Introduction
Submucosal (SM) injection is a critical step during endoscopic submucosal dissection
(ESD). In Japan, use of viscous solutions such as sodium hyaluronate (MucoUp, Seikagaku
Co. Japan and Boston Scientific Japan Co., Japan) is recommended due to its excellent
ability to facilitate a good lift and create a prolonged and sustained SM cushion.
However, this solution is expensive and only available in Japan [1 ]
[2 ]
[3 ]
[4 ]
[5 ]. For this reason, many Western researchers have developed solutions for SM injection
with different substances that could replace MucoUp, facilitating ESD and reducing
the rate of complications (perforation, hemorrhage) [1 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ]. Over the last 8 years, our group has been using a sterile teardrop solution made
of 0.4 % sodium hyaluronate with optimal results. This solution is commercially available
in standard pharmacies in Latin America at a low cost; approximately $ 10.00 US dollars
for a 10-cc bottle. The objective of this study was to present data on safety and
clinical effectiveness of off-label use of the sodium hyaluronate teardrops solution
for SM injection during gastric ESD.
Patients and methods
A retrospective study was carried out of all patients who underwent ESD for gastric
neoplasms using sodium hyaluronate as teardrops (Adaptis Fresh, Legrand Laboratory,
Brazil) for SM injection, in an academic and tertiary level hospital in Brazil between
2012 and 2019. Patients in whom substances different than sodium hyaluronate were
used as well as those with advanced tumors or presenting non-lifting sign were excluded.
Moreover, we also excluded patients who declined informed consent for ESD, reported
hypersensitivity to hyaluronic acid, presented with severe comorbidities or poor performance
status unsuitable to undergo general anesthesia, had coagulopathy or were using anticoagulants
continuously, which could not be withheld or for whom heparin-bridge therapy could
not be used. For those patients using oral anticoagulants or new antiplatelet drugs,
we discussed the management plan in a multidisciplinary fashion with prior classification
of risk in each patient. If possible, we suspended those medications before the ESD,
and when necessary, we administered low-molecular-weight heparin bridge therapy or
maintained acetylsalicylic acid.
The information was collected from a database generated prospectively. The following
clinicopathological data were reviewed: age, gender, histological type of the resected
specimen, tumor size, procedure duration, and adverse events (AEs). Likewise, the
rates of en-bloc resection, complete resection with negative margins (R0 resection)
and curative resection of epithelial lesions were calculated according to current
expanded criteria determined by Japanese guidelines (≥ 2 cm in diameter, predominantly
differentiated type pT1a without ulceration; < 3 cm predominantly differentiated type
pT1a with ulcer; < 2 cm predominantly undifferentiated type pT1a and no ulcer; < 3 cm
predominantly differentiated type pT1b (SM1) and no lymphatic or vascular invasion
and with negative surgical margins) [1 ]. En-bloc resection was defined as removal of the entire tumor in one piece. Curative
resection was calculated only for epithelial lesions and it was based on the histological
assessment of ESD specimen. If histology revealed compromised margins or poor prognostic
features such as lymph-vascular invasion, the procedure was deemed non-curative. Furthermore,
if deep SM invasion > 500 µm beyond the muscularis mucosae was noted in specimens
with adenocarcinoma, the resection was also considered non-curative. Patients with
non-curative resection were subsequently referred for surgical consultation and consideration
for gastrectomy, unless the clinical condition was deemed unfit for surgery. The management
plan for patients after curative ESD was to repeat EGD (control) at 3 months to check
on the healing process or any residual lesions, and subsequent annual surveillance
in search of recurrence or metachronous tumors.
All patients were treated by the same endoscopist (VA), who received formal theoretical
and practical training in Japan with opportunities to assist experts in human procedures
and to perform ESD under supervision on animal models. When use of the teardrop sodium
hyaluronate solution was initiated, the operator had already performed over 40 ESD
procedures, and thus, had enough experience to overcome the initial phase of the learning
curve.
For all ESD procedures, the following devices were utilized: Flush Knife BT 2.5 (Fujifilm
Co., Japan); a therapeutic gastroscopy was used with a working channel of 3.2 mm (EG-450
RD, Fujifilm Co., Japan) connected to the electrosurgical unit (ERBE VIO 200S, 200 D
or 300 D, Tubingen, Germany), a 4-mm cap (Top Co., Japan) attached to the tip of the
endoscope and a 25-gauge needle (Boston Scientific Co., United States) for SM injection.
The following steps were carried out during ESD: demarcation (Marking): soft coagulation
mode, effect 6, 100 watts; mucosal incision: Endocut I, effect 2, cut duration 3,
cut interval 2; SM dissection: forced coagulation mode effect 3, 50 watts; blood vessel
hemostasis: soft coagulation mode, effect 6, 100 watts. Blood vessels were sealed
with Flush Knife or coagulation forceps (Coagrasper, Olympus Co., Japan). Teardrop
sodium hyaluronate solution was used as is or, at the discretion of the endoscopist,
mixed with saline solution 1/1 and a low dose of epinephrine (0.02 mg corresponding
to a concentration of 1/100000). No dye was added to the solution. In addition to
SM injection of sodium hyaluronate teardrop, water jet saline injection into the SM
layer through the sheath of the knife during dissection was added at the discretion
of the endoscopist.
Statistical analysis
Tabulation of data was carried out using Microsoft Excel for Windows 2010 and the
statistical analysis was carried out using the Stata software version 15 (Stata Corporation,
College Station, Texas, United States), considering a 5 % significance level. A descriptive
analysis of data was performed with frequency and proportion for categorical and average
variables, standard deviation, median and mean ±SD for continuous variables.
Ethical considerations
The authors followed the Declaration of Helsinki recommendations concerning scientific
research, including data confidentiality of each of the enrolled patients. Institutional
review board approval was obtained for this retrospective study. All patients received
detailed information about the ESD intervention ahead of the procedure and were requested
to sign a consent form. Patients who declined to sign the consent form did not proceed
to ESD. Before using the product, scientific discussions were had with the pharmacy
department committee that approved the off-label use of teardrop sodium hyaluronate
during ESD procedures. There was no influence on this research from the company that
manufactures the substance, and the authors have no commercial relationship, patent
interest or conflict of interest to be declared.
Results
During the aforementioned study period, 83 gastric ESD procedures were performed (40
males/43 females). Five patients were excluded (6 %) due to the use of other solutions
apart from sodium hyaluronate, such as voluven (1), hydroxypropyl methylcellulose
(HPMC) (1) and saline solution (2), or due to presence of non-lifting sign (1). Thus,
a total of 78 patients underwent gastric ESD with the use of sodium hyaluronate teardrop
for SM injection and entered the study. The mean age was 68 years old (SD: ± 12.8
years). The mean size of the resected lesions was 28.4 mm (SD: ± 11.2 mm). The topographical
distribution of the resected lesions was as follows: lower third –25 cases (32 %);
middle third –47 cases (60 %); upper third –six cases (8 %).
The mean duration of the procedure was 105.3 minutes (SD: ± 51.6 minutes) Histology
of resected specimens revealed low-grade intraepithelial neoplasia: 12 patients (15.3 %);
high-grade intraepithelial neoplasia: 22 patients (28.3 %); adenocarcinoma: 29 cases
(37.2 %); neuroendocrine tumors (NET): two patients (2.5 %); polypoid lesions: five
patients (6.4 %) and subepithelial lesions in eight patients (10.2 %). Clinicopathological
characteristics of the patients are shown in [Table 1 ]. [Fig. 1 ], [Fig. 2 ], [Fig. 3 ], [Fig. 4 ], [Fig. 5 ], and [Fig. 6 ] are illustrative of use of teardrop sodium hyaluronate solution for SM injection
in a patient with superficial gastric neoplasm.
Table 1
Clinicopathological characteristics of the patients.
Types of gastric lesions with SH teardrop injection
n (%)
Intraepithelial neoplasia
12 (15.3 %)
22 (28.3 %)
29 (37.2 %)
28 (96.5 %)
1 (3.5 %)
Invasion depth (adenocarcinoma)
22 (75.8 %)
(24.2 %)
1 (14.3 %)
6 (85.7 %)
Other lesions
2 (2.5 %)
8 (10.2 %)
5 (6.4 %)
Mean procedure duration in minutes (range)
105.3 min
(SD: ± 51.6 minutes)
Mean tumor size (range)
28.4 mm
(SD: ± 11.2 mm)
SH, sodium hyaluronate; SM, submucosa.
Fig. 1 A depressed-type lesion (0IIc) in the antrum.
Fig. 2 Virtual chromoendoscopy with BLI (Blue Laser Imaging, Fujifilm Co., Japan).
Fig. 3 After placement of markings submucosal injection was performed with teardrop solution
with 0.4 % sodium hyaluronate showing an effective lifting.
Fig. 4 After semi-circumferential mucosal incision additional submucosal injection was added
demonstrating a clear view of the expanded submucosal space.
Fig. 5 Complete tumor resection was achieved en-bloc without injury to muscularis propria.
Fig. 6 The specimen revealed intraepithelial high-grade neoplasia limited to the epithelium
(M1) with free margins and no lymphatic or vascular invasion.
Regarding the 78 resected lesions included in this study, the en-bloc resection rate
was 96.1 % (75/78) and the R0 resection rate was 92.3 % (72/78) ([Table 2 ]). ESD was considered curative for epithelial lesions based on the expanded criteria
from the latest Japanese guidelines [1 ] in 83.8 % of the subjects (57/68). [Table 3 ] describes the list of 11 non-curative cases and subsequent clinical management.
A total of six patients (54.5 %) were referred to gastrectomy and a decision was made
for a conservative clinical management in the other five cases. Three patients with
positive lateral margins and one patient with minimal SM2 invasion (650 μm) were advised
to undergo close endoscopic surveillance with no recurrence thus far. The remaining
patient was elderly, had comorbidities and a tumor located in the cardia, and refused
to undergo surgery. This patient has more than 7 years of follow-up without recurrence
thus far.
Table 2
Clinical outcomes using sodium hyaluronate teardrops for submucosal injection in 78
patients.
Outcomes
n (%)
Procedure
75/78 (96.1 %)
72/78 (92.3 %)
57/68 (83.8 %)
Complications
2 (2.5 %)
3 (3.8 %)
0 (0.0 %)
0 (0.0 %)
Recurrence rate
2 (2.5 %)
0 (0 %)
Mean follow-up period
17 months
(SD: ± 14.5 months)
Table 3
List of patients with criteria for non-curative resection and management plan.
List of cases
Criteria for non-curative resection
Management plan
1
R0 resection with SM2 invasion (2000 μ) + lymphatic/vascular invasión
Conservative
2
R0 resection with SM2 invasion (1700 μ)
Gastrectomy
3
R0 resection undifferentiated adenocarcinoma (M3) with vascular invasion
Gastrectomy
4
SM2 invasion (700 μ) + compromise of deep margin + lymphatic/vascular invasión
Gastrectomy
5
R0 resection with SM2 invasion (1600 μ)
Gastrectomy (negative surgical specimen)
6
Focal compromise of lateral margins
Conservative
7
R0 resection with SM2 invasion (650 μ)
Conservative
8
SM2 invasion (1700 μ) + lymphatic/vascular invasión + compromised deep margin (converted
to piecemeal)
Gastrectomy
9
Focal compromise of lateral margins (converted to piecemeal)
Conservative
10
R0 resection SM1 invasion (200 μ) + lymphatic/vascular invasión + tumoral budding
Gastrectomy (stomach clear, 1 positive lymph node)
11
Focal compromise of lateral margins (lesion resected in 2 pieces)
Conservative
SM, submucosal; M3, muscularis mucosae.
A total of five patients (6.3 %) had complications related to ESD: perforation occurred
in two cases (2.5 %) and delayed bleeding in three cases (3.8 %), which were managed
successfully with thermal coagulation and clipping closure of the defect. It is worth
noting that there were no cases of mortality (0 %) or rescue emergency surgery, nor
systemic infection (bacteremia) or fever requiring antibiotics. The mean volume of
teardrop sodium hyaluronate solution used per patient was 10 cc (SD: ± 8 cc). A total
of 49 patients out of 78 included cases (62.8 %) returned for endoscopic postoperative
control, with a mean follow-up period of 17 months (SD: ± 14.5 months). At follow-up
EGD, no tumor recurrence was encountered and two patients developed metachronous gastric
tumors (2.5 %).
Discussion
SM injection is a critical step in the execution of a safe and effective ESD procedure.
For this reason, different research groups have attempted to investigate suitable
solutions for this procedure [1 ]
[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ]. In this study, we review our experience using an inexpensive and readily available
sodium hyaluronate solution commercialized as a sterile teardrop for use in ophthalmology.
The clinical outcome obtained in this study, which demonstrates a high rate of en-bloc
resection (96.1 %) and absolute absence of local or systemic complications related
to the use of this substance, presents a new solution for SM injection during ESD
operations. Teardrop sodium hyaluronate provides a long-lasting fluid cushion and
the majority of gastric ESD procedures can be completed with a single bottle of the
solution, without substantially increasing the cost of the intervention. Moreover,
the sodium hyaluronate teardrop solution was demonstrated to be useful for a broad
range of gastric lesions that may be resected by ESD, such as epithelial or subepithelial
tumors, neuroendocrine tumors, and polypoid lesions [11 ]
[12 ]
[13 ]
[14 ]
[15 ].
Viscous solutions are widely used by Japanese experts for SM injection in ESD because
of the excellent results with formation of a long-lasting cushion that facilitates
the process of SM dissection and improves the endoscopic view of the SM space [16 ]
[17 ]. One of the most representative studies demonstrating the benefit of these viscous
solutions compared with saline solution was the meta-analysis in which the authors
reviewed five prospective studies (504 patients) and concluded that viscous solutions
were superior to saline solution in terms of en-bloc resection rate (73.2 % vs. 67.3 %)
and local recurrence rate (11.6 % vs. 18.5 %) [18 ]. Nevertheless, in another systematic review that included 54 studies (792 patients/793
lesions), use of 0.4 % sodium hyaluronate for SM injection was not superior compared
with saline solution, and no statistically significant difference in the rate of complete
resection or complications was noted [19 ].
Gastric neoplasms were among the first conditions in which sodium hyaluronate was
used for SM injection in ESD, mainly in Japan with very good results, subsequently
having been applied successfully to other organs such as the esophagus and colorectum
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]. In a multicenter prospective study, an optimal elevation of gastric mucosa was
achieved in 73.5 % of cases (50/68 lesions) using sodium hyaluronate, facilitating
endoscopic resection in 88.3 % (60/69) of cases and resulting in an en-bloc resection
rate of 92.8 % [25 ]. These finding were reproduced in our investigation, but interestingly applied in
a different population while using a variant of the original solution of 0.4 % sodium
hyaluronate – MucoUp – which is available exclusively in Japan and is costly.
Over the last several years, experience with using 0.4 % sodium hyaluronate for ESD
in the treatment of superficial neoplasms of the gastrointestinal tract has been extended
to the esophagus, achieving excellent results in expert hands despite the higher degree
of technical and operative difficulty [26 ]
[27 ]. In one of the most important studies that showed the great advantages of using
0.4 % sodium hyaluronate in the esophagus, the en-bloc resection rate was 99 % in
86 patients with superficial squamous neoplasms of the esophagus (106/107 resected
lesions) and the complete resection rate was 93 % (99/107) with complications arising
in only 6 % (6/107) of cases [28 ]. This encouraged many researchers, especially Latin Americans, to reproduce this
experience; albeit the main drawback of the lack of availability of MucoUp solution
used in Japan; which subsequently motivates some research groups in the West to search
for other alternatives [29 ]
[30 ], which could result in similar rates of efficiency and safety. One of the few studies
representative of the benefits of the use of 0.4 % sodium hyaluronate teardrops for
SM injection of esophageal ESD was recently published by our group [31 ], using this same ophthalmologic compound for SM injection in 66 patients with superficial
neoplasms of the esophagus (70 esophageal ESD procedures) and achieving en-bloc, R0,
and curative resection rates of 97 %, 90 %, and 80 %, respectively, with a complication
rate of 4.28 % (3/70). This study showed the positive experience of using sodium hyaluronate
teardrops, as in gastric ESD, confirming and extending the excellent results obtained
in the esophagus to other segments of the digestive tract. We have also been using
sodium hyaluronate teardrop solution for colorectal ESD (almost 40 cases, unpublished
results), and observed the same benefit profile experienced in the esophagus and stomach.
Recently, new solutions for SM injection have been tested with promising results regarding
efficiency and safety for resection of early neoplasms of the gastrointestinal tract.
In the Western Hemisphere, some innovative viscous substances for submucosal injection
in ESD have been proposed such as hydroxyethyl starch (Hetastarch/Voluven), hydroxypropyl
methylcellulose (Gonak) and SIC-8000 (Eleview). Few head-to-head comparisons have
been done of the different substances. Recently a randomized controlled trial compared
the efficacy and safety of SIC-8000 and Hetastarch in EMR for colorectal lesions [32 ]. In a population of 158 patients (159 adenomas) the authors reported a mean Sydney
resection quotient of 9.3 for SIC-8000 and 8.1 for Hetastarch (P = 0.001), an en-bloc resection rate of 21 % (18/84 lesions) for SIC-8000 and 19 %
(14/75 lesions) for Hetastarch (P = 0.515). The mean volume used was 14.8 mL for SIC-8000 and 20.6 mL for Hetastarch
(P = 0.038). Both substances presented similar duration and elevation of the SM cushion.
The authors concluded that the use of SIC-8000 (Eleview) was more effective than Hetastarch
for SM injection in endoscopic resection [32 ].
Experimental studies also have investigated substances for SM injection for ESD in
pig models. Mehta et al reported that the solutions with the best indexes of mucosa
elevation (measured in mm) and the duration of the SM cushion (measured in minutes)
were hydroxyethyl starch and SIC-8000 (Eleview, Boston Scientific Co., United States)
enabling faster and easier dissection, both with better results than hydroxypropyl
methylcellulose [33 ]. However, it is important to note that in the same study, the 0.4 % sodium hyaluronate
solution performed similarly to the aforementioned substances, which highlight that
sodium hyaluronate solution seems to be ideally matched for this type of endoscopic
procedure [33 ]. Therefore, considering that standard sodium hyaluronate solution (MucoUp) is unavailable
outside Japan and is costly, the off-label use of 0.4 % sodium hyaluronate teardrops
for ESD, a substance easily available in standard drugstores, may be the perfect solution
to bridge this gap [34 ].
Our study had some limitations. It was a single-center experience and all procedures
were carried out by one trained operator and the results need to be reproduced in
other centers. In addition, the number of SM injections of teardrop sodium hyaluronate
made throughout the procedure, as well as the additional volume of saline solution
injected during dissection through the knife, were not measured. Another limitation
of our study was the relatively small population of patients enrolled in comparison
with Japanese studies. However, in Latin America and also in many Western countries,
the experience with gastric ESD ise still limited and inferior, in terms of number
of procedures, to the experience reported in Asia. Therefore, we acknowledge that
large-scale prospective studies with larger cohorts of patients and a longer follow-up
period are needed to extrapolate our results at a worldwide level. Hence, comparative
randomized trials with other solutions are also needed to better establish the role
of teardrop sodium hyaluronate in ESD.
Conclusion
In conclusion, off-label use of 0.4 % sodium hyaluronate teardrops for SM injection
in gastric ESD was demonstrated to be an excellent alternative in countries where
standard sodium hyaluronate is unavailable or too costly, facilitating high-quality
ESD procedures with efficiency and safety while obtaining clinical outcomes similar
to those achieved by Japanese experts in referral centers.
Vitor Arantes, Josue Aliaga Ramos, Rafiz Abdul Rani et al. Off-label use of 0.4 %
sodium hyaluronate teardrops: a safe and effective solution for submucosal injection
in gastric endoscopic submucosal dissection Endoscopy International Open 2020; 08: E1741–E1747. DOI: 10.1055/a-1265-6598
