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Kim, Kim, Song, and Chun: The appropriate surgical strategy for T1b gallbladder cancer incidentally diagnosed after a simple cholecystectomy
Original Article

Annals of Hepato-Biliary-Pancreatic Surgery 2019; 23(4): 327-333.

Published online: 29 November 2019

DOI: https://doi.org/10.14701/ahbps.2019.23.4.327

The appropriate surgical strategy for T1b gallbladder cancer incidentally diagnosed after a simple cholecystectomy

Byoung-Hyoung Kim, Seok-Hwan Kim, In-Sang Song, Gwang-Sik Chun

Department of Surgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.

Corresponding author: Seok-Hwan Kim. Department of Surgery, Chungnam National University Hospital, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea. Tel: +82-42-280-8385 (7175), Fax: +82-42-257-8024, kjxh7@cnuh.co.kr

Received 30 May 2019       Revised 14 July 2019       Accepted 25 July 2019

Copyright © 2019 by The Korean Association of Hepato-Biliary-Pancreatic Surgery

The Korean Association of Hepato-Biliary-Pancreatic Surgery

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Backgrounds/Aims

The appropriate surgical treatment was investigated for T1b gallbladder (GB) cancer through a retrospective analysis of the clinical outcomes of patients with incidental T1 GB cancer.

Methods

Patients with T1 GB cancer who were incidentally diagnosed while undergoing a simple cholecystectomy at Chungnam University Hospital from January 2004 to December 2017 were enrolled. Overall, 39 patients with T1 GB cancer, 17 patients with T1a, and 22 patients with T1b were included. We retrospectively analyzed the patients' clinical and pathologic findings and follow-up results.

Results

Among the 6490 patients who underwent cholecystectomy during the study period, 165 patients were diagnosed with GB cancer (T1=42 [25.5%]). The risk factor associated with recurrence and cancer-related death in patients with T1 GB cancer was lymphovascular invasion (recurrence, p=0.028; death, p=0.004). In the T1b group, the 5-year disease-free survival (DFS) rate showed a statistical difference between patients with and without lymphovascular invasion (45.7% vs. 83.6%, p=0.048). There was no statistically significant difference in 5-year DFS and overall survival rate between simple cholecystectomy and extended cholecystectomy in T1b GB cancer with lymphovasular invasion (p=0.054 and p=0.091, respectively).

Conclusions

In incidental T1b GB cancer, extended cholecystectomy was not superior to simple cholecystectomy in terms of the 5-year DFS rate and nor in overall survival rate or recurrence rate, even when lymphovascular invasion was identified after simple cholecystectomy. Therefore, simple cholecystectomy may be recommended as a primary surgical strategy for T1b GB cancer.

Keywords: Gallbladder, Cancer, Cholecystectomy

INTRODUCTION

Gallbladder carcinoma is one of the most common malignant tumors of the biliary tract. However, it remains debated whether curative resection is the most beneficial treatment for improving long-term survival in patients with this malignancy. GB cancer that is limited to the mucosa (T1a) or the mucularis (T1b) is classified as early cancer.123 Many studies recommend simple cholecystectomy as the surgical procedure of choice for T1a GB cancer, as it is a local disease. However, in the case of T1b GB cancer, several guidelines, including the National Comprehensive Cancer Network (NCCN) guidelines, recommend extended cholecystectomy as the initial treatment.456 It may be premature to conclude that extended cholecystectomy should be the surgical treatment of choice for T1b GB cancer because there remain controversies such as tumor spreading. Some studies considered T1b GB cancer as a local disease and therefore suggested simple cholecystectomy as the treatment method.78910
Recent studies have reported increased incidences of incidental diagnoses of T1 GB cancer, reaching up to 50–58%.11121314 Therefore, it is necessary to consider whether the surgical strategy will benefit the future recurrence rate and survival rate of simple cholecystectomy and extended cholecystectomy for these patients. In this retrospective study, we analyzed the clinicopathologic features of GB cancer to determine the predictive risk factors that affect recurrence and survival. This study aimed to establish the surgical criteria for patients with early GB cancer.

MATERIALS AND METHODS

From January 2004 to December 2017, a total of 6490 patients underwent cholecystectomy at a single center (Chungnam National University Hospital), excluding cases of cholecystectomy performed as an additional resection during surgery for other primary cancers (common bile duct cancer, hepatocellular carcinoma, pancreatic head cancer, etc.) and cases of preoperatively confirmed GB cancer. Our study protocol was approved by the institutional review board of our institution. Of the 6490 patients, 165 had an incidental diagnosis of GB cancer (T1=42 [25.5%], T2=88 [53.3%], T3=34 [34%], T4=1 [0.6%]), 42 cases of which were staged as T1. Because 3 cases had no pathology records, they were excluded, and a total of 39 cases (17 cases of T1a and 22 cases of T1b) were enrolled in the study (Fig. 1). The clinicopathologic findings and results of long-term follow-up observation in these patients were analyzed.
The staging was performed according to the TNM (tumor, node, metastasis) system of the American Joint Committee on Cancer (AJCC) 8th edition.1516 T1a GB cancer was defined as an invasion to the mucosa and T1b as an invasion to the muscular layer. The degree of lymph node extension was divided into N0 and N1. Concerning the surgical methods, simple cholecystectomy was defined as cholecystectomy alone, and extended cholecystectomy was defined as cholecystectomy with dissection of the surrounding lymph nodes with or without hepatic resection. Lymph node dissection was defined as resection involving the lymph nodes around the gallbladder and the hepatoduodenal ligament.
The mean follow-up period was 54.2 months (range, 1–181 months), and recurrence was confirmed using abdominopelvic computed tomography. Medical records and survival data were obtained through chart reviews and direct communication with the patients. Multivariate regression analysis was performed using Cox proportional hazard models to identify the independent prognostic factors for recurrence and survival. Statistically significant factors based on the results of the univariate analysis were entered into the multivariate analysis. Categorical data were compared using the chi-square test. Values of p<0.05 were considered statistically significant.

RESULTS

Characteristics of the study population

A total of 39 patients were included in this study, comprising 22 men (56.4%) and 17 women (43.6%). Of these, 17 patients (43.6%) had T1a tumor, and 22 patients (56.4%) had T1b tumor. The average age at the time of diagnosis was 66.8 years (range, 45–84 years), and the average follow-up period was 54.2 months (range, 1–181 months) (Table 1).

Types of surgical intervention

The surgical outcomes according to the surgical method are summarized in Table 2. Of the 27 patients who underwent simple cholecystectomy, 13 (76.47%) and 14 (63.63%) had T1a and T1b tumor, respectively (p=0.791). Among the 27 simple cholecystectomies, 26 (96.3%) were laparoscopic surgeries. In the remaining case, conversion to open simple cholecystectomy was needed owing to severe adhesions from previous operations.
Extended cholecystectomy was performed in 4 patients (23.5%) and 8 patients (36.3%) with T1a and T1b tumor, respectively (p=0.003). None of the extended cholecystectomy cases were laparoscopic surgeries (all were open surgeries). Among the 12 cases of extended cholecystectomy, 7 cases involved liver resections (wedge resection in 3 cases and segmental resection in 4 cases). In the 2 cases of secondary operations, which were performed after the diagnosis of GB cancer, both involved T1b tumor and 1 case involved liver wedge resection.

Pathologic outcomes

On histopathologic analysis, there were 6 cases (15.4%) of well-differentiated, 30 cases (76.9%) of moderately differentiated, and 3 cases (7.7%) of poorly differentiated T1 GB cancer. The histologic grade was a statistically valid risk factor for recurrence in univariate analysis (p=0.003) (Table 1). The T1b group included 4 cases (18.2%), 16 cases (72.7%), and 2 cases (9.1%) of well-differentiated, moderately differentiated, and poorly differentiated gallbladder cancer, respectively.

Lymphovascular invasion

Initially, we considered that lymph node metastasis would be the primary prognostic factor; however, among our patient population (n=39), none showed lymph node metastasis on the final pathology findings. Therefore, we proceeded to investigate lymphovascular invasion, which was pathologically observed in 2 cases (11.8%) in the T1a group and 8 cases (36.4%) in the T1b group (Table 3). Tumor recurrence and gallbladder cancer-related deaths seemed to be associated with lymphovascular invasion based on the univariate analysis (p=0.028 and p=0.004, respectively).

Tumor location

In our investigation, we wanted to consider various prognostic factors. We, therefore, stratified the patients according to the tumor location (peritoneal or hepatic side). The AJCC 8th edition uses tumor location as a distinguishing factor between T2a and T2b disease.15 In the T1a group, 13 cases (76.5%) were in the peritoneal side, and 4 cases (23.5%) were in the hepatic side. In the T1b group, 10 cases (45.5%) were in the peritoneal side, and 12 cases (54.5%) were in the hepatic side. Our univariate analysis showed that tumor location was not a significant prognostic factor of recurrence and DFS in T1 GB cancer (p=0.552 and p=0.192, respectively).

Recurrence

Recurrence was noted during the follow-up period in 6 patients with T1 GB cancer, including 1 case (6.3%) with T1a tumor and 5 cases (22.7%) with T1b tumor (Table 1). Of the 5 cases of T1b GB cancer recurrence, locoregional recurrence was present in 3 cases, and systemic recurrence occurred in 2 cases (Table 3). When categorized according to the surgical method, locoregional recurrence was noted in 2 cases (14.28%), and systemic recurrence was noted in 1 case (7.14%) in the simple cholecystectomy group. In the extended cholecystectomy group, one patient (12.5%) had a locoregional recurrence, and one patient (12.5%) had a systemic recurrence. Among the five recurrent T1b tumors, 3 (60%) were in the peritoneal side, and 2 (40%) were in the hepatic side. For the two hepatic side cases, hepatectomy was performed in 1 case but not in the other. There was no statistically significant correlation between tumor location and recurrence rate (p=0.552).

Survival rate

In T1b cases, the 1-, 3-, and 5-year DFS rates were 92.3%, 84.6%, and 72.5%, respectively, in the simple cholecystectomy group, and 100%, 57.1%, and 57.1%, respectively, in the extended cholecystectomy group (p=0.332); however, the differences were not statistically significant (Fig. 2A). In the T1b group, the 5-year DFS rate was statistically significantly different between patients with and without lymphovascular invasion (83.6% in patients without invasion, 45.7% in patients with invasion; p=0.048) (Fig. 2B). According to the surgical method, the 5-year DFS rate was 64.3% for simple cholecystectomy and 0% for extended cholecystectomy in patients with lymphovascular invasion (p=0.054), whereas the overall 5-year survival rate was 70.0% for simple cholecystectomy and 100% for extended cholecystectomy, with both showing no statistically significant differences (p=0.091) (Fig. 3).

DISCUSSION

Incidental gallbladder cancer is defined as GB cancer that is histologically diagnosed after cholecystectomy for gallstone, cholecystitis, or gallbladder polyps, and its rate of detection ranges from 0.2% to 2.9%.121718 In the present study, incidental gallbladder cancer was diagnosed in 2.46% of our patients. When early GB cancer is confirmed on frozen biopsy during surgery or histologically diagnosed after the operation, there is no definitive clinical guideline on whether extended cholecystectomy or revision of the initially planned simple cholecystectomy should be performed, or if the type of surgery is beneficial to survival.
In general, the rate of diagnosis of advanced-stage GB cancer is high.23 In our study, 123 of the 165 patients (75%) with an incidental diagnosis of GB cancer were confirmed to have stage T2 disease or higher at the time of diagnosis. Therefore, the level of research or evidence on the treatment of early GB cancer is, in fact, insufficient. Because the incidence of early gallbladder carcinoma has increased with the increasing use of laparoscopic cholecystectomy,131419 there is a growing need for surgical guidelines for early GB cancer. In Korea, a large-scale multicenter retrospective study was previously conducted to suggest the appropriate surgical method for T1 GB cancer.20 That nationwide study concluded that simple cholecystectomy is an appropriate treatment for T1a GB cancer, and there was no evidence of the superiority of extended cholecystectomy for T1b GB cancer over simple cholecystectomy. Therefore, the above study serves as a basis for recommending simple cholecystectomy for T1b GB cancer.820
For T1a GB cancer, which is limited to the mucosa, simple cholecystectomy including the resection margin has been considered the optimal treatment. This is a part of the NCCN guideline and has also been recommended at the highest level in the Korean domestic guidelines.45621 However, for T1b GB cancer, extended cholecystectomy is primarily recommended in the NCCN guideline, whereas other studies have shown that extended cholecystectomy was not more advantageous than simple cholecystectomy.4568 Furthermore, we did not find a relationship between extended cholecystectomy of T1b GB cancer and improvement in survival rate, and we did not obtain evidence that lymph node dissection has a therapeutic effect.202223242526 In other words, extended cholecystectomy was not superior to simple cholecystectomy in terms of survival rate and recurrence rate, and lymph node resection also did not improve the survival rate in T1b GB cancer. Based on these findings, simple cholecystectomy is being recommended as the appropriate surgical therapy for T1b GB cancer. Other guidelines also recommend simple cholecystectomy for the treatment of T1b GB cancer.820212728
Presence of lymph node metastasis is a well known prognostic factor in cancer and lymph node dissection is thought to be of benefit in raising survival rates. Although there is no definite guideline for the number of nodes to remove and the extent of resection in lymph node dissection in cholecystectomy, the 6th edition of the AJCC Staging Manual states, that removal of >3 lymph nodes is required to accurately determine the N stage.1516 The mean number of lymph nodes removed in this study was 8.2 (range, 2–19) in a total of 10 patients. In 2 cases, we removed <3 lymph nodes; however, both cases did not show recurrence. In this study, lymph node dissection in T1b cases did not significantly improve the survival or recurrence rate (27.3% vs. 72.2%, p=0.636). Initially, we considered lymph node metastasis as a general prognostic factor in this study. However, in the 39 total cases of incidental T1 GB cancer, none showed lymph node metastasis in final pathology findings.
T2 GB cancer was classified as T2a and T2b in the AJCC 8th edition, and it has been reported that patients with GB cancer in the hepatic side have a low survival rate.1529 In the T1b GB cancer cases in this study, the initial tumor location was the peritoneal side in 10 cases and the hepatic side in 12 cases. However, none of the 5 cases of gallbladder cancer recurrence were in the hepatic side or a local recurrence in the liver bed. In addition, we have previously mentioned that extended cholecystectomy in T1b cases did not improve the overall survival. Therefore, early GB cancer most likely does not require liver resection.
In this study, laparoscopic cholecystectomy was performed in 96.3% of T1 GB cancer cases treated with simple cholecystectomy and in 92.36% of patients with T1b tumor. We concluded that laparoscopic cholecystectomy might be a safe surgical procedure for T1 GB cancer because there was no significant difference in the survival rate and recurrence rate between simple cholecystectomy and extended cholecystectomy.
In patients with T1b tumor, the absence of lymphovascular invasion had a significant benefit in terms of the 5-year DFS rate and recurrence rate (Table 1) In T1b cases with lymphovascular invasion, the 5-year DFS rate was increased in patients treated with extended cholecystectomy, but not statistically significant (p=0.054), and there was no statistically significant difference in overall survival (p=0.091) (Fig. 3).
Given that extended cholecystectomy does not show a superiority in survival or recurrent rates, although NCCN guidelines recommend extended cholecystectomy in T1b cancer patients but there are realistic difficulties in domestic application Moreover, the results of our institution are also consistent with the domestic trend, and the simple cholecystectomy in T1b GB cancer can be considered as an appropriate surgical approach.421
This study has some limitations. The number of patients with incidental gallbladder cancer was relatively small. Moreover, the retrospective design of this study is also a limitation (a randomized controlled trial would have been ideal). Further investigations through large-scale randomized controlled trials are needed in the future.
In conclusion, extended cholecystectomy in T1 GB cancer does not offer an advantage in terms of the survival and recurrence rates. In T1b GB cancer, it seems questionable whether the recommendation for initially extended cholecystectomy including lymph node dissection is still valid. Therefore, when T1b GB cancer is incidentally diagnosed after a simple cholecystectomy, we believe that simple cholecystectomy may be recommended as the primary surgical strategy.

Figures and Tables

Fig. 1

Flowchart of patients registered in this study. GBC, gallbladder cancer.

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Fig. 2

Disease-free survival curves of patients with T1b gallbladder cancer compared between simple and extended cholecystectomy (A), and between negative and positive lymphovascular invasion (B). LVi, lymphovascular invasion.

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Fig. 3

Disease-free (A) and overall survival (B) curves of patients with lymphovascular invasion of T1b gallbladder cancer compared between simple and extended cholecystectomy.

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Table 1

Clinical outcome and analysis of prognostic factors in T1 gallbladder cancer

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GBC, gallbladder cancer; LV, lymphovascular; LN, lymph node

Table 2

Surgical outcomes of T1 gallbladder cancer

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Table 3

Recurrence pattern of T1b gallbladder cancer after surgical treatment

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CBD, common bile duct; LN, lymph node

References

1. Abramson MA, Pandharipande P, Ruan D, Gold JS, Whang EE. Radical resection for T1b gallbladder cancer: a decision analysis. HPB (Oxford). 2009; 11:656–663.
2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006; 56:106–130.
3. Reid KM, Ramos-De la Medina A, Donohue JH. Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg. 2007; 11:671–681.
4. Benson AB 3rd, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Saenz DA, et al. NCCN guidelines insights: hepatobiliary cancers, version 1.2017. J Natl Compr Canc Netw. 2017; 15:563–573.
5. Eckel F, Brunner T, Jelic S. ESMO Guidelines Working Group. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010; 21 Suppl 5:v65–v69.
6. Kondo S, Takada T, Miyazaki M, Miyakawa S, Tsukada K, Nagino M, et al. Japanese Association of Biliary Surgery, Japanese Society of Hepato-Biliary-Pancreatic Surgery, Japan Society of Clinical Oncology. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. J Hepatobiliary Pancreat Surg. 2008; 15:41–54.
7. Kim EK, Lee SK, Kim WW. Does laparoscopic surgery have a role in the treatment of gallbladder cancer? J Hepatobiliary Pancreat Surg. 2002; 9:559–563.
8. Lee SE, Jang JY, Lim CS, Kang MJ, Kim SW. Systematic review on the surgical treatment for T1 gallbladder cancer. World J Gastroenterol. 2011; 17:174–180.
9. Shirai Y, Yoshida K, Tsukada K, Muto T, Watanabe H. Early carcinoma of the gallbladder. Eur J Surg. 1992; 158:545–548.
10. Yildirim E, Celen O, Gulben K, Berberoglu U. The surgical management of incidental gallbladder carcinoma. Eur J Surg Oncol. 2005; 31:45–52.
11. Rathanaswamy S, Misra S, Kumar V, Chintamani , Pogal J, Agarwal A, et al. Incidentally detected gallbladder cancer- the controversies and algorithmic approach to management. Indian J Surg. 2012; 74:248–254.
12. Toyonaga T, Chijiiwa K, Nakano K, Noshiro H, Yamaguchi K, Sada M, et al. Completion radical surgery after cholecystectomy for accidentally undiagnosed gallbladder carcinoma. World J Surg. 2003; 27:266–271.
13. Butte JM, Matsuo K, Gönen M, D'Angelica MI, Waugh E, Allen PJ, et al. Gallbladder cancer: differences in presentation, surgical treatment, and survival in patients treated at centers in three countries. J Am Coll Surg. 2011; 212:50–61.
14. Shih SP, Schulick RD, Cameron JL, Lillemoe KD, Pitt HA, Choti MA, et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg. 2007; 245:893–901.
15. Chun YS, Pawlik TM, Vauthey JN. 8th edition of the AJCC cancer staging manual: pancreas and hepatobiliary cancers. Ann Surg Oncol. 2018; 25:845–847.
16. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010; 17:1471–1474.
17. Kwon AH, Imamura A, Kitade H, Kamiyama Y. Unsuspected gallbladder cancer diagnosed during or after laparoscopic cholecystectomy. J Surg Oncol. 2008; 97:241–245.
18. Romano F, Franciosi C, Caprotti R, De Fina S, Porta G, Visintini G, et al. Laparoscopic cholecystectomy and unsuspected gallbladder cancer. Eur J Surg Oncol. 2001; 27:225–228.
19. Zhang WJ, Xu GF, Zou XP, Wang WB, Yu JC, Wu GZ, et al. Incidental gallbladder carcinoma diagnosed during or after laparoscopic cholecystectomy. World J Surg. 2009; 33:2651–2656.
20. Lee SE, Jang JY, Kim SW, Han HS, Kim HJ, Yun SS, et al. Korean Pancreas Surgery Club. Surgical strategy for T1 gallbladder cancer: a nationwide multicenter survey in South Korea. Ann Surg Oncol. 2014; 21:3654–3660.
21. Lee SE, Kim KS, Kim WB, Kim IG, Nah YW, Ryu DH, et al. Korean Association of Hepato-Biliary and Pancreas Surgery. Practical guidelines for the surgical treatment of gallbladder cancer. J Korean Med Sci. 2014; 29:1333–1340.
22. Downing SR, Cadogan KA, Ortega G, Oyetunji TA, Siram SM, Chang DC, et al. Early-stage gallbladder cancer in the Surveillance, Epidemiology, and End Results database: effect of extended surgical resection. Arch Surg. 2011; 146:734–738.
23. Goetze TO, Paolucci V. Immediate re-resection of T1 incidental gallbladder carcinomas: a survival analysis of the German Registry. Surg Endosc. 2008; 22:2462–2465.
24. Jensen EH, Abraham A, Jarosek S, Habermann EB, Al-Refaie WB, Vickers SA, et al. Lymph node evaluation is associated with improved survival after surgery for early stage gallbladder cancer. Surgery. 2009; 146:706–711. discussion 711–713.
25. Mayo SC, Shore AD, Nathan H, Edil B, Wolfgang CL, Hirose K, et al. National trends in the management and survival of surgically managed gallbladder adenocarcinoma over 15 years: a population-based analysis. J Gastrointest Surg. 2010; 14:1578–1591.
26. Coburn NG, Cleary SP, Tan JC, Law CH. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg. 2008; 207:371–382.
27. Ouchi K, Mikuni J, Kakugawa Y. Organizing Committee, The 30th Annual Congress of the Japanese Society of Biliary Surgery. Laparoscopic cholecystectomy for gallbladder carcinoma: results of a Japanese survey of 498 patients. J Hepatobiliary Pancreat Surg. 2002; 9:256–260.
28. Park YJ, Hwang S, Kim KH, Lee YJ, Ahn CS, Moon DB, et al. Prognosis of patients with pT1b/T2 gallbladder carcinoma who have undergone laparoscopic cholecystectomy as an initial operation. Korean J Hepatobiliary Pancreat Surg. 2013; 17:113–117.
29. Shindoh J, de Aretxabala X, Aloia TA, Roa JC, Roa I, Zimmitti G, et al. Tumor location is a strong predictor of tumor progression and survival in T2 gallbladder cancer: an international multicenter study. Ann Surg. 2015; 261:733–739.
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