Efficacy of an over-the-scope clip for preventing adverse events after duodenal endoscopic submucosal dissection: a prospective interventional study

• Abstract
• Introduction
• Methods
• Study design and setting
• Patients and sample size estimation
• Preoperative endoscopic examination
• Duodenal ESD procedure and mucosal defect closure using OTSC
• Outcome measurements
• Statistical analysis
• Results
• Patient characteristics
• Diagnostic accuracy of preoperative biopsy and endoscopic findings predicting the presence of VCL 4/5
• Therapeutic outcomes
• Discussion
• References

Abstract

Background Duodenal endoscopic submucosal dissection (ESD) remains technically challenging, with a high risk of severe adverse events. Because exposure of the duodenal post-ESD mucosal defect to pancreatic juice and bile acid reportedly induces delayed perforation and bleeding, we examined whether defect closure using an over-the-scope clip (OTSC) system was useful for preventing postoperative adverse events.

Methods From April 2016 to February 2017, a total of 50 consecutive patients with superficial non-ampullary duodenal epithelial tumors (SNADETs) larger than 10 mm, with no more than semi-circumferential spread, were prospectively enrolled in this study. All of the lesions were treated by experienced ESD operators and the post-ESD mucosal defect was closed using OTSCs.

Results All of the SNADETs were completely removed by ESD, with an R0 resection rate of 88.0 %. The mean procedure and closure times were 67.3 ± 58.8 minutes and 9.8 ± 7.2 minutes, respectively. Although complete defect closure was achieved in 94.0 % of the patients (47/50), two patients required surgical conversion. Delayed perforation occurred in only one patient (2.1 %), who did not have successful closure of the defect, as misplacement of the OTSC exposed the muscle layer. Meanwhile, delayed bleeding occurred in three patients (6.3 %); however, the bleeding was easily controlled using endoscopic coagulation. The mean duration of postoperative hospitalization was 5.5 ± 7.2 days.

Conclusions Prophylactic defect closure using OTSCs may be effective in reducing severe adverse events after duodenal ESD.

Introduction

Although the prevalence of sporadic duodenal tumors is reportedly low [1], recent developments in endoscopic modalities have increased the chances of detecting them at an early stage [2] [3] [4]. Superficial non-ampullary duodenal epithelial tumor (SNADET) is defined as a non-invasive intraepithelial tumor arising in an area other than the ampulla and is considered to harbor a low risk of lymph node metastasis [5]. Although focal resection is permitted for the treatment of SNADETs [6] [7], surgical resection can be invasive owing to the anatomical complexities of the duodenum. Therefore, endoscopic resection has been used as a minimally invasive therapy for the treatment of SNADETs.

Recently, endoscopic submucosal dissection (ESD) has been applied for the treatment of larger SNADETs to enable an en bloc curative resection [8] [9] [10]. Compared with conventional endoscopic mucosal resection (EMR), ESD can reportedly achieve a high rate of complete resection without local recurrence [11] [12] [13]. However, the indications for duodenal ESD remain controversial as the procedure is technically difficult. In addition to a high incidence of intraoperative perforation, delayed perforation and bleeding are also known to be major adverse events after duodenal ESD [14]. Importantly, the incidence of such serious adverse events is high compared with ESD conducted in other areas of the gastrointestinal tract [15] [16] [17]. Moreover, once severe retroperitonitis has developed, surgical intervention can be difficult and sometimes has a fatal outcome. To overcome the disadvantages of duodenal ESD, standardized management for postoperative adverse events should be established.

Because the exposure of the duodenal post-ESD mucosal defect to pancreatic juice and bile acid can induce delayed perforation and bleeding, complete defect closure would seem to be effective for preventing such events. Although the use of conventional clips is recommended for the closure of mucosal defects, tumor size and location strongly affect the difficulty of this procedure [18]. Additional difficulty is probably associated with the insufficient grasping power of conventional clips, and adverse events can occur if several clips fail. Moreover, the thin wall of the duodenum is susceptible to transmural injury and the clip itself can induce severe perforation if it becomes anchored in a muscle layer. According to previous reports, delayed perforation can occur even if appropriate defect closure has been achieved using conventional clips [19] [20].

Recently, the endoscopic closure of iatrogenic gastrointestinal perforations using an over-the-scope clip (OTSC) system was reported to be a safe and effective method [21] [22] [23]. The OTSC system is designed to create a full-thickness closure using teeth arranged in the shape of a bear trap. Using a porcine model, Von Renteln et al. reported the efficacy of the OTSC technique for repairing duodenal perforations [24]. In humans, however, only a few retrospective reports have supported the efficacy of prophylactic closure of post-procedural mucosal defects using OTSCs [25].

In this prospective interventional study, we evaluated the safety and efficacy of duodenal ESD for the treatment of SNADETs. The post-ESD mucosal defect was closed using OTSCs and the incidence of post-ESD adverse events was determined. In addition, the accuracy of preoperative biopsy examination was evaluated to assess the validity of duodenal ESD. Our results will help to establish therapeutic strategies for SNADETs.

Methods

Study design and setting

This study was designed as a single-center, prospective, interventional study investigating the safety and efficacy of an OTSC system for the prevention of adverse events after duodenal ESD. All of the procedures were conducted at the NTT Medical Center Tokyo.

Written informed consent was obtained from each patient. This study was approved by the ethics committee of NTT Medical Center Tokyo and was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials (No. 000022435).

Patients and sample size estimation

According to previous data summarized by Shibagaki et al. [26], the prevalence of duodenal post-ESD adverse events, including surgical conversion, delayed perforation, and delayed bleeding, was estimated to be approximately 20 %. Based on a retrospective feasibility study conducted by Mori et al. [25], most postoperative adverse events were prevented when complete mucosal defect closure was achieved using OTSCs. Therefore, we estimated that a series of 50 patients would be capable of detecting a 90 % reduction in duodenal post-ESD adverse events, with a 5 % two-sided significance level and an 80 % power.

From April 2016 to February 2017, a total of 50 consecutive patients with SNADETs were enrolled in this study. The inclusion criteria were SNADETs larger than 10 mm with no more than semi-circumferential spread. Owing to the risk of acute pancreatitis, lesions were excluded when it was suspected that the incision line would involve the ampulla. Additionally, patients with lesions suspected of having submucosal invasion were also excluded, along with those with severe comorbidities who would be unable to tolerate surgery. All of the lesions were treated by two experienced ESD operators (T.T. and K.O.), and the post-ESD mucosal defect was closed using OTSCs. To avoid a selection bias, we did not select patients prior to ESD to ensure a good closure using OTSC. Instead, we used a laparoscopic full-thickness suture when OTSC closure failed.

The characteristics of the included patients, including age, sex, tumor characteristics (morphology, size, location and pathology), and their ESD outcomes (en bloc and R0 resection rates, procedure and closure times, prevalence of adverse events, and duration of hospital stay) were prospectively measured. The presence of Helicobacter pylori infection was detected using ¹³C-urea breath tests and/or serological testing.

Preoperative endoscopic examination

Preoperative endoscopic examination was performed using a front-view high-resolution video endoscopy device (H260Z; Olympus, Medical Systems Co., Tokyo, Japan) and tumor size, location, color, and macroscopic type were assessed. The macroscopic characteristics of SNADETs were classified into three types: protruded, flat elevated, and depressed. The predominant color or macroscopic type was used when the tumor showed multiple colors or macroscopic types. The depth diagnosis was made using endoscopic ultrasonography (EUS; UM-2 R system; Olympus) for suspected lesions. The predicted invasion depth was determined based on the findings for the third layer: a hypoechoic mass that had clearly invaded the third layer was defined as submucosal invasion.

In the present study, most of the patients were referrals from other hospitals and a preoperative biopsy had already been completed prior to their arrival at our institute. The histopathological assessments, based on the revised Vienna classification [27], were performed by two experienced pathologists. SNADETs were divided into three categories: low grade adenoma (Vienna classification [VCL] 3), high grade adenoma/intramucosal carcinoma (VCL 4), and carcinoma with submucosal invasion (VCL 5). If discrepancies occurred, the findings were reviewed simultaneously by both pathologists and a consensus was reached.

Duodenal ESD procedure and mucosal defect closure using OTSC

All of the procedures were performed in an operating theatre with the patient under general anesthesia. The ESD procedures were performed using an upper gastrointestinal endoscope (GIF260J; Olympus) with a transparent attachment cap; however, a lower gastrointestinal endoscope (PCF-PQ260L; Olympus) was optionally used for lesions located in the third part of the duodenum. All of the procedures were performed using a high frequency generator unit (VIO300D; Erbe Elektromedizin, Tübingen, Germany) and with carbon dioxide insufflation [28].

Boundary marking and local injection of sodium hyaluronate solutions were first performed. Circumferential incision and submucosal dissections were then performed using a DualKnife (KD650Q; Olympus) and ITknife nano (KD-612L; Olympus) ([Fig.1]). Because the duodenal luminal wall is thin and easy to perforate, extreme caution is required when performing duodenal ESD. When the cutting device was oriented perpendicular to the dissection surface, we hooked and pulled the tissue little by little using the disc tip of the DualKnife and exfoliated the tissue during submucosal dissection. We did not perform immediate defect closure for the management of intraoperative perforation as the clip itself can induce transmural injury if it becomes anchored in the muscle layer. Therefore, intraoperative perforation was simultaneously treated by subsequent OTSC closure. Hemostasis for procedural bleeding was attempted using the knife that was in use or hemostatic forceps (Coagrasper; Olympus).

After the specimen had been retrieved, closure of the mucosal defect was performed using a 9-mm OTSC (Ovesco Endoscopy GmbH, Tübingen, Germany). Sufficient aspiration of air is important to achieve complete closure of the mucosal defect as the target is suctioned into the application cap, which prevents escape of the two edges of normal mucosa surrounding the incision line ([Video 1]). A Twin Grasper (Ovesco Endoscopy GmbH) was optionally advanced through the working channel and both edges of the normal mucosa surrounding the incision line were grasped ([Fig .2]). For large mucosal defects (> 40 mm in diameter), complete closure was achieved using multiple OTSCs. When adequate aspiration was not achieved despite the use of the Twin Grasper, we used an endoloop snare (HX21L1, MAJ339; Olympus) to reduce the maximal diameter of the defect and enable successful defect closure ([Fig. 3]). A laparoscopic suture of the seromuscular layer was used when OTSC closure failed.

Video 1 Procedure of over-the-scope clip (OTSC) closure after duodenal endoscopic submucosal dissection (ESD). The post-ESD mucosal defect was approximately 40 mm in diameter. Both edges of normal mucosa surrounding the incision line were suctioned into the application cap and were completely closed using two OTSCs.

All patients were routinely hospitalized after duodenal ESD. As per the protocol criteria, oral intake was resumed using liquid food on the day after the ESD, progressing gradually to solid food each day thereafter. Because small intraoperative perforations can be completely closed using the OTSC system, these complications were managed conservatively. If somatic symptoms such as fever and abdominal pain occurred, the period of fasting was prolonged and antibiotics were administered. Abdominal computed tomography (CT) scanning was optionally performed to identify retroperitoneal perforations for patients with intense symptoms, such as a high fever or severe abdominal pain. Surgical conversion was conducted without hesitation because subsequent peritoneal abscesses can sometimes have a fatal outcome.

Outcome measurements

The primary outcome was the prevalence of post-ESD adverse events; specifically, the rate of surgical conversion, and the rates of delayed perforation and bleeding. Surgical conversion was undertaken when uncontrollable intraoperative adverse events and/or failure of prophylactic closure of the post-ESD mucosal defect occurred. Delayed bleeding was diagnosed as overt bleeding within 14 days after ESD that required an endoscopic hemostatic procedure using hemostatic forceps.

With regard to the preoperative endoscopic examinations, we compared the differences between preoperative biopsy findings and the final pathological diagnosis and assessed the accuracy, sensitivity, and specificity of the preoperative biopsy examinations. Additionally, we identified the endoscopic findings that predicted the presence of VCL 4 /5.

The secondary outcomes were: the en bloc and R0 resection rates, the complete closure rate using OTSCs, the procedure and closure times, the prevalence of intraoperative adverse events, and the duration of the hospital stay.

Statistical analysis

All the data are presented as the means ± standard deviation, unless otherwise specified. Differences in the clinical parameters between adenoma and cancer were analyzed using the Fisher’s exact test or the Student’s t test. The P values were two-sided, with P < 0.05 used to determine statistical significance. All of the analyses were performed using SPSS, ver. 11.0 (SPSS Inc., Chicago, Illinois, USA).

Results

Patient characteristics

The characteristics of the enrolled patients are shown in [Table1]. The patient age was 57.6 ± 10.1 years, and the male to female ratio was approximately equally (27:23). Only 13 patients (26.0 %) were diagnosed asH. pyloriinfection.

Diagnostic accuracy of preoperative biopsy and endoscopic findings predicting the presence of VCL 4/5

A depth diagnosis was made using EUS for five suspected VCL 5 lesions. During the experimental period, two lesions were excluded from the present study and were surgically resected because submucosal invasion was strongly suspected. The remaining three lesions were included, but one protruded type that was located at the duodenal bulb and of 20 mm in diameter was pathologically diagnosed as a VCL 5.

Preoperative EUS enabled the prediction of submucosal invasion with 67 % accuracy. The results of the preoperative endoscopic examinations are shown in [Table2]. The accuracy, sensitivity, and specificity of the pathological diagnoses based on the biopsied specimens were estimated as 63.0 %, 37.0 %, and 100 %, respectively.

SNADETs were predominantly located in the second portion of the duodenum (one in the first, 40 in the second, and nine in the third portion of the duodenum). Meanwhile, the main morphology was a flat elevated type (46/50; 92.0 %). There were no significant differences in the tumor location or morphology between VCL 3 and VCL 4/5 lesions (P = 0.64 and P = 0.19, respectively). As for the color of the lesions, a red color was more frequently observed for VCL 4/5 lesions (8.7 % vs. 74.1 %; P < 0.001). The mean diameter of VCL 4/5 lesions was significantly larger than that of VCL 3 lesions (27.4 ± 9.9 mm vs. 21.5 ± 8.5 mm; P = 0.03).

Therapeutic outcomes

All of the lesions were successfully resected using ESD. The treatment outcomes for the 50 SNADETs are summarized in [Table 3]. The rates of en bloc and R0 resection were 100 % and 88.0 %, respectively. The mean tumor size was 18.5 ± 8.6 mm (range 10 – 45 mm), and the mean diameter of the resected specimens was 25.1 ± 9.1 mm (range 13 – 50 mm). Pathological examination identified 23 VCL 3 lesions, 26 VCL 4 lesions, and one VCL 5 lesion. The procedure and closure times were 67.3 ± 58.8 minutes and 9.8 ± 7.2 minutes, respectively. Complete defect closure was achieved in 47/50 patients (94.0 %), requiring an average of 1.4 ± 0.5 OTSCs.

Surgical conversion was required in two patients, despite successful resection of the target lesion. A lesion located in the superior duodenal angulus required laparoscopic suturing because of difficulty in obtaining complete closure of the post-ESD mucosal defect. Meanwhile, a pancreaticoduodenectomy was required because of uncontrollable massive bleeding following resection of a lesion located near the ampulla.

Although intraoperative perforation occurred in four patients (8.0 %), these events were managed conservatively after successful mucosal defect closure using the OTSC. Mild to moderate submucosal fibrosis was found during duodenal ESD in 12 /50 patients (24.0 %). Of note, all of the patients with intraoperative perforation had at least mild to moderate submucosal fibrosis.

Because surgical conversion was required in two patients, the rates of delayed perforation and bleeding were calculated as 2.1 % (1/48) and 6.3 % (3/48), respectively. Delayed perforation occurred in only one patient, who did not have successful defect closure, as misplacement of the OTSC exposed the muscular layer. However, the patient was managed conservatively after endoscopic local re-closure using the OTSC system. Meanwhile, delayed bleeding occurred for three lesions located in the second portion of the duodenum, even after complete defect closure had been achieved using the OTSC; however, the bleeding was easily controlled by endoscopic coagulation using hemostatic forceps ([Fig.4]). The duration of postoperative hospitalization was 5.5 ± 7.2 days (range 3 – 52 days).

Discussion

Although prophylactic closure of the post-ESD mucosal defect, especially that achieved using the OTSC system, is known to reduce the risk of hazardous complications, the safety and efficacy of this strategy have rarely been investigated. Therefore, we conducted this prospective interventional study. Except for two patients who required surgical conversion, the overall prevalence of post-ESD adverse events was estimated as 8.3 %. Although we did not achieve the primary endpoint, almost all the delayed perforation was prevented after successful OTSC closure. Meanwhile, delayed bleeding sometimes occurred even after successful OTSC closure but was easily managed using endoscopic coagulation.

Because the prevalence of SNADETs is low, the epidemiology of SNADETs has not been fully investigated. Recently, Niwa et al. [29] revealed that the molecular basis of SNADETs can be classified into two different types. The gastric type, which is predominantly found in the proximal duodenum, is reportedly associated with gastric duodenal metaplasia and infection. Meanwhile, the intestinal type, which is predominantly found in the distal duodenum, develops through the adenoma–carcinoma sequence, similarly to colorectal cancer. In the present study, most of the SNADETs were located in the distal duodenum, which explains why the incidence of H. pylori infection was relatively low. Because SNADETs can be identified in younger patients without H. pylori infection, further attention should be paid during endoscopic examinations.

Duodenal ESD requires proficient endoscopic techniques, therefore appropriate therapeutic indication criteria should be established. Intraepithelial duodenal cancer reportedly harbors no risk of lymph node metastasis [5] [30], while the risk of lymph node metastasis for invasive cancer is approximately 5 % [31]. As a result, intramucosal cancer of the duodenum is a good candidate for endoscopic resection.

Consistent with previous reports [2] [32], we confirmed that tumor size and red coloration were predictive factors for the diagnosis of high grade dysplasia/intramucosal cancer. However, preoperative diagnostic difficulties persist for SNADETs. With regard to the depth diagnosis, submucosal invasion was difficult to predict, even after a precise EUS examination. Goda et al. reported that even SNADETs smaller than 10 mm are often diagnosed as cancer [2]. Of note, we also found that 14 of the 27 VCL 4 lesions (51.9 %) were smaller than 20 mm. Additionally, similarly to the results of previous studies [2] [33], we confirmed a diagnostic discrepancy between preoperative biopsy and postoperative final pathological diagnosis. Taken together, these results suggest that the accurate preoperative staging of SNADETs is difficult even when biopsy samples are available.

Moreover, we confirmed that biopsy sampling can induce mild to moderate submucosal fibrosis and complicate subsequent endoscopic treatment. Because the fibrosis found during duodenal ESD might have resulted from a previous forceps biopsy, we recommend resecting SNADETs without performing a preoperative pathological examination. Recently, the usefulness of magnifying endoscopy with narrow-band imaging (NBI) has been reported [3] [4], and this modality may help to establish a diagnostic algorithm for SNADETs.

Our results demonstrated that ESD can achieve an acceptable completion rate (100 %) and R0 resection rate (88.0 %) for SNADETs. Although intraoperative perforation does occasionally occur, as reported in previous studies [9] [11] [34], no abdominal symptoms were observed after complete OTSC closure, even in patients with comorbidities. Meanwhile, delayed perforation was almost completely prevented, the exception being one patient in whom technical success was not be achieved because of misplacement of the OTSC in an exposed muscle layer. Given that we included a large number of SNADETs located distal to the ampulla, where delayed perforation is common [19], the OTSC system seems to be valuable for managing both intraoperative and delayed perforation.

Delayed bleeding has been reported as occurring in 8.4 % of patients after duodenal ESD [14]. While the rate of delayed bleeding in our study was not negligible (6.3 %), we found that this complication could be easily managed using endoscopic coagulation hemostasis because a full-thickness suture substantially reduces the risk of subsequent delayed perforation. When the OTSC is used to grasp the normal epithelium appropriately on both sides of the post-ESD mucosal defect, the residual submucosa is sometimes inverted and can be directly exposed to pancreatic and bile juices ([Fig. 4 c]), which could also result in delayed bleeding. Therefore, we hypothesized that sufficient pre-coagulation of the exposed vessels on the inverted submucosa might be effective in preventing delayed bleeding, although this hypothesis will need to be confirmed by future investigations.

Short hospital stay is an important advantage of OTSC closure. Hoteya et al. recommended hospitalization for more than 1 week, even after successful duodenal ESD [18]. Our results indicated that a long fasting period is not necessary for patients who have achieved complete prophylactic OTSC closure.

Despite the high complete closure rate using OTSC (94.0 %), there are some important cautions that must be heeded to achieve safe and successful procedures. Firstly, tumor location strongly affects the difficulty of OTSC placement. For example, complete defect closure seems to be difficult for lesions located in the superior duodenal angulus. Additionally, lesions located on the medial side of the second portion near the ampulla are challenging to treat endoscopically because they are located close to the gastroduodenal artery and pancreas, which could induce significant bleeding. Of five such lesions, four were successfully removed using ESD and the mucosal defect was completely closed using OTSCs. However, in one patient, an emergent pancreaticoduodenectomy was required because of uncontrollable massive bleeding.

Secondly, successful OTSC closure depends on the secure suction of the target lesion into the application cap. We demonstrated that larger mucosal defects of over 30 mm in diameter can be closed using multiple OTSCs and/or an endoloop snare, although technical proficiency is required. Additionally, misplacement of the OTSC can cause severe perforation. Therefore, preparations for surgical conversion, including laparoscopic sutures, should be made.

Finally, the cost-effectiveness of this procedure needs to be considered. A single OTSC costs approximately US $800 or €600, and complete mucosal defect closure requires an average of 1.4 OTSCs; therefore, the cost of closure is reportedly 10-times higher than closure using conventional clips [25].

The present study had several limitations. Firstly, a major concern about our study is the lack of adequate validation that OTSC actually decreases the risk of adverse events, especially as we did not enroll a control group. Secondly, duodenal ESD is difficult to perform and is therefore limited to skilled operators who are capable of performing safe and reliable procedures. We recommend obtaining sufficient experience performing colorectal ESD before introducing duodenal ESD, as the required endoscopic techniques are similar. Thirdly, we could not present the long-term outcomes of duodenal ESD. We did however confirm the presence of a tumor-free margin before mucosal defect closure using OTSC, as not doing so could cause the implantation of residual tumor under the mucosa. Finally, this study was conducted at a single center that specializes in endoscopic treatment and included a relatively small sample. It would be interesting to compare the efficacy of OTSC closure against conventional clip closure after duodenal ESD in a multicenter prospective randomized control trial; however, the sample size may need to be huge as this would probably be a non-inferiority trial.

In conclusion, our results indicate that SNADETs can be successfully treated using ESD and subsequent prophylactic defect closure using OTSC is a feasible means of reducing post-duodenal ESD adverse events, such as delayed perforation and bleeding.

Competing interests

None.

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Corresponding author

• References

• 1 Alwmark A, Andersson A, Lasson A. Primary carcinoma of the duodenum. Ann Surg 1980; 191: 13-18
  CrossrefPubMedSearch in Google Scholar
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