Peroral Endoscopic Myotomy for the Treatment of Achalasia: A Clinical Comparative Study of Endoscopic Full-Thickness and Circular Muscle Myotomy

Peroral Endoscopic Myotomy for the Treatment of Achalasia: A Clinical Comparative Study of Endoscopic Full-Thickness and Circular Muscle Myotomy

Peroral Endoscopic Myotomy for the Treatment of Achalasia: A Clinical Comparative Study of Endoscopic Full-Thickness and Circular Muscle Myotomy Quan-...

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Peroral Endoscopic Myotomy for the Treatment of Achalasia: A Clinical Comparative Study of Endoscopic Full-Thickness and Circular Muscle Myotomy Quan-Lin Li, MD, Wei-Feng Chen, MD, Ping-Hong Zhou, MD, PhD, Li-Qing Yao, MD, Mei-Dong Xu, MD, PhD, Jian-Wei Hu, MD, Ming-Yan Cai, MD, Yi-Qun Zhang, MD, PhD, Wen-Zheng Qin, MD, Zhong Ren, MD, PhD A circular muscle myotomy preserving the longitudinal outer esophageal muscular layer is often recommended during peroral endoscopic myotomy (POEM) for achalasia. However, because the longitudinal muscle fibers of the esophagus are extremely thin and fragile, and completeness of myotomy is the basis for the excellent results of conventional surgical myotomy, this modification needs to be further debated. Here, we retrospectively analyzed our prospectively maintained POEM database to compare the outcomes of endoscopic full-thickness and circular muscle myotomy. STUDY DESIGN: According to the myotomy depth, 103 patients with full-thickness myotomy were assigned to group A, while 131 patients with circular muscle myotomy were assigned to group B. Symptom relief, procedure-related parameters and adverse events, manometry outcomes, and reflux complications were compared between groups. RESULTS: The mean operation times were significantly shorter in group A compared with group B (p ¼ 0.02). There was no increase in any procedure-related adverse event after full-thickness myotomy (all p < 0.05). During follow-up, treatment success (Eckardt score  3) persisted for 96.0% (95 of 99) of patients in group A and for 95.0% (115 of 121) of patients in group B (p ¼ 0.75). There were no statistically significant differences in pre- and post-treatment D-value of symptom scores and lower esophageal sphincter pressures between groups (both p > 0.05). The overall clinical reflux complication rates were also similar (21.2% vs 16.5%, p ¼ 0.38). CONCLUSIONS: Short-term symptom relief and manometry outcomes of each method were comparable. Fullthickness myotomy significantly reduced the procedure time but did not increase the procedure-related adverse events or clinical reflux complications. (J Am Coll Surg 2013;217: 442e451.  2013 by the American College of Surgeons) BACKGROUND:

Achalasia is a primary esophageal motor disorder characterized by the absence of peristalsis and a defective relaxation of the lower esophageal sphincter (LES), resulting in impaired bolus transport and stasis of food in the

esophagus.1 Diagnosis and surgical treatment of achalasia have been established, even if still debated, for a long time. The extent of open or laparoscopic Heller myotomy was defined on the basis of clinical and manometric

CME questions for this article available at http://jacscme.facs.org

Presented at Digestive Disease Week 2013, Orlando, FL, May 2013. Received February 6, 2013; Revised April 1, 2013; Accepted April 23, 2013. From the Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China. Correspondence address: Ping-Hong Zhou, MD, PhD, Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, 180 FengLin Rd, Shanghai 200032, P R China. email: [email protected]

Disclosure Information: Authors have nothing to disclose. Timothy J Eberlein, Editor-in-Chief, has nothing to disclose. Financial support: This study was supported by the grants from the Medical Leading Project of Shanghai Municipal Science and Technology Committee (10411969600), and the Major Project of Shanghai Municipal Science and Technology Committee (10411955900, 11411950502 and 11DZ2280400). Drs Quan-Lin Li and Wei-Feng Chen contributed equally to this work.

ª 2013 by the American College of Surgeons Published by Elsevier Inc.

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ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.04.033

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Abbreviations and Acronyms

EGD EGJ GER HRM LES POEM PPI

¼ ¼ ¼ ¼ ¼ ¼ ¼

esophagogastroduodenoscopy esophagogastric junction gastroesophageal reflux high-resolution manometry lower esophageal sphincter peroral endoscopic myotomy proton pump inhibitor

results.2 The standard surgical procedure involves complete division of both the longitudinal and circular muscles of the esophagus from the distal esophagus onto the proximal stomach while preserving the mucosa. Despite improvement in perioperative outcomes after laparoscopic myotomy, it is still an invasive procedure, causes significant pain and discomfort, and is relatively expensive. Peroral endoscopic myotomy (POEM) has recently been described as a scarless and less invasive surgical myotomy option for treatment of achalasia.3-8 Initial published experience in humans is more than encouraging despite a relatively short follow-up. A circular muscle myotomy preserving the longitudinal outer esophageal muscular layer is often recommended during POEM, which is different from the usual full-thickness myotomy performed surgically. Although selective circular muscle myotomy is designed in order to avoid entering the pleural space and decrease morbidity, it is often hard to achieve because the longitudinal muscle fibers of the esophagus are extremely thin, which frequently leads to an unintentional splitting of the muscle fibers during POEM. Either minor electrocautery damage, mechanical trauma from maneuvering the endoscope in the tunnel, or air insufflation alone can result in spreading of the longitudinal muscle fibers and adventitia and transmural openings into the mediastinum.8 In fact, a clear separation of circular (to be completely dissected) and longitudinal (to be left) muscular layers cannot be found any more at the esophagogastric junction (EGJ) and stomach. Moreover, although dissection of the circular muscle fibers alone led to a significant reduction of LES pressure as demonstrated by postoperative manometry in some studies,3,9 in the experience of others, completeness of myotomy is a prerequisite for sufficient and long-term reduction of LES pressure and is the basis for the excellent result of conventional surgical myotomy.8,10 Given the fact that an incomplete myotomy with possible fibrotic healing may be considered a major reason for postoperative recurrence,11,12 a full-thickness myotomy may reduce the incidence of fusion by further spreading of the cut muscular wall and theoretically inducing long-term

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symptom remission. For these considerations, POEM with a full-thickness myotomy has been performed in about half of the achalasia patients in our center. In this study, we retrospectively analyzed our prospectively maintained POEM database to compare the outcomes of endoscopic full-thickness and circular muscle myotomy, hypothesizing that full-thickness myotomy would be superior to circular muscle myotomy alone.

METHODS Study design This retrospective analysis was approved by the local research ethics committee. The analysis included consecutive patients who had primary achalasia and were treated with POEM successfully by a single operator (PH Zhou) at the authors’ institution between August 2010 and March 2012. Patients were eligible for enrollment in the study if they had an Eckardt symptom score 4. The diagnosis of achalasia was made on the basis of the absence of peristalsis and on impaired relaxation of the LES on established methods; barium swallow and esophagogastroduodenoscopy (EGD) were performed in all enrolled patients before POEM, and high resolution manometry (HRM) was performed in 127 of 234 of them. Exclusion criteria were severe cardiopulmonary disease or other serious disease leading to unacceptable surgical risk, pseudoachalasia, megaesophagus (diameter > 7 cm), and hiatal hernia (>2 cm). All included patients provided written informed consent to undergo POEM after detailed spoken and written explanations concerning the POEM procedure and other possible treatment options. Procedural details were recorded prospectively in a database. After thoroughly investigating the database and their medical records, patients were grouped in 2 sets according to myotomy depth: Group A underwent endoscopic full-thickness myotomy, including the internal circular and longitudinal muscular layer; group B underwent endoscopic circular muscle myotomy alone, involving only the internal circular muscular layer. Patients who had only limited damage of the longitudinal muscle fibers were also assigned to group B. In this study, an inadvertent full-thickness myotomy was performed in 37 of 154 enrolled patients before October 2011; an intentional full-thickness myotomy was performed in 66 of 80 enrolled patients subsequently after considering the hypothesis that full-thickness myotomy would be superior for the excellent result. Outcomes measurements The main outcomes measures that were compared between the 2 groups were:

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1. Therapeutic success at the follow-up assessment, defined as a reduction in the Eckardt score to 3;8 2. Procedure-related parameters such as procedure time, hospital stay, and myotomy length; 3. Procedure-related adverse events such as mucosal injury/perforation, subcutaneous emphysema, pneumothorax, pneumoperitoneum, pneumonia, focal atelectasis, pleural effusion, fever (temperature  38 C), severe postoperative pain (narcotic treatment such as fortanodyn and sauteralgyl), submucosal infection, delayed bleeding, etc. Pneumomediastinum occurred in nearly all patients with full-thickness myotomy, so it wasn’t considered a complication in this study; 4. Lower esophageal sphincter pressure on manometry pre- and post POEM; and 5. Clinical reflux complications at the follow-up assessment, defined as reflux symptoms or esophagitis on EGD. High resolution manometry Baseline and postmyotomy LES pressures were recorded using an HRM system (Sierra Scientific Instruments Inc), as previously described.13 Briefly, the HRM assembly was placed transnasally and the manometric catheter positioned to record from the hypopharynx to the stomach with approximately 5 intragastric sensors. Studies were performed with the patients in a supine position after at least a 6-hour fast. The manometric protocol included a 5-minute period to assess basal EGJ pressure; 10 water swallows of 5 mL; and 1 water swallow each of 1 mL (dry), 10 mL, and 20 mL. All manometric analysis was done using Mano-View software applied to the data tracings viewed in the color pressure topography mode and referenced to intragastric pressure. Peroral endoscopic myotomy procedures Peroral endoscopic myotomy was attempted with a singlechannel gastroscope (GIF-H260, Olympus Medical Systems Co) and a hybrid knife (ERBE, Erbe Elektromedizin GmbH), triangle-tip knife (KD-640L; Olympus), or a hook knife (KD-620LR, Olympus). A transparent cap (D-201-11802, Olympus) was attached to the tip of the gastroscope. Other equipment included injection needle (NM-4L-1, Olympus), hot biopsy forceps (FD-410LR, Olympus), clips (HX-610-90, HX-600-135, Olympus; Resolution), a high-frequency generator (VIO 200D, ERBE), and an argon plasma coagulation unit (APC300, ERBE). Room air was used for insufflations during the procedure before December 2011 and carbon dioxide gas was used for insufflations with a CO2 insufflator (UCR; Olympus) subsequently.

J Am Coll Surg

Patients were admitted 1 day before the POEM procedure to undergo EGD, cleaning out food remnants from the esophagus. Prophylactic intravenous antibiotics and proton pump inhibitors (PPI) were introduced 30 minutes before the procedure. The POEM procedure was performed under general anesthesia, as described previously.3 In brief, submucosal injection and an initial mucosal incision were first done in the 5 to 6 o’clock position on the posterior esophagus approximately 10 cm proximal to the EGJ. Then, a submucosal tunnel was created, passing over the EGJ, and about 3 cm into the proximal stomach. The myotomy was begun at 2 cm distal to the mucosal entry point, approximately 6 to 8 cm above the EGJ, and was extended for a distance of 2 to 3 cm to the stomach in all patients. Selective dissection of the circular muscle bundles was attempted in group B and the longitudinal muscle bundles were carefully protected and left intact at the limit of the dissected area. In group A, a full-thickness myotomy, including the internal circular and longitudinal muscular layer, was done. Substantial reduction of LES tonus was confirmed by opening the EGJ with gentle insufflation through the endoscope and easily passing an endoscope through the lumen of the esophagus. After careful hemostasis, the mucosal incision site was closed with 4 to 6 hemostatic clips. A mucosal injury or perforation, which was suspected on endoscopic control, was also clipped and a nasogastric tube was placed when necessary. An example of the endoscopic full-thickness myotomy procedure is shown in Fig. 1 and Video 1. Postprocedure management To evaluate procedure-related adverse events after POEM, such as subcutaneous emphysema, pneumothorax, and pleural effusion, a chest CT scan was carried out on the first day after operation in most patients. If patients developed a pneumothorax after the procedure, instead of inserting chest tube drainage, we inserted a central venous catheter at the third or fourth intercostal space. A 20-gauge needle was used to relieve the severe pneumoperitoneum during and after the procedure. Postoperative observations included analysis of chest pain, dyspnea, abdominal pain or distention, and cyanosis or signs of peritonitis. Postoperative medications included a double-dose PPI, antibiotics, and hemocoagulase injection. Patients were kept npo for 24 hours after POEM, and on a liquid diet for an additional 24 hours. Patients were discharged with double-dose PPI and a soft diet for 2 weeks. Patients were asked to discontinue PPI medication and start a regular diet 4 to 8 weeks after POEM.

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Figure 1. Peroral endoscopic myotomy (POEM) with a full-thickness myotomy. (A, B, C, D) Sequence of a full-thickness myotomy being performed at the right lateroposterior wall. Note after clinging to the longitudinal muscle fibers and lifting them up toward the esophageal lumen, the full-thickness muscle bundles being sectioned. (D) The arrow indicates the external coat of the distal esophagus.

Follow-up Patients were scheduled for a follow-up visit at 1 month after POEM for HRM. They also underwent follow-up EGD at 1, 3, 6, and 12 months after POEM and annually thereafter to view the healing of the wound and to check any objective sign of reflux esophagitis. Patients were contacted via telephone every 3 months postoperatively to assess for complications and to obtain a current Eckardt score. Symptomatic gastroesophageal reflux (GER) was assessed every 3 months postoperatively using the GerdQ questionnaire.14 A score 7 (scale 0 to 18) was considered positive for GER, in line with established usage of the questionnaire. A final checkup was performed in May 2012. Statistical analysis Statistical analysis was performed with SPSS 16.0 software. Measurement values were expressed as means and standard deviation. Statistical significance was evaluated using Student’s t-test for independent or paired samples, chi-square test, or Fisher’s exact test as appropriate. All reported p values were 2-tailed, and p values <0.05 were considered to indicate statistical significance.

RESULTS During the study period, POEM was attempted in a total of 238 consecutive patients with achalasia. In 4 patients (1.7%), submucosal tunneling failed for the following reasons: serious inflammation and adhesion (n ¼ 2); suspected cardia cancer (n ¼ 1); and absence of the submucosal layer (n ¼ 1). So, 234 patients of those underwent POEM successfully and were finally included in this analysis. According to myotomy depth, 103 patients with full-thickness myotomy were included in group A, and 131 patients with circular muscle myotomy were included in group B. Patient characteristics Table 1 summarizes the clinical characteristics of those patients. Patients in group A were younger than those in group B (37.6  13.2 vs 41.5  16.3 years, respectively, p ¼ 0.04). The mean duration of symptoms before undergoing POEM was similar between groups (7.2  7.7 vs 7.9  9.4 years, respectively, p ¼ 0.53). Before POEM, 39 patients in group A and 45 patients in group B had received other endoscopic therapy (dilation only,

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Table 1.

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Preoperative Patient Characteristics

Characteristic

n Sex, M/F, n Age, mean  SD, y Duration of symptoms, mean  SD, y Previous treatment, n (%) Other endoscopic therapy Heller myotomy POEM Sigmoid type 1 esophagus, n (%)

Group A (full-thickness myotomy)

Group B (circular muscle myotomy)

p Value

103 45/58 37.6  13.2 7.2  7.7

131 67/64 41.5  16.3 7.9  9.4

0.26 0.04 0.53

39 (37.9) 6 (5.8) 0 11 (10.7)

45 8 1 7

(34.4) (6.1) (0.8) (5.3)

0.58 0.93 1.00 0.13

POEM, peroral endoscopic myotomy.

30 vs 23; Botox only, 3 vs 2; temporary stenting, 3 vs 9; 2 or more methods, 3 vs 11, respectively; p ¼ 0.58). Fourteen patients after failed Heller myotomy (6 in group A vs 8 in group B, p ¼ 0.93), 18 patients with sigmoid type 1 esophagus (11 in group A vs 7 in group B, p ¼ 0.13), and 1 patient after failed initial POEM (in group B) were also included in the study. No patient was with sigmoid type 2 esophagus in the study. Procedure-related parameters As indicated in Table 2, mean operation times were significantly shorter in group A compared with group B (41.7  18.9 vs 48.9  28.6 minutes, p ¼ 0.02). The total lengths of the endoscopic myotomy were similar between groups (8.1  1.3 vs 7.9  1.3 cm in the esophagus and 2.2  0.6 vs 2.3  0.5 cm in the stomach; p ¼ 0.41 and p ¼ 0.07, respectively). Twenty-seven patients in group A (26.2%) and 23 patients in group B (17.6%) underwent POEM with the use of the hybrid knife (p ¼ 0.11). Procedure-related adverse events As shown in Table 2, during the operation, 13 patients in group A (12.6%) and 27 patients in group B (20.6%) had mucosal injury or small mucosal perforations (p ¼ 0.11). All perforations were clipped after myotomy and nasogastric tubes were placed in 10 patients. The submucosal penetration did not induce any clinical complications. Intraoperative subcutaneous emphysema was less in group A compared with group B (7.8% [8 of 103] vs 22.1% [29 of 131]; p ¼ 0.00). (Note that the study authors rounded down p values of < 0.005 to 0.00 in order to keep the same number of decimal places for all p values.) Of those, 1 patient in group A and 1 patient in group B suffered from pneumoperitoneum simultaneously, and Veress needle decompression of the pneumoperitoneum was required intraoperatively; 1 patient in group B developed both severe subcutaneous

emphysema and bilateral pneumothorax, which were treated with subcutaneous puncture and closed thoracic drainage intraoperatively. After these treatments, operations were continued and successfully completed. No patient had massive hemorrhage during the operation. A total of 84 patients in group A (81.6%) and 112 patients in group B (85.5%) underwent CT scans after the procedure. As judged on CT scan, there were no significant differences between groups A and B in postoperative pneumothorax (20.2% [17 of 84] vs 24.1% [27 of 112]; p ¼ 0.52), pneumoperitoneum (42.9% [36 of 84] vs 47.3% [53 of 112]; p ¼ 0.53), pleural effusion (66.7% [56 of 84] vs 59.8% [67 of 112]; p ¼ 0.33), pneumonia (48.8% [41 of 84] vs 54.5% [61 of 112]; p ¼ 0.43), and focal atelectasis (14.3% [12 of 84] vs 17.9% [20 of 112]; p ¼ 0.50), respectively. However, similar to intraoperative subcutaneous emphysema, the incidence of postoperative subcutaneous emphysema on CT scan was also less in group A (26.2% [22 of 84] vs 44.6% [50 of 112]; p ¼ 0.01). Among those who had pneumothorax, 7 patients in group A and 7 patients in group B needed closed thoracic drainage. Only 1% of patients (2 of 196) with pleural effusion needed intervention, and spontaneous absorption of the effusion was observed in other patients. Other findings on CT scans were minor problems without apparent clinical effect and did not need further intervention. In our study, room air was used for insufflation in fewer patients in group A (63 of 103 [61.2%] vs 124 of 131 [94.7%]; p ¼ 0.00), which seemed to be responsible for less intraoperative and postoperative subcutaneous emphysema. When we subdivided the patients via the insufflated gas during the procedure (room air vs CO2), we found that all intraoperative subcutaneous emphysema occurred in patients with room air insufflation. In patients with room air insufflation, there were no significant differences between groups A and B in postoperative subcutaneous emphysema (41.3%

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Table 2.

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Comparison of Procedure-Related Parameters and Adverse Events Between Group A and Group B

Variable

Group A (full-thickness myotomy) Group B (circular muscle myotomy) p Value

Mean operation time, mean  SD, min Myotomy length, mean  SD, cm Esophagus Stomach Use of hybrid knife, n (%) Room air insufflations, n (%) Intraoperative complications, n (%) Mucosal injury Subcutaneous emphysema Room air insufflation CO2 insufflation Pneumothorax Pneumoperitoneum Postoperative complications, n (%) Judged on CT scan (air vs CO2 insufflation), n Subcutaneous emphysema Room air insufflation CO2 insufflation Pneumothorax Room air insufflation CO2 insufflation Pneumoperitoneum Room air insufflation CO2 insufflation Pleural effusion Pneumonia Focal atelectasis Other Fever Severe postoperative pain Submucosal infection Delayed bleeding Length of antibiotics treatment, mean  SD, d Length of postoperative hospital stay, mean  SD, d

[19 of 46] vs 46.7% [50 of 107]; p ¼ 0.54), pneumothorax (34.8% [16 of 46] vs 25.2% [27 of 107]; p ¼ 0.23), and pneumoperitoneum (63.0% [29 of 46] vs 48.6% [52 of 107]; p ¼ 0.10). These results indicated that full-thickness myotomy did not increase the risk of any of these events and CO2 insufflation was vitally important to reduce gas-related compilations. Two patients in group A (1.9%) and 4 patients in group B (3.1%) developed signs of fever and temperature 38 C (p ¼ 0.59). A total of 92 patients had paired blood test pre- and post-treatment (34 in group A vs 58 in group B, p ¼ 0.08). There were significant increases in leukocyte count after POEM in both groups. Mean leukocyte count was 6.0  2.8  109/L pretreatment

41.7  18.9

48.9  28.6

0.02

8.1  1.3 2.2  0.6 27 (26.2) 63 (61.2)

7.9  1.3 2.3  0.5 23 (17.6) 124 (94.7)

0.41 0.07 0.11 0.00

13 (12.6) 8 (7.8) 8 0 0 1 (1.0)

27 (20.6) 29 (21.1) 29 0 1 (0.8) 1 (0.8)

0.11 0.00 0.08 1.00 1.00 1.00

46/38 22 (26.2) 19 3 17 (20.2) 16 1 36 (42.9) 29 7 56 (66.7) 41 (48.8) 12 (14.3)

107/5 50 (44.6) 50 0 27 (24.1) 27 0 53 (47.3) 52 1 67 (59.8) 61 (54.5) 20 (17.9)

0.01 0.54 1.00 0.52 0.23 1.00 0.53 0.10 1.00 0.33 0.43 0.50

2 (1.9) 13 (12.6) 1 (1.0) 0 2.4  1.0 2.7  1.1

4 (3.1) 11 (8.4) 0 1 (0.8) 3.2  2.0 3.6  2.7

0.59 0.29 0.44 1.00 0.00 0.00

and 10.1  3.6  109/L post-treatment in group A (p ¼ 0.00), and was 6.0  2.2  109/L and 10.8  3.5  109/L, respectively, in group B (p ¼ 0.00). A significant decrease in hemoglobin level also occurred after POEM. Mean hemoglobin level decreased from 13.7  1.4 g/dL to 12.4  1.4 g/dL in group A (p ¼ 0.00) and from 13.0  2.0 g/dL to 12.2  1.7 g/dL in group B (p ¼ 0.00). Thirteen patients in group A (12.6%) and 11 patients in group B (8.4%) had severe postoperative pain on the day of operation and received narcotic treatment (p ¼ 0.29). There were no differences in other complications between groups. One patient in group A had submucosal tunnel infection because of an opening at the submucosal

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entry and accumulation of a large amount of food; 1 delayed bleeding in the submucosal tunnel and 1 epileptic seizure occurred in group B. Both the average lengths of antibiotics treatment and postoperative hospital stay were significantly shorter for group A compared with group B (antibiotics treatment, 2.4  1.0 days vs 3.2  2.0 days, p ¼ 0.00; hospital stay, 2.7  1.1 days vs 3.6  2.7 days, p ¼ 0.00; respectively).

Eckardt scores from 8.0  2.0 (range 5 to 11) pretreatment to 5.5  2.0 (range 4 to 10) post-treatment (p ¼ 0.00). Of them, 5 underwent additional therapies with endoscopic balloon dilation, and the other patients didn’t request any further treatments until the final checkup. One patient with a treatment failure (with the same Eckardt score of 10, before and after POEM) died from cachexia in group A, while 1 patient with a treatment success died from lymphoma in group B.

Symptom relief The symptom score follow-up rate was extremely high, 96.1% (99 of 103) for group A and 92.4% (121 of 131) for group B (p ¼ 0.23). As shown in Table 3, the average observation period was significantly shorter for group A (6.1  4.3 months vs 10.5  3.8 months, p ¼ 0.00). Treatment success (Eckardt score  3) persisted for 96.0% (95 of 99) of patients in group A and for 95.0% (115 of 121) of patients in group B (p ¼ 0.75). Mean symptom score decreased from 7.6  2.0 to 1.2  1.5 in group A (p ¼ 0.00), and from 8.0  1.9 to 1.1  1.3 in group B (p ¼ 0.00). There was no statistical significant difference in pre/post-treatment D-value of symptom scores between the 2 groups (6.5  2.3 vs 7.0  2.2, p ¼ 0.11). The average gain in weight post-treatment was also similar between groups (5.7  5.0 kg vs 6.7  5.2 kg, p ¼ 0.18). During follow-up, 4 patients in group A and 6 patients in group B had treatment failure. These patients had

Manometry outcomes As shown in Table 3, more patients in group A had perprotocol HRM at 1 month postoperatively compared with group B (68 of 103 [66.0%] vs 51 of 131 [38.9%]; p ¼ 0.00). Other patients didn’t undergo follow-up manometry, due to the actual condition of our hospital (too many patients, shortage of equipment and professionals), loss to follow-up, discomfort related to the manometry procedure, and other personal reasons. Mean LES pressure decreased from a mean of 30.5  14.5 mmHg to 12.4  3.6 mmHg after POEM in group A (p ¼ 0.00); in group B, it decreased from 29.6  11.5 mmHg to 12.2  4.3 mmHg (p ¼ 0.00). There was no statistical significant difference of pre- or post-treatment D-values of LES pressure between the 2 groups (18.1  13.9 mmHg vs 17.4  10.2 mmHg, p ¼ 0.75). In 6 patients with treatment failure and per-protocol HRM mentioned earlier, LES pressures were 25.0  8.9

Table 3. Comparison of Symptom Relief, Manometry Outcomes, and Reflux Complications Between Group A and Group B Variable

Mean follow-up period, mean  SD, mo Symptom score follow-up rate, n (%) Eckardt score, mean  SD Pretreatment Post-treatment Pre/post-treatment D-value Treatment success (Eckardt score  3), n (%) Average gain in weight post-treatment, mean  SD, kg Manometry follow-up rate, n (%) Lower esophageal sphincter pressure, mean  SD, mmHg Pretreatment Post-treatment Pre/post-treatment D-value Clinical reflux complications, n (%) Symptomatic reflux only (GerdQ score  7) Esophagitis on EGD only Both Overall EGD, esophagogastroduodenoscopy.

Group A (full-thickness myotomy)

Group B (circular muscle myotomy)

p Value

6.1  4.3 99 (96.1)

10.5  3.8 121 (92.4)

0.00 0.23

7.6  2.0 1.2  1.5 6.5  2.3 95 (96.0) 5.7  5.0 68 (66.0)

8.0  1.9 1.1  1.3 7.0  2.2 115 (95.0) 6.7  5.2 51 (38.9)

0.11 0.75 0.18 0.00

30.5  14.5 12.4  3.6 18.1  13.9

29.6  11.5 12.2  4.3 17.4  10.2

0.75

8 2 11 21 (21.2%)

13 0 7 20 (16.5%)

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mmHg pretreatment and 12.0  4.9 mmHg posttreatment (p ¼ 0.06). Reflux complications At the same follow-up interval, 19 patients in group A and 20 patients in group B had a GerdQ score 7, indicating symptomatic GER. Thirteen patients in group A and 7 patients in group B were found to have mild or moderate esophagitis (Los Angeles classification B or C) on follow-up EGD. Among them, 11 patients in group A and 7 patients in group B had both esophagitis on EGD and a GerdQ 7. So the overall clinical reflux complication rates were similar between groups (21.2% [21 of 99] vs 16.5% [20 of 121]; p ¼ 0.38; Table 3).

DISCUSSION Peroral endoscopic myotomy incorporates concepts of natural orifice transluminal endoscopic surgery and expands on techniques used in endoscopic submucosal dissection in order to achieve a division of the esophageal circular muscle fibers across the EGJ and onto the stomach. The technical modification proposed by this previously published endoscopic method consists of partial-thickness myotomy involving the internal circular muscular fibers to decrease morbidity, which is different from the usual full-thickness myotomy performed surgically. However, because completeness of myotomy is the basis for the excellent result of conventional surgical myotomy, this modification needs to be further debated. Two recent studies reported that endoscopic fullthickness myotomy did not seem to be superior to partial-thickness myotomy, as demonstrated by postoperative manometry in pigs,9,15 and because this was a physiologic, nonachalasic animal model, comparisons to the clinical setting may not be valid. In achalasia patients, von Renteln D and colleagues8 demonstrated that a complete myotomy (full-thickness myotomy) at the cardia may be superior in providing rapid esophagogastric emptying, as demonstrated by postoperative barium swallow, despite the fact that there were no significant differences in the symptom score and a reduction in LES pressures between groups; however, their study population was not large enough (only 16 patients). In this study we compared the outcomes of endoscopic fullthickness and circular muscle myotomy in a total of 234 patients, which represented the largest POEM series to date. Our results demonstrated that short-term symptom relief and manometry outcomes of each method were comparable, which mirrored the finding of previous series.8,9,15

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Because recurrent dysphagia, which is most commonly caused by late scarring or fibrosis at the site of the myotomy, typically occurs more than 6 months after the initial procedure,12 the relatively short follow-up period (6.1  4.3 months in the full-thickness myotomy group and 10.5  3.8 months in the circular muscle myotomy group), to some extent, seems to be responsible for these short-term results. Further observations and follow-up to evaluate long-term outcomes have been initiated. In addition, other objective evaluations such as timed barium swallow8,16 and endoscopic functional luminal imaging probe,9,17 should be used to determine esophageal emptying and EGJ distensibility for predicting clinical success. Generations of surgeons were taught to stay away from the esophagus due to its “unforgiving” nature and the fact that this organ has no serosal lining. So, selective circular muscle myotomy is designed to avoid entering the pleural space and decrease morbidity during POEM. However, in this study, we found similar intra- and perioperative complication rates between the 2 procedures, providing initial evidence that full-thickness myotomy has a safety profile comparable to that of circular muscle myotomy alone. During circular muscle myotomy, a slight push of the tip of the endoscope could result in splitting the outer longitudinal muscle because of its thin and fragile nature. This might explain the occurrence of pneumomediastinum pneumothorax, pneumoperitoneum, and/or subcutaneous emphysema in patients with circular muscle myotomy alone. So, although the aim is to leave the layer of longitudinal muscle fibers intact, some degree of pneumomediastinum, and potentially, pneumoperitoneum, pneumothorax, and/or subcutaneous emphysema, will likely result regardless of technique. During full-thickness myotomy, visible complete transmural openings into the mediastinum and into the peritoneal cavity did occur and active gas insufflation during endoscopy was therefore expected to leak into the mediastinum and peritoneal cavity. However, pneumomediastinum, pneumoperitoneum, and/or subcutaneous emphysema alone are often of limited clinical significance. In fact, pneumomediastinum would usually not be considered a complication because during laparoscopic dissection at the hiatus, as it has a reported incidence as high as 85%, but resolves within few days.18 So care must be taken not to injure the underlying pleura and cause pneumothorax. We advocate using CO2 instead of room air for insufflation, reducing air insufflation as much as possible, and clinging to the longitudinal muscle fibers and lifting them up toward the esophageal lumen for dissection during full-thickness myotomy. Postoperative infectious complication is a critical concern for patients undergoing full-thickness myotomy.

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However, full-thickness myotomy was not associated with any infectious complications in our study. Two patients after full-thickness myotomy and 4 patients after circular muscle myotomy developed signs of fever. Only 1 patient after full-thickness myotomy had submucosal tunnel infection, but it was due to an opening at the submucosal entry and accumulation of a large amount of food. This supports the hypothesis that endoscopic 2-level perforation of the gastrointestinal wall using the submucosal technique, even into the mediastinum, is possible as long as the mucosal opening is sufficiently closed and ongoing spillage is avoided.19,20 Once the anatomic location of the mucosal perforation is separated from the muscular perforation, healing of both sites is possible without violating the principles of a full-thickness perforation of the esophagus. In our study, full-thickness myotomy created myotomies of similar length with significantly shorter operative times when compared with circular muscle myotomy. However, the advantage of full-thickness myotomy in terms of operative time may be not great enough and it is unknown whether these differences will translate into any concrete clinical benefits for patients. Although most circular muscular myotomies occurred early in the series, a learning curve effect may not be considered an important factor for the shorter procedure duration of full-thickness myotomy because all POEM procedures were performed by a single senior surgeon (PH Zhou) in this study, and the learning curve may plateau at about 20 cases for experienced endoscopists.21 In addition, we have demonstrated, in a prospective randomized trial (data not shown, discussed in another upcoming paper), that compared with the conventional electric knife, the use of the hybrid knife can lead to a significant decrease in POEM procedure time due to less replacement of accessories. However, the use of the hybrid knife was comparable between groups in this study and therefore did not contribute to the significantly shorter duration for the full-thickness myotomy group. In our experience, full-thickness myotomy can reduce operative times significantly because much time can elapse when we carefully protect the fragile longitudinal muscles. One refinement of POEM is the application of the endoscopic submucosal dissection technique to create the submucosal tunnel. This precaution is vital to avoid injuring the overlying mucosa while tunneling because mucosal injury may put the patient at the risk for a potential fistula with mediastinal sepsis, especially in patients who have a full-thickness myotomy. It is important to create the tunnel as close as possible to the muscular layers not only to avoid injury to the mucosal flap but also due to the lower vascularity adjacent to the muscle.

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However, as a consequence of tissue adhesions and limited space, mucosal injury or even perforation sometimes occurs, especially at the cardia. This area can be clipped with metallic clips after myotomy. When necessary, endoscope-assisted nasogastric tube placement can also be used for decompression. After mucosal integrity is repaired, the mucosal injury often does not induce any clinical complications, even in patients who have a full-thickness myotomy. The use of blunt dissection for submucosal tunneling, either balloon22 or other methods, may be considered an alternative to decrease the risk of incidental mucosal injury, especially for operators without sufficient endoscopic submucosal dissection experience. However, the disadvantage of balloon dilation is the inability to position the balloon accurately within the wall layers which, without visual control, may lead to unforeseen damage to esophageal structures. Recently, Khashab and associates23 described their initial experience with the use of a novel gel to facilitate esophageal submucosal tunneling during POEM. However, “auto-tunneling” by the dissecting gel stopped at the level of the LES, and further tunneling into the gastric cardia using the endoscopic submucosal dissection technique was needed. Moreover, because most mucosal injury occurs in difficult patients with significant submucosal adhesions, sigmoid type esophagus, or other previous treatments, the use of blunt dissection for submucosal tunneling is often difficult to achieve. Gastroesophageal reflux is the other critical concern for patients undergoing full-thickness myotomy. As opposed to Heller myotomy, POEM does not include an antireflux procedure, which could potentially result in increased rates of GER postoperatively. Then, preservation of the longitudinal muscle fibers is considered as an option to help prevent GER after POEM. However, because the integrity of natural antireflux mechanisms around the EGJ is important to prevent reflux,24 POEM with a full-thickness myotomy also achieves myotomy from the luminal side with minimal disturbance of these mechanisms. Similar to circular muscle myotomy alone, elimination of dissection at the level of the diaphragmatic hiatus thereby preserves the phrenoesophageal ligaments, which may be beneficial to avoid postmyotomy reflux in patients undergoing full-thickness myotomy. In this study, the overall clinical reflux complication rates were similar between groups (21.2% vs 16.5%; p ¼ 0.38). However, a study limitation is that no postoperative 24-hour pH studies were performed. Although the POEM procedure potentially indicated a lower reflux incidence, because more than 50% of laparoscopic Heller myotomy patients without a fundoplication will have

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pathologic reflux, and as many as 10% of patients with a Heller and partial fundoplication will have problems,25 continued clinical follow-up is essential to assess the longterm risk of GER after POEM. Weaknesses of our study include its retrospective design and current lack of some objective evaluations and longterm outcomes. Not all patients underwent manometry, timed-barium swallow, and 24-hour pH testing due to the medical condition of our hospital (too many patients, shortage of equipment and professionals), loss to followup, discomfort related to the procedure, and other personal reasons. We will continue to accrue data and are in the process of obtaining comprehensive objective physiology studies, as well as long-term follow-up.

CONCLUSIONS In summary, according to our short-term results of this large study, symptom relief and manometry outcomes were comparable between patients undergoing fullthickness and circular muscle myotomy. Full-thickness myotomy significantly reduced the procedure time but did not increase the procedure-related adverse events or clinical reflux complications. Author Contributions Study conception and design: Li, Zhou Acquisition of data: Li, Chen, Zhou, Yao, Xu, Hu, Cai, Zhang, Qin, Ren Analysis and interpretation of data: Li, Zhou Drafting of manuscript: Li, Chen, Zhou Critical revision: Zhou, Yao REFERENCES 1. Eckardt AJ, Eckardt VF. Treatment and surveillance strategies in achalasia: an update. Nat Rev Gastroenterol Hepatol 2011; 8:311e319. 2. Campos GM, Vittinghoff E, Rabl C, et al. Endoscopic and surgical treatments for achalasia: a systematic review and meta-analysis. Ann Surg 2009;249:45e57. 3. Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy 2010;42:265e271. 4. Swanstrom LL, Kurian A, Dunst CM, et al. Long-term outcomes of an endoscopic myotomy for achalasia: the POEM procedure. Ann Surg 2012;256:659e667. 5. Chiu PW, Wu JC, Teoh AY, et al. Peroral endoscopic myotomy for treatment of achalasia: from bench to bedside (with video). Gastrointest Endosc 2013;77:29e38. 6. Hungness ES, Teitelbaum EN, Santos BF, et al. Comparison of perioperative outcomes between Peroral Esophageal Myotomy (POEM) and laparoscopic Heller myotomy. J Gastrointest Surg 2013;17:228e235. 7. Zhou PH, Li QL, Yao LQ, et al. Peroral endoscopic remyotomy for failed Heller myotomy: a prospective single-center study. Endoscopy 2013;45:161e166.

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