placebo arm and 1.7% of the TAK-062 arm achieved remission.

Conclusion

Although TAK-062 did not demonstrate efficacy in the phase 2 trial, learnings from this study emphasize the need for well-trained readers with clear scoring criteria to help to minimize variability in quantitative scoring. Furthermore, Vh:Cd shows good performance and is recommended as a key endpoint for assessing changes in gut architecture in celiac disease studies.

Disclosure

JM, JC, MZ, and DAL, are employees and shareholders of Takeda Development Center Americas, Inc. and receive stock or stock options.
JI is the founder and owner of Jilab, Inc., which received funding from Takeda for work undertaken as part of this study, is a full Professor at Tampere University, Medical Faculty, and has a consulting agreement with Takeda.
AV has nothing to disclose.
MER is a consultant for Alimentiv, Bristol Myers Squibb, Perspectum, Teva Pharmaceutical Industries Ltd., Anokion and Takeda, and has received a grant from AstraZeneca.