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Author: Priya Hazrah Professor, Department of Surgery, Lady Hardinge Medical College, New Delhi. Email: priyahazrah@gmail.com, ORCID ID 0009-0008-1915-3978 Deborshi Sharma Director Professor Department of Surgey ABVIMS, New Delhi. Email: drdeborshi@gmail.com, ORCID ID 0000-0001-8251-8484 Sonali Mittal Assistant professor, Lady Hardinge Medical College, New Delhi Email: sonali.prachi@gmail.com, ORCID 0000-0002-6289-7656 Corresponding Author: Priya Hazrah Professor Department of Surgery, Lady Hardinge Medical College, New Delhi. Email: priyahazrah@gmail.com We read with tremendous interest your article entitled “Mastering the third space: Innovations in intramural endoscopic surgery for gastrointestinal disorders.” It was a very apt and concise review of commonly performed third space endoscopy (TSE) procedures, namely the C, Z, E, and G POEM (per oral endoscopic myotomy). Here, we would like to highlight other evolving procedures related to third space endoscopy and also the emerging concept of “fourth space endoscopy.” POETRE, peroral esophageal tunnelling for restoration of the esophagus, based on the principle of TSE, is an innovative technique of submucosal tunnelling proposed to be a useful therapeutic option in long-segment complete esophageal luminal obstruction in a few case series [1, 2]. PREM/PAEM (per rectal/per anal myotomy) is another novel use of TSE with limited exploration in patients with Hirschsprung’s disease [3]. STER (submucosal tunnelling endoscopic resection) and POET (peroral endoscopic excision of tumor) have been reported to be safe procedures for resection of extramucosal tumors in the upper gastrointestinal tract with acceptable complication rates vouched for in recent meta-analyses [4-7]. Further, TSE can be used to gain peritoneal access, as seen in POEM+F (POEM with fundoplication). Building upon the model of third space endoscopy is a forthcoming concept of fourth space endoscopy based on the technique of sub-serosal dissection for excision of extramucosal tumors in the upper gastrointestinal tract, like gastrointestinal stromal tumors, leiomyoma, hamartoma, etc., published in a limited case series [8]. The feasibility of using the principle of the fourth-space endoscopy procedure for vagotomy is investigational and has been reported currently in an anecdotal non-human study [9]. The fourth space is also utilized at times in POEM to enable a full-thickness myotomy [10]. References 1. Wagh MS, Draganov PV. Per-oral endoscopic tunneling for restoration of the esophagus: a novel endoscopic submucosal dissection technique for therapy of complete esophageal obstruction. Gastrointest Endosc. 2017 Apr;85(4):722-727. doi: 10.1016/j.gie.2016.08.035. Epub 2016 Sep 7. PMID: 27612924. 2. Félix C, Barreiro P, Rodrigues Azevedo J, Maia L, Küttner-Magalhães R, Pedroto I, Chagas C. Per-oral endoscopic tunneling for restoration of the esophagus (POETRE) in the management of a complete esophageal obstruction. Endosc Int Open. 2021 Jul;9(7):E1084-E1085. doi: 10.1055/a-1463-3059. Epub 2021 Jun 17. PMID: 34222634; PMCID: PMC8211479. 3. Bapaye A, Dashatwar P, Biradar V, Biradar S, Pujari R. Initial experience with per-rectal endoscopic myotomy for Hirschsprung's disease: medium and long term outcomes of the first case series of a novel third-space endoscopy procedure. Endoscopy. 2021 Dec;53(12):1256-1260. doi: 10.1055/a-1332-6902. Epub 2021 Mar 2. PMID: 33291158. 4. Onimaru M, Inoue H, Bechara R, Tanabe M, Abad MRA, Ueno A, Shimamura Y, Sumi K, Ikeda H, Ito H. Clinical outcomes of per-oral endoscopic tumor resection for submucosal tumors in the esophagus and gastric cardia. Dig Endosc. 2020 Mar;32(3):328-336. doi: 10.1111/den.13471. Epub 2019 Jul 22. PMID: 31234231. 5. Peng W, Tan S, Huang S, Ren Y, Li H, Peng Y, Fu X, Tang X. Efficacy and safety of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors with more than 1-year' follow-up: a systematic review and meta-analysis. Scand J Gastroenterol. 2019 Apr;54(4):397-406. doi: 10.1080/00365521.2019.1591500. Epub 2019 Mar 29. PMID: 30925071. 6. Song S, Wang X, Zhang S, Li Y, Zhang X, Chu X. Efficacy and complications of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors and exploration for influencing factors. Z Gastroenterol. 2018 Apr;56(4):365-373. English. doi: 10.1055/s-0043-123765. Epub 2018 Jan 18. PMID: 29346827. 7. Cao B, Lu J, Tan Y, Liu D. Efficacy and safety of submucosal tunneling endoscopic resection for gastric submucosal tumors: a systematic review and meta-analysis. Rev Esp Enferm Dig. 2021 Jan;113(1):52-59. doi: 10.17235/reed.2020.6989/2020. PMID: 33222480. 8. Liu F, Zhang S, Ren W, Yang T, Lv Y, Ling T, Zou X, Wang L. The fourth space surgery: endoscopic subserosal dissection for upper gastrointestinal subepithelial tumors originating from the muscularis propria layer. Surg Endosc. 2018 May;32(5):2575-2582. doi: 10.1007/s00464-017-5985-z. Epub 2017 Dec 20. PMID: 29264757. 9. Kadkhodayan K, Irani S. Endoscopic truncal vagotomy. Exploring the fourth space. A technical feasibility study in a porcine model. VideoGIE. 2025 Mar 4;10(7):340-344. doi: 10.1016/j.vgie.2025.02.012. PMID: 40642399; PMCID: PMC12237756. 10. Jiang T, Yang Y, Luo W. Application of the fourth space in peroral endoscopic myotomy (POEM) surgery for achalasia. Rev Esp Enferm Dig. 2025 Jun 27. doi: 10.17235/reed.2025.11331/2025. Epub ahead of print. PMID: 40575899.