Gastric ischemic conditioning increases neovascularizationand reduces inflammation and fibrosis during gastroesophagealanastomotic healing

Kyle A. Perry • Ambar Banarjee • James Liu •

Nilay Shah • Mark R. Wendling • W. Scott Melvin

Received: 30 March 2012 / Accepted: 30 July 2012 / Published online: 18 December 2012

� Springer Science+Business Media, LLC 2012

Abstract

Background The incidence of anastomotic leak and

stricture after esophagectomy remains high. Gastric

devascularization followed by delayed esophageal resec-

tion has been proposed to minimize these complications.

We investigated the effect of ischemic conditioning dura-

tion on anastomotic wound healing in an animal model of

esophagogastrectomy.

Methods North American opossums were randomized to

four study groups. Group A underwent immediate resection

and gastroesophageal anastomosis. Groups B, C, and D

were treated with delayed resection and anastomosis after a

gastric ischemic conditioning period of 7, 30, and 90 days,

respectively. Gastric conditioning was performed by

ligating the left, right, and short gastric vessels. An intra-

abdominal esophagogastric resection and anastomosis was

performed, followed by euthanasia 10 days later. Outcome

variables included anastomotic bursting pressure, micro-

vessel concentration, tissue inflammation, and collagen

deposition.

Results Twenty-four opossums were randomized to

groups A (n = 7), B (n = 8), C (n = 5), and D (n = 4).

Subclinical anastomotic leak was discovered at necropsy in

5 animals: 3 in group A, and 1 each in groups B and C

(p = 0.295). The anastomotic bursting pressure did not

differ significantly between groups (p = 0.545). A 7 day

ischemic conditioning time did not produce increased

neovascularity (p = 0.900), but animals with a 30 day

conditioning time showed significantly increased micro-

vessel counts compared to unconditioned animals (p =

0.016). The degree of inflammation at the healing anasto-

mosis decreased significantly as the ischemic conditioning

period increased (p = 0.003). Increasing delay interval was

also associated with increased muscularis propria preser-

vation (p = 0.001) and decreased collagen deposition at

the healing anastomosis (p = 0.020).

Conclusions Animals treated with 30 days of gastric

ischemic conditioning showed significantly increased

neovascularity and muscularis propria preservation and

decreased inflammation and collagen deposition at the

healing anastomosis. These data suggest that an ischemic

conditioning period longer than 7 days is required to

achieve the desired effect on wound healing.

Keywords Anastomotic healing � Anastomotic leak �Esophagectomy � Ischemic conditioning � Wound healing

The incidence of esophageal adenocarcinoma has increased

350 % since 1970, a rate outpacing all other solid malig-

nancies [1–3]. Esophageal resection remains the only

curative treatment for esophageal cancer, but this extensive

procedure carries major morbidity rates of 44–50 % and

mortality rates of up to 11 % [4–7]. Patient quality of life

represents an important outcome of esophageal cancer care,

and the occurrence of surgical complications is the main

predictor of reduced global quality of life, physical,

Presented at the SAGES 2012 Annual Meeting, March 7–10, 2012,

San Diego, CA.

K. A. Perry (&) � A. Banarjee � N. Shah �M. R. Wendling � W. S. Melvin

Division of General and Gastrointestinal Surgery,

Department of Surgery, Center for Minimally Invasive Surgery,

The Ohio State University, N711 Doan Hall, 410 W. 10th Ave,

Columbus, OH 43210, USA

e-mail: Kyle.perry@osumc.edu

J. Liu

Department of Pathology, The Ohio State University,

Columbus, OH, USA

123

Surg Endosc (2013) 27:753–760

DOI 10.1007/s00464-012-2535-6

and Other Interventional Techniques

and role functioning scores after esophagectomy [8, 9].

Therefore, reducing postoperative complication rates pro-

vides a target to improve esophageal cancer treatment

outcomes.

Gastric pull-up reconstruction after esophagectomy is

the most common method of esophageal replacement after

resection for malignant esophageal disease. Dehiscence

of the esophagogastric anastomosis remains a dreaded

and common complication that occurs in up to 20 % of

cases. After cervical anastomotic leak, more than 50 % of

patients subsequently develop anastomotic strictures that

require dilation [10–17]. Creation of the gastric conduit for

esophageal replacement requires the interruption of three

of the five vessels that provide blood flow to the gastric

fundus. Anatomic studies have demonstrated that division

of the left gastric, left gastroepiploic, and short gastric

vessels renders the gastric conduit almost solely dependent

on blood flow from the right gastroepiploic artery via a

network of intramural capillaries [18]. The resultant

ischemic changes within the anastomosed gastric fundus

have been implicated in the development of anastomotic

leak and stricture [18–23].

It has been postulated that gastric ischemic conditioning

(i.e., division of the short and left gastric vessels followed

by a delay period before esophageal resection and recon-

struction) allows the gastric fundus to recover from this

ischemic insult before the creation of the esophagogastric

anastomosis. Human and animal studies have shown that

gastric ischemic conditioning allows neovascularization of

this portion of the stomach, improves wound healing at this

tenuous anastomosis, and may reduce the incidence of

anastomotic complications [24–28]. Although improved

gastric conduit perfusion and anastomotic wound healing

have been demonstrated, the required duration of gastric

ischemic conditioning has not been determined.

We hypothesized that an ischemic conditioning period

of 30 days would improve gastric perfusion and wound

healing at the esophagogastric anastomosis compared to

a shorter ischemic conditioning period. This controlled

animal study aimed to identify the optimal duration of

ischemic delay to maximize improvements in wound

healing and potential reduction of perioperative morbidity

that would lead to improved patient quality of life.

Methods

Animal model

An opossum model for esophagogastric anastomosis was

used. The North American opossum (Didelphis virginiana)

was chosen for its physiologic and anatomic similarities

to the human foregut and for its long intraabdominal

esophagus [29]. All animals were managed under the reg-

ulations of the Institutional Animal Care and Use Com-

mittee of the Ohio State University. Animals underwent a

1 week acclimation period and were fasted for 12 h before

operation. All procedures were performed under general

endotracheal anesthesia with inhaled isoflurane and sup-

plemental oxygen; homoeostasis was maintained with heat

lamps, warming blankets, and fluid and oxygen supple-

mentation as needed.

Thirty-two animals were equally divided into four study

groups: immediate resection, 7-day delay, 30-day delay,

and 90-day delay. All animals underwent laparotomy with

vascular ligation. In the immediate group, esophagogas-

trectomy with intraabdominal esophagogastric anastomosis

was completed at the time of this initial laparotomy. In the

delayed animals, a second laparotomy was performed at the

designated delay interval, and esophagogastrectomy with

esophagogastric anastomosis was performed. Animals were

euthanized and the anastomoses collected 10 days after

esophagogastrostomy.

Surgical technique

The abdomen was accessed via a midline laparotomy. The

left, right, and short gastric vessels were ligated by ultra-

sonic dissection. The right gastroepiploic artery and vein

were identified from their origin and preserved. In the

delay groups, the abdomen was closed at this point,

whereas the procedure was completed in the immediate

reconstruction group. The esophagogastric junction was

resected, and a single-layer esophagogastrostomy was

completed using monofilament suture. The delay groups

underwent a second laparotomy 7, 30, or 90 days after

vessel ligation, and the resection and anastomosis were

performed in the same manner.

Anastomotic bursting pressure

After euthanasia, the distal esophagus, stomach, and

proximal duodenum were removed en bloc. Chilled normal

saline mixed with methylene blue dye (1:180 mL concen-

tration) was manually infused into the specimen. Infusion

occurred through the esophagus, and pressure (mmHg) was

continuously measured with a digital manometer attached

to the duodenum. Anastomotic failure (bursting pressure)

was recorded as the highest pressure obtained before frank

leakage of blue saline. This value corresponded to the

highest pressure obtained during infusion.

Tissue preparation and handling

Upon tissue collection, longitudinal tissue sections were

taken through the anastomosis. The tissue was fixed in

754 Surg Endosc (2013) 27:753–760

123

fresh 4 % paraformaldehyde in phosphate buffer, pH 7.4,

and kept overnight at room temperature. After fixation, the

tissue was embedded in paraffin and 5 lm thick sections

were placed on positively charged slides (SuperFrost,

CMS) for immunohistochemistry and histochemistry.

Positive and negative control sections were performed at

the same time with the experimental sections for simulta-

neous staining. The general histopathological appearance

of tissues was assessed after routine hematoxylin and eosin

staining, and all histologic analyses were performed by a

blinded pathologist.

Tissue inflammation and alignment

Hematoxylin and eosin-stained slides were evaluated for

semiquantitative assessment of acute inflammation and

muscularis propria alignment at the healing anastomosis.

Five fields per section were analyzed at random at 4009

magnification and scored as 0, 1, 2, or 3, corresponding to

the presence of numbers of neutrophils and macrophages

per high-power field (0 B 5; 1 = 5–25; 2 = 25–150;

3 C 150). For semiquantitative assessment of muscularis

propria alignment, three fields per section were analyzed at

209 and 1009 magnifications, respectively, and scored as

0, 1, or 2 corresponding to presence of complete, incom-

plete, or absent alignment of the muscularis propria.

Anastomotic collagen deposition

Trichrome stained sections were assessed for semiquanti-

tative assessment of anastomotic collagen deposition. An

average of five fields per section was analyzed at random at

2009 magnification, and the staining intensity in the areas

was scored as 0, 1, 2, or 3, corresponding to the presence of

negative, weak, intermediate, and strong tissue staining,

respectively.

Capillary quantification

Neovascular density and maturation was assessed using

established double immunostaining of endothelial cells

with anti-von Willebrand factor (vWF) antibody and

pericytes with anti-a-smooth muscle actin antibody.

Briefly, permanent sections were embedded in paraffin and

sectioned longitudinally. After slide fixation, the specimens

were incubated with vWF antibodies (A0062, Dako Inc.,

Glostrup, Denmark) for 60 min at a 1:1800 dilution, fol-

lowed by a secondary antibody for 30 min (rabbit IgG,

1:7500). After slide fixation, the specimens and endothelial

cells were stained with NovaRed to detect vWF binding

with methyl green for background staining.

Specimens were examined under low-power magnifi-

cation (409) to identify five areas corresponding to vas-

cular hot spots. These areas were examined under

high-power magnification (2009), and microvessels in

each hot spot were counted by two blinded observers who

followed an established protocol [30, 31].

Statistical analysis

Data were analyzed with the Stata 12 program (StataCorp,

College Station, TX). All data were tested for normality,

and parametric or nonparametric statistical tests were used

as appropriate. p values of \0.05 were considered signifi-

cant. One-way ANOVA and Student’s t test were used for

comparison of means. Fisher’s exact test was applied for

comparison of categorical variables. Where appropriate,

p values are presented as adjusted values using Tukey’s

method for multiple comparisons.

Results

Thirty-two animals were equally randomized into four

treatment groups, but eight animals died before beginning

the protocol. Two animals were found dead in their cages

during the acclimation period, and six died during the

initial induction of anesthesia. The final group allocation is

as follows: immediate reconstruction, 7 animals; 30-day

delay, 8 animals; 30-day delay, 5 animals; and 90-day

delay, four animals.

Twenty-four animals underwent successful laparotomy,

gastric devascularization, and immediate or subsequent

esophagogastric resection with esophagogastric anastomo-

sis. The clinical outcomes are outlined in Table 1. One

animal in the immediate reconstruction group developed

sepsis on postoperative day 9 resulting from necrosis of the

anterior gastric wall. Five animals developed subclinical

Table 1 Clinical outcomes

after esophagogastrectomy

and esophagogastric

anastomosis

Outcome Ischemic conditioning time (days) p value

0 7 30 90

(n = 7) (n = 8) (n = 5) (n = 4)

Subclinical anastomotic

leak, n (%)

3 (42.9) 1 (12.5) 1 (20.0) 0 (0) 0.443

Anastomotic bursting

pressure (mmHg)

32.3 ± 41.5 45.9 ± 40.0 52.0 ± 35.8 67.3 ± 21.9 0.545

Surg Endosc (2013) 27:753–760 755

123

anastomotic leaks that were discovered at the time of tissue

collection. Three occurred in the immediate reconstruction

group, compared to one in the 7-day-delay group and one

in the 30-day-delay group (p = 0.443). None of these

animals exhibited signs of systemic infection, and all were

eating and gaining weight by postoperative day 10. No

clinically evident anastomotic strictures occurred in this

study. The anastomotic bursting pressure did not differ

significantly between groups (p = 0.545); however,

there was a trend toward increasing bursting pressures

with increasing ischemic conditioning intervals (32.3 ±

41.5 mmHg in the immediate reconstruction group com-

pared to 67.3 ± 21.9 mmHg after a 90-day delay period).

Semiquantitative assessment of inflammation at the

anastomosis demonstrated moderate to severe inflamma-

tion in 85.7 % of animals in the immediate reconstruction

group compared to 25 % in the 7-day-delay group and 0 %

in the 30- and 90-day-delay groups (p = 0.003, Table 2).

The severity of inflammation was not significantly different

between the 7- and 30-day-delay groups (p = 0.487).

Complete preservation of the muscularis propria was not

present in any of the immediately reconstructed animals

compared to 12.5 % of 7-day-delay, 60 % of 30-day-delay,

and 100 % of 90-day-delay animals, respectively (p =

0.001, Table 2). There was no significant difference

between the immediate reconstruction group and the 7-day-

delay group (p = 0.533), but the 30-day-delay group

showed a significantly higher rate of complete muscularis

propria preservation compared to the immediate recon-

struction group (p = 0.045). The trend toward increased

muscularis propria preservation in the 30-day-delay group

compared to the 7-day-delay group did not reach statistical

significance (p = 0.119), and the 30- and 90-day-delay

groups were not significantly different (p = 0.444).

Increased duration of ischemic delay was associated

with significantly decreased collagen deposition at the

healing anastomosis (p = 0.020, Table 2). The 7-day-delay

group demonstrated significantly decreased collagen

deposition compared to the immediate reconstruction

group (p = 0.026, Fig. 1), but there was no difference in

trichrome stain intensity between the 7- and 30-day-delay

groups (p = 0.592).

The microvessel concentration in each treatment group

is expressed as microvessels/high power field (mv/hpf).

Representative histographs demonstrate a paucity of

microvessels in the immediate reconstruction group com-

pared to the 30-day-delay group (Fig. 2). The microvessel

concentration in the immediate reconstruction group

(19.5 ± 1.58 mv/hpf) was not significantly different from

that in the 7-day-delay group (19.0 ± 1.49 mv/hpf,

p = 0.900, Fig. 3). The 30-day-delay group had a signifi-

cantly higher microvessel density (22.6 ± 1.48 mv/hpf)

than the immediate reconstruction (p = 0.016) and the

7-day-delay groups (p = 0.003). The 90-day-delay group

showed a significantly lower microvessel density (14.3 ±

1.77 mv/hpf) compared to the immediate reconstruction

group (p \ 0.001).

Discussion

This study demonstrates that gastric ischemic conditioning

before esophageal resection and esophagogastrostomy

produces decreased inflammation and collagen deposition

while increasing neovascularization at the healing anasto-

mosis. Although a 7 day ischemic conditioning period

reduced inflammation, a longer delay period of 30 days led

to increased neovascularization and muscularis propria

Table 2 Histologic

assessment of tissue

inflammation, muscularis

propria alignment, and

collagen deposition at the

healing esophagogastric

anastomosis

Characteristics Ischemic conditioning time (days) p value

0 7 30 90

(n = 7) (n = 8) (n = 5) (n = 4)

Inflammation

None–mild 1 (14.3) 6 (75.0) 5 (100) 4 (100) 0.003

Moderate–severe 6 (85.7) 2 (25.0) 0 (0) 0 (0)

Muscularis propria

alignment

Complete 0 (0) 1 (12.5) 3 (60) 4 (100) 0.001

Incomplete 7 (100) 7 (87.5) 2 (40) 0 (0)

Collagen deposition

(intensity of trichrome

staining)

Negative 5 (71.4) 0 (0) 1 (20) 2 (50) 0.022

Weak 2 (28.6) 3 (37.5) 2 (40) 2 (50)

Intermediate 0 (0) 5 (62.5) 2 (40) 0 (0)

756 Surg Endosc (2013) 27:753–760

123

preservation and decreased collagen deposition. Although

not statistically significant, the anastomotic burst pressures

did trend toward increased pressures with longer ischemic

conditioning times. Finally, although there was a trend

toward increased subclinical anastomotic leak in the

immediate reconstruction group, this did not reach statis-

tical significance.

Creation of the gastric conduit for esophageal replace-

ment requires the interruption of three of the five vessels

that provide blood flow to the gastric fundus. Anatomic

studies have demonstrated that division of the left gastric,

left gastroepiploic, and short gastric vessels renders the

gastric conduit almost solely dependent on blood flow from

the right gastroepiploic artery via a network of intramural

capillaries [18]. Resultant ischemic changes within the

anastomosed gastric fundus have been implicated in the

development of anastomotic leak and stricture [18–23].

On this basis, it has been postulated that gastric ischemic

conditioning allows the gastric fundus to recover from this

ischemic insult before the creation of the esophagogastric

anastomosis. Human and animal studies have shown that

Fig. 1 Representative trichrome-stained section of the anastomosis

for semiquantitative assessment of anastomotic collagen deposition

based on intensity of staining. The 7 day-delay animal (A) shows

intense tissue staining indicative of increased collagen deposition

compared to a 30 day-delay animal with markedly reduced intensity

of staining (B)

Fig. 2 Capillary identification using double staining technique for

vWF and smooth muscle actin antibodies. Arrows indicate structures

identified as capillaries. Representative samples demonstrate signif-

icantly reduced microvessel density after immediate reconstruction

(A) compared to that after a 30 day delay (B)

Fig. 3 Microvessel density at the level of the healing anastomosis in

immediate reconstruction and ischemic conditioning groups

Surg Endosc (2013) 27:753–760 757

123

gastric ischemic conditioning allows neovascularization of

this portion of the stomach, improves wound healing at this

tenuous anastomosis, and may reduce the incidence of

anastomotic complications. The duration of ischemic con-

ditioning, however, has been variable, with animal studies

utilizing a delay interval of 14–30 days, compared to

4–7 days in most human studies to date.

Urschel performed gastric devascularization in rats and

found an 81 % increase in blood flow to the gastric fundus

after 14 days [24]. Subsequently, this group demonstrated

decreased anastomotic leak rates and increased anasto-

motic burst strength when the esophagogastric anastomosis

was performed 3 weeks after gastric devascularization

[25]. In an opossum model of esophagogastrostomy,

Reavis et al. [26] showed a marked decrease in fundic

blood flow after gastric devascularization, and a threefold

increase in blood flow at the level of the anastomosis after a

28-day delay compared to immediately reconstructed

animals.

Collagen deposition at the healing anastomosis repre-

sents an important measure of wound healing. Large

amounts of collagen deposition may occur during the

weeks after creation of an anastomosis in response to

healing ischemic tissue, especially in the setting of clinical

or subclinical anastomotic leak. Preclinical studies have

demonstrated decreased collagen deposition along with

increased microvessel counts and improved tissue perfu-

sion after an ischemic conditioning period [26]. Although

our study did show decreased inflammation at the anasto-

mosis after a 7-day delay interval compared to immediate

reconstruction, a longer interval of 30 days was required to

reproduce the benefits of increased neovascularization and

decreased collagen deposition seen in previous studies.

We also evaluated preservation of the muscularis pro-

pria in the region of the anastomosis, as studies of small

bowel ischemia have demonstrated that loss of the inner

layer of muscularis propria occurs in the setting of tissue

ischemia [32]. Similar to previous ischemic conditioning

studies, we found that the delay groups showed increased

muscularis propria preservation compared to immediately

reconstructed animals. It is important to note, however, that

this effect also required a prolonged ischemic delay per-

iod—30 days—to achieve a significant improvement.

Animals undergoing a 30 day ischemic conditioning per-

iod were found to have significantly increased neovasculari-

zation compared to animals in the immediate reconstruction

of 7-day-delay groups. After gastric devascularization, tissue

hypoxia stimulates the production of angiogenic factors

including vascular endothelial growth factor (VEGF) and

platelet-derived growth factor. Increased VEGF expression

and angiogenesis have been shown to improve blood flow to

myocutaneous flaps and graft survival after ischemic condi-

tioning in a rat model [33]. Administration of VEGF at the

esophagogastric anastomotic site in an opossum model of

esophagogastrectomy demonstrated increased angiogenesis,

blood flow, and bursting pressure at the healing gastro-

esophageal anastomosis [34, 35]. If angiogenesis is the pri-

mary factor driving the alterations in wound healing after

gastric ischemic conditioning, it is imperative that the con-

ditioning interval be adequate to allow these changes to occur

before performing the anastomosis.

The application of gastric ischemic conditioning has

also shown promise in the clinical arena. Akiyama et al.

[36] sought to increase blood flow to the tip of the gastric

conduit via preoperative embolization of the right gastric,

left gastric, and splenic arteries. Patients who underwent

successful embolization followed by esophagectomy had

an anastomotic leak rate of 2 %, compared to 8 % of

patients undergoing reconstruction without gastric devas-

cularization. Despite the apparent improvement in gastric

perfusion, this approach was associated with complications

including abdominal pain, nausea, vomiting, splenic

infarction, and pancreatitis. Another group performed

laparoscopic gastric mobilization, devascularization, and

gastric conduit creation followed 4 days later by transtho-

racic esophagectomy and intrathoracic esophagogas-

trostomy. This series demonstrated that gastric ischemic

conditioning can be performed safely with an intratho-

racic anastomotic leak rate of 6 % [27]. Oezcelik et al.

[28] reported a series of patients successfully managed

with delayed esophagogastrostomy after developing

significant conduit ischemia during creation of the

gastric tube. These patients were left with a cervical

gastrostomy for approximately 3 months followed by

delayed esophagogastrostomy. At the time of anasto-

mosis, all patients had well perfused gastric conduits and

none subsequently developed anastomotic leaks. Similar

to the preceding animal studies, these findings suggest

that a longer duration of ischemic conditioning may

further increase gastric blood flow, and potentially lead

to improved anastomotic healing and lower complication

rates.

The present study was limited by the animal model, rel-

atively small sample size, and lack of an objective measure of

blood flow at the anastomotic site. We elected to use an

opossum model because of the anatomic and physiologic

similarities to the human foregut, as well as the technical

simplicity of performing a completely transabdominal sur-

gery. However, because the gastroesophageal anastomosis

remains within the abdominal cavity, it is not subjected to the

theoretical compression with resultant venous congestion

that occurs when it resides within the posterior mediastinum.

Also, this anastomosis is not subject to the tension that may

be present after gastric pull-up reconstruction. Although the

sample size was adequate to demonstrate significant differ-

ences in anastomotic wound healing between the

758 Surg Endosc (2013) 27:753–760

123

experimental groups, it was not sufficient to demonstrate a

difference in the clinically relevant outcomes of anastomotic

burst pressure and anastomotic dehiscence. Also, the lack of

an objective measure of blood flow to the gastric conduit did

not allow us to correlate the histologic findings with

increased oxygen delivery to the healing site.

Although this study and others suggest that ischemic

conditioning may improve gastroesophageal anastomotic

wound healing, it remains to be proven that this approach

will lead to improved clinical outcomes. A combination of

laparoscopic cancer staging and gastric devascularization

provides an opportunity for translation of this concept to the

clinical arena, but careful studies to optimize the surgical

approach and assess the true effect of ischemic conditioning

on relevant clinical outcomes are required. It remains unclear

which vessels must be divided to produce sufficient tissue

ischemia to replicate the effects seen in preclinical studies,

and the effect of radiotherapy on gastroesophageal anasto-

motic wound healing remains largely unstudied. Finally,

accurate, objective methods to assess the effect of gastric

devascularization and ischemic conditioning on oxygen

delivery to the anastomotic site are needed to facilitate the

clinical application of this technique.

Conclusions

Compared to animals undergoing immediate resection and

anastomosis, those treated with 30 days of gastric ischemic

conditioning showed significantly increased neovascularity

and muscularis propria preservation at the healing anasto-

mosis, whereas these changes were not evident after 7 days

of ischemic conditioning. These data suggest that gastric

ischemic conditioning has the potential to improve gas-

troesophageal anastomotic healing, but a conditioning

period longer than 7 days is likely required to achieve the

desired effect. Studies are needed to further define the

mechanisms of this effect, and larger clinical studies will

be required to assess the impact of ischemic conditioning

on the development of anastomotic complications.

Acknowledgments This work was supported by a research grant

from the Society of American Gastrointestinal and Endoscopic Sur-

geons (KAP).

Disclosures Drs. Kyle A. Perry, Ambar Banarjee, Nilay Shah, Mark

R. Wendling, James Liu, and W. Scott Melvin have no conflicts of

interest or financial ties to disclose.

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