1Department of Gastroenterological and Pediatric Surgery, 2Center for Community Medicine, Oita UniversityFaculty of Medicine, 3Department of Surgery, Tenshindo Hetsugi Hospital, 4Oita University, Oita, and5Department of Research and Development Section, Kaigen Pharma Co., Ltd, Osaka, Japan
Background and Aim: We have focused on sodium alginate(SA) solution as a potential submucosal injection material forendoscopic submucosal dissection (ESD). A previous SA solutionhad high viscosity and problems such as difficult handling. Afterits properties were adjusted, SA solution was examined in vitroand its clinical safety was evaluated.
Methods: With 0.4% sodium hyaluronate (SH) solution as acontrol, catheter injectability and mucosa-elevating capacity of0.3–0.8% SA solutions were evaluated. Next, 0.6% SA solution wasused for ESD in 10 patients with early gastric cancer in a prospec-tive clinical study.
Results: Compared with 0.4% SH solution, 0.6% SA solutionexhibited no significant difference in catheter injectability butsignificant superiority in mucosa-elevating capacity. In the clinicalstudy, no adverse events were observed in any patient.
Conclusion: The safety of 0.6% SA solution as a submucosalinjection material was confirmed and it is suggested that its effi-cacy should be investigated in a larger number of cases.
ENDOSCOPIC MUCOSAL RESECTION (EMR) hasbeen widely carried out to treat early gastrointestinal
cancer, but residual recurrence after EMR has been aproblem because of piecemeal resection in cases with largelesions.1,2 Therefore, endoscopic submucosal dissection(ESD) that enables en-bloc resection of a larger lesionwithout compromising curability has been developed andhas rapidly become prevalent.3–6 However, as ESD requireshigh skill levels and is indicated for larger lesions, there is apossibility of longer operation time and higher risks ofbleeding and perforation.7
From these points of view, it is important to maintainsufficient elevation of the lesion and the surrounding mucosa
for easy and safe ESD. Currently, 0.4% sodium hyaluronate(SH) solution is widely used as an endoscopic submucosalinjection material, but its high cost calculated by theNational Health Insurance in Japan remains a problem.Therefore, for an endoscopic submucosal injection material,we have focused on sodium alginate (SA) with high viscositythat is less expensive and does not compromise mucosa-elevating capacity, compared with 0.4% SH solution.
SA was extracted from algae for the first time in 1883,8
and it has low acute toxicity by any administration route (i.e.oral, i.v. and i.p. routes).9 In Japan, it was designated as afood additive in 1957, and its use has been approved as‘Generally Recognized as Safe’ (GRAS) in the USA.10 In thefood industry, SA has been widely used as viscosity-enhancing stabilizers and coagulators.11 In the pharmaceuti-cal field, it has been clinically used in anti-peptic ulcer agentsbased on its mucosal protection properties12 and in hemo-static agents based on its properties of platelet aggregation13
and accelerating fibrin formation.14
In 2011, we reported the utility of SA solution as anovel endoscopic submucosal injection material in ESD.15
Corresponding: Tsuyoshi Etoh, Department of Gastroenterologi-cal and Pediatric Surgery, Oita University Faculty of Medicine, 1-1Hasama-machi, Yufu, Oita 879-5593, Japan. Email: [email protected] 13 December 2013; accepted 3 February 2014.
However, the 3% SA solution used in that study had mark-edly high viscosity and was difficult to inject. Moreover,although it was rare, some cases had problems such asskewed mucosal elevation and induction of contraction ofthe gastric mucosa. As a result of these problems, weadjusted the properties of the SA solution and examined thecatheter injectability of the solutions, their mucosa-elevatingcapacity, and tissue injury caused by the solutions in pigs.Furthermore, the safety of SA solution was prospectivelyevaluated in a clinical study.
METHODS
In vitro and in vivo studies
MaterialsAccording to size exclusion chromatography with multipleangle laser light scattering (SEC-MALLS) detection, SAwith an average molecular weight of approximately 250 000was dissolved in phosphate-buffered saline, filtered througha membrane with a pore size of 0.2 μm for sterilization,and transferred fully into a vial aseptically. Then, SAsolutions at different concentrations were made. All equip-ment was used after autoclave sterilization or dry heatsterilization, and contamination with microorganisms orendotoxin was avoided. In the examinations of catheterinjectability and mucosa-elevating capacity of SA solution,0.4% SH solution (MucoUp®; Seikagaku Corporation,Tokyo, Japan) and physiological saline (Isotonic sodiumchloride solution; Otsuka Pharmaceutical Factory, Inc.,Tokushima, Japan) were used as the control and referencematerials, respectively.
For evaluation of tissue injury in swine, 0.6% SA solutionwas used with physiological saline as a negative control and50% glucose (Otsuka Pharmaceutical Factory, Inc.) as apositive control. In the clinical study, 0.6% SA solution wasused.
AnimalsFor evaluation of the mucosa-elevating capacity of SA solu-tion, extracted swine stomach from eight pigs was used. Theexperiment was started within 2 h after extraction. For evalu-ation of tissue injury, two large, white, and duroc (LWD) pigs(age, 3–4 months old; bodyweight, 38–42 kg) were used.The animal experiments in this study were approved by theAnimal Committee of Oita University.
Methods
Subjective assessment of injectability of SA solution intocatheter Under conditions equivalent to those clinicallyused in ESD, a 10-mL injection syringe (Terumo syringe®;Terumo Corporation, Tokyo, Japan) and a 25-G endoscopic
injection needle (Top Endoscopic Injection Needle Super-Grip; Top Corporation, Tokyo, Japan) were used. Six adultmales and females were asked to carry out catheter injectionof 0.3–0.8% SA solution and 0.4% SH solution using acatheter only. The subjects were asked to rate how difficult itwas to carry out catheter injection of each solution by thevisual analogue scale (VAS), with a higher score indicatingmore difficulty in injection. The 12 subjects carried out cath-eter injection of the 0.3–0.8% SA solution and 0.4% SHsolution in a blind manner.
Objective assessment of the mucosa-elevating capacity of SAsolution in extracted swine stomach A 2.5-mL injectionsyringe (TERUMO Cathelin Needle®; Terumo Corporation)was filled with 0.3–0.6% SA solution or 0.4% SH solution,and 1 mL each was injected horizontally into the submucosafrom the edge of the gastric specimen with a 23-G injectionneedle (Terumo CathelinNeedle®; Terumo Corporation)(n = 8 extracted swine stomach). The injection site was theupper third of the stomach, where the thickness of the mucosawas comparable to that of the human gastric wall,16 and asquare gastric specimen of approximately 7 × 7 cm was used.The height of the mucosal elevation was the distance from themucosal surface before injection to the top of the elevation.
Study on tissue injury caused by SA solution in swine Underrespirator management with inhalation anesthetic sevoflu-rane (Mylan Institutional LLC; Mylan Corporation, Osaka,Japan) (4.0% at 3.0 L/min), 2 mL of 0.6% SA solution,physiological saline, or 50% glucose solution was injectedinto the submucosa at different sites on the greater curvatureof the upper third of the stomach in two pigs. For evaluationof acute and late tissue injury, one pig was killed at 30 min or1 week later, respectively. Then, the stomach was extracted,fixed in 10% neutral buffered formaldehyde solution, andembedded in paraffin. Each paraffin block was sectioned andstained with hematoxylin and eosin for histological exami-nation. These procedures were done according to the guide-lines for animal experiments at our hospital.
Prospective clinical study using0.6% SA solutionAfter approval by the ethical committee of our hospital, ESDwas carried out with 0.6% SA solution in 10 patients whogave informed consent between December 2011 and August2012. Patients with early gastric cancer or adenoma who hadan absolute indication or expanded indication for ESDaccording to the guidelines for gastric carcinoma treatment17
were enrolled in this study. As ESD devices, a 25-G endo-scopic injection needle (Top Endoscopic Injection NeedleSuperGrip; Top Corporation), an IT-knife 2 (KD-611 L;Olympus Corporation, Tokyo, Japan), and a Flex knife (KD-630-L; Olympus Corporation) were used. ERBE VIO 300 D(Erbe, Tübingen, Germany) was set at ‘dry cut’ mode (Effect
2 T. Kusano et al. Digestive Endoscopy 2014; ••: ••–••
4, 50 W) for submucosal dissection. Two endoscopists (T.E.and H.S.) certified by the Japan Gastroenterological Endos-copy Society carried out ESD; one of these endoscopists hadhandled more than 200 ESD cases, whereas the other hadexperiences of less than 50 cases.
This study is the first prospective clinical study to confirmthe safety of 0.6% SA solution. According to the CommonTerminology Criteria for Adverse Events version 4.0, theprimary endpoints were determined as intraoperative orpostoperative bleeding of grade 3 or higher and gastric per-foration of grade 2 or higher. The secondary endpoints wereoperation time, rate of en-bloc resection, recurrence rate,perioperative complications, pathological curative resectionrate, and the ulcer healing process after ESD.
At our hospital, a clinical pathway for ESD has beenintroduced and the patients in the clinical study were treatedaccording to the clinical pathway. On the day before ESD, aproton pump inhibitor was started and continued for 8 weeksafter ESD. On the day after ESD, esophagogastroduodenos-copy (EGD) was carried out to confirm that there was nobleeding from the resected site and meals were started. Forconfirmation of the healing process of the artificial ulcerafter ESD, EGD was done at 2 and 8 weeks after ESD. Thisclinical study, which was registered at the University Hospi-tal Medical Information Network (No. 000009000), fol-lowed the ethical guidelines for clinical studies.18
Statistical analysisAll data were expressed as means ± standard deviation. Theresults of catheter injectability and mucosa-elevating capacitywere analyzed by Dunnett’s multiple comparison parametrictest to compare the 0.4% SH solution and several SA solu-tions.All statistical analyses were done with SPSS® Statistics17.0 software (SPSS Inc., Chicago, IL, USA). A two-sidedP-value <0.05 was considered statistically significant.
RESULTS
Catheter injectability of SA solution
TABLE 1 SHOWS THE viscosity, pH, and osmotic pres-sure of 0.3%, 0.4%, 0.5%, 0.6%, 0.7% and 0.8% SA
solutions and 0.4% SH solution. Figure 1 shows the resultsof catheter injectability. Catheter injectability revealed resis-tance depending on the concentration of SA solution. Com-pared with the 0.4% SH solution, 0.3–0.6% SA solutions hadno problems in catheter injectability.
Mucosa-elevating capacityThe mucosa-elevating capacity by submucosal injection ofSA solution in the extracted swine stomach was positively
correlated with the concentration of SA solution (Fig. 2).The height of the mucosal elevation upon injection of 0.3–0.5% SA solutions showed no significant differences fromthat by 0.4% SH solution at all times from immediately afterinjection until 30 min later. Meanwhile, 0.6% SA solutioncreated an excellent mucosal elevation in height immediately
Table 1 Specifications of SA solutions at different concentra-tions and 0.4% SH solution
Material Viscosity (mPa·s) pH Osmotic pressure†
0.3% SA solution 9.4 7.4 1.00.4% SA solution 17.0 7.3 1.00.5% SA solution 28.9 7.4 1.00.6% SA solution 45.9 7.4 1.00.7% SA solution 69.8 7.3 1.00.8% SA solution 101.6 7.3 1.00.4% SH solution 67.8 7.5 1.1
†Ratio compared with physiological saline.SA, sodium alginate; SH, sodium hyaluronate.
Figure 1 Catheter injectability of 0.3–0.8% sodium alginate (SA)solutions compared with 0.4% sodium hyaluronate (SH) solution.The average visual analogue scale (VAS) score for the 0.4% SHsolution was 3.69 ± 1.02, whereas those for the 0.3% and 0.4%SA solutions were 0.89 ± 0.52 and 1.47 ± 0.51, respectively,and they were significantly lower than that for the 0.4% SHsolution (P < 0.01 each). The average VAS scores for the 0.5%and 0.6% SA solutions were 2.56 ± 0.68 and 4.19 ± 1.40, respec-tively, and there were no significant differences comparedwith that for the 0.4% SH solution (P = 0.07 and 0.76, respec-tively). Furthermore, the VAS scores for the 0.7% and 0.8%SA solutions were significantly higher at 5.96 ± 1.55 and6.85 ± 1.46, respectively, than that for the 0.4% SH solution(P < 0.01 each). Individuals were asked to rate the difficulty ofcatheter injection of the solutions by the VAS scale. The resultsare shown as mean and standard deviation. **P < 0.01. NS, notsignificant.
Digestive Endoscopy 2014; ••: ••–•• SA as submucosal injection material 3
after injection (P < 0.01). Then, a significantly highermucosal elevation was maintained at all time points until30 min later (P < 0.05). Figure 3 shows typical images of themucosal elevation upon injection of 0.6% SA solution and0.4% SH solution.
Tissue injury by SA solutionBased on the results of experiments 1 and 2 described above,tissue injury in swine was examined with 0.6% SA solutionthat had shown no difficulty in catheter injectability and hadthe best mucosa-elevating capacity. SA solution (0.6%) wasinjected into the submucosa at different sites on the greatercurvature of the upper third of the stomach. Pathohistologi-cal examination showed edema in the muscular layer of thetissue 30 min after injection of 50% glucose solution, whichserved as a positive control. One week after injection, find-ings of foreign-body granuloma were observed in additionto muscular layer edema after injection of 50% glucosesolution.
Meanwhile, pathohistological examination of the tissue30 min and 1 week after injection of 0.6% SA solution orphysiological saline, which served as a negative control,showed no findings suggestive of tissue injury (Fig. 4).
Clinical studyTable 2 shows the characteristics of the 10 patients whounderwent ESD with 0.6% SA solution. Their average agewas 69.2 ± 6.6 years, male-to-female ratio 8:2, averagediameter of the resected specimen 35.4 ± 7.3 mm, andaverage tumor diameter 16.3 ± 6.4 mm. As to the primaryendpoints, none of them demonstrated intraoperative andpostoperative bleeding that required surgery, or gastric per-
foration. With regard to the secondary endpoints, operationtime was 130.5 ± 92.1 min and en-bloc resection was done inall cases. Although the follow-up period was short (median,14.5 months), no case showed recurrence. Furthermore,there were no perioperative complications such as liver dys-function and renal dysfunction.
In the resected specimens, all cases showed negative hori-zontal and vertical margins. In the two cases with invasiondepth at SM2, laparoscopy-assisted distal gastrectomy wascarried out as additional surgical resection in one case,whereas the other case was followed up without interventiondue to the wishes of the patient after a detailed explanationwas given.
Figure 5 shows an endoscopic image taken during ESDwith 0.6% SA solution. Injection of 0.6% SA solution main-tained excellent height of the mucosal elevation and visibil-ity. Figure 6 shows endoscopic images of the healing processof the artificial ulcer after ESD. No case showed bleeding orvisible vessels requiring hemostasis, and EGD carried out 8weeks after ESD showed excellent healing of the artificialulcer and scarring in all cases.
DISCUSSION
TO DATE, SUBMUCOSAL injection of physiologicalsaline,19 glucose solution,20 glycerol solution,21 and SH
solution for creating mucosal elevation has been investi-gated, and SH solution has been widely used clinicallybecause of its high efficacy and safety.22,23However, the highcost of SH solution is a problem and development of lessexpensive endoscopic submucosal injection materials hasbeen anticipated. Since the 0.6% SA product has yet to beapproved in compliance with the Pharmaceutical AffairsLaw in Japan, it is not possible to state the cost of 0.6% SAsolution at the present time. However, as to the raw materials,SA derived from brown algae and SH from rooster combcosts 101 JPY/g (0.97 USD/g) and 111 000 JPY/g(1067 USD/g), respectively. In addition, some institutionsuse diluted SH solution for gastric ESD. Although mucosalelevation by the 0.3% and 0.4% SA solutions was lower thanthat observed with the 0.6% SA solution in our preliminarystudy, we could safely carry out ESD using the diluted SAsolution as well as the SH solution. Therefore, the 0.6% SAsolution is assumed to cost less than the 0.4% SH solution.
Eun et al.24 demonstrated that mucosa-elevating capacitywas comparable between the 1% SA solution and the 0.5%SH solution, and SA was an effective material for submuco-sal injection. However, the SA solution used by Eun et al.was created by dilution with physiological saline of the oralmedicine that had been approved as an anti-ulcer agent and,
Figure 2 Time–course change in the height of mucosal elevationupon injection of 0.3–0.6% sodium alginate (SA) solution (com-pared with 0.4% sodium hyaluronate (SH) solution) in theextracted swine stomach.**P < 0.01; *P < 0.05.
4 T. Kusano et al. Digestive Endoscopy 2014; ••: ••–••
therefore, there remained an essential problem in evaluatingthe performance of the SA solution as a material for endo-scopic submucosal injection.
Fujishiro et al.25 examined tissue injury caused by submu-cosal injection of various materials, and demonstrated that
hypertonic solutions caused cell dehydration and influencedthe resected specimens of EMR and healing of artificialulcer. Therefore, the properties of SA solution were adjustedafter it was made isotonic, and the safety of SA solution wasexamined by using pigs and clinically.
Figure 3 Typical mucosal elevations inswine gastric specimens. (a) Immedi-ately and 30 min after injection of 0.6%sodium alginate (SA) solution. (b) Imme-diately and 30 min after injection of 0.4%sodium hyaluronate (SH) solution. Com-pared with 0.4% SH solution, 0.6% SAsolution produced significantly highermucosal elevation immediately afterinjection (P < 0.01). Similarly, 0.6% SAsolution produced a significantly highermucosal elevation than 0.4% SH solutionat 30 min after injection (P < 0.05).
Figure 4 Influence on gastric tissue 30 min and 1 week after submucosal injection of 0.6% sodium alginate (SA) solution in swine. (a) 50%glucose solution (hematoxylin-eosin [HE] staining, ×10). (b) 0.6% SA solution (HE staining, ×10). (c) Physiological saline (HE staining, ×10).
Digestive Endoscopy 2014; ••: ••–•• SA as submucosal injection material 5
In 2011, we reported the utility of SA solution as a novelsubmucosal injection material.15 In the present study, theproperties of SA solution were adjusted and three problemssuggested in the previous report were solved. The first onewas high resistance at injection. Catheter injectability wascomparable between 0.6% SA solution and 0.4% SH solu-tion. The viscosity of 0.4% SH solution was 67.8 mPa•s,whereas that of 0.6% SA solution was as low as 45.9 mPa•s,but the results of the catheter injectability test were compa-rable statistically. It was considered that these differenceswere attributable to different rheological properties of SAand SH solutions.
The second problem was skewed elevation after injectionand loss of appropriate submucosal cushion properties. Theappropriate cushion properties were considered to be a criti-cal factor for creating mucosal elevation and dissection.26
The optimal concentration of SA solution was determined as0.6% and sufficient mucosal elevation in an ideal shape wascreated. Furthermore, appropriate submucosal cushion prop-erties were obtained.
The third problem was mucosal contraction. As the 0.6%SA solution used in the present study was isotonic, no caseshowed mucosal contraction and excellent mucosal elevationwas maintained. In addition, as the resected specimensshowed neither findings of tissue injury nor influence onpathological diagnosis, isotonic adjustment of 0.6% SAsolution was considered appropriate. Thus, the concentrationof SA solution was set at 0.6% according to the subjectiveand objective assessments in our study.
Although we have carried out ESD with 0.4% SH solutionregularly, we had no discomfort in using 0.6% SA solution asto catheter injectability and maneuverability in a series ofTa
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Figure 5 Endoscopic view of mucosal elevation in a patient whounderwent endoscopic submucosal dissection using 0.6%sodium alginate (SA) solution. Submucosal injection of 0.6% SAsolution produced excellent mucosal elevation.
6 T. Kusano et al. Digestive Endoscopy 2014; ••: ••–••
practical ESD techniques, including mucosal dissection inthe present prospective clinical study. This study is not aprospective clinical study to compare the 0.6% SA solutionwith the 0.4% SH solution. Regarding the coagulation, hard-ness, and speed, it was not possible to directly compare theformer with the latter. In the future, it is necessary to dem-onstrate the usefulness of 0.6% SA solution as a submucosalinjection solution for gastric ESD in a large number ofpatients.
From the technical point of view, such as en-bloc resect-ion rate and rate of negative surgical margins, 0.6% SAsolution was satisfactory. In addition, it was confirmed thatsufficient mucosal elevation was obtained even in caseswith a UL(+) lesion accompanying submucosal fibrosis,for which mucosal elevation was difficult to obtain. Takentogether, including the results of in vitro studies, the excellentmucosa-elevating capacity of 0.6% SA solution wasrecognized clinically.
Perforation and postoperative bleeding are major treat-ment complications of ESD. It was reported that the fre-quency of perforation and postoperative bleeding wasapproximately 3% and 1–6%, respectively, and 95% ofpostoperative bleeding cases occurred within 6 h afterESD.27,28 In the present study, no treatment-associated com-plication such as perforation and postoperative bleeding wasobserved. Furthermore, to confirm healing of the artificialulcer after ESD, EGD was done up to 8 weeks after ESD, andno case showed delayed healing. Taken together, it was elu-cidated that 0.6% SA solution, with excellent mucosa-elevating capacity, was a submucosal injection material thatdoes not cause tissue injury.
CONCLUSIONS
THE 0.6% PROPERTY-ADJUSTED SA solution demon-strated excellent mucosa-elevating capacity without
causing any adverse events. The results warrant further
investigation of the usefulness of this material as a submu-cosal injection solution for gastric ESD in a large number ofpatients.
CONFLICT OF INTERESTS
AUTHORS DECLARE NO conflict of interests for thisarticle.
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