Introduction

Endoscopic mucosal resection (EMR) is a minimally invasive technique for removing large non-pedunculated colorectal polyps (LNPCP), traditionally using hot snare EMR (H-EMR) with electrocautery. While effective, H-EMR poses risks including delayed bleeding and thermal injury, which cold snare EMR (C-EMR) may reduce by avoiding electrocautery. With emerging evidence in support of C-EMR, this systematic review and meta-analysis compares its safety and effectiveness compared to H-EMR for LNPCP.

Aims & Methods

The objective of this systematic review and meta-analysis is to compare the safety and effectiveness of C-EMR versus H-EMR for adenomas and serrated lesions ≥15mm. Relevant studies were identified through systematic searches of the PubMed, Medline, Cochrane, and Google Scholar databases through March 2025. Quality assessment was conducted using the Cochrane Risk of Bias (RoB2) tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa Scale (NOS) for retrospective studies. A random-effects meta-analysis was performed to generate pooled odds ratio (OR) and risk ratios (RR) with 95% confidence intervals. Subgroup analyses were conducted to explore potential sources of heterogeneity, if present.

Results

Seven studies, including four RCTs and three non-randomized comparative studies, were included in the analysis, with a pooled sample of 2898 LNPCP (1029 C-EMR and 1869 H-EMR). Technical success rates were comparable between C-EMR and H-EMR (OR 0.46, 95% CI [0.13–1.64]; I² = 19%). However, C-EMR was associated with significantly lower risks of intraprocedural bleeding (RR 0.66), delayed bleeding (RR 0.39), perforation (RR 0.22), and post-polypectomy syndrome (RR 0.58), all with I² = 0%. Conversely, C-EMR was linked to a significantly higher risk of polyp recurrence (RR 1.91, 95% CI [1.29–2.81]; I² = 53%). Subgroup analyses confirmed this increased recurrence in RCTs (RR 2.01). Specifically, for large adenomatous lesions ≥20mm, recurrence was significantly higher with C-EMR compared to H-EMR (RR 1.79, 95% CI [1.40-2.30]; I² = 0%), whereas no significant difference was observed between techniques for serrated lesions (RR 1.49, 95% CI [0.66–3.33]; I² = 34%). Regarding safety, subgroup analysis of large adenomatous lesions–including two studies exclusively evaluating this group–revealed higher rates of delayed bleeding (RR 0.24) and perforation (RR 0.51) in the H-EMR group. In contrast, for serrated lesions, van Hattem et al.–the only study exclusively evaluating this subtype–reported no adverse events with C-EMR, whereas delayed bleeding and perforation occurred in 5.1% and 0.8% of cases, respectively, in the H-EMR group.

Conclusion

Both C-EMR and H-EMR are effective for resecting LNPCP. For adenomas, H-EMR demonstrates lower recurrence rates but carries higher risks of bleeding and perforation. If recurrence is a concern, H-EMR is preferred; however, C-EMR, which offers superior safety, may be a better option for frail patients, those with comorbidities or on anticoagulation therapy. Comparatively, for serrated lesions, recurrence rates are similar between the two techniques, but C-EMR is safer and should be the technique of choice. The decision should be individualized, taking into account lesion characteristics, patient factors, and operator expertise to ensure an optimal balance between procedural safety and long-term outcomes.

References

Nogales O, Carbonell-Blanco C, Pina SM, et al. Cold snare endoscopic mucosal resection versus standard hot technique for large flat non-pedunculated colonic lesions: Results of the CS-EMR 2019 randomized controlled trial. Endoscopy, 2025.
O'Sullivan T, Cronin O, van Hattem WA, et al. Cold versus hot snare endoscopic mucosal resection for large (≥15 mm) flat non-pedunculated colorectal polyps: A randomized controlled trial. Gut, 2024
Steinbrück I, Ebigbo A, Kuellmer A, et al. Cold versus hot snare endoscopic resection of large nonpedunculated colorectal polyps: Randomized controlled German CHRONICLE trial. Gastroenterology, 2024
Pohl H, Rex D, Barber J, et al. Cold snare endoscopic resection for large colon polyps – a randomized trial. Gastrointestinal Endoscopy, 2024.
Ladna M, King WW, Ijaz Z, et al. Cold versus hot endoscopic mucosal resection of large (>20 mm) colonic polyps: A single-center retrospective study. Gastrointestinal Endoscopy, 2024.
Rashid M, Swartz A, Alomari M, et al. Cold vs. hot EMR for large colon polyps (≥20 mm): Analysis of effectiveness, safety, and cost-benefit. Gastrointestinal Endoscopy, 2023.
van Hattem WA, Shahidi N, Vosko S, et al. Piecemeal cold snare polypectomy versus conventional endoscopic mucosal resection for large sessile serrated lesions: a retrospective comparison across two successive periods. Gut, 2021

Introduction

Helicobacter pylori (H. pylori) infection is a major cause of gastric diseases, with the virulence factor CagA carried by exosomes playing a crucial role in regulating inflammation. Ferroptosis and M1 polarization are key mechanisms in promoting inflammation, yet the role of CagA in inducing macrophage ferroptosis and M1 polarization to exacerbate gastric mucosal inflammation remains unclear.

Aims & Methods

CagA-positive (CagA+) and CagA-negative (CagA-) H. pylori strains were co-cultured with gastric epithelial cells, and their supernatants were collected. Exosomes were isolated using ultracentrifugation to obtain CagA+Exo and CagA-Exo. Changes in macrophage M1/M2 polarization markers and ferroptosis markers were analyzed under CagA+Exo and CagA-Exo treatment. The activation of the JAK/STAT1 signaling pathway was assessed by Western blot, and STAT1 expression in the nucleus was evaluated using a nuclear protein extraction kit. Chromatin immunoprecipitation (ChIP) was used to identify the binding site of STAT1 on the SLC7A11 promoter. Biopsy samples from the gastric mucosa of gastritis patients infected with CagA+ or CagA- H. pylori were analyzed for macrophage polarization and ferroptosis markers.

Results

Exosomal CagA was found to induce macrophage M1 polarization and ferroptosis, with the ferroptosis inhibitor SLC7A11 playing a key role in CagA-induced ferroptosis. Exosomal CagA activated the JAK/STAT1 signaling pathway, leading to M1 polarization and ferroptosis. Additionally, CagA+Exo increased nuclear STAT1 expression, which subsequently bound to the SLC7A11 promoter to regulate its transcription. In gastric mucosa biopsies from CagA+ H. pylori-infected gastritis patients, increased levels of iNOS (a marker of M1 polarization) and decreased expression of SLC7A11 were observed.

Conclusion

Our findings indicate that exosomal CagA promotes macrophage M1 polarization and ferroptosis through the JAK/STAT1 signaling pathway. This study provides new insights and potential therapeutic targets for H. pylori-associated gastritis.