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New Methods Experimental Endoscopy: Editorial| Volume 93, ISSUE 2, P514-516, February 2021

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The journey to develop the ideal submucosal injection solution for endoscopic submucosal dissection

      Abbreviations:

      ESD (endoscopic submucosal dissection), HPMC (hydroxypropyl methylcellulose), SA (sodium alginate), SH (sodium hyaluronate)
      Endoscopic resection has been widely accepted as a minimally invasive treatment option for GI neoplasms without lymph node metastasis. Specifically, endoscopic submucosal dissection (ESD) allows for higher en bloc and R0 resection rates than does EMR. It provides long-term outcomes comparable with those of surgery while preserving organ function. However, ESD is technically challenging to perform, with longer procedure times and higher perforation rates than EMR. To avoid extraordinary struggle and intraoperative perforation during ESD, it is essential to have good visualization and access to the submucosal space. The procedural safety and efficiency of both EMR and ESD increase with a long-lasting submucosal cushion. This is especially important in esophageal and colorectal ESD, which have thin luminal walls and require long procedure times.
      • Saito Y.
      • Otake Y.
      • Sakamoto T.
      • et al.
      Indications for and technical aspects of colorectal endoscopic submucosal dissection.
      Although normal saline solution is safe, inexpensive, and commonly available throughout the world, it is unable to achieve and maintain an optimal submucosal lift. Thus, the scientific evaluation to identify suitable submucosal injection solutions have occurred in parallel with the development of ESD.
      The ideal submucosal injection solution should provide a long-lasting high elevation submucosal fluid cushion while preserving lesion tissue for accurate histopathologic assessment.
      • Uraoka T.
      • Saito Y.
      • Yamamoto K.
      • et al.
      Submucosal injection solution for gastrointestinal tract endoscopic mucosal resection and endoscopic submucosal dissection.
      Also, the ease of injection and cost should be considered. Several kinds of submucosal injection solutions have been developed not only in Japan but also in the West. Japanese studies have shown the efficacy of Glycerol (Glyceol, Chugai Pharmaceutical Co, Tokyo, Japan) as a submucosal injection fluid, a hypertonic solution consisting of 10% glycerin and 5% fructose in a normal saline solution that has been used intravenously to treat cerebral edema.
      • Uraoka T.
      • Saito Y.
      • Yamamoto K.
      • et al.
      Submucosal injection solution for gastrointestinal tract endoscopic mucosal resection and endoscopic submucosal dissection.
      Yamamoto et al
      • Yamamoto H.
      • Yube T.
      • Isoda N.
      • et al.
      A novel method of endoscopic mucosal resection using sodium hyaluronate.
      reported the usefulness of sodium hyaluronate (SH), which was initially approved for intra-articular injection for osteoarthritis and eye surgery. Because comparative studies showed excellent submucosal elevation with 0.4% SH, it is commonly used as one of the standard submucosal injection solutions in Japan.
      • Fujishiro M.
      • Yahagi N.
      • Kashimura K.
      • et al.
      Comparison of various submucosal injection solutions for maintaining mucosal elevation during endoscopic mucosal resection.
      However, its disadvantages are its high cost (U.S. $495-$1280/10 mL in the United States) and commercial unavailability in Western countries.
      Instead, other submucosal injection solutions have been developed in the West. Several studies have shown the efficacy of hydroxypropyl methylcellulose (HPMC) as a submucosal injection fluid, a cellulose derivative with viscoelastic properties that is used by ophthalmologists as artificial tears. It is less expensive than SH (0.83% HPMC costs U.S. $1.5-7.5/10 mL as a generic product) and is readily available in the United States.
      • Uraoka T.
      • Saito Y.
      • Yamamoto K.
      • et al.
      Submucosal injection solution for gastrointestinal tract endoscopic mucosal resection and endoscopic submucosal dissection.
      However, a recent ex-vivo comparative study, including HPMC, by Mehta et al
      • Mehta N.
      • Strong A.T.
      • Franco M.
      • et al.
      Optimal injection solution for endoscopic submucosal dissection: a randomized controlled trial of Western solutions in a porcine model.
      showed that Eleview (Aries Pharmaceuticals, San Diego, Calif, USA) and 6% hydroxyethyl starch were the best-performing Western solutions for ESD. Eleview, a proprietary mixture of medium chain triglycerides, poloxamer 188, polyoxyl-15-hydroxystearate, sodium chloride, and methylene blue in water, showed submucosal elevation comparable with that of SH.
      • Mehta N.
      • Strong A.T.
      • Franco M.
      • et al.
      Optimal injection solution for endoscopic submucosal dissection: a randomized controlled trial of Western solutions in a porcine model.
      Although it is approved as a submucosal injection fluid in the United States, its high cost (U.S. $81/10 mL) and its tendency to form bubbles that can obscure endoscopic view during dissection are concerns among Western endoscopists. Later, ORISE gel (Boston Scientific, Marlborough, Mass, USA) was developed. Its advantages are a premixed, predyed syringe agent and no bubble formation. Its disadvantages include its high cost ($150/10 mL), submucosal amorphous deposits that may have to be differentiated from mucinous tumors, and possible development of lifting agent granulomas.
      Sodium alginate (SA) is extracted from algae, and on the basis of its use as a viscosity-enhancing stabilizer and coagulator in the food industry, it has been approved as “Generally Recognized as Safe” in the United States. In the pharmaceutical field, it has been used as a treatment of peptic ulcers because of its mucosal protection properties and as a hemostatic agent based on its properties of platelet aggregation and accelerating fibrin formation. The clinical utility of 3.0% SA as a submucosal injection solution was investigated in 2011. Although it created a sufficient submucosal elevation, the original 3.0% SA solution was too viscous to inject. Thus, Kusano et al
      • Kusano T.
      • Etoh T.
      • Akagi T.
      • et al.
      Evaluation of 0.6% sodium alginate as a submucosal injection material in endoscopic submucosal dissection for early gastric cancer.
      explored the optimal concentration of SA and concluded that 0.6% diluted SA demonstrated higher submucosal elevation height with catheter injectability comparable with that of 0.4% SH and did not cause mucosal contraction or tissue injury on histologic assessment. A multicenter randomized controlled trial from Japan demonstrated the noninferiority of 0.6% SA against 0.4% SH in the ability to maintain lesion elevation.
      • Uemura N.
      • Oda I.
      • Saito Y.
      • et al.
      Efficacy and safety of 0.6% sodium alginate solution in endoscopic submucosal dissection for esophageal and gastric neoplastic lesion: a randomized controlled study.
      On the basis of this randomized controlled trial, 0.6% SA was approved for clinical use as a submucosal injection solution in Japan. Nevertheless, to date, all the best available submucosal injection solutions are highly viscous, which need high-hand-pressure catheter injection and a high-flow injection needle with a 2.5-mL small syringe. Therefore, improved submucosal injection fluids that achieve higher and longer-lasting submucosal elevation with easy catheter injectability have been desired.
      In this issue of Gastrointestinal Endoscopy, Hirose et al
      • Hirose R.
      • Nakaya T.
      • Naito Y.
      • et al.
      An innovative next-generation endoscopic submucosal injection material with a 2-step injection system (with video).
      present their evaluation of a novel next-generation submucosal injection solution that involves a 2-step injection process. First, 2.0% calcium chloride solution is injected in the submucosa, and then 0.4% SA is injected. Although both solutions have low viscosity, the addition of calcium chloride solution to 0.4% SA resulted in immediate ionic cross-linking and gelation, dramatically increasing the viscoelasticity of SA in the submucosa. Of note, 0.4% SA has better catheter injectability than 0.4% SH.
      • Kusano T.
      • Etoh T.
      • Akagi T.
      • et al.
      Evaluation of 0.6% sodium alginate as a submucosal injection material in endoscopic submucosal dissection for early gastric cancer.
      The ex-vivo study revealed that the submucosal elevation height of the 2-step unique injection was significantly higher than that of 0.4% SH after injection and at 30 minutes. Moreover, the ESD procedure times with the use of 0.4% SA plus calcium chloride solution were significantly shorter than those with the use of 0.4% SH or 0.4% SA, in an ex-vivo porcine colon model. The total volume of injection for 0.4% SA plus calcium chloride solution was considerably lower than those for 0.4% SH or 0.4% SA alone. Moreover, there was no tissue damage in the resected specimen. Despite the use of 2 solutions, it was considerably less expensive than 0.4% SH, the current standard submucosal injection fluid in Japan (SA costs approximately $3.7/10mL (AL500; KIMICA, Tokyo, Japan), and calcium chloride solution costs about $0.45/10mL).
      • Hirose R.
      • Nakaya T.
      • Naito Y.
      • et al.
      An innovative next-generation endoscopic submucosal injection material with a 2-step injection system (with video).
      The 2-step injection could be a candidate for the best available injection solution, although further studies are warranted for clinical use. It is a cost-effective injection solution, particularly for inexperienced endoscopists, who tend to perform more frequent injections than do experts. Typically, when using SH, we initially inject normal saline solution into the submucosa, forming a submucosal bleb, then inject SH into the bleb. This method helps avoid the inadvertent injection of SH into the muscularis propria. With the 2-step injection system, it will be important to confirm that the first injection is submucosal before the second injection of SA to avoid creating a highly viscous gel in the muscularis propria.
      On the basis of our clinical experience, we suggest using the promising injection solution in combination with current innovative ESD devices and techniques.

      Abe S, Wu SYS, Ego M, et al. Efficacy of current traction techniques for endoscopic submucosal dissection. Gut Liver. Epub 2020 Jan 2.

      Safe and efficient submucosal dissection should be achieved by both good submucosal elevation and tissue traction. With long-lasting submucosal injection fluids, care must be taken to avoid excessive injection in narrow spaces, like the pylorus and the ileocecal valve, where it may cause poor endoscope manipulation and unstable endoscope position. Also, further evaluations are warranted to see whether the 2-step injection fluids can be delivered through an ESD knife with injection capability. Although advantageous for ESD, the 2-step injection may not be optimal for EMR because the firm submucosal cushion could interfere with appropriate snare capture.
      As ESD is gradually accepted in Western countries, an important article in favor of en-bloc ESD resection was recently published from the West. Mehta et al

      Mehta N, Abushahin A, Sadaps M, et al. Recurrence with malignancy after endoscopic resection of large colon polyps with high-grade dysplasia: incidence and risk factors. Surg Endosc. Epub 2020 May 29.

      showed that invasive cancer can recur after piecemeal resection of large colon polyps with high-grade dysplasia, and they concluded that en-bloc resection should be the goal for large colon polyps. We hope that the development of improved submucosal injection solutions will make ESD easier and safer to perform, and we encourage Western endoscopists toward the use of en-bloc ESD resection.

      Disclosure

      Dr Abe and Dr Saito are the recipients of financial assistance from Keigen Pharma Co, Ltd. Dr Bhatt is a consultant for Boston Scientific, Medtronics, Lumendi, and Aries pharmaceuticals and the recipient of royalties from Medtronics.

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      1. Abe S, Wu SYS, Ego M, et al. Efficacy of current traction techniques for endoscopic submucosal dissection. Gut Liver. Epub 2020 Jan 2.

      2. Mehta N, Abushahin A, Sadaps M, et al. Recurrence with malignancy after endoscopic resection of large colon polyps with high-grade dysplasia: incidence and risk factors. Surg Endosc. Epub 2020 May 29.

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