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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 52  |  Issue : 3  |  Page : 76-83

Evaluation of risk factors for postoperative pancreatic fistula following pancreaticoduodenectomy


1 Department of Surgical Gastroeneterology, Zydus Hospital, Ahmedabad, Gujarat, India
2 Department of Surgical Gastroenterology, Nishtha Surgical Hospital and Research Centre, Patan, Gujarat, India

Date of Submission04-Nov-2018
Date of Decision09-Dec-2018
Date of Acceptance16-Jan-2019
Date of Web Publication17-Jun-2019

Correspondence Address:
Dr. Vipul D Yagnik
77, Siddhraj Nagar, Rajmahal Road, Patan - 384 265, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_118_18

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  Abstract 


Background: Pancreatic fistula (PF) remains the most common and challenging complication following pancreaticoduodenectomy (PD), with an incidence of 2%–28%. The primary objective of this study was to assess the correlation of fatty infiltration and fibrosis of the pancreas with postoperative pancreatic fistula (POPF). Secondary objectives were to investigate the correlations of POPF with the main pancreatic duct size and subjective intraoperative assessment of pancreatic texture and to determine if diabetes mellitus (DM), body mass index, or increased serum bilirubin correlate with POPF. Materials and Methods: This prospective study was performed at Sudhamayi Hospital, Kochi, India. Forty-six patients were included and divided into either the fatty infiltration group (n = 20) or fibrosis group (n = 17); nine patients had neither fatty nor fibrotic glands. Data were analyzed using analysis of variance and Chi-square test, utilizing SPSS software version 20 (IBM Inc., Armonk, NY, USA). Results: Patients with fatty pancreas had a ten times higher incidence of PF than those with fibrotic pancreas (odds ratio, 10.8; 95% confidence interval [CI], 2.2–52.4; P = 0.003). POPF was 7.9 times higher in patients with a nondilated duct compared to patients with a dilated duct (95% CI, 2.118–29.5; P = 0.003). Preoperative elevated serum bilirubin, body mass index, and DM were not found to be significant risk factors for POPF. Conclusion: We demonstrated that fatty pancreas and small pancreatic duct size (≤3 mm) are risk factors for POPF. Preoperative elevated serum bilirubin, body mass index, and DM were not found to be significant risk factors.

Keywords: Body mass index, fatty pancreas, pancreatic duct, pancreaticoduodenectomy, postoperative pancreatic fistula, serum bilirubin


How to cite this article:
Patel AC, Yagnik VD. Evaluation of risk factors for postoperative pancreatic fistula following pancreaticoduodenectomy. Formos J Surg 2019;52:76-83

How to cite this URL:
Patel AC, Yagnik VD. Evaluation of risk factors for postoperative pancreatic fistula following pancreaticoduodenectomy. Formos J Surg [serial online] 2019 [cited 2019 Sep 21];52:76-83. Available from: http://www.e-fjs.org/text.asp?2019/52/3/76/260438




  Introduction Top


Pancreatic fistula (PF) remains the most common and challenging complication following pancreaticoduodenectomy (PD), with an incidence of 2%–28%.[1] A soft pancreas is the most consistent risk factor for postoperative pancreatic fistula (POPF) following PD. In addition to organ consistency, other potential risk factors include pancreatic duct size, body mass index (BMI), diabetes mellitus (DM), and preoperative elevated serum bilirubin. The mortality rate following PD is <5%, while the morbidity rate is high (30%–60%); therefore, the focus has now shifted to reducing morbidity.[2] The most feared complication is POPF, which is responsible for the majority of postprocedure morbidity and mortality. While many studies have addressed the etiology of POPF, few have analyzed the correlations among pancreatic duct size, gland morphology, and the development of POPF. The results of published studies are often conflicting due to nonstandard definitions for complications; this has recently been addressed by the International Study Group of Pancreatic Surgery (ISGPS). The primary objective of this study was to assess the correlation of fatty infiltration and fibrosis of the pancreas with POPF. Secondary objectives were to investigate the correlations of POPF with the main pancreatic duct size and subjective intraoperative assessment of pancreatic texture and to determine if DM, BMI, and increased serum bilirubin correlate with POPF.


  Materials and Methods Top


This prospective study was performed at Sudhamayi Hospital, Kochi, India. Patients who underwent PD between November 2012 and May 2014 were enrolled. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local Ethics Committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study. Patients who had remnant viable pancreatic tissue following PD and those with a follow-up of at least 1 month were included in the study. Patients with distal pancreatic resection or who required total pancreatectomy due to extensive disease or positive pancreatic head margins were excluded from the study. Finally, 46 patients were enrolled and divided into the fatty infiltration group, the fibrosis group, or the group without fatty infiltration or fibrosis.

All specimens were reviewed by a senior pathologist. Histopathological diagnosis, tumor size, tumor differentiation (well, moderate, poor, and none), lymph node status (positive, negative), surgical margin status (positive, negative), histological grading of pancreatic fatty infiltration, and degree of fibrosis were evaluated. The margins analyzed included those of the common bile duct, pancreatic neck, and duodenum or stomach. The scoring system is described as follows: the score of pancreatic fatty infiltration was obtained by adding the scores of perilobular and intralobular fatty infiltration. Perilobular fatty infiltration was defined as the presence of adipocytes within the interlobular space and was scored as follows: 0 = no fatty infiltration, 1 = some adipocytes, and 2 = numerous adipocytes separating the lobules. Intralobular fatty infiltration was scored as 0 = no or rare adipocytes in some lobules, 1 = scattered adipocytes among most of the lobules, and 2 = numerous adipocytes among most of the lobules forming clusters of more than ten cells. Samples with a global score that ranged from 0 to 2 were considered to be free of fatty infiltration, whereas those with a global score of 3 or 4 were considered to have fatty infiltration.

Similarly, the score of pancreatic fibrosis was obtained by adding the scores of perilobular and intralobular fibrosis. Perilobular fibrosis was defined as the presence of connective tissue within the interlobular space and scored as follows: 0 = no connective tissue, 1 = mild deposits, and 2 = moderate or severe deposits. Intralobular fibrosis was defined as an extension of the perilobular fibrosis into the lobules: 0 = no fibrosis, 1 = mild deposits of fibrosis, and 2 = moderate or severe amounts of fibrosis. Samples with a global score ranging from 0 to 2 were considered not fibrotic, whereas those with a global score of 3 or 4 were considered a fibrotic gland. If fibrosis and fatty infiltration were observed in the same gland, it was categorized based on the predominant component (fibrosis or fat), sampled from tissue away from the tumor.

Furthermore, we evaluated the morphological and pathological features; comorbidities; and pre-, peri-, and intra-operative surgical details.

Following detailed clinical assessment, all baseline laboratory tests, tumor markers, MDCT scan with pancreatic protocol and endosonography (in case of diagnostic dilemma), PET scan for metastases in amenable patients, and biopsy were performed, including endoscopic biopsy in all cases of peri-ampullary malignancy. Preoperative biliary drainage was considered in case of cholangitis, very high bilirubin (>18 mg/dL), and significant malnutrition. Vitamin K, deep-vein thrombosis prophylaxis, and prophylactic antibiotics were administered as indicated. A Chevron incision was preferred and following proximal resection, reconstruction was performed using a single loop of the jejunum passed through the mesocolon. A pancreaticojejunal anastomosis via the duct to mucosa (Blumgart–Kelly) or the invagination (Buchler) end-to-side techniques was performed. Ductal transanastomotic stent was used selectively in patients with a soft pancreas or small PD. Prophylactic octreotide was given subcutaneously (intraoperative 100 μg before neck transection) and continued postoperatively (100 μg every 8 h) in patients considered at high risk of PF based on gland texture and duct size. The pancreatic duct was measured after proximal resection, and gland consistency was assessed by a senior surgeon during mobilization. POPF and DGE were diagnosed according to ISGPS. Postoperative mortality was defined to include intraoperative death and death within 30 days.

Statistical analysis

Data were analyzed using SPSS software v. 20 (IBM Inc., Armonk, NY, USA). Analysis of variance was used to test the statistical significance of differences in the mean values among the two groups. Chi-square test with Yates correction was used to test the significance of the associations of fatty infiltration and pancreatic fibrosis with the incidence of POPF.


  Results Top


The study included 46 patients, with a mean age of 56 years (range, 30–73 years); 65% (n = 30) were male. In this cohort, 22% (n = 10) of patients were over 65 years of age. Overall, 46 patients underwent PD; of these, 20 had fatty pancreas, 17 had fibrotic pancreas, and nine had neither fatty nor fibrotic glands.

Prevalence of comorbidity in the study population

Several patients had significant medical comorbidities, with 32 patients (70%) having at least one [Table 1]. The median BMI was 22.65 kg/m 2 (standard deviation, 4.05; range, 14.2–35.7).
Table 1: Characteristics of the study population

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Preoperative laboratory investigations

Preoperative laboratory values are presented in [Table 2]. In brief, 35% (n = 16) of the patients had a serum bilirubin >10 mg/dL, 15% (n = 7) had low serum albumin (<3 mg/dL), and 2% (n = 1) had an elevated serum creatinine (>1.5 mg/dL).
Table 2: Preoperative variables

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Surgical details

A soft pancreas was present in 52% (n = 24) and a firm pancreas in 48% (n = 22) of patients. Furthermore, 46% (n = 21) of patients had a small pancreatic duct (diameter ≤3 mm).

Forty (87%) patients underwent duct-to-mucosa type of pancreaticojejunal anastomosis and six patients (13%) underwent dunking-type pancreaticojejunal anastomosis. The mean operative time was 475 min (median, 480 min; range, 300–800). Mean blood loss was 740 ml (median, 600 mL; range, 250–3500), and intraoperative blood transfusion was required in 35% (n = 16) of patients.

Histological analyses

Pancreatic neck specimens at the transection margin or ≥1 cm away from the tumor margin were graded (0–2) for the presence of fat and fibrosis in perilobular (interlobular) and intralobular acini, with total scores ranging from 1 to 4. A score of ≥3 was considered to indicate a fatty pancreas; similar scoring was used for a fibrotic pancreas.

Pancreatic histology and incidence of fistula

The patients with fatty pancreas had a ten times higher incidence of PF than those with fibrotic pancreas (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.2–52.4; P = 0.003) [Table 3].
Table 3: Correlation of pancreatic fatty infiltration and fibrosis with pancreatic fistula

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Pancreatic duct size and association with pancreatic fistula

Of the 46 patients, 21 (46%) had a nondilated (≤3 mm) pancreatic duct; among them, 15 (71%) developed PF. Of the 25 patients with a dilated pancreatic duct (≥3 mm), only six (24%) developed PF [Table 4]. The OR of POPF was 7.9 in patients with a nondilated duct in comparison to those with a dilated duct (95% CI, 2.118–29.5; P = 0.003).
Table 4: Association of pancreatic duct size with incidence of postoperative pancreatic fistula

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On the receiver operating characteristic curves [Figure 1], 3.5 mm was identified as the cutoff point, with an area under curve of 0.786 and both sensitivity and specificity for PF of 72% (P = 0.001). The positive and negative predictive values for developing PF at ≤3 mm duct size were 71% and 76%, respectively.
Figure 1: Receiver operating characteristic curve for pancreatic duct size and correlation with pancreatic fistula

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Patients with a small duct had elevated fat scores as well as decreased fibrosis scores [Figure 2]. Of the patients with fibrotic gland score ≥3, 80% had a dilated pancreatic duct (>3 mm).
Figure 2: Scatter plot of the correlation of pancreaticoduodenectomy size with fatty

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Correlation between subjective intraoperative pancreatic texture and postoperative pancreatic fistula

Of the 24 patients with a soft pancreas, 17 (70%) developed PF. Conversely, only four of the 22 (18.2%) patients with a firm pancreas developed PF [Table 5]. The OR of PF was 10.9 for patients with a soft gland compared to those with a firm gland (95% CI, 2.7–44.1; P < 0.001)
Table 5: Clinical consistency of the pancreas and its correlation with pancreatic fistula

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Correlation between clinical consistency of pancreas and pancreatic histology

Intraoperative assessment of pancreatic consistency (soft/firm) was categorized as either fatty or fibrotic, based on the assumption that fat increases softness. Among the 46 patients, 20 had a fatty pancreas and 17 had a fibrotic pancreas; they were compared with those with nonfatty and nonfibrotic glands (n = 9). Of the twenty patients with a soft pancreas, 15 (75%) glands were positive for fatty pancreas (OR, 2.4; 95% CI, 0.4–12.6), and of the 17 firm glands, 13 (76.5%) had a fibrotic pancreas (OR, 4; 95% CI, 0.7–22.7). Though gland texture correlated with histology, this did not reach statistical significance (P = 0.396 and P = 0.194, respectively).

Postoperative morbidity

POPF grades as per ISGPS classification are shown in [Figure 3]. Overall, eight patients (17%) had Grade A PF, 10 (22%) Grade B, and 3 (7%) Grade C; thus, overall, 13 patients (28%) had clinically significant PF (Grade B/C). Of those with Grade C fistulae, one patient developed delayed leaks after 1 month and all the three patients had fatty pancreas.
Figure 3: Pie chart of the incidence of pancreatic fistula in the study group

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Risk factors for PF were evaluated by univariate analysis to identify significant factors [Table 6]. All statistical tests were two tailed with a significance level set at 5%. Multivariate analysis could not be performed due to insufficient sample size. Patients with a BMI greater versus less than 25 kg/m 2 were compared. The fat infiltration score was higher in those with BMI ≥25 kg/m 2; of the 13 patients with a high BMI, nine (69%) had Grade 3 fatty infiltration of the pancreas (P = 0.046). BMI positively correlated with pancreatic fat and negatively correlated with fibrosis: only three patients (23%) had fibrotic glands and one had neither fatty nor fibrotic gland. However, a statistically significant correlation with POPF (P = 0.205) was not observed.
Table 6: Univariate risk analysis of postoperative pancreatic fistula

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Negative correlation was observed between total fibrosis and fat score (Spearman's Rho test, r = −0.40; P = 0.007) [Table 7], with a statistically significant difference noted in the mean fibrosis score between those with and without fistulae.
Table 7: Correlation of total fibrosis with fat score

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  Discussion Top


PF is a major cause of morbidity following PD. Multiple factors have been investigated to identify possible causes that may help prevent, minimize, or treat fistulae. Fatty infiltration may be a contributing factor for POPF. Similarly, the presence of fibrosis, especially that manifesting as firmness, is presumed to be protective, although evidence for both of these factors is lacking.

Of the 46 patients, clinically significant PF was observed in 13 (29%). On univariate analysis, risk factors associated with PF were histological fatty infiltration, duct size ≤3 mm, and soft consistency [Table 3], [Table 4], [Table 5]. Age, sex, BMI, preoperative levels of serum bilirubin, international normalized ratio (INR), and creatinine did not correlate with PF [Table 6]. Fibrotic pancreas and firmness were associated with decreased risk of PF.

Analysis of risk factors having a significant correlation with pancreatic fistula

Clinical consistency of the pancreas

The distinction between a hard and firm pancreas remains subjective and is hardly reproducible. To minimize bias, we used only two categories of texture – firm and soft – since firmness of a gland is more easily appreciated than “softness.” Pancreatic parenchymal texture, particularly softness, is reportedly associated with a higher incidence of PF, while firmness is associated with a lower incidence.[3]

In our study, PF was more common in patients with soft consistency (70%) than in those with firm consistency (18%) (P = 0.001) [Table 5]. Shimoda et al. retrospectively analyzed 203 patients who underwent PD; of those, 26% developed POPF; BMI and soft pancreas were reported to be important risk factors for PF (P = 0.040 and P = 0.005, respectively).[4] Mathur et al. suggested that fatty infiltration would enhance the perception of “softness” of the gland.[5] Conversely, pancreatic fibrosis is thought to increase the firmness of the gland.[6]

We analyzed the correlation between a soft pancreatic parenchymal texture and fatty infiltration and between a firm texture and a fibrotic pancreas. Of the twenty patients with soft pancreas, 15 (75%) glands were positively for fatty pancreas (OR, 2.4) and of the 17 firm glands, 13 (76.5%) had a fibrotic pancreas (OR, 4). Identification of gland composition through palpation was more common in firm glands than in soft glands, but it did not reach statistical significance for either (P = 0.194 and P = 0.396, respectively). Conversely, Rosso et al. found no correlation between parenchymal texture and the amount of fatty infiltration, although they reported that pancreatic fibrosis correlated more strongly with gland firmness.[7]

Pancreatic duct size

Duct size ≤3 mm has been implicated as a contributing factor for PF. A fatty soft pancreas with a small duct requires technically challenging anastomosis, which may leak postoperatively. Pratt et al. analyzed 233 consecutive patients who underwent PD and reported that duct size <3 mm was an independent risk factor for clinically relevant POPF (Grades B/C).[8] Similarly, in their prospective, randomized trial with 120 patients, Poon et al. reported that duct diameter <3 mm was associated with a higher incidence of POPF.[9] A study by Faith et al. did not find any correlation of POPF with duct size and texture.[10]

In our study, patients with a small duct size [Figure 2] were found to have elevated fat scores as well as decreased fibrosis scores, thus confirming that fatty pancreas correlates with small duct size, a known risk factor for PF. Similar observations were reported by other studies.[5],[11],[12]

Fatty infiltration

Factors that increase fat infiltration of the pancreas include age, obesity, and Cushing syndrome.[13],[14] The impact of BMI and fatty pancreas on POPF following PD has also specifically been studied.

In their study of 100 patients, Gaujoux et al. observed that a BMI >25 kg/m 2 was an independent predictor of postoperative PF.[15] Furthermore, two other studies found elevated BMI to be a significant risk factor for POPF.[16],[17] In our analysis, the total fat score was higher in patients with BMI ≥25 kg/m 2 (P = 0.046). It also correlated positively with pancreatic fat and negatively with fibrosis. The mean score of fatty infiltration was higher in those with PF than in those without PF [Table 7]. Our findings agree with those of Mathur et al., who reported that BMI positively correlated with pancreatic fat and negatively with fibrosis and vessel density.[5]

Rosso et al. reported that advanced age and BMI were significantly associated with a >10% rate of pancreatic fat and fistula.[18] Conversely, Sandini et al. reported that, rather than BMI, the distribution of excessive abdominal fat, measured by preoperative CT, is a strong risk factor for POPF.[19] A study by House et al. and three other studies reported similar findings.[20],[21],[22],[23] We also observed a higher rate of PF in patients with fatty pancreas (70%) than in those with fibrotic pancreas (18%), P = 0.003 [Table 3].

The effect of DM on PF following PD is controversial. Srivastava et al. investigated 120 patients with pancreatic and periampullary tumors and found that patients with DM had an increased incidence of PF (OR, 4.60; 95% CI, 1.23–17.18).[24] Chu et al. also reported that DM was an independent risk factor for POPF after adjusting for age, comorbidities, BMI, preoperative albumin level, type of operation, surgery time, and pancreatic quality.[25] Conversely, some studies have suggested that DM has protective effects against PF,[26],[27] possibly because these patients have less pancreatic fat and more pancreatic fibrosis. De Oliveira et al.[28] and Lv et al.[29] reported that DM was not a significant predictor of POPF following PD. In our study, the prevalence of DM in patients who developed PF (n = 21) and those who did not (n = 25) was 57% (n = 12) and 52% (n = 13), respectively. On subanalysis, DM was more prevalent in patients with fatty pancreas (65%) than in those with fibrotic pancreas (47%). Our findings match those of DeOliveira et al. and Lv et al., although this result warrants further exploration.

Type of malignancy

Fatty infiltration of the pancreas may promote tumor dissemination and mortality as well as increase the risk of POPF.[30] In experimental animal models, fatty infiltration can be induced in the pancreas by obstructing the duct or vasculature.[31] In a recent study, Hori et al. observed a significantly higher OR for pancreatic ductal adenocarcinoma (PDAC) in areas of fatty infiltration in the pancreas (P < 0.001) after adjusting for confounding factors including sex, age, BMI, DM, and family history of pancreatic cancer.[32]

In our study, 27 patients were diagnosed with PDAC; of them, 14 (51%) had fatty infiltration. Furthermore, we observed a higher incidence of DM (73%, n = 17) in patients with PDAC, which is in agreement with the findings of Everhart et al. However, to prove that fatty infiltration is a risk factor for PDAC, we would need to determine the incidence of pancreatic cancer in a long-term, prospective, cohort study with controls identified having incidentally detected fatty infiltration on cross-sectional imaging.

A retrospective study of 581 patients by Veillette et al. reported a POPF incidence of 27% for ampullary carcinoma, in contrast to an incidence of 5% for PDAC.[33] These findings were confirmed by de Castro et al., who reported that bile duct cancer was found to be an independent risk factor for POPF.[34] Our study included three patients with bile duct cancer, one of whom developed POPF.

A recent study by Rungsakulkij et al. identified preoperative serum bilirubin >3.0 mg/dL as the predominant risk factor for clinically relevant POPF.[35] Kimura et al. also reported that serum bilirubin >2.0 mg/dL was a significant preoperative risk factor for higher 30-days post operative and in-hospital mortality rates following PD.[36] In our study, preoperative serum bilirubin level did not correlate with POPF (P = 0.063).

Fibrotic pancreas

Patients with pancreatic head malignancies, especially ductal adenocarcinoma, and chronic pancreatitis, can have increased fibrosis due to obstructive pancreatitis. Buchler et al. and Yeh et al. reported lower incidences of PF following PD in the fibrotic pancreas.[37],[38]

A fibrotic pancreas with a dilated duct may make duct-to-mucosa anastomosis easier. Decreased exocrine activity and pancreatic secretion could reduce the risk of PF.[11],[39] Therefore, a fibrotic gland producing less pancreatic enzymes is less likely to develop PF and therefore, less prone to intra-abdominal complications. This observation was also seen in our study.

Limitations of the study

As a prospective study with limited follow-up, the ideal group size of 25 was not achieved. Overlapping of fatty infiltration and fibrosis was observed in 4% of the study cohort; therefore, we selected only patients with a predominant gland pattern for further histological sampling.


  Conclusion Top


In this study, we demonstrated that fatty pancreas and small pancreatic duct size (≤3 mm) are risk factors for POPF. Preoperative elevated serum bilirubin, BMI, and DM were not found to be significant risk factors for POPF. Randomized, controlled trials with larger cohorts are required to further validate the findings of this study and clarify the association between POPF and increased serum bilirubin, BMI, bile duct cancer, and DM.

Acknowledgment

We would like to acknowledge the help provided by Dr Puneet Dhar (Professor and Head, Department of GI surgery) and Dr. Roopa Paulose (Associate professor department of pathology) at Amrita institute of medical science, Kochi for their valuable suggestions and guidence throuhout the study period. We would also like to acknowledge the help provided by Dr. Sushil Dawka (Professor of Surgery, Mauritius) for his kind assistance in editing the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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