Preliminary Data on Anti-scarring Agents in the Prevention of Post Esophageal Endoscopic Submucosal Dissection (eesd)

Yuhsin V Wu, MD, Eric M Pauli, MD, Steve J Schomisch, PhD, Cassandra N Cipriano, Amitabh Chak, MD, Jeffrey L Ponsky, MD, Jeffrey M Marks, MD

University Hospitals Case Medical Center

Introduction: Esophageal endoscopic submucosal dissection (EESD) is an effective minimally invasive therapy for early esophageal cancer and high grade Barrett’s dysplasia. However, severe esophageal stricture formation following circumferential or large EESDs has limited its wide adoption. Mitomycin C (DNA crosslinker), Halofuginone (an inhibitor of type I collagen synthesis), and Transforming Growth Factor β3 (TGFβ3) (naturally found in healing wounds) exhibit anti-scarring effects which may be of benefit in preventing stricture formation after EESD.

Methods: An endoscopic band ligator and snare were used for the initial mucosa incision in a porcine model. An 8-10 cm circumferential mucosal segment was then excised using standard ESD techniques. The exposed muscularis was either left without intervention (Control n=5) or received 4 quadrant, 1 cm interval injections of anti-scarring drug immediately and followed by weekly injections for up to three weeks. Three drugs were used in both high and low doses: Mitomycin C 5mg (n= 2), 0.5mg (n=2); Halofuginone 1.5mg (n=2), 0.5mg (n=2); TGFβ3 2ug (n=2), 0.5ug (n=2). The degree of esophageal stricture formation was assessed endoscopically and with a barium swallow on a weekly basis. Animals were followed clinically and euthanized when stricture formation prevented further therapy.

Results: The control group had a mean luminal diameter reduction of 77.7 +/- 12.1% by two weeks and was euthanized by 3 weeks. Compared at two weeks, the halofuginone group showed decreased stricture formation with a luminal diameter reduction of 68.4 +/-13.3% (low dose) and 57.7+/-38.3% (high dose). The TGFβ3-low dose group luminal diameter reduction was 65.3 +/- 2.0% compared to TGFβ3-high dose group of 76.2%. The second animal in the TGFβ3-high dose group was euthanized after one week with a stricture of 64.1%, preventing further therapy. Mitomycin C was the most effective in stricture prevention with luminal diameter reduction of 53.6+/-11.8% (low dose) and 35+/-10.2% (high dose). Of concern, gross inspection of the mitomycin C treated esophageal wall appeared to be necrotic and lead to perforation after three weeks in one animal. In contrast, the resected area of TGF-β3 and halofuginone animals appeared re-epithelialized and healthy. Final histology of the tissues is pending.

Conclusion: From our primary data with a small number of animals, anti-scarring drugs such as mitomycin C, halofuginone, and TGFβ3 show promise in reducing post-EESD stricture formation. Repeat experiments and further investigations on optimal dose and delivery systems need to be studied to prevent complications and determine overall efficacy of anti-scarring therapy.