Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 7  |  Page : 1606-1612

Transurethral endoscopic submucosal en bloc dissection for nonmuscle invasive bladder cancer: A comparison study of HybridKnife-assisted versus conventional dissection technique


Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China

Date of Web Publication19-Dec-2018

Correspondence Address:
Yong-yi Cheng
Department of Urology, Shaanxi Provincial People's Hospital, 256 Youyi West Road, Xi'an, Shaanxi
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_786_17

Rights and Permissions
 > Abstract 


Subjects: The aim of this study is to compare the efficacy and safety of en bloc bladder tumor-endoscopic submucosal dissection (BT-ESD) and conventional transurethral resection of BT (TURBT) in nonmuscle invasive bladder cancer (NMIBC) patients.
Methods: A retrospective cohort study was carried out in Shaanxi Provincial People's Hospital. A total of 193 eligible NMIBC (Ta/T1) patients were enrolled in this study (95 cases in BT-ESD group and 98 cases in TURBT group), between November 2013 and January 2017. The operation time, blood loss, postoperative bladder irrigation time, catheter indwelling time, hospital stay time, and complications were compared. Data were presented as median (range). Chi-squared or rank-sum test, two-way ANOVA, and Mantel–Cox (Log-Rank) test were performed using statistical software. A threshold of P < 0.05 was defined as statistically significant.
Results: The average operation time in the BT-ESD group was longer than that of in the TURBT group (40.0 [5.0, 100.0] min vs. 19.5 [3.0, 55.5] min); however, no significant longer operating time (P < 0.05) were observed in the smaller tumor (0 cm–3 cm). The postoperative bladder irrigation time, catheter indwelling time, and hospital stay in BT-ESD group were significantly shorter than that of in TURBT group (9.0 [5.0, 18.0] h, 2.5 [1.0, 4.0] d and 3.5 [2.0, 5.0] d for BT-ESD; 18.0 [12.0, 48.0] h, 3.5 [2.0, 7.0] d, and 4.5 [3.0, 8.0] d for TURBT). In addition, the BT-ESD group showed the decreased overall incidence of complications (2.1% vs. 9.2%). The univariate and multivariate analyses indicated an association between surgical option and tumor recurrence (hazard ratio = 5.624, odds ratio = 95% confidence interval = 1.582–19.991), Kaplan–Meir analysis showed significant difference in recurrence-free survival (RFS) (94.7% for ESD group vs. 78.4% for TURBT group) at 33 months.
Conclusions: The application of the HybridKnife lead to a decrease in complications and RFS rate, which was a more safe and effective approach for NMIBC than conventional TURBT.

Keywords: En bloc dissection, endoscopic submucosal dissection, HybridKnife, nonmuscle invasive bladder cancer, transurethral resection of bladder tumor


How to cite this article:
Cheng Yy, Sun Y, Li J, Liang L, Zou Tj, Qu Wx, Jiang Yz, Ren W, Du C, Du Sk, Zhao Wc. Transurethral endoscopic submucosal en bloc dissection for nonmuscle invasive bladder cancer: A comparison study of HybridKnife-assisted versus conventional dissection technique. J Can Res Ther 2018;14:1606-12

How to cite this URL:
Cheng Yy, Sun Y, Li J, Liang L, Zou Tj, Qu Wx, Jiang Yz, Ren W, Du C, Du Sk, Zhao Wc. Transurethral endoscopic submucosal en bloc dissection for nonmuscle invasive bladder cancer: A comparison study of HybridKnife-assisted versus conventional dissection technique. J Can Res Ther [serial online] 2018 [cited 2019 Jan 24];14:1606-12. Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1606/247729




 > Introduction Top


Transurethral resection of bladder tumor (TURBT) is currently the standard treatment for nonmuscle invasive bladder cancer (NMIBC). However, the high recurrence rate of the post-TURBT tumor has drawn clinical attentions. The recurrence of the tumor may be related to the implantation of tumor cells or the incomplete resection of the primary tumor.[1] Tumor tissues destroyed and fragmented by resection technology, which lead to the pathologically understaging of the tumor. Furthermore, the deviation affected the efficacy of postoperative therapeutic plans and increased the rate of tumor recurrence.[2]

Therefore, it was necessary to develop a new method for NMIBC treatment, which could acquire more accurate pathological information of the tumor and reduce postoperative tumor recurrence rate as well as the progression rate.

Endoscopic submucosal dissection (ESD) with the Hybridknife, an emerging new technology, has been reported to be safely and effectively applied in treating epithelial tumors such as a gastric and colonic tumor.[3],[4],[5] This method guaranteed the greatest chance of en bloc resection of tumor tissues, thus allowing accurate diagnosis of tumor grading and staging. Meanwhile, the chance of tumor cell implantation into the bladder wall may be reduced by the en bloc resection of tumor tissues. Thus, the rate of recurrence may be decreased. We have employed this approach for treating urothelial carcinoma during the past 2 years and named it as bladder tumor-ESD (BT-ESD). This retrospective cohort study aimed to compare the safety and effectiveness of BT-ESD with conventional TURBT in the treatment of NMIBC.


 > Subjects and Methods Top


Study population

The study was approved by the hospital review board with a waiver of informed consent, we retrospectively evaluated the data from 193 NMIBC (Ta/T1) patients (including 137 males and 56 females; ages from 41 to 89 (average 63.5 ± 11.4) years old, who received BT-ESD or TURBT between November 2013 and January 2017 [Table 1]. All the patients were consecutively included for this study. The inclusion criteria were as follows: primary NMIBC (pT1/pTa), over 18-year-old, and the Eastern Cooperative Oncology Group score 0–1. The exclusion criteria were as follows: less than 18-year-old, recurrent-NMIBC, MIBC, carcinoma in situ (CIS), and pregnancy.
Table 1: Comparison of patient characteristics and tumor histopathological information between two groups

Click here to view


All cases were preoperatively confirmed by B ultrasonography, computed tomography, cystoscopic examination, and biopsy. All the clinical specimens were pathologically diagnosed with pTa/pT1 by two independent pathologists. The adjuvant intravesical chemotherapy was adopted after TURBT or BT-ESD. The chemotherapy drug was the pirarubicin for immediate single instillation (Low-risk group) or 1-year chemotherapy (intermediate-risk tumor and high-risk tumor). None of the patients received adjuvant immunotherapy due to the inaccessibility of Bacillus Calmette-Guérin in our hospital.

All the patients were followed up with cystoscopy examination every 3 months during the first 2 years, every 6 months between the 3rd and 4th year. The visible recurrent lesions were resected, and histological diagnosis was performed after that. The endpoints of this study were pathologically confirmed tumor recurrence. The patients who were still alive without recurrence were recorded at the date of the last available follow-up cystoscopy before Jan 2017.

All patients were under postoperative observation from 1 to 33 months. Among these patients, 138 manifested with painless gross hematuria and 45 were observed with suspected tumors by ultrasonography at initial diagnosis. A total of 135 patients had a single tumor and 58 patients had multiple tumors in the bladder. Tumor size was from 0.5 cm to 4.0 cm. All the cases were primary tumors. Patients were divided into two groups who received BT-ESD (95 cases) or TURBT (98 cases) treatments, and the statistical analysis showed that there was no significant difference in baseline or tumor characteristics for patients between two groups [P > 0.05, [Table 1]].

Surgical procedure

Bladder tumor-endoscopic submucosal dissection procedure

After epidural anesthesia, lithotomy position and cystoscopic examination of the bladder with irrigation by 5% mannitol, transurethral ultrasonography was performed to determine the infiltration degree of the tumor and confirm the disease as NMIBC [Figure 1]a. With narrowband imaging [NBI, [Figure 1]b], the margin of the tumor was recognized and marked by electrical coagulation with Hybrid-knife [Figure 1]b. The water-jet applicator of the Hybrid-knife was then placed on normal mucosa surrounding the tumor (1 cm away from the margin), and the water jet was activated for the needleless submucosal injection of saline colored with Indigo carmine with optimal pressure through an axial jet nozzle [Figure 1]c. The course was applied to make a fluid cushion elevating the bladder mucosa and submucosa separated from the muscular layer. The Hybrid-knife was applied for mucosal and submucosal incision, further dissection, and for repeated saline injection when needed to avoid perforation and bleeding which was prevented by the hydrodistention [Figure 1]d and [Figure 1]e. By taking these advantages, the Hybrid-knife could dissect the tumor en bloc.
Figure 1: (a) Intraluminal ultrasound suggested that the lesion was confined in the mucosal layer; (b) Tumor boundary was marked under narrow band imaging; (c) Tissue elevation was achieved after submucosal fluid injection with HybridKnife; (d and e) Submucosal incision with HybridKnife; (f) narrow band imaging was applied again after en-bloc resection of tumor to confirm that there were no more lesions left; (g) Superficial muscular layer was shown after en-bloc resection; (h) Spreading and fixation of tumor tissue

Click here to view


After hemostasis with the electrosurgical function of the Hybrid-knife, the NBI [6],[7] was applied again to make sure none of the potential lesions were omitted [Figure 1]f and [Figure 1]g. Biopsy specimens of the tumor edges and bases were collected by biopsy forceps for the further histopathological evaluations. Finally, tumor was endoscopically extracted with a nylon retrieval bag, and a catheter was placed. The tumor samples and biopsies were stretched and mounted immediately by pins on a corkboard with the mucosal layer face up, and fixed with 10% formalin [Figure 1]h. The specimens were sectioned perpendicularly to the mucosa for evaluating the type and the grade of neoplasia, depth of tumor invasion, and completeness of vertical and lateral resection of neoplasia to define differentiation of R0 (tumor-free margins, en bloc resection) and R1 (tumor-infiltrated margins) [see details at the attached Video 1].

Transurethral resection of bladder tumor procedure

After epidural anesthesia and lithotomy position, a 25.5 F Olympus resectoscope with 5% mannitol irrigation was applied to examine the tumor location, number, and size, and determine the extent needed to be resected in the bladder. Set the power of electroresection at 110W and electrocoagulation at 40W. The tumor was circumferentially incised from the bladder, and when the dissection reached to the muscular layer, electrical coagulation was performed in the normal mucosa extended to a macroscopic safety margin of 1 cm. Biopsy specimens of the tumor edges and bases were collected with biopsy forceps for further histopathological evaluations and to define completeness of resection. Subsequently, continuous bladder irrigation was generally applied after the operation.

Bladder tumor-endoscopic submucosal dissection technical devices

The Hybrid-knife (ERBE, Germany) was a multifunctional probe combining water-jet and electrosurgical technology. The water jet was applied through a stainless steel tube incorporating a microcapillary lumen with a diameter of 120 μm, which was connected with a generator, and can rapidly elevate the bladder mucosa and submucosa by the fluid cushion. During the operation, the Hybrid-knife was fixed into the sheath of a 24 F WOLF cystoscope, which allowed the flexible movement to adjust the distance to tissue.

Follow-up and outcome parameters

Intraoperative complications such as bladder perforation, obturator nerve reflex, and detailed operative time were recorded. Postoperative bladder irrigation time, catheter indwelling time, hospital stay, change of hemoglobin, and other complications were measured. The endpoints of this study were recurrence-free survival (RFS) time from randomization to the date of the first bladder recurrence. Patients, who were still alive and without recurrence, were censored at the date of the last available follow-up cystoscopy before January 2017.

Statistical analysis

Data were presented as a mean ± standard deviation. Chi-squared or rank-sum test were employed for analyzing patient characteristics and tumor histopathological information between two groups; two-way ANOVA was applied to compare outcome parameters between two groups. Mantel-Cox (Log-Rank) test was involved in survival analysis. All statistical analyses were performed with statistical software (version 22.0, SPSS, IBM company, Armonk, New York). A threshold of P < 0.05 was defined as statistically significant.


 > Results Top


The average operation time of BT-ESD group was longer than that of in TURBT group [P = 2.062 × 10−4, [Table 2], however, for the tumor diameter <3 cm, there was no significant difference in the operating time between BT-ESD and TURBT [P = 0.388 for ≤1 cm, and P = 0.257 for >1, ≤2 cm, [Table 2]. The postoperative bladder irrigation time, catheter indwelling time, and hospital stay time in BT-ESD group were 9.0 (5.0,18.0) h, 2.5 (1.0,4.0) d, and 3.5 (2.0,5.0) d, respectively, which were much shorter than that of in TURBT group with the measurements of 18.0 (12.0,48.0) h, 3.5 (2.0,7.0) d, and 4.5 (3.0,8.0) d [Table 2].
Table 2: Procedural details and outcomes in both groups

Click here to view


In BT-ESD group, the tumors of four cases were 1 cm distant from the ureteric orifices, although without placing double-J-catheter during the procedure, no postoperative backache and hydronephrosis was observed. In addition, obturator nerve reflex was observed in two cases and prevented from reducing the power of electric resection during the procedures. No perforation was observed. The overall rate of complications in BT-ESD group was 2.1% (2/95). In TURBT group, obturator nerve reflex was observed in seven cases, and the tumors were carefully resected by reduction of electric resection power. Perforation occurred in two cases, and resection was terminated immediately, and an indwelling transurethral catheter was placed to avoid external fistula of urine. The tumor of 1 case was around the ureteric orifice, and postoperatively, ureteral stricture and upper hydroureterosis were observed. A double-J-catheter was then placed in this case, and the follow-up showed a good prognosis. The overall complication rate of TURBT was 9.2% (9/98), which was much higher than that of in BT-ESD [P = 0.034, [Table 2]. However, preoperative and postoperative changes in hemoglobin showed no significant difference between two groups [P = 0.281, [Table 2].

In BT-ESD group, the largest tumor dissected by HybridKnife was 4 cm, and all specimens were endoscopically extracted completely. All specimens and cystoscopic biopsy specimens of the base were defined by pathology, one case showed that R1 resection and the R0 rate of resected neoplasia was 98.9%, however, in TURBT group, five cases showed that R1 resection and the R0 rate of resected neoplasia was 94.8%. The results of biopsy specimens showed no invasive tumors in the muscular layer, but residual tumor cells were found in the nonmuscular tissue of tumor edges. All the R1 patients received Re-TUR within 3 weeks.

The univariate of recurrence showed that the tumor size [P = 1.898 × 10−5, [Table 3], pathological stage [P = 0. 003, [Table 3], tumor grade [P = 9.088 × 10−5, [Table 3], and surgical options [P = 0.004, [Table 3] were significantly associated with tumor recurrence; however, no significant association was observed between gender, age, tumor number, tumor location, operation time, and bladder perforation rate with tumor recurrence [P > 0.05, respectively, [Table 3]. We further performed the Cox regression analysis to show that surgical options were independently associated with tumor recurrence [hazard ratio = 5.624, 1.582–19.991, P = 0.008, [Table 3], the application of BT-ESD was associated with the lower recurrent rate.
Table 3: Univariate and multivariable analysis of recurrence

Click here to view


The analysis of RFS was conducted on NMIBC patients underwent BT-ESD or TURBT since November 2013. The significantly different RFS [95.498% for BT-ESD vs. 79.544% for TURBT, P = 0.028, [Figure 2] was observed.
Figure 2: Kaplan–Meier curves describing the recurrence-free survival rates for the bladder tumor-endoscopic submucosal dissection versus transurethral resection of bladder tumor (log-rank test result: 0.028). The survival rate of recurrence-free survival for bladder tumor-endoscopic submucosal dissection group and transurethral resection of bladder tumor group are 95.498% and 79.544%. Cum = cumulative; RFS = recurrence-free survival

Click here to view



 > Discussion Top


Bladder cancer is a common malignant urinary tumor with a high rate of recurrence and quick progression, the increasing literature have been focusing on the molecularly early detection [8] and more effective therapeutic approach. The high recurrence of NMIBC- may be related to the implantation of tumor cells or the incomplete resection of primary tumors. En bloc dissection of tumor tissue has currently been more popular.

The ESD by Hybrid-knife has been a new technology for the safe and effective treatment of tumors in the gastrointestinal tract as recent studies have shown.[9] Bladder wall shared the similar histological structure with the gastrointestinal tract, and with a thicker lamina propria in the mucosa. Thus, it should be much safer to perform ESD in BT than that of gastrointestinal tumors. This study is aimed to compare the safety and efficacy of ET-ESD and conventional TURBT.

Fritschen et al.[10] reported that the diameter of largest resected tumor was 7.5 cm (the largest tumor resected was 4.0 cm in the present study). For those small papillary tumors <1 cm, there was no real benefit in BT-ESD compared with TURBT that could also be dissected en bloc by the common resection loops. In addition, in the cases with multiple lesions, large tumors or flat lesions which were suspicious of CIS, the operating time of BT-ESD was longer than that of in TURBT.

For the limitation of equipment, operating technique and samples, our data showed that conventional TURBT was more suitable for the larger mass (>3 cm). The postoperative bladder irrigation time, catheter retention time, and hospital stay treated with BT-ESD was decreased compared with that of TURBT group. In addition, no significant difference was observed between two groups regarding preoperative and postoperative hemoglobin changes. However, relevant to complications and risk of recurrence, there was a significant difference between the two methods. In TURBT group, obturator nerve reflex was observed in four cases, and perforation was observed in 2. The high-frequency current in TURBT was thought to be resulted from the bladder perforation, and the low-frequency current stimulated the occurring of obturator nerve reflex. The perforation would lead to the external fistula of urine and spillage of tumor cells. However, in BT-ESD group, no perforation was observed, and obturator nerve reflex was disappeared in 2 cases by turning down the power of resection. Reduced risks of perforation and obturator nerve reflex in BT-ESD were likely due to the characteristic of Hybrid-knife. The fluid cushion made by the jet nozzle of Hybrid-knife separated the mucosa from the muscular layer. Thus, the muscle layer itself was not touched, and the stimulation of obturator nerve during the dissection was greatly reduced. In addition, blood vessels were squeezed and even blocked by the fluid cushion. Thus, risk of bleeding was also significantly reduced.

Furthermore, for the tumors close to ureteric orifices, ureteral stricture, and other upper urethra tract complications were usually not occurred in TURBT. However, distal ureteral stricture was reported to generally occur in 16% of cases treated with TRUBT, leading to hydronephrosis.[11] In the present study, 1 case with tumor closed to the ureteric orifice in TURBT group exhibited postoperatively distal ureteral stricture and hydroureterosis. However, in BT-ESD group, 4 cases of tumors were 1 cm distant from the ureteric orifices, and double-J-catheters were not placed during the procedure, no ureteral stricture and hydronephrosis were observed. This may be the advantages of BT-ESD which could precisely protect the superficial muscular layer of the bladder and the integrity of Waldeyer sheaths of the ureter. This prevented the occurrence of postoperative vesicoureteral reflux and reduced the risk of ureteral stricture.

In both TURBT and BT-ESD group, NBI was applied during the tumor resection. Compared to white light, the 1-year tumor recurrence rate could be reduced by at least 10% with the application of NBI.[7] The RFS in BT-ESD group was decreased compared to TURBT group. The low recurrent rate associated with BT-ESD was that the Hybrid-knife was able to separate the mucosa and muscular layer during the operation, and en bloc dissect the base of the tumor and surrounding normal tissue, thus reducing the implantation of tumor cells into the bladder wall, by which the principles of oncological surgery were well followed. The underestimate staging of the tumor after initial TURBT was mainly due to the destruction of the histological structure and the missing of tumor basal layer after the electroresection. A repeat transurethral resection (Re-TUR) can help to improve the evaluation of tumor stage. In contrast to TURBT, BT-ESD preserved the histological structures on account of the nonthermal water cushion, which can help the pathologist to make a definite differentiation between R0 and R1 resection, thereby decreasing the need for an unnecessary Re-TUR, providing more rationally postoperative treatment plans, dramatically decreasing the risk of tumor recurrence and progression, and reducing socioeconomic costs.

BT-ESD as a novel approach applied for NMIBC appeared to be a feasibly safe and applicable approach compared with conventional TURBT. BT-ESD applied the en bloc resection technique following the principles of oncologic surgery by Hybrid-knife to facilitate histopathologic assessment more accurate and reach an R0 resection easily. This was much critical for planning strategy of intravesical instillation, assessing prognosis, and determining the protocol of follow-up, with respective potential advantages in decreasing rates of tumor recurrence and progression, and reducing socioeconomic costs.


 > Conclusions Top


The application of the Hybrid-Knife lead to a decrease in complications and RFS rate, which was a more safe and effective approach for NMIBC than conventional TURBT. The limitations of the present study were the short retrospective observation with limited samples. The long-term, multi-centre prospective analysis of BT-ESD and TURBT approach for highly selected NMIBC treatment should be performed and assessed in the further.

Acknowledgment

The authors would like to thank for ERBE China of Technical Support.

Financial support and sponsorship

This study was financially supported by the National Natural Science Foundation of China (81172436, 81502205), and National Natural Science Foundation of Shaanxi (2017ZDXM-SF-050, 2017SF-152).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage ta T1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49:466-5.  Back to cited text no. 1
    
2.
Jakse G, Algaba F, Malmström PU, Oosterlinck W. A second-look TUR in T1 transitional cell carcinoma: Why? Eur Urol 2004;45:539-46.  Back to cited text no. 2
    
3.
Balmadrid B, Hwang JH. Endoscopic resection of gastric and esophageal cancer. Gastroenterol Rep (Oxf) 2015;3:330-8.  Back to cited text no. 3
    
4.
Repici A, Hassan C, Pagano N, Rando G, Romeo F, Spaggiari P, et al. High efficacy of endoscopic submucosal dissection for rectal laterally spreading tumors larger than 3 cm. Gastrointest Endosc 2013;77:96-101.  Back to cited text no. 4
    
5.
Schumacher B, Charton JP, Nordmann T, Vieth M, Enderle M, Neuhaus H, et al. Endoscopic submucosal dissection of early gastric neoplasia with a water jet-assisted knife: A Western, single-center experience. Gastrointest Endosc 2012;75:1166-74.  Back to cited text no. 5
    
6.
Naselli A, Introini C, Timossi L, Spina B, Fontana V, Pezzi R, et al. A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non-muscle-invasive bladder cancer recurrence. Eur Urol 2012;61:908-13.  Back to cited text no. 6
    
7.
Jecu M, Geavlete B, Mulţescu R, Stănescu F, Moldoveanu C, Adou L, et al. NBI cystoscopy in routine urological practice – From better vision to improve therapeutic management. J Med Life 2014;7:282-6.  Back to cited text no. 7
    
8.
Kang Z, Li Y, Yu Y, Guo Z. Research progress on bladder cancer molecular genetics. J Cancer Res Ther 2014;10 Suppl:C89-94.  Back to cited text no. 8
    
9.
Nagele U, Kugler M, Nicklas A, Merseburger AS, Walcher U, Mikuz G, et al. Waterjet hydrodissection:First experiences and short-term outcomes of a novel approach to bladder tumor resection. World J Urol 2011;29:423-7.  Back to cited text no. 9
    
10.
Fritsche HM, Otto W, Eder F, Hofstädter F, Denzinger S, Chaussy CG, et al. Water-jet-aided transurethral dissection of urothelial carcinoma: A prospective clinical study. J Endourol 2011;25:1599-603.  Back to cited text no. 10
    
11.
Mano R, Shoshany O, Baniel J, Yossepowitch O. Resection of ureteral orifice during transurethral resection of bladder tumor: Functional and oncologic implications. J Urol 2012;188:2129-33.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Subjects and Methods>Results>Discussion>Conclusions>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed246    
    Printed3    
    Emailed0    
    PDF Downloaded12    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]