Feasibility and effectiveness of laparoscopic transgastric stapler-assisted circumferential esophageal mucosectomy and simultaneous fundoplication in a pig model

Feasibility and effectiveness of laparoscopic transgastric stapler-assisted circumferential... SUMMARY Laparoscopic transgastric stapler-assisted mucosectomy (SAM) has been described for minimally invasive circumferential en bloc resection of Barrett's esophagus (BE). Conceivably long-term disease control might be achieved by adding antireflux surgery after resection of BE by SAM. The aim of this study was to assess the feasibility of combined SAM and fundoplication in one laparoscopic procedure in six pigs. Furthermore, the competence of the gastroesophageal junction (GEJ) was assessed at baseline, after SAM, and after subsequent laparoscopic fundoplication. At each measuring point reflux measurements were repeated 6 times in each pig. Blue-colored water was infused into the stomach to provoke reflux. Intragastric yield pressure and volume were recorded until drainage of blue solution (DBS) was noted. Time to reflux was measured by DBS and by multichannel intraluminal impedance (MII). In all animals SAM followed by laparoscopic fundoplication was feasible in a single session. A weakening of the GEJ was found after SAM, indicated by decreased yield pressure (11.5 mmHg vs. 8.5 mmHg; P < 0.001), time to DBS (90 seconds vs. 60 seconds; P = 0.008) and MII (80 seconds vs. 33 seconds; P < 0.001). After additional Nissen fundoplication the GEJ competence was restored, with measurements returning to baseline values (time to DBS 99 seconds; P = 0.15; MII 76 seconds; P = 0.84). The yield pressure increased from 11.5 mmHg at baseline to 19.7 mmHg after SAM and fundoplication (P < 0.001). Laparoscopic fundoplication and SAM may be combined in a single laparoscopic session. Although the GEJ was weakened after SAM, Nissen fundoplication restored the GEJ as an effective reflux barrier in this experiment. For clinical validation, the results need to be confirmed in a prospective human trial. ABBREVIATIONS ABBREVIATIONS BE Barrett's esophagus DBS drainage of blue solution EAC esophageal adenocarcinoma EMR endoscopic mucosa resection GEJ gastroesophageal junction GER gastroesophageal reflux GERD gastroesophageal reflux disease MII multichannel intraluminal impedance measurement RFA radiofrequency ablation SAM stapler-assisted mucosectomy INTRODUCTION Barrett's esophagus (BE) is a transformation of esophageal squamous epithelium into metaplastic columnar epithelium. In this complex process of tissue transformation severe and ongoing gastroesophageal reflux disease (GERD) plays an important role and has been identified as a risk factor for the development of BE.1,2 The incidence of BE in the Western population is estimated to be 1.5%.3 A minority of patients with BE develop dysplasia.4 The risk of development of high-grade dysplasia (HGD) may be as high as 9% per year.5 The annual progress rate of HGD to esophageal adenocarcinoma (EAC) is 10–25%.6,7 Endoscopic therapy has become an alternative to esophagectomy for dysplastic BE and early adenocarcinoma of the esophagus in the past decade. Nevertheless, when histopathologic risk factors for lymph node involvement are present and depending on the depth of submucosal infiltration, esophagectomy may still be required.8,9 Endoscopic therapy consists in endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). In large, close to or wholly circumferential lesions EMR may be performed stepwise in two or more sessions.10 Alternatively, EMR is limited to the dysplastic region while the remaining BE is treated by an ablative technique such as radiofrequency ablation (RFA), cryoablation, or argon beam coagulation.11,12 Drawbacks of endoscopic therapy are the piecemeal technique, vulnerable to incomplete resection13,14; the risk of postintervention stenosis10,12; and the limitation of the maximum area that is resectable. Furthermore, GERD as the underlying disease remains untreated. GERD in the context of BE is usually treated either medically, typically involving administration of a proton pump inhibitor, or by laparoscopic fundoplication. It remains controversial whether antireflux surgery indeed reduces the risk of disease progression in BE more effectively than drug treatment.15 However, postfundoplication studies have shown a regression in length of BE, a loss of BE, and a loss of dysplasia in some patients.16–18 In a 5-year observation study none of 85 patients with BE undergoing antireflux surgery developed disease progression to HGD or EAC.19 Conflicting conclusions were drawn by metaanalyses of BE progression towards EAC after antireflux surgery compared with drug treatment. While two such studies failed to show a difference between medical and surgical treatment,16,19 the most recent metaanalysis demonstrated a strong tendency toward a decreased risk of EAC in patients who underwent fundoplication.20 The analysis of seven studies showed a decreased pooled incidence rate ratio of EAC of 0.46 (95% confidence interval 0.20–1.08) in patients treated with antireflux surgery compared with the medically treated patients. As an alternative to EMR or ESD, a novel surgical minimally invasive technique for laparoscopic transgastric stapler-assisted esophageal mucosectomy (SAM) has been proposed.21 In brief, the BE is resected circumferentially using a circular endostapler and by repositioning of laparoscopic trocars through the anterior gastric wall, the mucosal aspect of the gastroesophageal junction (GEJ) is visualized. With the aid of rigid laparoscopic instruments and an endostapler, the BE is circumferentially resected while the mucosal borders are sutured by staples (Fig. 1). This obtains a circumferential, oriented mucosectomy specimen, thus facilitating pathologic work-up. Unlike in EMR or ESD no mucosal defect remains. Previously, wound healing and stricture formation has been compared after open esophageal mucosectomy in two conditions: either leaving the defect uncovered or advancing the mucosa and closing the defect with hand sutures. While no stenosis was observed in covered defects, dense fibrotic strictures formed when the defect was left uncovered after 6 weeks in a porcine experiment.22 These findings were confirmed when SAM was compared to EMR. In a pig model after 6 weeks’ survival no strictures occurred in SAM while all animals of the EMR group showed a significant narrowing of the esophageal lumen.21 Fig. 1 View largeDownload slide (a) Principle of transgastric stapler-assisted mucosectomy: with the aid of three transabdominal–transgastric trocars, two mucosal purse-string sutures are placed in the distal esophagus orally and aborally from the Barrett epithelium. The anvil of the circular stapler is inserted and the purse-string sutures are tightened around the spine of the anvil. By firing the stapler a circumferential mucosectomy specimen is obtained. Staples approximate the mucosal borders and no mucosal defect is left open. (b) After mobilization, the fundus is positioned in a loose manner around the esophagus. The 360°Nissen fundoplication is secured with three sutures. Fig. 1 View largeDownload slide (a) Principle of transgastric stapler-assisted mucosectomy: with the aid of three transabdominal–transgastric trocars, two mucosal purse-string sutures are placed in the distal esophagus orally and aborally from the Barrett epithelium. The anvil of the circular stapler is inserted and the purse-string sutures are tightened around the spine of the anvil. By firing the stapler a circumferential mucosectomy specimen is obtained. Staples approximate the mucosal borders and no mucosal defect is left open. (b) After mobilization, the fundus is positioned in a loose manner around the esophagus. The 360°Nissen fundoplication is secured with three sutures. Combination of SAM and Nissen fundoplication might achieve control of BE and GERD, an important underlying cause of BE, in a single session of laparoscopic surgery. This experimental study aimed to assess the feasibility of combined SAM and 360°Nissen fundoplication in a single laparoscopic session in a porcine in vivo reflux model. Furthermore, the effectiveness of reflux control by means of Nissen fundoplication after SAM was evaluated. MATERIALS AND METHODS This in vivo study was performed in a porcine model using six German Landrace pigs of both sexes weighting 34–42 kg. Ethical approval was obtained from the Animal Care Committee of Karlsruhe, Germany (reference number: 95-3185.81/G-62/15). Treatment of the animals was in accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines for animal research.23 All procedures were performed by the same attending surgeon (D.C.S.). He has extensive experience in laparoscopic surgery and holds a certificate in advanced laparoscopic surgery from the Swiss Association for Laparoscopic and Thoracoscopic Surgery. Study design The hypothesis was that the combination of SAM and fundoplication is feasible and that fundoplication represents an effective reflux barrier after SAM. For this pilot study on a novel surgical technique there are no literature data on which a sample size calculation might be based. The reproducibility of a new procedure is, however, usually determined after it has been performed in six pigs.24,25 The feasibility of fundoplication after SAM was assessed. SAM was judged successful when a circumferential, complete mucosal resection was achieved. Competence of the GEJ was assessed intraoperatively at three time points: at baseline, after SAM, and after subsequent fundoplication. At each time point the measurements were repeated six times in each animal. The competence of the GEJ was assessed in four ways: (i) blue-colored water was infused in the gastric lumen, and the time until drainage of blue solution (DBS) over an esophageal tube was measured; (ii) the intragastric volume infused until DBS was recorded (yield volume); (iii) the intragastric pressure when DBS occurred was recorded (yield pressure); and (iv) while infusing the blue-colored water, the time until first appearance of gastroesophageal reflux (GER) as detected by intraesophageal multichannel intraluminal impedance (MII) was documented. The infusion was stopped if an intragastric pressure of 45 mmHg was reached and no reflux had occurred. The GEJ was then declared insurmountable for provoked reflux. Experimental setting The animals fasted for 24 hours and were premedicated intramuscularly with ketamine (10 mg/kg), azaperone (4 mg/kg), and midazolam (0.5 mg/kg). Subsequently each animal was intubated and general anesthesia was maintained using sevoflurane. No muscle relaxants were administered. A transverse laparotomy in the left upper quadrant was performed. The greater omentum was dissected along the gastroepiploic vessels, and the short gastric vessels were divided. A 24-Fr catheter was inserted into the gastric lumen through a small ventral gastrostomy and secured using a purse-string suture. This tube was connected to a roll-pump (Heidolph PD Series, Heidolph Instruments GmbH & Co. KG, Schwabach, Germany) for infusion of blue-colored water (Toluidin, F. Köhler Chemie GmbH, Bensheim, Germany) at a constant flow rate of 14 mL/s. Constant low-pressure suction was applied via an esophageal tube placed 5 cm above the GEJ. A further small gastrostomy was performed for insertion of a tube for intragastric pressure monitoring using a portable pressure gauge (Digital LCD manometer, Rise Ltd, Hong Kong). A third gastrostomy was created to empty the stomach of the blue solution by means of suction after each measurement. During the measurements this gastrostomy was temporarily closed with a clamp. The duodenum was mobilized and clamped to avoid run-off of blue solution into the intestine (Fig. 2). Fig. 2 View largeDownload slide Setting for intraoperative measurement of the competence of the gastroesophageal junction: (A) clamp to close the duodenum; (B) gastrostomy for suction of blue-colored water between measurements; (C) tube and instrument for intragastric pressure measurement; (D) tube for infusion of blue-colored water by means of a roll-pump. Fig. 2 View largeDownload slide Setting for intraoperative measurement of the competence of the gastroesophageal junction: (A) clamp to close the duodenum; (B) gastrostomy for suction of blue-colored water between measurements; (C) tube and instrument for intragastric pressure measurement; (D) tube for infusion of blue-colored water by means of a roll-pump. Stapler-assisted mucosectomy Before the SAM procedure the transverse laparotomy was closed with peritoneal and fascial running sutures to allow the establishment of pneumoperitoneum. A 12-mmHg pneumoperitoneum was established and three 12-mm trocars (Kii® Fios, Applied Medical, Rancho Santa Margarita, CA, USA) were placed left subcostal, epigastric, and in the left upper quadrant. The technique of laparoscopic transgastric SAM has been reported before and is shown in Figure 1.21 After redeployment of the trocars through the ventral gastric wall, 12-mmHg pneumogastrium was established. Two submucosal purse-string sutures were placed in the distal esophagus. The left subcostal facial incision was subsequently enlarged to 2.5 cm and a wound protector was inserted into the stomach (Alexis XXS, Applied Medical, Rancho Santa Margarita, CA, USA). The anvil of a 25-mm circular stapler (CDH25A, 25 mm/5.5 mm, Ethicon, Somerville, NJ, USA) was inserted in the esophagus. The purse-string sutures were knotted and the anvil connected to the endostapler. An en bloc mucosectomy was performed by means of the circular endostapler. Gastrotomies were closed by sutures. The procedure was terminated after an air leak test and intracutaneous wound closure. Contrary to the original description of the technique, the hiatus was not mobilized in this experiment. After SAM the laparotomy was reopened for the measurements. 360° Nissen fundoplication Before laparoscopic fundoplication the laparotomy was closed. Four 12-mm trocars were placed the right subcostal, epigastric, and in the middle and left upper abdomen. A 12-mmHg pneumoperitoneum was established. A liver retractor was introduced via the right subcostal trocar and the left liver lobe was lifted to expose the hiatus. The hiatus was completely mobilized using the monopolar hook. The gastric fundus was then mobilized and the remaining short gastric vessels were cut using LigaSure (Medtronic plc, Dublin, Ireland). A 36-Fr gastric tube was inserted transorally for calibration of the fundoplication. The fundus was positioned in a loose manner behind the esophagus. The fundoplication was secured with three braided sutures (Fig. 1). The large gastric tube was removed. Subsequently the pneumoperitoneum was released, the trocars removed, and the laparotomy reopened for measurements. Measurements A six-channel impedance probe containing eight measuring segments between 2 and 13 cm (SI-ZNIS-L, Standard Instruments GmbH, Karlsruhe, Germany) was used for impedance measurement. A Vizion® portable system was used for registration and ViMeDat software (Standard Instruments GmbH, Karlsruhe, Germany) for analysis. For detection of DBS a 14-Fr gastric tube was employed. The two catheters were fixed together using hydrophobic scotch tape (Fig. 3). The tip of the gastric probe was positioned 5 cm above the GEJ. After insertion of the combined catheter the tip of the MII was positioned at the GEJ, guided by digital palpation. The distance of the tip from the incisor teeth was marked. The correct position of the tube was controlled after each measurement. After each measurement the ventral gastrostomy was opened by removal of the clamp and the intragastric fluid was aspirated. The volume of aspirated fluid was recorded. Then a further 14-Fr gastric tube was inserted retrograde into the esophagus via the gastrostomy and the fluid remaining in the esophagus was removed using a low-pressure suction device. Subsequently the correct positioning of the measurement probe was checked. Fig. 3 View largeDownload slide Combined impedance probe and gastric tube. Fig. 3 View largeDownload slide Combined impedance probe and gastric tube. Definition of GER GER as detected by DBS was defined as time to first visible appearance of blue-colored solution.20 The intragastric yield pressure was defined as the pressure at onset of DBS. GER as detected by MII was defined as a decrease in impedance of at least 50% for the baseline registered in the first segment from the tip. The decrease of impedance had to be sequential, beginning in the measuring segment most distal from the tip of the probe (Fig. 4). Fig. 4 View largeDownload slide Detection of provoked reflux by multichannel intraluminal impedance (MII) measurement at baseline: (A) start of infusion of blue-colored water into stomach; (B) time to detection of reflux by MII; (C) line connecting the time points when decrease in impedance occurs at different impedance segments. Fig. 4 View largeDownload slide Detection of provoked reflux by multichannel intraluminal impedance (MII) measurement at baseline: (A) start of infusion of blue-colored water into stomach; (B) time to detection of reflux by MII; (C) line connecting the time points when decrease in impedance occurs at different impedance segments. Statistical analysis Statistical analysis was performed using SPSS software (IBM® SPSS® Statistics, Version 22, Chicago, IL, USA). The results of parametric data were expressed as mean and 95% confidence interval. Normal distributions of the values for each measuring point were tested using the Kolmogorov–Smirnov test. Nonparametric data were expressed as median and interquartile range. Comparisons between the different measuring points of the results were performed using a paired Student’s t-test. Multiple group comparisons were performed using one-way ANOVA. The level of significance for a difference between the measuring points was set at a P value of ≤0.05. RESULTS The median weight of the animals was 39.5 kg [range 36.3–41.3]. The median operating times for SAM and for fundoplication were 90 minutes [80–107] and 35 minutes [24–86], respectively. Feasibility Fundoplication was feasible without any technical difficulties after SAM. Furthermore, the SAM procedure yielded an intact circumferential mucosectomy specimen. Macroscopically the specimens did not contain muscle portions. No transmural resection occurred. Measuring parameters The mean time until reflux as detected by DBS and by MII, yield volume, and yield pressure for the measurements at baseline and after SAM are depicted in Table 1 and Figures 5–7. After SAM and fundoplication, in 19 of 36 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the time point after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked (Table 1; Figs 5–7). Fig. 5 View largeDownload slide Mean time and 95% confidence interval for first detection of reflux by drainage of blue solution (DBS) and multichannel intraluminal impedance (MII) at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 5 View largeDownload slide Mean time and 95% confidence interval for first detection of reflux by drainage of blue solution (DBS) and multichannel intraluminal impedance (MII) at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 6 View largeDownload slide Mean time and 95% confidence interval for yield volume at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 6 View largeDownload slide Mean time and 95% confidence interval for yield volume at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 7 View largeDownload slide Mean time and 95% confidence interval for yield pressure at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 7 View largeDownload slide Mean time and 95% confidence interval for yield pressure at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Table 1 Time to reflux detected by drainage of blue solution (DBS) and by decrease of multichannel intraluminal impedance (MII), intragastric yield pressure at DBS, and intragastric volume at DBS Baseline (N = 36) After SAM (N = 36) P† After SAM and fundoplication‡ (N = 17) P† DBS (seconds) (95% CI) 90 (74–106) 72 (63–80) 0.008 99 (89–109) 0.147 MII (seconds) (95% CI) 80 (62–97) 33 (29–38) <0.001 76 (68–84) 0.84 Yield pressure (mmHg) (95% CI) 11.5 (10.4–12.7) 8.5 (7.7–9.4) <0.001 19.7 (18.1–21.3) <0.001 Yield volume (mL) (95% CI) 1248 (1024–1472) 987 (870–1104) 0.007 1474 (1324–1623) 0.106 Baseline (N = 36) After SAM (N = 36) P† After SAM and fundoplication‡ (N = 17) P† DBS (seconds) (95% CI) 90 (74–106) 72 (63–80) 0.008 99 (89–109) 0.147 MII (seconds) (95% CI) 80 (62–97) 33 (29–38) <0.001 76 (68–84) 0.84 Yield pressure (mmHg) (95% CI) 11.5 (10.4–12.7) 8.5 (7.7–9.4) <0.001 19.7 (18.1–21.3) <0.001 Yield volume (mL) (95% CI) 1248 (1024–1472) 987 (870–1104) 0.007 1474 (1324–1623) 0.106 †Compared with baseline. ‡Values for fundoplications that yielded to intragastric infusion (17/36 measurements). CI, confidence interval; SAM, stapler-assisted mucosectomy. View Large Table 1 Time to reflux detected by drainage of blue solution (DBS) and by decrease of multichannel intraluminal impedance (MII), intragastric yield pressure at DBS, and intragastric volume at DBS Baseline (N = 36) After SAM (N = 36) P† After SAM and fundoplication‡ (N = 17) P† DBS (seconds) (95% CI) 90 (74–106) 72 (63–80) 0.008 99 (89–109) 0.147 MII (seconds) (95% CI) 80 (62–97) 33 (29–38) <0.001 76 (68–84) 0.84 Yield pressure (mmHg) (95% CI) 11.5 (10.4–12.7) 8.5 (7.7–9.4) <0.001 19.7 (18.1–21.3) <0.001 Yield volume (mL) (95% CI) 1248 (1024–1472) 987 (870–1104) 0.007 1474 (1324–1623) 0.106 Baseline (N = 36) After SAM (N = 36) P† After SAM and fundoplication‡ (N = 17) P† DBS (seconds) (95% CI) 90 (74–106) 72 (63–80) 0.008 99 (89–109) 0.147 MII (seconds) (95% CI) 80 (62–97) 33 (29–38) <0.001 76 (68–84) 0.84 Yield pressure (mmHg) (95% CI) 11.5 (10.4–12.7) 8.5 (7.7–9.4) <0.001 19.7 (18.1–21.3) <0.001 Yield volume (mL) (95% CI) 1248 (1024–1472) 987 (870–1104) 0.007 1474 (1324–1623) 0.106 †Compared with baseline. ‡Values for fundoplications that yielded to intragastric infusion (17/36 measurements). CI, confidence interval; SAM, stapler-assisted mucosectomy. View Large Correlation of measuring parameters Time to reflux as detected by DBS was positively correlated to the time until decrease of MII (r = 0.973, P < 0.0001), to the intragastric yield pressure at DBS (r = 0.765, P < 0.0001), and to the intragastric volume at DBS (r = 1.0, P < 0.0001). DISCUSSION While EMR does not treat GERD, the underlying disease of BE, our experiment shows that SAM may be combined with a laparoscopic fundoplication in a single session. The intragastric yield pressure and the yield volume when reflux occurs were decreased after SAM, indicating a weakening of the GEJ competence as reflux barrier. It seemed that SAM impaired GEJ competence, at least for a short time after surgery. Macro- and microscopic studies, however, did not reveal resection of muscle tissue by SAM.21 Therefore, resection of parts of the esophageal sphincter apparatus can be excluded. A possible explanation for the finding is that the stiff circular stapler line holds the esophageal lumen open. Moreover, introducing the anvil of the circular stapler may have widened the GEJ, although a lag time of at least 30 minutes between SAM and measurement was respected. After fundoplication, however, the reflux barrier was restored in all animals. SAM was developed and evaluated in a previous experiment.21 It was considered safe in a 6-week porcine survival experiment comparing SAM and circumferential EMR. All animals thrived well after surgery. Circumferential intact specimens were obtained in all pigs. The median maximum length resected was 22 mm using a circular endostapler with 25-mm circumference. The muscularis layer including muscularis mucosae was preserved in all specimens, but the submucosa was present only in half of the mucosectomies. However, the resection did not involve the muscularis propria. Interestingly, 6 weeks after intervention stricture formation was observed in all animals undergoing EMR but in none after SAM, despite the significantly larger resection area in the SAM group. Two out of six animals in the EMR were sacrificed prematurely due to symptomatic stenosis. At necropsy the lumen at the level of resection was narrowed in EMR but not in SAM (7.45 mm vs. 16.8 mm, P < 0.001). The ratio of the esophageal width at the level of resection to the width proximal to the resection zone was 0.71 for EMR and 0.98 for SAM (P < 0.001). In EMR, in three out of six pigs damage and collagen deposits were found in the tunica muscularis. In contrast, with SAM mucosal healing without stenosis or fibrosis was demonstrated. Frantzides et al. reported treatment of human HGD with laparoscopic mucosal resection by scissors via an anterior gastrotomy in combination with Nissen fundoplication.26–28 A resection extending 5 cm from the Z-line was described as feasible. However, access by transgastric endoscopy and the use of a circumferential endostapler for mucosectomy in SAM, as proposed here, is novel. In the technique described by Frantzides et al.,26–28 the mucosal wound was left open to heal. Consequently, in 2 of 11 patients stenosis necessitating endoscopic dilatation occurred. In a previous porcine study Farrell reported circular mucosal resection of segments of the distal esophagus up to 5 cm in length in an open surgical technique.22 The defects were then covered and hand sutures used to restore mucosal integrity. As in SAM no or only mild fibrosis and no stenosis were observed. EMR of HGD followed by RFA of the remaining BE is currently considered the first-line treatment.7 Nevertheless, despite EMR and RFA in a cohort of 335 patients from the UK National Halo RFA Registry, 86% of patients were clear of HGD and only 62% of BE at 12 months after a mean of 2.5 RFA procedures. Invasive cancer developed in 3% of patients despite endoscopic treatment.29 The US Multicenter Consortium Recurrence reports complete remission of BE in 56% of cases at 24 months after combined EMR and RFA. The rate of BE recurrence by 2 years after complete eradication was 33%.30 These findings warrant close lifetime follow-up with repeated endoscopy studies in patients treated for HGD with EMR and RFA. In a decision analysis model, the effectiveness of combined EMR-RFA and esophagectomy was compared. EMR-RFA seemed to be equivalent to esophagectomy irrespective of patients’ age.31 Nevertheless, alternative treatment options may be indicated in patients preferring a single, definitive treatment and those who require a surgical antireflux procedure. Moreover, in the subgroup of patients suffering from extensive or even circumferential HGD beyond the limits of combined EMR and RFA, SAM combined with fundoplication may represent a safe alternative to esophagectomy. Currently the extent of resection is limited by the capacity of the circular stapler to contain tissue. The circular staplers we used were designed not for resection but to fashion anastomoses. The relatively short resection may also explain the absence of the submucosal layer in some of the specimens. In the further development of SAM a modified circular stapler must be designed with the capacity to resect longer segments. The specific advantages of SAM versus endoscopic treatment are (i) the circular en bloc mucosectomy, increasing the probability of complete BE eradication; (ii) the capacity for more accurate microscopic evaluation of the lateral and deep resection margins; (iii) a low probability of postintervention stenosis; and (iv) the option for concomitant antireflux surgery, providing not only eradication of BE and HGD but also cure of the underlying GERD. These advantages of SAM compared with endoscopic therapy must be weighed against the increased invasiveness and potential occurrence of serious complications such as intraabdominal infection, wound infection, leak of the gastrostomy closure, and esophageal perforation. CONCLUSIONS This porcine in vivo experiment demonstrated that laparoscopic SAM and fundoplication may be combined in a single session. Although the GEJ was weakened after SAM Nissen fundoplication restored it as an effective reflux barrier in this experiment. Clinical validation requires confirmation of the results in a prospective human trial. Notes The results of this study were presented at the 25th International Congress of the European Association for Endoscopic Surgery, June 14–17, 2017, Frankfurt, Germany. Specific author contributions: D.C.S. and P.C.M. designed the study, performed the experiments, analyzed the data. and drafted the manuscript. A.C.S. performed the experiments and carried out critical revision. G.R.L., A.Z., and B.P.M. designed the study and carried out critical revision. All authors gave their final approval. Funding: The German Research Foundation (DFG) funded the study (STE 2590/1-1). Impedance monitoring instruments were loaned free of charge from Standard Instruments GmbH, Werftstrasse 12, 76,189 Karlsruhe, Germany. Conflicts of interest: The authors declare that they have no conflict of interest. ACKNOWLEDGMENTS D.C.S. is supported by the Swiss National Science Foundation (Grant P300PB-161,099/1) and the Margarete and Walter Lichtenstein Foundation, Basel, Switzerland (DMS2321). REFERENCES 1. Lagergren J , Bergstrom R , Lindgren A et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma . N Engl J Med 1999 ; 340 : 825 – 31 . Google Scholar CrossRef Search ADS PubMed 2. Ireland C J , Fielder A L , Thompson S K et al. Development of a risk prediction model for Barrett's esophagus in an Australian population . 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Gut 2008 ; 57 : 1200 – 6 . Google Scholar CrossRef Search ADS PubMed 15. de Jonge P J , Spaander M C , Bruno M J et al. Acid suppression and surgical therapy for Barrett's oesophagus . Best Pract Res Clin Gastroenterol 2015 ; 29 : 139 – 50 . Google Scholar CrossRef Search ADS PubMed 16. Chang E Y , Morris C D , Seltman A K et al. The effect of antireflux surgery on esophageal carcinogenesis in patients with Barrett esophagus . Ann Surg 2007 ; 246 : 11 – 21 . Google Scholar CrossRef Search ADS PubMed 17. DeMeester S R , DeMeester T R . Columnar mucosa and intestinal metaplasia of the esophagus: fifty years of controversy . Ann Surg 2000 ; 231 : 303 – 21 . Google Scholar CrossRef Search ADS PubMed 18. Knight B C , Devitt P G , Watson D I et al. Long-term efficacy of laparoscopic antireflux surgery on regression of Barrett's esophagus using BRAVO wireless pH monitoring . Ann Surg 2017 ; 266 : 1000 – 5 . Google Scholar CrossRef Search ADS PubMed 19. Hofstetter W L , Peters J H , DeMeester T R et al. Long-term outcome of antireflux surgery in patients with Barrett's esophagus . Ann Surg 2001 ; 234 : 532 – 9 ; discussion 538–9 . Google Scholar CrossRef Search ADS PubMed 20. Maret-Ouda J , Konings P , Lagergren J et al. Antireflux surgery and risk of esophageal adenocarcinoma . Ann Surg 2016 ; 263 : 251 – 7 . Google Scholar CrossRef Search ADS PubMed 21. Steinemann D C , Zerz A , Muller P C et al. Laparoscopic transgastric circumferential stapler-assisted vs. endoscopic esophageal mucosectomy in a porcine model . Endoscopy 2017 ; 49 : 668 – 74 . Google Scholar CrossRef Search ADS PubMed 22. Farrell T M , Archer S B , Metreveli R E et al. Resection and advancement of esophageal mucosa . Surg Endosc 2001 ; 15 : 937 – 41 . Google Scholar CrossRef Search ADS PubMed 23. Kilkenny C , Browne W J , Cuthill I C et al. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research . PLoS Biol 2010 ; 8 : e1000412 . Google Scholar CrossRef Search ADS PubMed 24. Bordeianou L , Sylla P , Kinnier C V et al. Perineal sigmoidopexy utilizing transanal endoscopic microsurgery (TEM) to treat full thickness rectal prolapse: a feasibility trial in porcine and human cadaver models . Surg Endosc 2015 ; 29 : 686 – 91 . Google Scholar CrossRef Search ADS PubMed 25. Zdichavsky M , Krautwald M , Meile T et al. Single-port live donor nephrectomy using a novel curved radius r2 Surgical System in an in vivo model . Minim Invasive Ther Allied Technol 2015 ; 24 : 63 – 67 . Google Scholar CrossRef Search ADS PubMed 26. Frantzides C T , Carlson M A , Keshavarzian A et al. Laparoscopic transgastric esophageal mucosal resection: 4-year minimum follow-up . Am J Surg 2010 ; 200 : 305 – 7 . Google Scholar CrossRef Search ADS PubMed 27. Frantzides C T , Daly SC , Frantzides A T et al. Laparoscopic transgastric esophageal mucosal resection: a treatment option for patients with high-grade dysplasia in Barrett's esophagus . Am J Surg 2016 ; 211 : 534 – 6 . Google Scholar CrossRef Search ADS PubMed 28. Frantzides C T , Madan A K , Moore R E et al. Laparoscopic transgastric esophageal mucosal resection for high-grade dysplasia . J Laparoendosc Adv Surg Tech A 2004 ; 14 : 261 – 5 . Google Scholar CrossRef Search ADS PubMed 29. Haidry R J , Dunn J M , Butt M A et al. Radiofrequency ablation and endoscopic mucosal resection for dysplastic barrett's esophagus and early esophageal adenocarcinoma: outcomes of the UK National Halo RFA Registry . Gastroenterology 2013 ; 145 : 87 – 95 . Google Scholar CrossRef Search ADS PubMed 30. Gupta M , Iyer PG , Lutzke L et al. Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US Multicenter Consortium . Gastroenterology 2013 ; 145 : 79 – 86.e1 . Google Scholar CrossRef Search ADS PubMed 31. Hu Y , Puri V , Shami V M et al. Comparative effectiveness of esophagectomy versus endoscopic treatment for esophageal high-grade dysplasia . Ann Surg 2016 ; 263 : 719 – 26 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Feasibility and effectiveness of laparoscopic transgastric stapler-assisted circumferential esophageal mucosectomy and simultaneous fundoplication in a pig model

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The International Society for Diseases of the Esophagus
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© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
ISSN
1120-8694
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1442-2050
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10.1093/dote/doy030
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Abstract

SUMMARY Laparoscopic transgastric stapler-assisted mucosectomy (SAM) has been described for minimally invasive circumferential en bloc resection of Barrett's esophagus (BE). Conceivably long-term disease control might be achieved by adding antireflux surgery after resection of BE by SAM. The aim of this study was to assess the feasibility of combined SAM and fundoplication in one laparoscopic procedure in six pigs. Furthermore, the competence of the gastroesophageal junction (GEJ) was assessed at baseline, after SAM, and after subsequent laparoscopic fundoplication. At each measuring point reflux measurements were repeated 6 times in each pig. Blue-colored water was infused into the stomach to provoke reflux. Intragastric yield pressure and volume were recorded until drainage of blue solution (DBS) was noted. Time to reflux was measured by DBS and by multichannel intraluminal impedance (MII). In all animals SAM followed by laparoscopic fundoplication was feasible in a single session. A weakening of the GEJ was found after SAM, indicated by decreased yield pressure (11.5 mmHg vs. 8.5 mmHg; P < 0.001), time to DBS (90 seconds vs. 60 seconds; P = 0.008) and MII (80 seconds vs. 33 seconds; P < 0.001). After additional Nissen fundoplication the GEJ competence was restored, with measurements returning to baseline values (time to DBS 99 seconds; P = 0.15; MII 76 seconds; P = 0.84). The yield pressure increased from 11.5 mmHg at baseline to 19.7 mmHg after SAM and fundoplication (P < 0.001). Laparoscopic fundoplication and SAM may be combined in a single laparoscopic session. Although the GEJ was weakened after SAM, Nissen fundoplication restored the GEJ as an effective reflux barrier in this experiment. For clinical validation, the results need to be confirmed in a prospective human trial. ABBREVIATIONS ABBREVIATIONS BE Barrett's esophagus DBS drainage of blue solution EAC esophageal adenocarcinoma EMR endoscopic mucosa resection GEJ gastroesophageal junction GER gastroesophageal reflux GERD gastroesophageal reflux disease MII multichannel intraluminal impedance measurement RFA radiofrequency ablation SAM stapler-assisted mucosectomy INTRODUCTION Barrett's esophagus (BE) is a transformation of esophageal squamous epithelium into metaplastic columnar epithelium. In this complex process of tissue transformation severe and ongoing gastroesophageal reflux disease (GERD) plays an important role and has been identified as a risk factor for the development of BE.1,2 The incidence of BE in the Western population is estimated to be 1.5%.3 A minority of patients with BE develop dysplasia.4 The risk of development of high-grade dysplasia (HGD) may be as high as 9% per year.5 The annual progress rate of HGD to esophageal adenocarcinoma (EAC) is 10–25%.6,7 Endoscopic therapy has become an alternative to esophagectomy for dysplastic BE and early adenocarcinoma of the esophagus in the past decade. Nevertheless, when histopathologic risk factors for lymph node involvement are present and depending on the depth of submucosal infiltration, esophagectomy may still be required.8,9 Endoscopic therapy consists in endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). In large, close to or wholly circumferential lesions EMR may be performed stepwise in two or more sessions.10 Alternatively, EMR is limited to the dysplastic region while the remaining BE is treated by an ablative technique such as radiofrequency ablation (RFA), cryoablation, or argon beam coagulation.11,12 Drawbacks of endoscopic therapy are the piecemeal technique, vulnerable to incomplete resection13,14; the risk of postintervention stenosis10,12; and the limitation of the maximum area that is resectable. Furthermore, GERD as the underlying disease remains untreated. GERD in the context of BE is usually treated either medically, typically involving administration of a proton pump inhibitor, or by laparoscopic fundoplication. It remains controversial whether antireflux surgery indeed reduces the risk of disease progression in BE more effectively than drug treatment.15 However, postfundoplication studies have shown a regression in length of BE, a loss of BE, and a loss of dysplasia in some patients.16–18 In a 5-year observation study none of 85 patients with BE undergoing antireflux surgery developed disease progression to HGD or EAC.19 Conflicting conclusions were drawn by metaanalyses of BE progression towards EAC after antireflux surgery compared with drug treatment. While two such studies failed to show a difference between medical and surgical treatment,16,19 the most recent metaanalysis demonstrated a strong tendency toward a decreased risk of EAC in patients who underwent fundoplication.20 The analysis of seven studies showed a decreased pooled incidence rate ratio of EAC of 0.46 (95% confidence interval 0.20–1.08) in patients treated with antireflux surgery compared with the medically treated patients. As an alternative to EMR or ESD, a novel surgical minimally invasive technique for laparoscopic transgastric stapler-assisted esophageal mucosectomy (SAM) has been proposed.21 In brief, the BE is resected circumferentially using a circular endostapler and by repositioning of laparoscopic trocars through the anterior gastric wall, the mucosal aspect of the gastroesophageal junction (GEJ) is visualized. With the aid of rigid laparoscopic instruments and an endostapler, the BE is circumferentially resected while the mucosal borders are sutured by staples (Fig. 1). This obtains a circumferential, oriented mucosectomy specimen, thus facilitating pathologic work-up. Unlike in EMR or ESD no mucosal defect remains. Previously, wound healing and stricture formation has been compared after open esophageal mucosectomy in two conditions: either leaving the defect uncovered or advancing the mucosa and closing the defect with hand sutures. While no stenosis was observed in covered defects, dense fibrotic strictures formed when the defect was left uncovered after 6 weeks in a porcine experiment.22 These findings were confirmed when SAM was compared to EMR. In a pig model after 6 weeks’ survival no strictures occurred in SAM while all animals of the EMR group showed a significant narrowing of the esophageal lumen.21 Fig. 1 View largeDownload slide (a) Principle of transgastric stapler-assisted mucosectomy: with the aid of three transabdominal–transgastric trocars, two mucosal purse-string sutures are placed in the distal esophagus orally and aborally from the Barrett epithelium. The anvil of the circular stapler is inserted and the purse-string sutures are tightened around the spine of the anvil. By firing the stapler a circumferential mucosectomy specimen is obtained. Staples approximate the mucosal borders and no mucosal defect is left open. (b) After mobilization, the fundus is positioned in a loose manner around the esophagus. The 360°Nissen fundoplication is secured with three sutures. Fig. 1 View largeDownload slide (a) Principle of transgastric stapler-assisted mucosectomy: with the aid of three transabdominal–transgastric trocars, two mucosal purse-string sutures are placed in the distal esophagus orally and aborally from the Barrett epithelium. The anvil of the circular stapler is inserted and the purse-string sutures are tightened around the spine of the anvil. By firing the stapler a circumferential mucosectomy specimen is obtained. Staples approximate the mucosal borders and no mucosal defect is left open. (b) After mobilization, the fundus is positioned in a loose manner around the esophagus. The 360°Nissen fundoplication is secured with three sutures. Combination of SAM and Nissen fundoplication might achieve control of BE and GERD, an important underlying cause of BE, in a single session of laparoscopic surgery. This experimental study aimed to assess the feasibility of combined SAM and 360°Nissen fundoplication in a single laparoscopic session in a porcine in vivo reflux model. Furthermore, the effectiveness of reflux control by means of Nissen fundoplication after SAM was evaluated. MATERIALS AND METHODS This in vivo study was performed in a porcine model using six German Landrace pigs of both sexes weighting 34–42 kg. Ethical approval was obtained from the Animal Care Committee of Karlsruhe, Germany (reference number: 95-3185.81/G-62/15). Treatment of the animals was in accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines for animal research.23 All procedures were performed by the same attending surgeon (D.C.S.). He has extensive experience in laparoscopic surgery and holds a certificate in advanced laparoscopic surgery from the Swiss Association for Laparoscopic and Thoracoscopic Surgery. Study design The hypothesis was that the combination of SAM and fundoplication is feasible and that fundoplication represents an effective reflux barrier after SAM. For this pilot study on a novel surgical technique there are no literature data on which a sample size calculation might be based. The reproducibility of a new procedure is, however, usually determined after it has been performed in six pigs.24,25 The feasibility of fundoplication after SAM was assessed. SAM was judged successful when a circumferential, complete mucosal resection was achieved. Competence of the GEJ was assessed intraoperatively at three time points: at baseline, after SAM, and after subsequent fundoplication. At each time point the measurements were repeated six times in each animal. The competence of the GEJ was assessed in four ways: (i) blue-colored water was infused in the gastric lumen, and the time until drainage of blue solution (DBS) over an esophageal tube was measured; (ii) the intragastric volume infused until DBS was recorded (yield volume); (iii) the intragastric pressure when DBS occurred was recorded (yield pressure); and (iv) while infusing the blue-colored water, the time until first appearance of gastroesophageal reflux (GER) as detected by intraesophageal multichannel intraluminal impedance (MII) was documented. The infusion was stopped if an intragastric pressure of 45 mmHg was reached and no reflux had occurred. The GEJ was then declared insurmountable for provoked reflux. Experimental setting The animals fasted for 24 hours and were premedicated intramuscularly with ketamine (10 mg/kg), azaperone (4 mg/kg), and midazolam (0.5 mg/kg). Subsequently each animal was intubated and general anesthesia was maintained using sevoflurane. No muscle relaxants were administered. A transverse laparotomy in the left upper quadrant was performed. The greater omentum was dissected along the gastroepiploic vessels, and the short gastric vessels were divided. A 24-Fr catheter was inserted into the gastric lumen through a small ventral gastrostomy and secured using a purse-string suture. This tube was connected to a roll-pump (Heidolph PD Series, Heidolph Instruments GmbH & Co. KG, Schwabach, Germany) for infusion of blue-colored water (Toluidin, F. Köhler Chemie GmbH, Bensheim, Germany) at a constant flow rate of 14 mL/s. Constant low-pressure suction was applied via an esophageal tube placed 5 cm above the GEJ. A further small gastrostomy was performed for insertion of a tube for intragastric pressure monitoring using a portable pressure gauge (Digital LCD manometer, Rise Ltd, Hong Kong). A third gastrostomy was created to empty the stomach of the blue solution by means of suction after each measurement. During the measurements this gastrostomy was temporarily closed with a clamp. The duodenum was mobilized and clamped to avoid run-off of blue solution into the intestine (Fig. 2). Fig. 2 View largeDownload slide Setting for intraoperative measurement of the competence of the gastroesophageal junction: (A) clamp to close the duodenum; (B) gastrostomy for suction of blue-colored water between measurements; (C) tube and instrument for intragastric pressure measurement; (D) tube for infusion of blue-colored water by means of a roll-pump. Fig. 2 View largeDownload slide Setting for intraoperative measurement of the competence of the gastroesophageal junction: (A) clamp to close the duodenum; (B) gastrostomy for suction of blue-colored water between measurements; (C) tube and instrument for intragastric pressure measurement; (D) tube for infusion of blue-colored water by means of a roll-pump. Stapler-assisted mucosectomy Before the SAM procedure the transverse laparotomy was closed with peritoneal and fascial running sutures to allow the establishment of pneumoperitoneum. A 12-mmHg pneumoperitoneum was established and three 12-mm trocars (Kii® Fios, Applied Medical, Rancho Santa Margarita, CA, USA) were placed left subcostal, epigastric, and in the left upper quadrant. The technique of laparoscopic transgastric SAM has been reported before and is shown in Figure 1.21 After redeployment of the trocars through the ventral gastric wall, 12-mmHg pneumogastrium was established. Two submucosal purse-string sutures were placed in the distal esophagus. The left subcostal facial incision was subsequently enlarged to 2.5 cm and a wound protector was inserted into the stomach (Alexis XXS, Applied Medical, Rancho Santa Margarita, CA, USA). The anvil of a 25-mm circular stapler (CDH25A, 25 mm/5.5 mm, Ethicon, Somerville, NJ, USA) was inserted in the esophagus. The purse-string sutures were knotted and the anvil connected to the endostapler. An en bloc mucosectomy was performed by means of the circular endostapler. Gastrotomies were closed by sutures. The procedure was terminated after an air leak test and intracutaneous wound closure. Contrary to the original description of the technique, the hiatus was not mobilized in this experiment. After SAM the laparotomy was reopened for the measurements. 360° Nissen fundoplication Before laparoscopic fundoplication the laparotomy was closed. Four 12-mm trocars were placed the right subcostal, epigastric, and in the middle and left upper abdomen. A 12-mmHg pneumoperitoneum was established. A liver retractor was introduced via the right subcostal trocar and the left liver lobe was lifted to expose the hiatus. The hiatus was completely mobilized using the monopolar hook. The gastric fundus was then mobilized and the remaining short gastric vessels were cut using LigaSure (Medtronic plc, Dublin, Ireland). A 36-Fr gastric tube was inserted transorally for calibration of the fundoplication. The fundus was positioned in a loose manner behind the esophagus. The fundoplication was secured with three braided sutures (Fig. 1). The large gastric tube was removed. Subsequently the pneumoperitoneum was released, the trocars removed, and the laparotomy reopened for measurements. Measurements A six-channel impedance probe containing eight measuring segments between 2 and 13 cm (SI-ZNIS-L, Standard Instruments GmbH, Karlsruhe, Germany) was used for impedance measurement. A Vizion® portable system was used for registration and ViMeDat software (Standard Instruments GmbH, Karlsruhe, Germany) for analysis. For detection of DBS a 14-Fr gastric tube was employed. The two catheters were fixed together using hydrophobic scotch tape (Fig. 3). The tip of the gastric probe was positioned 5 cm above the GEJ. After insertion of the combined catheter the tip of the MII was positioned at the GEJ, guided by digital palpation. The distance of the tip from the incisor teeth was marked. The correct position of the tube was controlled after each measurement. After each measurement the ventral gastrostomy was opened by removal of the clamp and the intragastric fluid was aspirated. The volume of aspirated fluid was recorded. Then a further 14-Fr gastric tube was inserted retrograde into the esophagus via the gastrostomy and the fluid remaining in the esophagus was removed using a low-pressure suction device. Subsequently the correct positioning of the measurement probe was checked. Fig. 3 View largeDownload slide Combined impedance probe and gastric tube. Fig. 3 View largeDownload slide Combined impedance probe and gastric tube. Definition of GER GER as detected by DBS was defined as time to first visible appearance of blue-colored solution.20 The intragastric yield pressure was defined as the pressure at onset of DBS. GER as detected by MII was defined as a decrease in impedance of at least 50% for the baseline registered in the first segment from the tip. The decrease of impedance had to be sequential, beginning in the measuring segment most distal from the tip of the probe (Fig. 4). Fig. 4 View largeDownload slide Detection of provoked reflux by multichannel intraluminal impedance (MII) measurement at baseline: (A) start of infusion of blue-colored water into stomach; (B) time to detection of reflux by MII; (C) line connecting the time points when decrease in impedance occurs at different impedance segments. Fig. 4 View largeDownload slide Detection of provoked reflux by multichannel intraluminal impedance (MII) measurement at baseline: (A) start of infusion of blue-colored water into stomach; (B) time to detection of reflux by MII; (C) line connecting the time points when decrease in impedance occurs at different impedance segments. Statistical analysis Statistical analysis was performed using SPSS software (IBM® SPSS® Statistics, Version 22, Chicago, IL, USA). The results of parametric data were expressed as mean and 95% confidence interval. Normal distributions of the values for each measuring point were tested using the Kolmogorov–Smirnov test. Nonparametric data were expressed as median and interquartile range. Comparisons between the different measuring points of the results were performed using a paired Student’s t-test. Multiple group comparisons were performed using one-way ANOVA. The level of significance for a difference between the measuring points was set at a P value of ≤0.05. RESULTS The median weight of the animals was 39.5 kg [range 36.3–41.3]. The median operating times for SAM and for fundoplication were 90 minutes [80–107] and 35 minutes [24–86], respectively. Feasibility Fundoplication was feasible without any technical difficulties after SAM. Furthermore, the SAM procedure yielded an intact circumferential mucosectomy specimen. Macroscopically the specimens did not contain muscle portions. No transmural resection occurred. Measuring parameters The mean time until reflux as detected by DBS and by MII, yield volume, and yield pressure for the measurements at baseline and after SAM are depicted in Table 1 and Figures 5–7. After SAM and fundoplication, in 19 of 36 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the time point after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked (Table 1; Figs 5–7). Fig. 5 View largeDownload slide Mean time and 95% confidence interval for first detection of reflux by drainage of blue solution (DBS) and multichannel intraluminal impedance (MII) at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 5 View largeDownload slide Mean time and 95% confidence interval for first detection of reflux by drainage of blue solution (DBS) and multichannel intraluminal impedance (MII) at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 6 View largeDownload slide Mean time and 95% confidence interval for yield volume at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 6 View largeDownload slide Mean time and 95% confidence interval for yield volume at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 7 View largeDownload slide Mean time and 95% confidence interval for yield pressure at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Fig. 7 View largeDownload slide Mean time and 95% confidence interval for yield pressure at baseline, after stapler-assisted mucosectomy (SAM), and after SAM and fundoplication. After fundoplication, in 19 measurements the reflux barrier was insurmountable and no reflux could be provoked. The values for the measurements after SAM and fundoplication are those of the remaining 17 measurements when reflux could still be provoked. Table 1 Time to reflux detected by drainage of blue solution (DBS) and by decrease of multichannel intraluminal impedance (MII), intragastric yield pressure at DBS, and intragastric volume at DBS Baseline (N = 36) After SAM (N = 36) P† After SAM and fundoplication‡ (N = 17) P† DBS (seconds) (95% CI) 90 (74–106) 72 (63–80) 0.008 99 (89–109) 0.147 MII (seconds) (95% CI) 80 (62–97) 33 (29–38) <0.001 76 (68–84) 0.84 Yield pressure (mmHg) (95% CI) 11.5 (10.4–12.7) 8.5 (7.7–9.4) <0.001 19.7 (18.1–21.3) <0.001 Yield volume (mL) (95% CI) 1248 (1024–1472) 987 (870–1104) 0.007 1474 (1324–1623) 0.106 Baseline (N = 36) After SAM (N = 36) P† After SAM and fundoplication‡ (N = 17) P† DBS (seconds) (95% CI) 90 (74–106) 72 (63–80) 0.008 99 (89–109) 0.147 MII (seconds) (95% CI) 80 (62–97) 33 (29–38) <0.001 76 (68–84) 0.84 Yield pressure (mmHg) (95% CI) 11.5 (10.4–12.7) 8.5 (7.7–9.4) <0.001 19.7 (18.1–21.3) <0.001 Yield volume (mL) (95% CI) 1248 (1024–1472) 987 (870–1104) 0.007 1474 (1324–1623) 0.106 †Compared with baseline. ‡Values for fundoplications that yielded to intragastric infusion (17/36 measurements). CI, confidence interval; SAM, stapler-assisted mucosectomy. View Large Table 1 Time to reflux detected by drainage of blue solution (DBS) and by decrease of multichannel intraluminal impedance (MII), intragastric yield pressure at DBS, and intragastric volume at DBS Baseline (N = 36) After SAM (N = 36) P† After SAM and fundoplication‡ (N = 17) P† DBS (seconds) (95% CI) 90 (74–106) 72 (63–80) 0.008 99 (89–109) 0.147 MII (seconds) (95% CI) 80 (62–97) 33 (29–38) <0.001 76 (68–84) 0.84 Yield pressure (mmHg) (95% CI) 11.5 (10.4–12.7) 8.5 (7.7–9.4) <0.001 19.7 (18.1–21.3) <0.001 Yield volume (mL) (95% CI) 1248 (1024–1472) 987 (870–1104) 0.007 1474 (1324–1623) 0.106 Baseline (N = 36) After SAM (N = 36) P† After SAM and fundoplication‡ (N = 17) P† DBS (seconds) (95% CI) 90 (74–106) 72 (63–80) 0.008 99 (89–109) 0.147 MII (seconds) (95% CI) 80 (62–97) 33 (29–38) <0.001 76 (68–84) 0.84 Yield pressure (mmHg) (95% CI) 11.5 (10.4–12.7) 8.5 (7.7–9.4) <0.001 19.7 (18.1–21.3) <0.001 Yield volume (mL) (95% CI) 1248 (1024–1472) 987 (870–1104) 0.007 1474 (1324–1623) 0.106 †Compared with baseline. ‡Values for fundoplications that yielded to intragastric infusion (17/36 measurements). CI, confidence interval; SAM, stapler-assisted mucosectomy. View Large Correlation of measuring parameters Time to reflux as detected by DBS was positively correlated to the time until decrease of MII (r = 0.973, P < 0.0001), to the intragastric yield pressure at DBS (r = 0.765, P < 0.0001), and to the intragastric volume at DBS (r = 1.0, P < 0.0001). DISCUSSION While EMR does not treat GERD, the underlying disease of BE, our experiment shows that SAM may be combined with a laparoscopic fundoplication in a single session. The intragastric yield pressure and the yield volume when reflux occurs were decreased after SAM, indicating a weakening of the GEJ competence as reflux barrier. It seemed that SAM impaired GEJ competence, at least for a short time after surgery. Macro- and microscopic studies, however, did not reveal resection of muscle tissue by SAM.21 Therefore, resection of parts of the esophageal sphincter apparatus can be excluded. A possible explanation for the finding is that the stiff circular stapler line holds the esophageal lumen open. Moreover, introducing the anvil of the circular stapler may have widened the GEJ, although a lag time of at least 30 minutes between SAM and measurement was respected. After fundoplication, however, the reflux barrier was restored in all animals. SAM was developed and evaluated in a previous experiment.21 It was considered safe in a 6-week porcine survival experiment comparing SAM and circumferential EMR. All animals thrived well after surgery. Circumferential intact specimens were obtained in all pigs. The median maximum length resected was 22 mm using a circular endostapler with 25-mm circumference. The muscularis layer including muscularis mucosae was preserved in all specimens, but the submucosa was present only in half of the mucosectomies. However, the resection did not involve the muscularis propria. Interestingly, 6 weeks after intervention stricture formation was observed in all animals undergoing EMR but in none after SAM, despite the significantly larger resection area in the SAM group. Two out of six animals in the EMR were sacrificed prematurely due to symptomatic stenosis. At necropsy the lumen at the level of resection was narrowed in EMR but not in SAM (7.45 mm vs. 16.8 mm, P < 0.001). The ratio of the esophageal width at the level of resection to the width proximal to the resection zone was 0.71 for EMR and 0.98 for SAM (P < 0.001). In EMR, in three out of six pigs damage and collagen deposits were found in the tunica muscularis. In contrast, with SAM mucosal healing without stenosis or fibrosis was demonstrated. Frantzides et al. reported treatment of human HGD with laparoscopic mucosal resection by scissors via an anterior gastrotomy in combination with Nissen fundoplication.26–28 A resection extending 5 cm from the Z-line was described as feasible. However, access by transgastric endoscopy and the use of a circumferential endostapler for mucosectomy in SAM, as proposed here, is novel. In the technique described by Frantzides et al.,26–28 the mucosal wound was left open to heal. Consequently, in 2 of 11 patients stenosis necessitating endoscopic dilatation occurred. In a previous porcine study Farrell reported circular mucosal resection of segments of the distal esophagus up to 5 cm in length in an open surgical technique.22 The defects were then covered and hand sutures used to restore mucosal integrity. As in SAM no or only mild fibrosis and no stenosis were observed. EMR of HGD followed by RFA of the remaining BE is currently considered the first-line treatment.7 Nevertheless, despite EMR and RFA in a cohort of 335 patients from the UK National Halo RFA Registry, 86% of patients were clear of HGD and only 62% of BE at 12 months after a mean of 2.5 RFA procedures. Invasive cancer developed in 3% of patients despite endoscopic treatment.29 The US Multicenter Consortium Recurrence reports complete remission of BE in 56% of cases at 24 months after combined EMR and RFA. The rate of BE recurrence by 2 years after complete eradication was 33%.30 These findings warrant close lifetime follow-up with repeated endoscopy studies in patients treated for HGD with EMR and RFA. In a decision analysis model, the effectiveness of combined EMR-RFA and esophagectomy was compared. EMR-RFA seemed to be equivalent to esophagectomy irrespective of patients’ age.31 Nevertheless, alternative treatment options may be indicated in patients preferring a single, definitive treatment and those who require a surgical antireflux procedure. Moreover, in the subgroup of patients suffering from extensive or even circumferential HGD beyond the limits of combined EMR and RFA, SAM combined with fundoplication may represent a safe alternative to esophagectomy. Currently the extent of resection is limited by the capacity of the circular stapler to contain tissue. The circular staplers we used were designed not for resection but to fashion anastomoses. The relatively short resection may also explain the absence of the submucosal layer in some of the specimens. In the further development of SAM a modified circular stapler must be designed with the capacity to resect longer segments. The specific advantages of SAM versus endoscopic treatment are (i) the circular en bloc mucosectomy, increasing the probability of complete BE eradication; (ii) the capacity for more accurate microscopic evaluation of the lateral and deep resection margins; (iii) a low probability of postintervention stenosis; and (iv) the option for concomitant antireflux surgery, providing not only eradication of BE and HGD but also cure of the underlying GERD. These advantages of SAM compared with endoscopic therapy must be weighed against the increased invasiveness and potential occurrence of serious complications such as intraabdominal infection, wound infection, leak of the gastrostomy closure, and esophageal perforation. CONCLUSIONS This porcine in vivo experiment demonstrated that laparoscopic SAM and fundoplication may be combined in a single session. Although the GEJ was weakened after SAM Nissen fundoplication restored it as an effective reflux barrier in this experiment. Clinical validation requires confirmation of the results in a prospective human trial. Notes The results of this study were presented at the 25th International Congress of the European Association for Endoscopic Surgery, June 14–17, 2017, Frankfurt, Germany. Specific author contributions: D.C.S. and P.C.M. designed the study, performed the experiments, analyzed the data. and drafted the manuscript. A.C.S. performed the experiments and carried out critical revision. G.R.L., A.Z., and B.P.M. designed the study and carried out critical revision. All authors gave their final approval. Funding: The German Research Foundation (DFG) funded the study (STE 2590/1-1). Impedance monitoring instruments were loaned free of charge from Standard Instruments GmbH, Werftstrasse 12, 76,189 Karlsruhe, Germany. Conflicts of interest: The authors declare that they have no conflict of interest. ACKNOWLEDGMENTS D.C.S. is supported by the Swiss National Science Foundation (Grant P300PB-161,099/1) and the Margarete and Walter Lichtenstein Foundation, Basel, Switzerland (DMS2321). REFERENCES 1. Lagergren J , Bergstrom R , Lindgren A et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma . N Engl J Med 1999 ; 340 : 825 – 31 . Google Scholar CrossRef Search ADS PubMed 2. Ireland C J , Fielder A L , Thompson S K et al. Development of a risk prediction model for Barrett's esophagus in an Australian population . 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Gastroenterology 2013 ; 145 : 79 – 86.e1 . Google Scholar CrossRef Search ADS PubMed 31. Hu Y , Puri V , Shami V M et al. Comparative effectiveness of esophagectomy versus endoscopic treatment for esophageal high-grade dysplasia . Ann Surg 2016 ; 263 : 719 – 26 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Diseases of the EsophagusOxford University Press

Published: May 21, 2018

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