Original article

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Authors

Sun-Young Lee1, Hye S. Han2, Jae M. Cha3, Yu K. Cho4, Gwang H. Kim5, Il-Kwun Chung6

Institutions

Institutions are listed at the end of article.

submitted 24. December 2013 accepted after revision 24. March 2014

Background and study aims: Pronase, a proteolytic enzyme, is known to improve mucosal visibility during esophagogastroduodenoscopy (EGD), but little is known about its effects on gastric biopsy. This study assessed whether endoscopic flushing with pronase improves the quality of gastric biopsy. Patients and methods: Consecutive patients who underwent EGD were randomly assigned to either the control group or the pronase group in a prospective setting. The first biopsy of the identified lesion was performed during endoscopy. Endoscopic flushing with either 50 mL of water and dimethylpolysiloxane (DMPS; control group) or 50 mL of water, pronase, sodium bicarbonate, and DMPS (pronase group) was then applied to the lesion. After 5 minutes, the second biopsy was performed 2 – 3 mm away from the first biopsy site. The thickness of mucus, depth of the specimen, overall diagnostic adequacy, anatomical

orientation, and crush artifact were measured to assess the quality of the biopsy. Results: Of the 208 patients, 10 were not analyzed due to the absence of an identifiable lesion. Compared with the control group, the pronase group showed significantly decreased thickness of mucus (P < 0.001), increased depth of biopsy (P < 0.001), improved anatomical orientation (P = 0.010), and improved overall diagnostic assessment (P = 0.011) in the second biopsied specimen following endoscopic flushing. The crush artifact and hemorrhage did not differ between the groups. Conclusions: Endoscopic flushing with pronase not only improved the depth of biopsy but also the anatomical orientation and overall diagnostic adequacy. Pronase can be recommended for flushing during EGD to improve the quantity and quality of biopsy.

Introduction

agent is as effective in terms of improving endoscopic mucosal visibility as a pre-endoscopy drink of the same agents [9]. Results showed that endoscopic spraying of these bubble-bursting and mucolytic agents was not able to offer equivalent improvements in endoscopic mucosal visibility when compared with the standard pre-endoscopy drink of these agents. Despite these publications on pronase, little is known about the mucolytic effect of pronase on gastric biopsy. There is no study on the effect of endoscopic flushing with pronase on the gastric biopsy specimen in terms of quality and quantity. The aim of the current study was to assess whether endoscopic flushing of pronase improves the quality and quantity of the gastric biopsy. The thickness of mucus covering the mucosa and the thickness of the biopsy specimen were also measured.

Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1365811 Published online: 14.7.2014 Endoscopy 2014; 46: 747–753 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Il-Kwun Chung, MD Department of Internal Medicine Soonchunhyang University College of Medicine Cheonan Republic of Korea Fax: +82-41-5745762 [email protected]

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Antifoaming and mucolytic agents are used as premedication for esophagogastroduodenoscopy (EGD). The most commonly used antifoaming, bubble-bursting agent is dimethylpolysiloxane (DMPS), which does not have a mucolytic effect. Mucolytic agents, such as pronase or N-acetylcysteine, are known to improve mucosal visibility during EGD including chromoendoscopy, narrow band imaging endoscopy, and endoscopic ultrasonography [1 – 4]. In addition, pronase does not interfere with Helicobacter pylori identification using the rapid urease test or culture [1, 5, 6]. Most of the previous studies used pronase as an oral premedication before EGD, and found that pronase significantly improved endoscopic visualization and decreased the frequency of water flushing required during EGD [7, 8]. Recently, a study investigated whether endoscopic flushing with a bubble-bursting agent and a mucolytic

Lee Sun-Young et al. Pronase for improved gastric biopsy … Endoscopy 2014; 46: 747–753

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Endoscopic flushing with pronase improves the quantity and quality of gastric biopsy: a prospective study

Original article

Patients and methods !

Patients A consecutive series of patients who attended the Digestive Disease Center for EGD between 2012 and 2013 were included in a prospective setting. All patients gave their written informed consent at the outpatient clinic before the procedure. Patients were excluded if they were younger than 20 years, had a systemic disease that required treatment, or were under medication including acid suppressants and antithrombotics. The study was approved by the institutional review board of the Konkuk University Medical Center (KUH 1010382) and then registered at the Korean government Clinical Trial Center (registration number: KCT0000528).

Preparation for endoscopic examination Patients were asked to drink 100 mL of warm water mixed with 80 mg of DMPS (Gasocol; Taejoon Pharmaceutical Co., Ltd., Seoul, Korea), 10 minutes before moving to the endoscopy room for EGD. Patients were randomized to either the control group or the pronase group using a table of random numbers. Aliquots of water and DMPS were prepared for the control group to wash the mucosal surface during EGD, and aliquots of water containing DMPS, 20 000 units of pronase (Endonase; Pharmbio Korea, Co., Ltd., Korea), and 1 g of sodium bicarbonate were prepared for the pronase group.

Table 1 Criteria for measuring the gastric biopsy specimen taken during esophagogastroduodenoscopy.

Quantity 1. Depth in μm 2. Depth in layers (1) superficial mucosa (2) deep mucosa (3) muscularis mucosa (4) submucosa

Quality 1. Anatomical orientation (1) good (2) intermediate (3) poor 2. Overall diagnostic adequacy (1) adequate (2) suboptimal (3) inadequate

Artifact 1. Crush artifact (1) none (2) minimal (3) mild 2. Hemorrhage (1) absent (2) present

as a specimen that did not match either “good” or “poor” criteria. For the crush artifact, “minimal” was defined as only a negligible amount of crush visible on the slide, which could not be easily detected at first sight. “Mild” was defined as crush that was easily visible. For the overall diagnostic adequacy, “adequate” was defined as full-thickness mucosa regardless of the presence of muscularis mucosa. “Suboptimal” was defined as epithelium and mucosa, but not full thickness. “Inadequate’’ was defined as either superficial mucosa/epithelium or deep mucosa, but not both. Hemorrhage was recorded to assess the complications induced by pronase. H. pylori infection was recorded if Giemsa staining was positive.

Endoscopic examination and gastric biopsy EGD was performed by one endoscopist (S.Y.L.) in order to exclude any interobserver variability in the performance of gastric biopsy. The GIF-Q260 endoscope (Olympus Co., Ltd., Tokyo, Japan) was used in all procedures, and gastric biopsy was performed using a reusable biopsy forceps (FB-21K-1; Olympus). The first biopsy specimen was taken from the lesion (if detected) during EGD. After the initial biopsy, the area was flushed with either 50 mL aliquots of water and DMPS (control group) or 50 mL aliquots of water, pronase, sodium bicarbonate, and DMPS (pronase group). After 5 minutes, the second biopsy specimen was taken, 2 – 3 mm away from the first biopsy site. Each gastric biopsy specimen was assigned a unique specimen record number, and the samples were anonymized before sending to the pathologist.

Pathological evaluation of the biopsy specimen All of the specimens were assessed at × 40, × 100, and × 200 high power field by one authorized pathologist (H.S.H) who was unaware of the randomization. Biopsy specimens were fixed in formalin and stained with hematoxylin and eosin and modified Giemsa stain. After the pathological diagnosis, specimens were compared microscopically to determine the quantity and quality of the biopsy, as described previously [10]. The thickness of mucus and the depth of the specimen were measured to assess the quantity of the biopsy. Anatomical orientation (good, intermediate, or poor), crush artifact (none, minimal, or mild), and overall diagnostic adequacy (adequate, suboptimal, or inadequate) were measured " Table 1). to assess the quality of the biopsy (● For anatomical orientation, “good” was defined as a rectangularshaped sample showing clearly demarcated layers that were parallel from the gastric luminal part to the intrinsic deeper part. “Poor” was defined as a sample that was closer to a circular shape than a rectangular shape, and had layers that were not parallel from the luminal to the deeper parts. “Intermediate” was defined

Study outcomes The primary outcome was the depth of biopsy specimen in layers and micrometers. Secondary outcomes were the anatomical orientation and overall pathological assessment.

Statistical analysis Continuous and categorical demographic data were compared by Student’s t test and chi-squared tests, respectively. The depth of the biopsied specimen and age were expressed as mean (± SD. Continuous variables that appeared to have skewed distributions (e. g. the thickness of mucus) were expressed as median with range using the Mann – Whitney test. A P value of less than 0.05 was considered statistically significant. Sample size was calculated with a 5 % significance level and a statistical power of 80 %. By estimating a follow-up loss of 20 % of the initially enrolled patients, a decision was made to enroll more than 62 patients in each group.

Results !

Baseline characteristics of patients A total of 208 patients were randomly assigned to one of the two " Fig. 1). A total of 10 patients were not analyzed due to groups (● absence of a discolored lesion. The baseline characteristics of the patients and the biopsied specimen did not differ between the " Table 2). Two patients were newly diagnosed two groups (● with gastric cancers during EGD. One patient in the control group was confirmed as having a well-differentiated adenocarcinoma of the cardia. One patient in the pronase group was diagnosed with a poorly differentiated adenocarcinoma of the mid-body. Other pathology included benign lesions such as regenerative gland, foveolar hyperplasia, lymphoid follicle, lymphoid cell ag-

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748

Original article

gregation, erosion, fibromuscular proliferation, fundic gland hyperplasia, and dilated gland.

Completed informed consent (n = 208)

First biopsy specimens before endoscopic flushing

Pronase group (n = 104)

First biopsy of gastric lesion during endoscopy Endoscopic flushing 50 mL of water and DMPS

Endoscopic flushing 50 mL of water, pronase, sodium bicarbonate, and DMPS

Second biopsy (3 mm away from first biopsy) after 5 minutes Patients analyzed n = 102

Patients analyzed n = 96

Fig. 1 Study flow of patients. Of the 208 patients enrolled, 102 in the control group and 96 in the pronase group completed the study. A total of 10 patients were excluded from the study as they did not undergo gastric biopsy due to the absence of a discolored lesion. DMPS, dimethylpolysiloxane.

Control group (n = 102) Age, mean ± SD, years

The median thickness of mucus above the mucosa in the gastric biopsy specimen was 27.8 μm (range 5 – 150 μm) in the control group and 32.7 μm (range 0 – 150 μm) in the pronase group. The mean depths, anatomical orientation, and overall diagnostic adequacy of the biopsy specimens did not differ between the groups " Table 2). before the endoscopic flushing (● The most common biopsy depth was deep mucosa in both the control group (58.8 %) and the pronase group (62.5 %). The proportions of superficial mucosa, deep mucosa, muscularis mucosa, and submucosa showed no significant difference between the groups in the first biopsy specimen (P = 0.225).

Second biopsy specimens after endoscopic flushing A total of 92 patients showed decreased thickness of mucus after " Table 3; ● " Fig. 2). In addition, measured endoscopic flushing (● depths were deeper in 48 patients after endoscopic flushing " Fig. 3). Compared with the control group, the pronase group (● showed significantly decreased thickness of mucus (P < 0.001), increased depth of biopsy (P < 0.001), improved anatomical orientation (P = 0.010), and improved overall diagnostic adequacy (P = 0.011) in the biopsy specimen after endoscopic flushing " Table 3). (●

Pronase group (n = 96)

53.7 ± 15.6

53.8 ± 15.3

Male

47

42

Female

55

54

Antrum

60

64

Body

39

27

Sex, n

Helicobacter pylori infection, n (%)

3 31 (30.4)

5 36 (37.5)

44 (43.1)

Foveolar hyperplasia

26 (25.5)

19 (19.8)

Lymphoid follicle or cell aggregation

16 (15.7)

18 (18.8)

Regenerative gland

7 (6.9)

6 (6.3)

Erosion

2 (2.0)

2 (2.1)

Fibromuscular proliferation

1 (1.0)

2 (2.1)

Fundic gland hyperplasia

2 (2.0)

2 (2.1)

45 (46.9)

Dilated gland

3 (2.9)

1 (1.0)

Adenocarcinoma

1 (1.0)

1 (1.0)

27.8 (5 – 150) 885.7 ± 237.2

32.7 (0 – 150) 896.0 ± 308.0

Depth in layer, n (%) Superficial mucosa

7 (7.3)

Deep mucosa

60 (58.8)

60 (62.5)

Muscularis mucosa

37 (36.3)

27 (28.1)

3 (2.9)

2 (2.1)

88 (86.3)

81 (84.4)

Intermediate

9 (8.8)

14 (14.6)

Poor

5 (4.9)

1 (1.0)

93 (91.2)

86 (89.6)

Anatomical orientation, n (%) Good

0.145

Overall diagnostic adequacy, n (%) Adequate

0.258 0.798 0.225

2 (2.0)

Submucosa

0.182 0.540

Chronic gastritis only

Thickness of mucus, median (range), μm

Table 2 Baseline characteristics of the patients and findings of the first biopsy specimen.

0.298

Pathology, n (%)

Depth, mean ± SD, μm

0.965 0.776

Location, n

Fundus

P value

0.579

Suboptimal

9 (8.8)

9 (9.4)

Inadequate

0 (0)

1 (1.0)

Lee Sun-Young et al. Pronase for improved gastric biopsy … Endoscopy 2014; 46: 747–753

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Control group (n = 104)

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Original article

Table 3 Findings of the second biopsy specimen compared with the first specimen.

Control

Pronase

group

group

(n = 102)

(n = 96)

Mucus, n

< 0.001 28

9

Similar

41

28

Thinner

33

59

Shallower

19

1

Similar

79

51

Deeper

4

44

Worsened

15

3

Similar

81

82

6

11

9

1

91

88

2

7

Depth, n

< 0.001

Anatomical orientation, n

Improved

0.010

Overall diagnostic adequacy, n Worsened Similar Improved

0.011

Pathological diagnosis (first → second), n (%) 12 (11.8)

12 (12.5)

Pathology 1 → chronic gastritis

13 (12.7)

12 (12.5)

1 (1.0)

1 (1.0)

Adenocarcinoma → Adenocarcinoma 1

0.963

Chronic gastritis → pathology 1

Pathology included benign lesions such as regenerative gland, foveolar hyperplasia, lymphoid follicle, lymphoid cell aggregation, erosion, fibromuscular proliferation, fundic gland hyperplasia, and dilated gland.

Depth of biopsy The proportions of superficial mucosa, deep mucosa, muscularis mucosa, and submucosa did not differ before and after the endoscopic flushing in the control group, whereas they showed a sig" Fig. 4). In the pronase nificant difference in the pronase group (● group, the most common deepest layer was the deep mucosa before the endoscopic flushing (62.5 %), but this changed to the deeper muscularis mucosa layer after flushing (58.3 %). In the control group, the most common deepest layer was deep mucosal layer both before (58.8 %) and after (63.7 %) endoscopic flushing.

Fig. 2 A gastric biopsy specimen that showed decreased mucus thickness after endoscopic flushing with pronase. a Arrow indicates mucus noticed above the gastric mucosa on the first biopsy specimen (hematoxylin and eosin [H&E] × 200). The thickness of mucus was 75 μm in this image. b After endoscopic flushing, the thickness of mucus was decreased on the second biopsy specimen (H&E × 200).

overall diagnostic accuracy. One showed marked improvement, from inadequate to adequate, following endoscopic flushing with pronase.

Changes in anatomical orientation Anatomical orientation showed improvement in 11 patients (11.5 %) in the pronase group and in 6 patients (5.9 %) in the con" Table 3). Four patients showed marked improvetrol group (● ment from poor to good orientation, whereas most showed only a mild improvement from poor to intermediate orientation (n = 12) or intermediate to good orientation (n = 1). In 18 patients anatomical orientations worsened after endoscopic flushing: 15 patients (14.7 %) in the control group showed lower levels of anatomical orientation after endoscopic flushing compared with only 3 patients (3.1 %) in the pronase group (P = 0.010).

Changes in overall diagnostic adequacy Overall diagnostic adequacy changed in 11 patients (10.8 %) in the control group and 8 patients (8.3 %) in the pronase group. Of the 11 patients in the control group, the overall diagnostic accuracy worsened in 9 and improved, from inadequate to subopti" Table 3). By contrast, of the eight patients mal, in 2 patients (● with changes in the pronase group, seven showed improved

Presence of crush artifact and hemorrhage

" Fig. 5 a) did not differ between The presence of crush artifact (● the groups for both the first and second biopsy specimens. In the control group, crush artifacts were present in 15 (14.7 %) of the first biopsy specimens and 17 (16.7 %) of the second biopsy specimens compared with 22 (22.9 %) and 14 (14.6 %), respectively, in the pronase group. There was no significant difference in the changes of crush artifact between the groups (P = 0.070). " Fig. 5 b) The presence of hemorrhage in the biopsy specimen (● did not differ between the groups. Hemorrhage was noticed in 3 (2.9 %) of the control group and 2 (2.1 %) of the pronase group before endoscopic flushing. On the second biopsy specimen, hemorrhage was noticed in 3 (2.9 %) of the control group and 5 (5.2 %) of the pronase group. There was no significant difference in the changes in hemorrhage rate between the groups (P = 0.676).

Lee Sun-Young et al. Pronase for improved gastric biopsy … Endoscopy 2014; 46: 747–753

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Thicker

P value

% 100

% 100

80

80

60

60

40

40

20

20

0

Before

After

Control group (P = NS)

0

Before

After

Pronase group (P = 0.001)

Submucosa

Deep mucosa

Muscularis mucosa

Superficial mucosa

Fig. 4 A comparison of the depths in layer between the first and the second biopsy specimen. Significant improvement of the depth in layers was noticed before and after the endoscopic flushing only in the pronase group (P < 0.001).

Fig. 3 A gastric biopsy specimen that showed improved orientation and depth in layer after endoscopic flushing with pronase. a Poor orientation was noticed at the first biopsy (hematoxylin and eosin [H&E] × 40). b Arrow indicates the submucosal layer obtained at the second biopsy (H&E × 40). Good orientation was noticed at the second biopsy after endoscopic flushing.

Discussion !

In this study, the pronase group showed decreased thickness of mucus, increased depth of biopsy, improved anatomical orientation, and improved overall diagnostic assessment in the second biopsy specimens after endoscopic flushing compared with the control group. Notably, the use of pronase did not increase complications such as hemorrhage or crush artifact of the biopsied specimen. The results suggest that endoscopic flushing with pronase can be recommended for flushing during EGD in order to improve the quantity and the quality of a biopsy without complication. Most of the previous studies on pronase have focused on oral premedication, mucosal visibility, and the diagnosis of H. pylori infection [1, 3 – 8]. Based on previous findings, there is no doubt that drinking pronase would improve the visibility, but pronase might not reach some portions of the stomach in sufficient quantity when the patient is in certain positions. For example, when the patient is in the left lateral decubitus position, the distal part of the stomach might not be washed thoroughly by pronase. Therefore, the current study used endoscopic flushing rather than drinking in order to target the lesion that required biopsy. Through endoscopic flushing, the endoscopist could confirm that pronase had reached the target lesion.

Fig. 5 Crush artifact and hemorrhage. a Arrow indicates crush artifact noticed in the deep mucosal layer (hematoxylin and eosin [H&E] × 200). b Arrow indicates hemorrhage noticed in the deep mucosal layer (H&E × 100).

Lee Sun-Young et al. Pronase for improved gastric biopsy … Endoscopy 2014; 46: 747–753

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Original article

Original article

By measuring the real thickness of mucus above the mucosa and the depth of the gastric biopsy specimens, only the pronase group showed a marked improvement in the depth of gastric biopsy due to a decrease in the thickness of mucus. In addition, the proportions of superficial mucosa, deep mucosa, muscularis mucosa, and submucosa were significantly different in the second biopsy specimen in the pronase group. The most common depth in layer taken by a gastric biopsy forceps is known to be the deep mucosa, but this changed to the deeper muscularis mucosa layer after endoscopic flushing with pronase. Because such improvements were significantly different between the pronase and control groups, it is assumed that these results are related to the mucolytic effect of the pronase used to wash away the mucus during EGD. There are few studies on endoscopic flushing using pronase [9, 11]. A study that compared the efficacy of endoscopic flushing of pronase with that of oral premedication with pronase showed no improvements in endoscopic mucosal visibility when endoscopic flushing was applied [9]. As the results were compared only in terms of visibility, it is not possible to compare these results with those of the current study because the latter focused on the quality and quantity of the biopsy specimen. Hemorrhage was not found to be a problem after endoscopic flushing with pronase. A previous study on endoscopic flushing of pronase assessed the safety of topical therapy for H. pylori eradication in 66 patients with H. pylori infection [11]. The topical therapy included 100 mL of 7 % sodium bicarbonate solution, bismuth subnitrate, amoxicillin, metronidazole, and 18 000 units of pronase. The solution was applied to the stomach during EGD, and kept in the stomach for 2 hours. The patient’s position was changed every 15 minutes, from sitting to supine, prone, and right lateral positions, in order to expose the entire gastric mucosa to the solution. Only two cases of transient loose stools and one case of transient loss of appetite were reported as complications. Similarly, another study using endoscopic flushing of pronase showed no clinically detectable complications [9]. In the current study, anatomical orientation and overall diagnostic adequacy were used instead of pathological diagnosis as criteria for the quality of biopsy. Only minor changes were observed in the pathological diagnosis between the two biopsy specimens " Table 3). Previous studies on gastric biopsies [12, 13] have (● shown that endoscopic biopsy is a prerequisite for histopathological diagnosis, but that other factors such as overall surface area, diameter, depth, adequacy, artifacts, anatomical orientation, and vitality were evaluated independently from diagnostic results to assess the quality of biopsy. In the current study, only minor differences in histological findings were noticed between the two groups of biopsy specimens, and these differences did not alter the pathological diagnosis. There are several limitations to the study. First, the study cannot demonstrate that pronase can improve false-negative biopsies because only two cancers were detected and no difference was found between the groups; in addition, it would be unethical to conduct a study in only cancer patients. Second, comparing the anatomical orientations of the biopsy specimens would be impractical because the final orientation can also be affected by sample direction when embedding the specimen into the paraffin block. Third, aliquots for endoscopic flushes were prepared in the endoscopy room in the presence of the endoscopist, although the pathologist was fully blinded to the use of pronase. However, it was assumed that the conclusion would not be changed by these limitations for the following reasons. First, all of the ali-

quots were prepared by the attending nurse not the endoscopist. Second, it is not easy for an endoscopist to manipulate the biopsy technique during each procedure, because a crush artifact or hemorrhage might occur in the biopsy specimen when a deeper sample is taken. The current findings showed that the rates of crush artifact and hemorrhage were not different between the pronase group and the control group in both the first and second biopsy specimens. This indicates that all biopsies were taken in a consistent way, without significant variation. Third, all of the samples were sent directly to the pathologists without any information on the flushing solution used. As the outcomes of this study were pathological findings rather than endoscopic findings, results provided by the pathologists could not have been biased by the use of pronase. In conclusion, endoscopic flushing with pronase not only improved the depth of the biopsy but also the anatomical orientation and overall diagnostic adequacy, without complications. Pronase can be recommended for flushing during EGD to improve both the quantity and the quality of biopsy. Competing interests: None Institutions 1 Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea 2 Department of Pathology, Konkuk University School of Medicine, Seoul, Republic of Korea 3 Department of Internal Medicine, University of Kyunghee College of Medicine, Seoul, Republic of Korea 4 Department of Internal Medicine, The Catholic University College of Medicine, Seoul, Republic of Korea 5 Department of Internal Medicine, Pusan National University School of Medicine, Busan, Republic of Korea 6 Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea

Acknowledgment !

This study was supported by Pharmbio Korea. The company did not participate in the study.

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Lee Sun-Young et al. Pronase for improved gastric biopsy … Endoscopy 2014; 46: 747–753

Endoscopic flushing with pronase improves the quantity and quality of gastric biopsy: a prospective study.

Pronase, a proteolytic enzyme, is known to improve mucosal visibility during esophagogastroduodenoscopy (EGD), but little is known about its effects o...
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