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Advances in imaging and endoscopic therapy in Barrett’s esophagus

Alvarez Herrero, L.

Link to publication

Citation for published version (APA):Alvarez Herrero, L. (2014). Advances in imaging and endoscopic therapy in Barrett’s esophagus.

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Download date: 10 May 2020

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13Steroid and botulin injection directly after

extensive endoscopic resection do not prevent

severe stenosis in an esophageal porcine model

L. Alvarez Herrero, M. Visser, J.J.G.H.M. Bergman, B.L.A.M. Weusten

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Part III: Experimental endoscopy: stenosis and endoscopic therapy in a porcine model

Abstract

Introduction: In the esophagus a high stenosis risk results from extensive endoscopic resection

(ER), i.e. ≥3cm in length and ≥75% circumference. Steroids are used for treatment of benign

stenosis, while botulin may prevent stenosis formation by relaxing the muscularis propria. Aim:

to determine the efficacy of steroid and botulin injections immediately after extensive ER to

prevent severe stenosis in a porcine model. Methods: A total of 8 pigs were included. In each

pig 3 ER areas were created of 3cm in length and 75% circumference. Each of the 3 created

wounds were injected after randomization with triamcinolone (40 mg), botulin (100 E), or saline.

After 42 days all pigs were euthanized and esophagi were harvested for histological evaluation.

Endpoints were number and severity of stenosis and depth of fibrosis in the esophageal wall.

Results: Stenosis occurred in all ER areas injected with steroid, botulin or saline. The ratio of the

circumference at the center and the upper edge of the ER area was not significantly different

between the area injected with steroid 0.19 (±0.07), botulin 0.18 (±0.07) or saline 0.22 (±0.03).

Fibrosis reached always the muscularis propria in areas injected with steroid or botulin and in 6/8

areas injected with saline. Fibrosis was seen transmurally in 2/8 ER areas injected with steroid,

1/8 injected with botulin and 0/8 injected with saline. Conclusions: Extensive ER results in deep

fibrosis reaching the muscularis propria, which is probably the cause of severe stenosis. Steroid

and botulin injections in the ER wound do not prevent stenosis formation after extensive ER in

this porcine model.

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Stenosis prevention in porcine model

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Introduction

In the last decade endoscopic therapy has become the therapy of choice for esophageal cancer

with limited invasion as it has been proven to be safe and effective.1, 2 The corner stone of

endoscopic therapy is endoscopic resection which results in histological staging of the tumor

and is therefore crucial for deciding adequate therapy according to the invasion depth of the

tumor. Several endoscopic resection techniques are being used in the esophagus such as the

cap technique, the multi-band mucosectomy technique or endoscopic submucosal dissection.3-13

An important drawback of endoscopic resection is the risk of stenosis. Stenosis rate is known to

increase with the extent of the resected area in the esophagus. With resections comprising 75%

of the circumference or more, stenosis rate has been reported in up to 90% of the patients.13-15

Stenosis reduces patient’s quality of life and repetitive dilations are usually necessary. Another

important consequence is that stenosis may hamper further endoscopic therapy that might be

necessary for complete removal of neoplasia.

New methods to prevent stenosis after widespread resection are thus necessary. A possible strategy

to prevent stenosis is by trying to interfere in the processes of wound healing. Normally, wound

healing consists of three phases: inflammation, proliferation and remodeling. The inflammatory

phase occurs quickly after the wound is created and persists during the first days. During the

inflammatory phase cytokines are released and cells are recruited. Several days after the wound is

created, the proliferation phase starts. During the proliferation phase epithelialization of the wound

occurs in combination with fibroblast proliferation and concomitant production of collagens.

After several weeks re-epithelialization is completed and remodeling starts by maturation of the

collagen matrix, including collagen cross-linking. The remodeling phase continues for a prolonged

time and can extend over a year.16

A possible method to interfere with the wound healing and prevent stenosis is the use of

intralesional steroids. On the one hand steroids might prevent excessive inflammation and thereby

excessive fibroblast proliferation and collagen production, and therefore stenosis formation. On

the other hand steroids might inhibit inflammation necessary for re-epithelialization and healing,

therefore giving problems in the healing process. In addition, steroids are believed to prevent

collagen cross-linking during the remodeling phase.17 This might be the explanation why several

studies have shown that injection of steroids into recurrent or refractory benign esophageal

stenoses may improve the outcome after esophageal dilation.18-21

Another possible strategy to prevent stenosis formation after widespread endoscopic resection

might be the use of botulin injections into the proper muscle layer. Botulin is a toxin that inhibits

the release of acetylcholine in the nerve endings and therefore prevents the neuromuscular

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impulse transmission resulting in muscle relaxation. Inhibition of this transmission is temporally

and restores gradually in approximately twelve weeks as nerve endings make new contacts.

Botulin injections in the proper muscle layer of the esophagus might thus result in temporary

muscle relaxation. This muscle relaxation might impede contraction of the esophagus at the

resection wound during the proliferation phase of the healing and therefore possibly preventing

severe stenosis formation.

The aim of this study was therefore to determine the efficacy of steroid and botulin injections

immediately after extensive endoscopic resection to prevent severe stenosis in a porcine model.

Methods

For the purpose of this study a porcine model was used consisting of a total 8 female pigs with

a weight of 46-53 kg. Experiments were performed at the Animal Research Institute AMC (ARIA)

after protocol approval by the Animal Ethical Committee at the Academic Medical Center in

Amsterdam, Netherlands.

Animal handling

Animal care was in accordance with European Union guidelines. All pigs entered the animal

facilities 13 days prior to the start of the experiments for acclimatizing purposes. Pigs received

a semi liquid diet and were placed on a grid 2 days before the experiment and fasted with free

access to water 16 hours before the experiment. For the experiment, pigs were sedated with

intramuscular midazolam 1 mg/kg and ketamine 15 mg/kg, followed by endotracheal intubation.

After induction with propofol 3 mg/kg, anesthesia was maintained with propofol 6mg/kg/h and

supported by 2% isoflurane when necessary. Pigs were placed in left lateral and anti-Trendelburg

position.

Endoscopic resection

Endoscopic resection was performed with the cap technique by using a hard oblique cap (12

mm diameter) attached to the tip of the endoscope. First, the treatment area was lifted with

submucosal injection of diluted adrenaline (1:100.000 NaCl 0.9%) with an injection needle

(Interject, Boston Scientific, Natick, Massachusetts). After placing the cap on the tip of the

endoscope and prelooping a crescent shaped snare (EMR Kit, Olympus Europe, Hamburg,

Germany) in the distal rim of the cap, the mucosa was sucked into the cap. By tightening the

snare a pseudopolyp was created that was resected using 45 Watt pure coagulation current


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(Erbotom ICC 200, ERBE Elektromedizin GmbH, Tuebingen, Germany). In case of subsequent

resections in the treatment area, submucosal lifting was repeated and a new snare was used.

Experiment

For all procedures a therapeutic endoscope was used (GIF-1T140 Olympus, Tokyo, Japan). Food

remnants in the stomach were removed with endoscopic suction and the esophagus was rinsed

with water. In each pig 3 treatment areas were marked by placing electrocoagulation marks with

the tip of the snare. Each treatment area was 3 cm long and included 75% of the circumference

(Figure 1). Treatment areas were resected with the above described cap technique. Subsequently

each resection wound was injected with one of the following substrates: triamcinolone, botulin

toxin, or saline. Triamcinolone acetonide 40 mg (Kenacort-A ‘40’ 1 ml ampoule, Bristol-Meyers

Squibb, Princeton, New Jersey) was dissolved in 3 ml of saline 0.9% and 1 ml aliquots (10 mg)

were injected into the submucosa at 4 locations in the resection wound. Botulin toxin 100 E

(Botox, Allergan, Irvine, California) was dissolved in 4 ml of saline 0.9% and 0.5 ml aliquots (12.5

E) were injected into the muscularis propria at 8 locations in the resection wound. Saline (0.9%)

was injected in 1 ml aliquots at 4 locations in the resection wound as control. For each solution

separate injection needles (Interject, Boston Scientific, Natick, Massachusetts) and syringes were

used. Treatment areas were randomized prior to injection resulting in: distal steroid, mid saline,

proximal botulin; or distal botulin, mid saline, proximal steroid. At the end of the procedure, all

treatment areas were marked just proximal with two tattoos (SPOT endoscopic marker, GI Supply,

Camp Hill, Pennsylvania) and the pigs were detubated.

Figure 1 Placement of markers prior to endoscopic resection of a treatment area (A). After endoscopic resection with the cap technique the resection wound was 3cm in length and contained 75% of the circumference (B).

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Follow-up

Pigs received a semi liquid diet and were placed on a grid for 3 days in order to prevent sawdust

perforating the esophageal wounds. After 3 days pigs progressively received a more solid diet.

In case of regurgitation, i.e. stenosis, pigs were offered again a semi liquid diet which was

supplemented with milk protein if additional caloric intake was necessary.

Pigs were euthanized with an intra venous overdose of pentobarbital after which the esophagus

was harvested for histology 42 days after the experiment.

Histology

After harvesting the esophagus, the treatment areas were identified by opening the esophagus

in longitudinal direction. The treatment areas were cut out and stretched on paraffin with pins

(Figure 2). After stretching on paraffin and before fixation in formalin the mucosal circumference

of each treatment area was measured with a ruler at the center of the treatment area and

at the upper edge of the treatment area (Figure 3). To correct for anatomic differences in the

macroscopic circumferential measurements, a ratio was calculated: the circumference of the

center of the stenosis was divided by the circumference 2 cm proximal of the stenosis. After at

least 24 hours fixation in 10% formalin solution each treatment area was cut into 4 mm slices

resulting in several slices per treatment area. Each slice was embedded in paraffin and cut in 4 μm

slides for standard haemotoxilin & eosin staining.

Histological evaluation was performed by a gastro-intestinal expert pathologist (MV). Specimens

were evaluated for the presence and depth of inflammation, fibrosis and necrosis. The deepest

layer with damage due to inflammation and/or fibrosis was recorded.

Endpoints

Primary endpoint was the number and severity of stenosis after botulin, steroid or saline injection

at 42 days. Secondary endpoint was the depth of fibrosis in the esophageal wall on histology

after steroid, botulin or saline injection at 42 days.

Statistical analysis

Statistical analysis was performed with the Statistical Software Package version 16.0.2 for

windows (SPSS, Chicago, Illinois, USA). For descriptive statistics, mean with standard deviation

was used. Differences in the ratio of the circumference at the center and the upper edge of the

endoscopic resection area were tested with the paired T-test.


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Figure 2 One of the harvested esophagi (A), opened in longitudinal direction showing the white mucosa (B): on the left the distal part on the right the proximal part. Treatment areas were separated and stretched on paraffin (C, E, F). Treatment areas were directly after endoscopic resection injected with botulin in the muscularis propria (C), saline (D) and steroid in the submucosa (E).

Figure 3 After opening an esophagus in longitudinal direction, treatment areas were separated and stretched on paraffin. Next, in each treatment area the circumference of the mucosa at the center of the stenosis (A) and the circumference of the mucosa 2 cm proximal of the stenosis (B) was measured in cm. To correct for anatomic differences a ratio of the center (A) to the proximal circumference (B) was calculated.

Results

Baseline characteristics

Eight female pigs started with a mean weight of 48 kg (range 43-53 kg) and ended with a mean

weight of 74kg (range 61-90 kg) after 42 days. During this experiment no acute or delayed

perforations occurred.

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Mean circumference of the untreated esophagus after 42 days was 8 cm when stretched,

the calculated diameter based on this circumference was 25 mm. Mean circumference of the

untreated proximal esophagus after 42 days was 8.5 cm when stretched, the calculated diameter

based on this circumference was 27 mm. Mean circumference of the untreated mid esophagus

after 42 days was 7.7 cm when stretched, the calculated diameter based on this circumference

was 25 mm. Mean circumference of the untreated distal esophagus after 42 days was 7.9 cm

when stretched, the calculated diameter based on this circumference was 25 mm.

Stenosis rate

Symptoms of regurgitation were first observed after a mean of 12 days (range 4-28 days). Severe

stenosis occurred in all pigs in all endoscopic resection areas injected with steroid, botulin or

saline after 42 days (Figure 2). Mean circumference of the endoscopic resection areas after 42

days when stretched was 1.5 cm after steroids injection, 1.4 cm after botulin injection and 1.7

cm after saline injection (Table 1). Mean calculated diameter based on this circumference was

5 mm after steroids injection, 4 mm after botulin injection and 5 mm after saline injection. The

ratio of the circumference at the center and the upper edge of the endoscopic resection area was

not significantly different between the areas injected with steroids (0.19), botulin (0.18) or saline

(0.22) (Table 1).

Table 1. Severity of stenosis for botulin, steroid and saline injection directly after extensive endoscopic resection.

Mucosal circumference Ratiocenter

cm (±SD)proximal cm (±SD)

center/proximal (±SD)

p-value

Steroid injection 1.5 (±0.5) 8.1 (±1.4) 0.19 (±0.07)

NSBotulin injection 1.4 (±0.5) 8.2 (±0.8) 0.18 (±0.07)Saline injection 1.7 (±0.2) 7.7 (±0.5) 0.22 (±0.03)

SD standard deviation.

Depth of fibrosis in esophageal wall

Fibrosis reached always the muscularis propria in endoscopic resection areas injected with steroid

or botulin and in 6 of the 8 endoscopic resection areas injected with saline. Fibrosis was seen

transmurally (i.e in all layers of the esophagus and through the complete muscularis propria) in 2

of the 8 endoscopic resection areas injected with steroid, 1 of the 8 endoscopic resection areas

injected with botulin and none of the 8 endoscopic resection areas injected with saline (Table 2).


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Table 2. Deepest layer with fibrosis 42 days after extensive endoscopic resection directly injected with botulin, steroid or saline.

Steroids Botulin SalineSubmucosa - - 25% (2/8)Muscularis propria 75% (6/8) 88% (7/8) 75% (6/8)Transmural 25% (2/8) 12% (1/8) 0% (0/8)

Discussion

Although steroid and botulin can hypothetically prevent stenosis, steroid injection into the

submucosa and botulin injection in to the muscularis propria directly after endoscopic resection

do not prevent stenosis formation after extensive endoscopic resection in this porcine model.

Extensive endoscopic resection results in deep fibrosis reaching the muscularis propria, which is

probably the cause of severe stenosis.

Stenosis was severe in all endoscopic resection areas treated directly with submucosal steroid

(triamcinolone 40mg) injection. Others have also reported no preventive effect on stenosis

formation of triamcinolone 80mg injection directly after endoscopic resection in a porcine

model.22 In addition, peri-esophageal abscess formation was observed in these pigs, while in our

study no complications were observed. Reports in patients on the preventive effect on stenosis

after endoscopic resection are more promising as stenosis is only seen in 5-19% of the patients

that underwent extensive (>75% of the circumference) endoscopic resection followed by some

form of steroid treatment combined with dilation in case of dysphagia.23-25 Apart from the fact

that we used a porcine model without performing dilations, the human studies used higher doses

(100mg triamcinolone),23 repeated injections,24 and oral administration.25 It might therefore be

that the dose of 40mg triamcinolone we used is too low or was not administrated at the most

optimal moment.

The timing of steroid administration is probably important. As mentioned in the introduction

healing consists of three different phases. Although it seems logical to administer steroids directly

after endoscopic resection in order to have a maximum inhibiting effect on inflammation, it

might be more effective to inhibit the healing at another phase. By injecting steroids several days

after endoscopic resection the proliferation phase might be inhibited more optimal and thereby

the fibroblast proliferation and collagen production. Inhibiting the inflammation phase as well

the proliferation phase might have even an additional effect on inhibiting fibrosis formation and

therefore stenosis. Hashimoto et al injected steroids several days after endoscopic resection, at

day 3, 7 and 10.24 Also Yamaguchi et al started 3 days after endoscopic resection but prolonged

the oral steroids for 8 weeks.25 In our experiment we did not perform the repeated steroid

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injections as repeated anesthesia was necessary which would lead in our opinion to an unethical

burden for the pigs.

In this study fibrosis reached always the muscularis propria after steroid or botulin injection. This

effect seems not to be related to steroid or botulin as even in the control areas fibrosis reached

the muscularis propria in the majority of cases. Furthermore, during the endoscopic procedure

the muscularis propria never appeared damaged. Fibrosis reaching the muscularis propria after

endoscopic resection has been observed in dogs as well.26 A possible explanation might be that

the coagulation current of the snare damages deeper layers that appear not damaged directly

after endoscopic resection. Another possible explanation might be that inflammation during

healing invades the muscularis propria destroying its fibers which as a consequence are replaced

by fibrosis.

The major limitation of this study is that a porcine esophagus is not completely comparable to a

human esophagus. Although al layers present in a human esophagus are present in the porcine

esophagus, the layers are much thinner. In addition, the muscularis mucosae is almost as thick

as the muscularis propria in the distal part of the porcine esophagus, while the proximal part has

almost no muscularis mucosae and a very thick submucosa. It might be possible that due to these

differences in the esophageal wall architecture, stenosis is formed more severely in pigs therefore

reducing the effect of botulin and steroid to a minimum that is not appreciated in the low number

of pigs used in this experiment. Nevertheless, we can exclude a large preventive effect on stenosis

from triamcinolone 40mg and botulin 100E injected directly after extensive endoscopic resection

in our porcine model.

Although this study did not show any preventive effect on stenosis formation of submucosal

steroid injection directly after endoscopic resection, it seems still valuable to explore strategies

that interfere with the process of wound healing in order to prevent stenosis formation. Not

only because it seems plausible that with inhibition of inflammation fibroblast proliferation and

collagen production will be reduced and therefore stenosis formation can be prevented, but also

because results in patients are promising and encourage to evaluate this strategy further.23-25

Besides steroids, another possible way of inhibiting excessive inflammation and therefore fibrosis

might be the use of non-steroidal anti-inflammatory drugs. For example in rats, stenoses after

caustic ingestion were less severe when ibuprofen was administrated. 27 Other strategies that

might prevent stenosis formation after endoscopic resection are also being explored. Recently,

endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets

was applied in nine patients after widespread endoscopic resection and stenosis only developed in

one patient.28 Another strategy is the use of an extracellular matrix scaffold placed endoscopically


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directly after endoscopic resection that prevented esophageal stricture formation in dogs.29

In conclusion, steroid directly injected in the submucosa and botulin toxin injection into the proper

muscle layer after endoscopic resection do not prevent the stenosis formation after extensive

endoscopic resection in this porcine model. Furthermore, extensive endoscopic resection results

in deep fibrosis reaching the muscularis propria, which is probably the cause of severe stenosis.

Other therapies preventing excessive fibrosis and therefore stenosis after extensive endoscopic

resection still need to be explored.

Acknowledgements

The authors thank Nico Attevelt and Sanne Hackmann for their biotechnical assistance.

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