Long-Term Outcome of Gastric Per-Oral Endoscopic 63 6 64 7 Pyloromyotomy in Treatment of Gastroparesis 65 8 66 9 Q9 Mohamed M

Clinical Gastroenterology and Hepatology 2020;-:-–-

1 59 2 60 3 61 4 62 5 Long-Term Outcome of Gastric Per-Oral Endoscopic 63 6 64 7 Pyloromyotomy in Treatment of Gastroparesis 65 8 66 9 Q9 Mohamed M. Abdelfatah, Alan Noll, Neil Kapil, Rushikesh Shah, Lianyong Li, 67 10 Rosemary Nustas, Baiwen Li, Hui Luo, Huimin Chen, Liang Xia, 68 11 Parit Mekaroonkamol, Nikrad Shahnavaz, Steven Keilin, Field Willingham, 69 12 Jennifer Christie, and Qiang Cai 70 13 71 14 72 Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia 15 73 16 74 BACKGROUND & AIMS: Gastric per oral endoscopic pyloromyotomy (GPOEM) is a promising treatment for gastro- 17 paresis. There are few data on the long-term outcomes of this procedure. We investigated long- 75 18 term outcomes of GPOEM treatment of patients with refractory gastroparesis. 76 19 77 20 METHODS: We conducted a retrospective case-series study of all patients who underwent GPOEM for re- 78 21 fractory gastroparesis at a single center (n [ 97), from June 2015 through March 2019; 90 79 22 patients had more than 3 months follow-up data and were included in our final analysis. We 80 23 collected data on gastroparesis cardinal symptom index (GCSI) scores (measurements of 81 24 postprandial fullness or early satiety, nausea and vomiting, and bloating) and SF-36 question- 82 25 naire scores (measures quality of life). The primary outcome was clinical response to GPOEM, 83 26 defined as a decrease of at least 1 point in the average total GCSI score with more than a 25% 84 fi 27 decrease in at least 2 subscales of cardinal symptoms. Recurrence was de ned as a return to 85 28 baseline GCSI or GCSI scores of 3 or more for at least 2 months after an initial complete 86 response. The secondary outcome was the factors that predict GPOEM failure (no response or 29 87 gastroparesis recurrence within 6 months). 30 88 31 89 RESULTS: At initial follow-up (3 to 6 months after GPOEM), 73 patients (81.1%) had a clinical response 32 and significant increases in SF-36 questionnaire scores (indicating increased quality of life) 90 33 whereas 17 patients (18.9%) had no response. Six months after GPOEM, 7.1% had recurrence. 91 34 At 12 months, 8.3% of patients remaining in the study had recurrence. At 24 months, 4.8% of 92 35 patients remaining in the study had a recurrence. At 36 months, 14.3% of patients remaining in 93 36 the study had recurrence. For patients who experienced an initial clinical response, the rate of 94 37 loss of that response per year was 12.9%. In the univariate and multivariate regression anal- 95 38 ysis, a longer duration of gastroparesis reduced the odds of response to GPOEM (odds ratio 96 39 [OR], 0.092; 95% CI, 1.04–1.3; P [ .001). On multivariate logistic regression, patients with high 97 – [ 40 BMIs had increased odds of GPOEM failure (OR, 1.097; 95% CI, 1.022 1.176; P .010) and 98 41 patients receiving psychiatric medications had a higher risk of GPOEM failure (OR, 1.33; 95% CI, 99 0.110–1.008; P [ .052). 42 100 43 101 CONCLUSIONS: In retrospective analysis of 90 patients who underwent GPOEM for refractory gastroparesis, 44 102 81.1% had a clinical response at initial follow-up of their procedure. 1 year after GPOEM, 69.1% 45 of all patients had a clinical response and 85.2% of initial responders maintained a clinical 103 46 response. Patients maintained a clinical response and improved quality of life for as long as 3 104 47 years after the procedure. High BMI and long duration gastroparesis were associated with 105 48 failure of GPOEM. 106 49 107 50 Keywords: Therapy; Diabetes; Gastric Emptying; Psychologic. 108 51 109 52 110 53 111 54 112 55 113 Abbreviations used in this paper: BMI, body mass index; GCSI, Gastro- 56 paresis Cardinal Symptom Index; GE, gastric emptying; GES, gastric 114 57 electrical stimulators; GP, gastroparesis; GPOEM, gastric per-oral endo- © 2020 by the AGA Institute 115 scopic pyloromyotomy; ICC, interstitial cells of Cajal; J-tube, jejunostomy 1542-3565/$36.00 58 tube; SF-36, Short Form-36. https://doi.org/10.1016/j.cgh.2020.05.039 116

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117 Q6 Q5 astroparesis (GP) is a chronic, debilitating motility 175 118 Gdisorder characterized by nausea, vomiting, early What You Need to Know 176 119 satiety, and postprandial fullness.1,2 In 2007, the age- 177 Background 120 adjusted prevalence of GP per 100,000 persons was 178 121 approximately 4-fold higher in women than men: 37.8 Gastric per oral endoscopic pyloromyotomy 179 122 and 9.6, respectively.3 Furthermore, incidence of GP hos- (GPOEM) is a promising treatment for gastroparesis, 180 123 pitalization seems to be rising, reported as high as a yet there are few data on the long-term outcomes of 181 124 300% increase from 1997 to 2013, with an estimated this procedure. 182 4 125 annual health care cost of $568 million. GP can have a Findings 183 126 significant adverse impact on the overall quality of life In retrospective analysis of 90 patients who under- 184 5 127 of the affected patient. No definitive cure for GP went GPOEM for refractory gastroparesis, 80% had 185 128 currently exists with most available treatment options an initial clinical response and more than 90% 186 129 focusing on symptom control with diet modification maintained that response 1 year after the procedure. 187 130 and prokinetic medications. Unfortunately, prokinetic Patients maintained a clinical response and 188 131 medication use is often limited by possible dangerous improved quality of life for as long as 3 years after 189 132 side effects including arrhythmia, tardive dyskinesia, the procedure. 190 133 and tachyphylaxis. 191 134 Gastric electrical stimulators (GES) are an interven- Implications for patient care 192 135 tional therapeutic option, particularly for nausea- GPOEM minimize health care utilization and improve 193 136 predominant GP in patients with diabetes; however, ef- the long term quality of life of patient with refractory 194 137 ficacy of such devices has proven underwhelming.6 It is gastroparesis. High body mass index and long 195 138 estimated that 20% of patients receive no benefit from duration gastroparesis are associated with failure of 196 139 such devices, with open-label studies reporting 1-year GPOEM—these factors should be considered when 197 140 clinical response rates between 45% and 74%.7–13 selecting treatment for patients with gastroparesis. 198 141 Durability of clinical response further limits broad 199 142 adoption of this technology with 1 study reporting only 200 143 25% of patients who found clinical benefit maintaining to evaluate the long-term outcomes of GPOEM in treat- 201 144 response at 3 years and only 26% and 44% of patients ment of patients with refractory GP and identify factors 202 145 reporting reductions in nausea and vomiting, respec- that predict failure of GPOEM. 203 146 tively, at 10 years. In addition to the need for laparo- 204 147 scopic implantation of the device and removal before Materials and Methods 205 148 magnetic resonance imaging, device-related complica- 206 149 tions are reported in 15% of patients. These include 207 After approval by the institutional review board at 150 bowel obstruction, perforation, lead migration, and 208 Emory University, we conducted a retrospective case series 151 wound complications. Complications are associated with 209 – of all patients who underwent GPOEM for refractory GP 152 a removal rate of 6.3%–12.8%.8 10,12,14 210 between June 2015 and March 2019. The procedures were 153 Another therapeutic intervention is pyloric disruptive 211 performed by an endoscopist experienced with the pro- 154 therapy. Laparoscopic pyloromyotomy has been shown 212 cedure and typically assisted by an advanced endoscopy 155 to improve symptom scores by 83%–86% and improves 213 fellow. The Gastroparesis Cardinal Symptom Index (GCSI) 156 or normalizes gastric emptying (GE) in nearly 60%–90% 214 score was calculated by averaging the mean score of 3 157 of GP patients.15 Widespread use of this surgical 215 subscales: (1) postprandial fullness/early satiety, (2) 158 approach is limited by postoperative adverse events 216 nausea/vomiting, and (3) bloating.28 Eight aspects of 159 including leaks, suture line bleeding, and wound in- 217 quality of life, including physical functioning, role limitation 160 fections.15 Alternatively, gastric per-oral endoscopic 218 caused by physical health, bodily pain, general health, vi- 161 myotomy (GPOEM) is an endoscopic pyloric disruptive 219 tality, social functioning, role limitation caused by 162 therapy for GP wherein a submucosal tunnel is created to 220 emotional problems, and mental health were assessed us- 163 approach and then myotomize the pyloric muscle. 221 ing the Short Form-36 (SF-36) questionnaire. The scores 164 GPOEM was debuted in 2013 following the adoption of 222 were calculated using a revised International Resource 165 per-oral endoscopic myotomy for treatment of acha- 223 Center for Health Care Assessment scoring system and 166 lasia.8 Since that time, several studies have reported an 224 reported as a median of each category. An average score of 167 average of 83.9% (62%–90%) short-term (6 months to 1 225 – all 8 domains was used to assess the overall quality of life 168 year) clinical success on GPOEM in GP patients.16 26 226 similar to our previous publication.29,30 169 Benefits of GPOEM over laparoscopic pyloroplasty 227 170 include shorter operative time, less intraprocedural 228 171 blood loss, and a shorter length of stay.27 Definitions 229 172 Despite the initial promising short-term results, proof 230 173 of longer-term outcome is fundamental for wider adop- Refractory gastroparesis. GP with poor response to 231 174 tion of GPOEM for treatment of GP. Thus, our study aims greater than 6 months of dietary modifications and trial 232

233 of maximally tolerated doses of prokinetic medications failure. A P value of less than 0.05 was considered sta- 291 234 after ruling out mechanical obstruction. tistically significant. Data were analyzed using SPSS 292 235 Radiologic criteria. Radiologic criteria for the diag- version 22.0 statistical software (IBM Corporation, 293 236 nosis of GP was retention percentage of more than 10% Armonk, NY). 294 237 at 4 hours during a GE study using a standard low-fat, 295 238 low-calorie meal. 296 239 Clinical response. Decrease of at least 1 point in the Results 297 240 average total GCSI score with more than a 25% decrease 298 241 in at least 2 subscales of cardinal symptoms. Clinical Outcomes 299 242 Nonresponders. Patients who underwent GPOEM and 300 243 did not experience a decrease of GCSI score by 1 point. Ninety-seven patients (18 males and 79 females) 301 244 Recurrence. Defined as recurrence of GP symptoms underwent GPOEM from June 2015 to March 2019. 302 245 and return to the baseline GCSI or GCSI 3 lasting at Ninety (17 males and 73 females) patients had more 303 246 least 2 months after initial complete response. than 3 months follow-up and were included in the final 304 247 Clinical failure. No clinical response (as defined pre- analysis with a technical success (complete pylo- 305 248 viously) at initial follow-up or patients with recurrence romyotomy) rate of 100% (Table 1). The mean age was 306 249 of symptoms within 6 months. 47 14 years, and the mean duration of symptoms was 307 250 Body mass index. Body mass index (BMI) was classi- 5.3 4.4 years. Average GCSI before GPOEM was 3.8 308 251 fied according to the World Health Organization defini- 0.6. Average total procedure time (from esophageal 309 252 tion: underweight, BMI <18.5 kg/m2; normal weight, intubation to removal of the endoscope from the mouth) 310 253 BMI 18.5–25 kg/m2; obese, BMI 30–40 kg/m2; and was 50 13 minutes. 311 254 morbidly obese, BMI 40 kg/m2. Seventy-four patients underwent a GES before and 312 255 after the GPOEM: 47 (63%) patients had normalized GES 313 256 after the procedure, 25 (34%) patients had improvement 314 257 Technical Detail of the GE, and 2 (3%) patients had worsening of the GE. 315 258 Overall, there was a significant improvement in gastric 316 259 The procedure has been described in detail in our retention at 4 hours from an average baseline of 50.6% 317 15,16 fi 260 prior published studies. After identi cation of the 27.3% to 20.1% 23.5% at 2 month post-procedure 318 261 pyloric ring, a selective single or double circular myot- (t ¼ -6.4; P < .01) (Figure 1). 319 fi 262 omy was performed. Double myotomy was de ned as a Out of the 90 patients, 73 (81%) exhibited a clinical 320 263 second selective myotomy was performed at the 4- or 5- response and 17 (19%) patients did not exhibit a clinical 321 ’ 264 o clock position with at least 1 cm maintained between response at initial follow-up between 3 and 6 months 322 265 the 2 pyloromyotomies. All patients were given pro- 323 266 phylactic antibiotics during the procedure. Patients were 324 Table 1. Perioperative Baseline Characteristics 267 kept NPO the remainder of the day of the procedure and 325 268 discharged the following morning after tolerating a liquid GPOEM (n ¼ 90) 326 269 diet unless there was suspicion of procedural complica- 327 270 tion (eg, abdominal pain, bleeding). Female, n (%) 73 (81) 328 GE studies were obtained 4–8 weeks post- Age, y 42.4 12.6 271 Age >60 15 329 272 intervention. Impact of GPOEM on nutrition was 2 330 – BMI pre-GPOEM, kg/m 27.65 7.4 273 measured by transition from feeding tube predominant Etiology, n (%) 331 274 diet to oral intake predominant and reduction or Diabetes 38 (42) 332 275 discontinuation of antiemetic medications during the Idiopathic 42 (47) 333 study period. Hospitalization rate and emergency room Others 10 (11) 276 334 visitation rate was reported 6 months before and 6 Duration of disease, y 5.3 4.4 277 Pharmacotherapy, n (%) 335 278 months after GPOEM. Erythromycin 55 (61) 336 279 Metoclopramide 86 (96) 337 280 Domperidone 43 (48) 338 Statistical Analysis Other antiemetics 51 (57) 281 Nutritional support, n (%) 339 282 Comparative analyses, total average GCSI, and sub- PPN and TPN 6 (7) 340 283 scale scores pre- and post-GPOEM were performed using J-tube 11 (12) 341 284 repeated measures, analysis of variance, and post hoc Previous therapy, n (%) 3 (13) 342 285 Q7 Botulinum injection 6 (7) 343 paired Student ttest with Bonferroni correction. The Gastric electrical stimulation 14 (16) 286 univariate analysis was made using the chi-square test GCSI pre-GPOEM 3.8 0.6 344 287 and multivariate analysis using linear logistic regression. 345 288 Kaplan-Meier graph with estimates with error bars was 346 289 BMI, body mass index; GCSI, Gastroparesis Cardinal Symptom Index; 347 used to calculate recurrence. A stepwise logistic regres- GPOEM, gastric per-oral endoscopic pyloromyotomy; J-tube, jejunostomy 290 sion was used to evaluate the factors that predict clinical tube; PPN, peripheral parenteral nutrition; TPN, total parenteral nutrition. 348

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349 following GPOEM (Table 2). Seven patients were unable significant correlation between the clinical response and 407 350 to be tracked during the follow-up period (4 died and 3 improvement in SF-36 score (P ¼ .001). Subgroup anal- 408 351 were otherwise unreachable). ysis showed a significant improvement in physical 409 352 At 6 months, 5 (7.1%) patients had recurrence of functioning, role limitation caused by physical health, 410 353 symptoms and 65 patients (92.9%) maintained clinical general health, vitality, social functioning, role limitation 411 354 response. At 12 months, 4 (8.3%) patients had recur- caused by emotional problems, and mental health. 412 355 rence of symptoms and 44 (91.7%) patients maintained 413 356 414 clinical response. At 24 months, 1 (4.8%) patient had a Nutrition and Antiemetic Medications 357 recurrence and 20 (95.2%) patients maintained clinical 415 358 416 response. At 36 months, 1 patient (14%) had recurrence Before GPOEM, 12 patients relied on jejunostomy 359 417 and 6 (86%) patients maintained clinical response tubes (J-tubes) for feeding and 5 patients relied on total 360 418 (Table 2). One year after receiving GPOEM, 69.1% of all parenteral nutrition. Of the 12 J-tube-dependent patients, 361 419 patients had a clinical response and 85.2% of initial re- 9 managed to tolerate oral intake and forego J-tube 362 420 sponders maintained a clinical response. For patients nutritional dependence following their procedure. Of the 363 421 who experienced an initial clinical response, from 6 to 36 total parenteral nutrition–dependent patients, 3 were 364 422 months of follow-up the rate of loss of that response was able to discontinue therapy. 365 423 12.9% per year. Before GPOEM 55 (61%) patients were on erythro- 366 424 mycin, 86 (96%) patients were on metoclopramide, 43 367 425 Health Care Use Following Gastric Per-Oral (48%) patients were on domperidone, and 51 (57%) 368 426 patients were on other antiemetics. Six months following 369 Endoscopic Pyloromyotomy 427 GPOEM 59 (66%) patients discontinued the schedule 370 428 antiemetics. 371 In patients with clinical success following GPOEM, GP 429 372 hospitalizations decreased from 8.2 12 in the 6 months 430 373 before GPOEM to 0.7 1.5 in the 6 months after GPOEM Factors Predicting Failure of Gastric Per-Oral 431 ¼ 374 (t 3.6). Additionally, monthly emergency room visits Endoscopic Pyloromyotomy 432 375 decreased from average 2.0 2.9 pre-GPOEM to 0.3 433 ¼ ¼ 376 0.7 post-GPOEM (t 3.4; P .02). There was no sta- We evaluated the impact of age, gender, resistance to 434 fi 377 tistically signi cant change in the rate of health care use endoscope passage, gastric pacemaker placement, 435 378 in nonresponders following GPOEM. smoking, history of abdominal pain, history of opioids 436 379 use, history of chronic narcotic use, history of psychiatric 437 380 Quality of Life disorder, etiology of GP, BMI, and initial GCSI score 438 381 (including subcategories). 439 382 Throughout the follow-up period of the responders In univariate and multivariate regression analysis, a 440 383 (mean, 16 months), there was a significant improvement longer duration of GP reduced the odds of response to 441 384 in quality of life on SF-36 survey following GPOEM (P < GPOEM (odds ratio, 1.4; 95% confidence interval, 442 385 .001). A total of 73%, 65%, 51%, and 45% had 1.07–1.8; P ¼ .002). In univariate analysis, higher BMI, 443 386 improvement in quality of life during 6 months (n ¼ 48), history of psychiatric medication use, and history of pain 444 387 12 months (n ¼ 32), 24 months (n ¼ 21), and 36 months medication use all increased odds of GPOEM failure. In 445 388 (n ¼ 16) following GPOEM. There was a statistically multivariate logistic regression, patients with high BMIs 446 389 had increased odds of GPOEM failure (odds ratio, 1.097; 447 390 95% confidence interval, 1.022–1.176; P ¼ .010) and 448 391 patients receiving psychiatric medications had a higher 449 392 risk of GPOEM failure (odds ratio, 1.33; 95% confidence 450 393 interval, 0.110–1.008; P ¼ .052) (Table 3). 451 394 452 395 Complications 453 396 454 397 Most of the patients (80%) were discharged within 455 398 24-hour observation. The length of hospital stay was 2.2 456 399 2.0 days. Four patients had adverse events following 457 400 458 FPO the procedure (2 mild and 2 moderate adverse event). = 401 One incident of tension capnoperitoneum and another of 459 402 bleeding from the ulcer at the mucostomy site occurred 460 403 during the timeframe evaluated in this study. The patient 461 404 with tension capnoperitoneum was managed by needle 462 print & web 4C 405 Figure 1. Gastric emptying results following gastric per-oral decompression and had a good clinical outcome. The 463 406 endoscopic pyloromyotomy. patient with a bleeding ulcer was managed by 464

465 523 466 524 467 525 468 526 469 527 470 528 471 529 472 530 473 531 474 532 475 533 476 534 477 535 478 536 479 537 480 538 481 539 482 540 483 541 484 542 485 543 486 544 487 545 488 546 489 547 FPO 490 = 548 491 549 492 550 493 551 494 print & web 4C 552 Figure 2. Total gastroparesis cardinal symptom score during the study period. 495 553 496 554 497 endoscopic treatment and oral proton pump inhibitors Our results demonstrate that following GPOEM, 81% of 555 498 and likewise did well. A single patient had abdominal patients had a significant clinical response at time of first 556 499 pain after the procedure. There was a negative computed follow-up 3–6 months post-procedurally. Moreover, 1 year 557 500 tomography scan of the abdomen for pneumoperitoneum after their GPOEM, 85.2% of initial responders maintained 558 501 or leak. The patient was managed with pain control, brief their clinical response (69.1% of patients overall). 559 502 hospitalizations, and ultimately was discharged home Furthermore, clinical response to GPOEM was found to be 560 503 without further issues. One patient had an exacerbation durable with only 12.9% of initial responders losing that 561 504 of preexisting chronic obstructive pulmonary disease response per year up to 36 months post-procedurally. 562 505 that was believed to anesthesia-related. No patients Although only 7 patients were able to be followed at 3 563 506 required surgical intervention following their procedure, years or greater post-GPOEM, 6 maintained clinical 564 507 nor was any procedure-related mortality witnessed. response, suggestive of promising durability of the pro- 565 508 cedural benefit. To our knowledge, this is the longest 566 509 comprehensive follow-up study on the outcome of GPOEM. 567 510 Discussion The first 30 patients in our cohort were previously 568 511 published in a study comparing the clinical success and 569 512 Despite the initial promising results, GPOEM is still increase in quality of life with a control group of patients 570 513 considered an experimental procedure. Several factors who did not receive GPOEM.30 The initial 40 patients 571 514 have as of yet precluded a wider adoption of GPOEM in were published in a study comparing diabetic with 572 515 treatment of GP. First, there is a steep learning curve nondiabetic GP.19 573 516 associated with performing this procedure because of a This study has a different objective than our previous 574 517 difficult scope position in the short tunnel compared 2 publications. First, this study centers on calculating 575 518 with per-oral endoscopic myotomy. Second, the current long-term clinical and quality-of-life outcomes following 576 519 body of evidence suggests that up to one-third of pa- GPOEM. Second, we seek to calculate the risk of recur- 577 520 tients may not exhibit clinical response to treatment.19,20 rence during the follow-up period. Finally, via multivariate 578 521 Third, there exists a paucity of data on the long-term analysis we seek to identify factors predictive of GPOEM 579 522 outcomes of GPOEM. failure. 580

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581 639 582 640 583 641 584 642 585 643 586 644 587 645 588 646 589 647 590 648 591 649 592 650 593 651 594 652 595 653 596 654 597 655 598 656 599 657 FPO 600 = 658 601 659 602 660 603 Figure 3. Kaplan-Meier 661

604 curves for the 3-year suc- print & web 4C 662 605 cess rate of GPOEM. 663 606 664 607 There exists a limited understanding of GP patho- Another explanation of recurrence of symptoms or 665 608 physiology. In healthy patients, GE is mediated by a nonresponse to GPOEM is the multifactorial nature of GP 666 609 complex system including the interstitial cells of Cajal and worsening of other phases of gastric digestion. It is 667 610 (ICC) and enteric neurons that regulate fundic accom- hypothesized that GPOEM eliminates pylorospasm and 668 611 modation, antral contraction, and pyloric relaxation.31 It improves antropyloroduodenal coordination; however, 669 612 is theorized that 1 of the underlying causes of GP is an there is no impact on other pathophysiologic features of 670 613 initial immune insult leading to universal fibrosis and GP including fundic hypocontractility, antral hypo- 671 614 physiological changes in the gastrointestinal tract.32 motility, gastric arrhythmia, and autonomic neuropa- 672 615 Histologic studies show defects in the morphology of thy.34 As such, the benefit of adding GES to patients with 673 616 enteric neurons, smooth muscle cells, and ICC, as well as unfavorable outcomes to GPOEM is an important area of 674 617 increased concentrations of inflammatory cells in gastric future study. Finally, GPOEM does not preclude the im- 675 618 tissue.33 Other studies have reported damage to intrinsic mune reactions that result in damage to the enteric 676 619 neurons, loss of ICC, and loss of heme oxygenase-1.21 neurons and loss of ICC. Thus, the continuous loss of ICC 677 620 This dysregulated inflammatory response reported in cells can lead to terminal GP that is refractory to pylorus- 678 621 prior studies on GP may contribute to the recurrence of targeted therapy.35,36 679 622 symptoms that a minority of the patients in our cohort In our study, 2 patients who were nonresponders 680 623 experienced. Namely, fibrosis of the pyloric myotomy site underwent Roux-en-Y gastric bypass and laparoscopic 681 624 could result in contraction and stricture of the pyloric ring gastrectomy with subsequent improvement in their GP 682 625 and subsequent recurrence of symptoms. The combina- symptoms. Given the relatively safe profile of GPOEM 683 626 tion of lack of separation of the pyloric muscle following and high technical success rate, it may be used to triage 684 627 myotomy (unlike the separation in esophageal muscle patients with suspected terminal refractory GP for more 685 628 following per-oral endoscopic myotomy) in addition to the definite surgical resection once identified as non- 686 629 underlying increase in inflammatory response and fibrosis responders to GPOEM. 687 630 in GP patients may explain recurrence during the first The impact of GP on quality of life may be 688 631 years following GPOEM. Two patients with initial positive underestimated. Many patients had an extremely 689 632 response followed by a recurrence of symptoms within limited quality of life that impacted their profes- 690 633 the first year following GPOEM underwent upper endos- sional, interpersonal, and social life. Our long-term 691 634 copy revealing of increased resistance of scope passage results demonstrated the significant and sustainable 692 635 through the pylorus. Repeat GPOEM showed fibrosis at impact of GPOEM on the improvement in quality of 693 636 the myotomy site, likely resulting in stricture of the py- life. Consistent with previous studies on the topic, 694 637 loric ring. Repeat myotomy in these patients resulted in our results suggest decreased health care use and 695 638 regaining clinical response. improved quality of life following GPOEM.30,37 696

697 Table 2. Long-Term Outcome of GPOEM 755 698 756 699 Initial follow-up 757 > < 700 ( 3 mo and 6mo 6-mo follow- 12-mo follow- 18-mo follow- 24-mo follow- 36-mo follow- 758 701 post-GPOEM) up (%) up (%) up (%) up (%) up (%) 759 702 Patients eligible for survey 90 73 48 35 21 7 760 703 Patients who achieved initial 73 (81.1) 761 704 clinical response 762 705 Patients who failed to achieve 17 (18.9) 763 initial clinical response 706 Lost to follow-up 0 (0) 3 (4.1) 0 (0) 4 (11.4) 0 (0) 0 (0) 764 707 Surveyed patients who lost 5 (7.1) 4 (8.3) 3 (9.7) 1 (4.8) 1 (14) 765 708 initial clinical response 766 709 Surveyed patients who 65 (92.9) 44 (91.7) 28 (90.3) 20 (95.2) 6 (86) 767 710 maintained clinical 768 response 711 Mean GCSI subcategory 1.9 1.0 (P < .001) 1.9 1.0 2.3 1.3 1.9 1.2 1.6 1.2 1.1 1.2 769 712 scorea (P ¼ .01) (P ¼ .12) (P ¼ .03) (P ¼ .35) (P ¼ .37) 770 713 GCSI Nausea/ 1.7 1.4 (P < .001) 2.0 1.6 2.1 1.6 1.8 1.5 1.6 1.5 1.2 1.2 771 714 subcategory vomiting (P ¼ .006) (P ¼ .04) (P ¼ .05) (P ¼ .9) (P ¼ .34) 772 a 715 score Bloating 2.3 1.4 (P < .001) 2.4 1.6 2.5 1.7 2.4 1.6 1.7 1.5 1.7 1.8 773 (P ¼ .001) (P ¼ .007) (P ¼ .35) (P ¼ .21) (P ¼ .36) 716 Early 1.8 1.1 (P < .001) 1.9 1.4 2.5 1.6 1.8 1.5 1.3 1.5 1.4 1.1 774 717 satiety (P ¼ .01) (P ¼ .68) (P ¼ .21) (P ¼ .75) (P ¼ .64) 775 718 776 719 777 720 GCSI, Gastroparesis Cardinal Symptom Index; GPOEM, gastric per-oral endoscopic pyloromyotomy. 778 aGCSI scores before GPOEM: mean GCSI 3.8 0.6, nausea/vomiting 4.3 1.1, bloating 3.4 1.5, early satiety 3.6 1. 721 779 722 780 723 781 724 Additionally, among those previously dependent on To identify the factors that predict clinical failure of 782 725 J-tube or total parenteral nutrition, most of our GPOEM, we elected to analyze patients with initial 783 726 affected cohort was able to decrease reliance on nonresponse in addition to 6-months recurrence. As the 784 727 these alternative methods of nutrition. At 3-year placebo effect has been demonstrated in prior GPOEM 785 728 follow-up, almost half of the patients with main- studies, this interval was selected as to account for its 786 729 tained clinical response had a significant reduction potential impact in the short-term on GCSI scoring 787 730 in health care use. Given the estimated health care following the procedure. Frequency of emergency room 788 731 cost of GP patients in the United States of $568 visitation and hospitalization provided further objective 789 732 million annually, extrapolation of this finding sug- measures of symptomatology following GPOEM. Our re- 790 733 gests a significant opportunity for health care sav- sults suggest an association between high BMI and fail- 791 734 ings. Identification of patients who are most likely ure of GPOEM. Likewise, long-duration GP was also 792 735 to benefit from GPOEM, including the validation of associated with poor outcomes of GPOEM. These results 793 736 endoluminal functional lumen imaging probes, is a correlate with our prior finding.16 794 737 critical area for future research. This, along with Strengths of our study include a large sample size 795 738 continued refinement of the pyloromyotomy tech- relative to the novelty of this procedure, the long-term 796 739 nique to avoid fibrosis and symptom recurrence, is follow-up of clinical response, and the identification of 797 740 key for the widespread adoption of GPOEM. factors predictive of clinical failure. Nevertheless, our 798 741 799 742 800 743 Table 3. Factors Predicting Failure of GPOEM 801 744 Univariate Multivariate 802 745 803 746 95% CI 95% CI 804 747 805 748 Variables OR Lower UpperP value P value OR Lower Upper P value 806 749 Body mass index 1.070 1.000 1.130 .04 .010 1.097 1.022 1.176 .010 807 750 Duration of GP 1.143 1.023 1.278 .019 .002 1.4 1.07 1.8 .002 808 751 Psych medications 1.434 0.165 1.144 .091 .052 1.33 0.110 1.008 1.33 809 752 Pain medication 3.9 1.2 12.6 .02 .469 0.703 0.271 1.825 .703 810 753 811 754 CI, confidence interval; GP, gastroparesis; GPOEM, gastric per-oral endoscopic pyloromyotomy; OR, odds ratio. 812

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813 study has several limitations. First, it is a retrospective electrical stimulation for medically refractory gastroparesis. 871 814 study from a single center, which inherently limits Surgery 2018;164:760–765. 872 815 generalizability. Second, because of the longitudinal na- 15. Shada AL, Dunst CM, Pescarus R, et al. Laparoscopic 873 816 ture of data collection, there exists an unequal number of pyloroplasty is a safe and effective first-line surgical 874 817 patients at each time. Third, we did experience loss of therapy for refractory gastroparesis. Surg Endosc 2016; 875 – 818 follow-up on some patients, which is at least in part 30:1326 1332. 876 819 attributable to the referral nature of our tertiary care 16. Khashab MA, Stein E, Clarke JO, et al. Gastric peroral endo- 877 scopic myotomy for refractory gastroparesis: first human 820 institution. We overcame this limitation by conducting 878 821 endoscopic pyloromyotomy (with video). Gastrointest Endosc 879 surveys via telephone for patients unable to be seen in 2013;78:764–768. 822 880 clinic for follow-up to evaluate the GCSI, SF-36 score, and 17. Chaves DM, de Moura EG, Mestieri LH, et al. Endoscopic 823 881 report emergency room visits and admissions. Finally, pyloromyotomy via a gastric submucosal tunnel dissection for 824 patient-reported GCSI outcomes are inherently subject to the treatment of gastroparesis after surgical vagal lesion. Gas- 882 825 recall bias; however, we relied on other objective mea- trointest Endosc 2014;80:164. 883 826 sures including improvement of GE and health care use 18. Chung H, Dallemagne B, Perretta S, et al. Endoscopic pylo- 884 827 following GPOEM to validate our results. romyotomy for postesophagectomy gastric outlet obstruction. 885 828 Endoscopy 2014;46(Suppl 1 UCTN):E345–E346. 886 References 829 19. Mekaroonkamol P, Patel V, Shah R, et al. Association between 887 830 1. Wang YR, Fisher RS, Parkman HP. 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929 30.MekaroonkamolP,DachaS,WangL,etal.Gastric 992 930 peroral endoscopic pyloromyotomy reduces symptoms, Reprint requests 993 Address requests for reprints to: Qiang Cai, MD, PhD, Emory University School 931 increases quality of life, and reduces health care use for of Medicine, 1365 Clifton Road, B1262, Atlanta, Georgia 30322. e-mail: qcai@ 994 932 patients with gastroparesis. Clin Gastroenterol Hepatol emory.edu; fax: (404) 778-2578. Q2 995 933 2019;17:82–89. 996 934 fi Acknowledgments 997 31. Camilleri M, Parkman HP, Sha MA, et al. Clinical guideline: The abstract was selected as an oral presentation at Digestive Disease Week Q8 935 management of gastroparesis. Am J Gastroenterol 2013; 2019 in San Diego, California. Q4 998 936 108:18–37; quiz 8. 999 937 CRediT Authorship Contributions 1000 32. Moraveji S, Bashashati M, Elhanafi S, et al. Depleted interstitial Mohamed M. Abdelfatah, MD, MS (Conceptualization: Lead; Data curation: 938 1001 cells of Cajal and fibrosis in the pylorus: novel features of gas- Lead; 939 Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Supervi- 1002 troparesis. Neurogastroenterol Motil 2016;28:1048–1054. 940 sion: Lead; 1003 33. Grover M, Farrugia G, Lurken MS, et al. Cellular changes in Writing – original draft: Lead; Writing – review & editing: Lead) 941 Alan Noll, MD (Data curation: Equal; Writing – review & editing: Equal) 1004 diabetic and idiopathic gastroparesis. Gastroenterology 2011; 942 Neil Kapil, MD (Data curation: Equal; Writing – review & editing: Supporting) 1005 140:1575–1585. Rushikesh Shah, MD (Data curation: Supporting; Writing – review & editing: 943 Supporting) 1006 944 34. Pasricha PJ. Future directions in the treatment of gastroparesis. Lianyong Li, MD (Writing – review & editing: Supporting), 1007 – – 945 Gastroenterol Clin North Am 2015;44:185 189. Rosemary Nustas, MD (Writing review & editing: Supporting) 1008 – 35. Bernard CE, Gibbons SJ, Mann IS, et al. Association of low Baiwen Li, MD (Writing review & editing: Supporting) 946 Hui Luo, MD (Writing – review & editing: Supporting) 1009 947 numbers of CD206-positive cells with loss of ICC in the gastric Huimin Chen, MD (Writing – review & editing: Supporting) 1010 – 948 body of patients with diabetic gastroparesis. Neuro- Liang Xia, MD (Writing review & editing: Supporting) 1011 – Parit Mekaroonkamol, MD (Data curation: Supporting; Supervision: Sup- 949 gastroenterol Motil 2014;26:1275 1284. porting; Writing – review & editing: Supporting) 1012 950 36. Grover M, Bernard CE, Pasricha PJ, et al. Diabetic and idio- Nikrad Shahnavaz, MD (Writing – review & editing: Supporting) 1013 – pathic gastroparesis is associated with loss of CD206-positive Steven Keilin, MD (Writing review & editing: Supporting) 951 Field Willingham, MD (Writing – review & editing: Supporting) 1014 952 macrophages in the gastric antrum. Neurogastroenterol Motil Jennifer Christie, MD (Writing – review & editing: Supporting) 1015 953 2017;29:e13018. Qiang Cai, MD (Methodology: Lead; Supervision: Lead; Validation: Lead; 1016 Writing – review & editing: Lead) 954 37. Dacha S, Mekaroonkamol P, Li L, et al. Outcomes and quality- 1017 955 of-life assessment after gastric per-oral endoscopic pylo- Conflicts of interest 1018 956 romyotomy (with video). Gastrointest Endosc 2017;86:282–289. The authors disclose no conflicts. Q3 1019 957 1020 958 1021 959 1022 960 1023 961 1024 962 1025 963 1026 964 1027 965 1028 966 1029 967 1030 968 1031 969 1032 970 1033 971 1034 972 1035 973 1036 974 1037 975 1038 976 1039 977 1040 978 1041 979 1042 980 1043 981 1044 982 1045 983 1046 984 1047 985 1048 986 1049 987 1050 988 1051 989 1052 990 1053 991 1054