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Over the last few decades, we have seen the further advancement and progress of the field of interventional and therapeutic endoscopy, bringing us to undiscovered areas of the gut's lumen. The development of peroral endoscopic myotomy (POEM) created a breakthrough in the field of therapeutic endoscopy by bringing us to the so-called "third space," which is an artificially created space in the submucosal layer. The rise of third space endoscopy brought us novel and fundamental aspects into therapeutic endoscopy by paving the way to interventions throughout the gastrointestinal (GI) tract. With the success of POEM, the same third space principles have become the foundation for the development of other third space endoscopic techniques for the management of motility disorders of the GI tract, giving rise to a number of POEM offshoots. Since motility disorders of the GI tract are commonly encountered in clinical practice, the development of third space endoscopic interventions to address these disorders was seemingly timely, providing patients optimal care. In this chapter, we would like to offer a closer look and provide the readers a general overview of POEM and other POEM-based techniques which have been developed for the management of motility disorders of the GI tract.

Background and Aims: Peroral endoscopic myotomy (POEM) is conducted for patients with esophageal motility disorders based on high-resolution manometry (HRM) findings. However, the impact of POEM on HRM findings and the associations between post-POEM HRM and outcomes have not been clarified., Methods: In a multicenter, observational, cohort study, patients with achalasia treated by POEM received follow-up HRM. Associations between patient characteristics, POEM procedures, and post-POEM HRM findings, including integrated relaxation pressure (IRP) and distal contractile integral (DCI), were investigated. Furthermore, POEM procedure outcomes were compared with post-POEM HRM findings., Results: Of 2171 patients, 151 (7.0%) showed residual high post-POEM IRP (≥26 mm Hg; Starlet [Starmedical Ltd, Tokyo, Japan]). In a multivariate analysis, high pre-POEM IRPs (odds ratio [OR], 24.3) and gastric myotomy >2 cm (OR, .22) were found to be positive and negative predictive factors of high post-POEM IRPs, respectively. Peristalsis recovery (DCI ≥500 mm Hg/cm/s, at least 1 swallow; Starlet) was visible in 121 of 618 patients (19.6%) who had type II to III achalasia. High pre-POEM IRP (OR, 2.65) and DCI ≥500 (OR, 2.98) predicted peristalsis recovery, whereas esophageal dilation (OR, .42) predicted a risk of no recovery. Extended myotomy did not reveal a significant impact on peristalsis recovery. High or low post-POEM IRP and DCI did not increase the incidence of clinical failure, reflux esophagitis, or symptomatic GERD., Conclusions: Extended gastric myotomy decreased IRP values, whereas peristalsis recovery depended on the characteristics of achalasia. A residual high post-POEM IRP does not necessarily mean clinical failure. Routine HRM follow-up is not recommended after POEM., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Peroral endoscopic myotomy (POEM) is effective for the management of achalasia and its variants; however, it can be ineffective in some patients. We aimed to develop and validate a risk scoring system to predict the clinical failure of POEM preoperatively., Methods: Consecutive patients who underwent POEM in 14 high volume centers between 2010 and 2020 were enrolled in this study. Clinical failure was defined as an Eckardt score of ≥ 4 or retreatment. A risk scoring system to predict the short-term clinical failure of POEM was developed using multivariable logistic regression and internally validated using bootstrapping and decision curve analysis., Results: Of the 2740 study patients, 112 (4.1 %) experienced clinical failure 6 months after POEM. Risk scores were assigned for three preoperative factors as follows: preoperative Eckardt score (1 point), manometric diagnosis (-4 points for type II achalasia), and a history of prior treatments (1 point for pneumatic dilation or 12 points for surgical/endoscopic myotomy). The discriminative capacity (concordance statistics 0.68, 95 %CI 0.62-0.72) and calibration (slope 1.15, 95 %CI 0.87-1.40) were shown. Decision curve analysis demonstrated its clinical usefulness. Patients were categorized into low (0-8 points; estimated risk of clinical failure < 5 %) and high risk (9-22 points; ≥ 5 %) groups. The proportions of clinical failure for the categories were stratified according to the mid-term outcomes (log-rank test, P  < 0.001)., Conclusions: This risk scoring system can predict the clinical failure of POEM preoperatively and provide useful information when making treatment decisions., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: Reports on learning curve for peroral endoscopic myotomy (POEM) in therapeutic endoscopy nonexperts are limited. We aimed to assess the number of cases required to achieve POEM proficiency for endoscopic submucosal dissection (ESD) experts and nonexperts., Methods: This is a retrospective study at the largest POEM referral center in Japan. POEM between April 2014 and December 2020 were included. Nonexperts and ESD experts were divided by training phases: A, 1-20; B, 21-40; C, 41-60; D, 61-80; and E, 81-100 cases. Primary outcome was operation time, and the phase to reach target time (83 min) was investigated. Secondary outcomes were clinical success rate, adverse events, and post-POEM gastroesophageal reflux disease (GERD)., Results: Five hundred and sixty-six cases were performed by 14 nonexperts, and 555 cases by 15 ESD experts. As the primary outcome, operation time in nonexperts was: A, 95 (79-115.8); B, 86.5 (71-105); C, 80 (70-100); D, 73 (64.5-100.5); and E, 73.5 (57.8-88.8) min, while in ESD experts: A, 90 (74-128); B, 77 (70-92); and C, 77 (70-93.5) min (median [interquartile range]). Operation time decreased significantly as experience increased in both groups (P < 0.001), and nonexperts required 41-60 cases to achieve proficiency, while experts required 21-40 cases. As secondary outcomes, in nonexperts, clinical success was 96.9-100%, adverse events were 5.0-9.2%, symptomatic GERD was 11.8-26.5%, and proton pump inhibitor (PPI) intake was 11.5-18.7% in each phase. While in experts, clinical success was 96.2-100%, adverse events were 3.0-5.8%, symptomatic GERD was 14.6-22.0%, and PPI intake was 12.6-17.9%. There were no significant differences among training phases., Conclusions: Non-ESD experts require more cases to achieve proficiency in POEM. These results are useful for establishing POEM training programs and institutional implementation of the procedure., (© 2022 Japan Gastroenterological Endoscopy Society.)

Third-space endoscopy, also known as submucosal endoscopy, allows for a wide range of therapeutic interventions within the submucosal layer and even into the muscular or subserosal layers of the gastrointestinal lumen. The technical development of peroral endoscopic myotomy (POEM) for achalasia has revolutionized the field of therapeutic endoscopy and the method has been continuously refined and modified. Although POEM has been applied to treat primary achalasia, it shows a favorable clinical response in other esophageal motility disorders and as a salvage treatment after previously failed intervention. Gastroesophageal reflux after POEM has drawn considerable attention and there have been major advancements in its prevention and management. POEM has led to advantageous derivatives such as peroral endoscopic tumor resection or submucosal tunneling endoscopic resection for resection of subepithelial lesions, Zenker POEM for hypopharyngeal diverticula, diverticular POEM for epiphrenic esophageal diverticula, and gastric POEM for refractory gastroparesis. These techniques have a similar concept, which constitutes submucosal tunneling with a mucosal flap valve and secure mucosal incision closure. The submucosal tunneling technique is widely accepted and continues to evolve. This study aimed to review in detail the indications, outcomes, and technical variations in POEM and explore several emerging submucosal tunneling procedures. This review will benefit future studies by providing a summary of recent developments in this field., (© 2022 Japan Gastroenterological Endoscopy Society.)

Objectives: Patients with esophageal motility disorders (EMDs) including achalasia after gastric surgery have not been thoroughly characterized. Furthermore, the efficacy of peroral endoscopic myotomy (POEM) in this population should be clarified., Methods: In this retrospective multicenter study of 3707 patients with EMDs, 31 patients (0.8%) had a history of gastric surgery. Patient characteristics and POEM efficacy were compared between patients with and without previous gastric surgery., Results: In patients with EMD after gastric surgery, age at EMD diagnosis was higher (72.0 years), male sex was predominant (90.3%), and the American Society of Anesthesiologists physical status score was higher (≥II, 48.4%). High-resolution manometry (HRM) findings did not reveal significant differences. In patients who underwent gastric surgery, atrophic gastritis was common (80.6%), and gastric cancer was the primary surgical indication (32.3%). Distal gastrectomy was performed in 28 patients (90.3%). POEM was effective (3.3% adverse events; 100% treatment success). The incidence rates of reflux esophagitis (RE) and symptomatic gastroesophageal reflux disease (GERD) were 60.0% and 16.7%, respectively, without significant intergroup differences, and severe RE was not observed in the long-term follow-up. Extended gastric myotomy was a risk factor for RE., Conclusion: Patients with gastric surgery often present severe disease manifestations; the surgical indication is mainly gastric cancer. HRM findings can be similarly used for diagnosis in patients with and without gastric surgery. POEM maintains safety and efficacy with acceptable RE and symptomatic GERD rates. To prevent RE, extended myotomy should be avoided., (© 2022 Japan Gastroenterological Endoscopy Society.)

Background and Aims: The etiology of chest pain in achalasia-related esophageal motility disorders and the frequency and risk factors of persistent chest pain after peroral endoscopic myotomy (POEM) remain unclear., Methods: A multicenter cohort study including 14 hospitals was conducted to elucidate the characteristics of patients with chest pain and the efficacy of POEM., Results: Consecutive cases of achalasia-related esophageal motility disorders included 2294 (64.2%) and 1280 (35.8%) patients with and without chest pain, respectively. Among the 2107 patients with chest pain who underwent POEM, we observed complete remission in 1464 patients (69.5%) and nonremission in 643 patients (30.5%), including a partial response in 619 patients (29.4%) and resistance in 24 patients (1.1%). Multivariate analysis revealed that advanced age (odds ratio [OR], .28), male sex (OR, .70), prior treatment (OR, 1.39), and sigmoid type (OR, .65) were related to the prevalence of chest pain. Long disease duration (OR, .69) and esophageal dilation (OR, .79) were related to decreased severity. POEM improved patients' quality of life that was hindered by chest pain. Early onset (OR, 1.45), advanced age (OR, .58), male sex (OR, .79), prior treatment (OR, 1.37), and posterior myotomy (OR, 1.42) were associated with nonremission after POEM; high-resolution manometry (HRM) findings and myotomy length showed no statistical significance on pain etiology and persistence after POEM., Conclusions: The prevalence and severity of chest pain were dependent on age, sex, disease duration, prior treatment, and esophageal morphology rather than HRM findings. The efficacy of POEM is satisfactory; however, residual pain was often observed. Excessively long myotomy can be avoided, and anterior myotomy may be recommended., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

BACKGROUND : Gastroesophageal reflux disease (GERD) and reflux esophagitis remain problems after peroral endoscopic myotomy (POEM). This study aimed to elucidate the risk factors and long-term course of reflux esophagitis and symptomatic GERD after POEM. METHODS : This multicenter cohort study involved 14 high volume centers. Overall, 2905 patients with achalasia-related esophageal motility disorders treated with POEM were analyzed for reflux esophagitis, severe reflux esophagitis (Los Angeles classification C or D), and symptomatic GERD. RESULTS : Reflux esophagitis was diagnosed in 1886 patients (64.9 %). Age ≥ 65 years (risk ratio [RR] 0.85), male sex (RR 1.11), posterior myotomy (RR 1.12), esophageal myotomy > 10 cm (RR 1.12), and gastric myotomy > 2 cm (RR 1.17) were independently associated with reflux esophagitis. Severe reflux esophagitis was diagnosed in 219 patients (7.5 %). Age ≥ 65 years (RR 1.72), previous treatments (RR 2.21), Eckardt score ≥ 7 (RR 0.68), sigmoid-type achalasia (RR 1.40), and esophageal myotomy > 10 cm (RR 1.59) were factors associated with severe reflux esophagitis. Proton pump inhibitors (PPIs) were more effective for reflux esophagitis at 5-year follow-up ( P  = 0.03) than after 1 year ( P  = 0.08). Symptomatic GERD was present in 458 patients (15.9 %). Symptom duration ≥ 10 years (RR 1.28), achalasia diagnosis (RR 0.68), integrated relaxation pressure ≥ 26 (RR 0.60), and posterior myotomy (RR 0.80) were associated with symptomatic GERD. The incidence of symptomatic GERD was lower at 5-year follow-up compared with that after 1 year ( P  = 0.04), particularly in PPI users ( P  < 0.001). CONCLUSIONS : The incidence of severe reflux esophagitis was low after POEM, but excessive myotomy for older patients with previous treatments should be avoided. Early phase symptomatic GERD is non-acid reflux dependent and the natural course is favorable, basically supporting conservative treatment., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: Indications for peroral endoscopic myotomy (POEM) and endoscopic submucosal dissection (ESD) in patients with achalasia concomitant with esophageal carcinoma (EC) are unclear. This study aimed to clarify the role of POEM in cases of achalasia concomitant with EC and to elucidate the indications for ESD and efficient surveillance for EC., Methods: We conducted a multicenter cohort study at 14 hospitals in Japan, including 3707 cases of achalasia-related esophageal motility disorders (EMDs). Factors contributing to EC risk, the characteristics of EC, and clinical outcomes of POEM/ESD were analyzed., Results: In patients undergoing POEM, screening and surveillance endoscopy throughout a 1-year period resulted in diagnosis of 72.1% new EC cases. Of 62 patients with 123 ECs, 40.3% had multiple or metachronous lesions within 37.5 months. EC was predominantly observed in the middle thoracic esophagus (58.5%) and posteriorly (73.2%). POEM had comparable safety and efficacy in cases of concomitant EC even after ESD. Endoscopic en bloc resection was performed in 95.8% and 89.3% of ECs diagnosed before and after POEM, respectively (P = 0.351); however, ESD on the POEM-line was impaired by fibrosis. Multivariate analysis revealed risk factors for EC, including regular alcohol consumption, a history of smoking, advanced age, and extended disease duration. Alcohol intake and smoking had a synergistic effect on EC development., Conclusions: Screening and surveillance of POEM help in detecting EC. ESD is feasible in achalasia, although on the POEM-line is challenging. Surveillance endoscopy for EC is recommended for cases with specific risks and a history of ECs., (© 2021 Japan Gastroenterological Endoscopy Society.)

Geriatric patients with existing studies on the safety and efficacy of peroral endoscopic myotomy (POEM) for achalasia involve small sample sizes and single institutions. However, multi-center, large-scale data analyses are lacking. The study aimed to clarify the characteristics of geriatric patients with esophageal motility disorders (EMDs) and determine the procedure-related outcomes and clinical course following POEM. This cohort study included 2,735 patients with EMDs who were treated at seven Japanese facilities between 2010 and 2019. The patients' characteristics and post-POEM clinical courses were compared between the geriatric (age ≥ 75 years; n = 321) and non-geriatric (age < 75 years; n = 2,414) groups. Compared with the non-geriatric group, the geriatric group had higher American Society of Anesthesiologists physical status scores; more recurrent cases; lower incidence of chest pain; and higher incidence of type III achalasia, distal esophageal spasm, and Jackhammer esophagus. Furthermore, the incidence of sigmoid esophagus was higher, although esophageal dilation was not severe in this group. POEM was safe and effective for geriatric patients with treatment-naïve and recurrent EMDs. Furthermore, compared with the non-geriatric group, the geriatric group had lower post-POEM Eckardt scores, fewer complaints of refractory chest pain, and a lower incidence rate of post-POEM reflux esophagitis. Geriatric patients are characterized by worse clinical conditions, more spastic disorders, and greater disease progression of EMDs, which are also the indications for minimally invasive POEM. POEM is more beneficial in geriatric patients as it has lowering symptom scores and incidence rates of reflux esophagitis., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Peroral endoscopic myotomy (POEM) is standard treatment for achalasia. Gastroesophageal reflux disease (GERD) after POEM has been an important challenge since the early days of POEM implementation. The esophagogastric junction anti-reflux barrier consists of internal lower esophageal sphincter (LES) (i.e., intrinsic muscles of distal esophagus with sling fibers) and external LES (crural diaphragm and phrenoesophageal ligament anchors the distal esophagus to the crural diaphragm). During conventional POEM, the entire internal LES is unintentionally dissected. Preservation of the sling fiber may reduce post-POEM GERD, but its safety and effectiveness have been unclear. In this study, we investigated the safety and effectiveness of sling fiber preservation POEM (SP-POEM) for reducing severe post-procedural erosive esophagitis., Methods: We analyzed data of 236 patients who underwent POEM; of these, 203 patients underwent posterior myotomy without (Group 1) or with attempted (Group 2) sling fiber preservation. Group 1 (N = 79; sling fiber excision, N = 68) and Group 2 (N = 90; sling fiber preservation, N = 81) were compared. Post-procedural erosive esophagitis (Los Angeles classification) were assessed and the area (direction and length) of mucosal break was also investigated. The gastroesophageal flap valve was evaluated by Hill's classification., Results: Severe erosive esophagitis exceeding grade C (Los Angeles classification) occurred in 44.1% of patients (30/68) in Group 1 and in 18.5% of patients (15/81) in Group 2. In mapping of erosive esophagitis, mucosal breaks appeared widely in all directions in Group 1; they tended to be limited in Group 2 (especially in the 2 o'clock direction). Assessment using the Hill's classification showed that the gastroesophageal flap valve was preserved after SP-POEM., Conclusion: SP-POEM is safe and effective, with a success rate of 90%. The rate of severe erosive esophagitis can be decreased by preserving sling fibers., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: To elucidate the impact of the coronavirus disease 2019 (COVID-19) on the practice of high-resolution manometry (HRM) and peroral endoscopic myotomy (POEM) in Japan., Methods: We utilized a large-scale database involving 14 high-volume centers in Japan to investigate changes in the numbers of HRM and POEM procedures performed and outcomes of POEM between 2019 and 2020. A questionnaire survey was also conducted to analyze pandemic-associated changes in the HRM and POEM protocols., Results: Compared to that in 2019, the number of HRM and POEM procedures decreased by 17.2% (1587-1314) and 20.9% (630-498), respectively. These declines were prominent during the state of emergency from April to May 2020, particularly in pandemic areas. HRM and POEM in nonpandemic areas were relatively unaffected. From 2019 to 2020, there was a 0.4% (254-248) decrease in POEM cases within the prefecture, but the number outside the prefecture decreased by 33.6% (372-247). During the pandemic, the safety and efficacy of POEM were maintained. The implementation of personal protective equipment (PPE) measures varied among facilities, and PPE for POEM was relatively insufficient compared to that for HRM., Conclusion: The COVID-19 pandemic influenced HRM and POEM practices in Japan. It is necessary to establish a sufficient system for HRM and POEM in each hospital as well as countrywide to overcome the effects of the pandemic., (© 2021 Japan Gastroenterological Endoscopy Society.)

Background and Aim: The perioperative management and clinical course of per-oral endoscopic myotomy for patients receiving antithrombotic therapy remains unknown. This study aimed to clarify the status of antithrombotic therapy in per-oral endoscopic myotomy and to determine its safety and efficacy., Methods: Patients treated with per-oral endoscopic myotomy from 2010 to 2019 in seven high-volume centers in Japan were retrospectively investigated. The patients' characteristics and antithrombotic agent management were analyzed; clinical outcomes were compared with those without antithrombotic agents., Results: Of 2752 patients who underwent per-oral endoscopic myotomy, 120 patients on antithrombotic therapy (mean age 71.0 years, American Society of Anesthesiologists class II-IV [67.5%]) were identified. Antiplatelet, anticoagulant, and a combination of antithrombotic agents were used in 82, 30, and 8 patients, respectively. The perioperative management adhered to the therapeutic endoscopy guidelines published by the Japanese Society of Gastroenterological Endoscopy in most patients (88.3%). A poorer clinical baseline status (American Society of Anesthesiologists class II-IV; 67.0% vs 24.3%) and the sigmoid type (40.7% vs 22.3%) were more frequently observed in patients with achalasia on antithrombotic therapy. However, the clinical success (Eckardt score ≤ 3; 97.6% vs 94.6) and adverse event rates, such as bleeding and thromboembolic events (5.5% vs 4.7%), did not show inferiority., Conclusions: Per-oral endoscopic myotomy on antithrombotic therapy is safe and effective. However, caution is required as patients on antithrombotic therapy tend to have poorer baseline health and achalasia statuses. Our experience should help establish perioperative management with antithrombotic therapy., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Artificial intelligence (AI) and computer vision (CV) have revolutionized image analysis. In surgery, CV applications have focused on surgical phase identification in laparoscopic videos. We proposed to apply CV techniques to identify phases in an endoscopic procedure, peroral endoscopic myotomy (POEM)., Methods: POEM videos were collected from Massachusetts General and Showa University Koto Toyosu Hospitals. Videos were labeled by surgeons with the following ground truth phases: (1) Submucosal injection, (2) Mucosotomy, (3) Submucosal tunnel, (4) Myotomy, and (5) Mucosotomy closure. The deep-learning CV model-Convolutional Neural Network (CNN) plus Long Short-Term Memory (LSTM)-was trained on 30 videos to create POEMNet. We then used POEMNet to identify operative phases in the remaining 20 videos. The model's performance was compared to surgeon annotated ground truth., Results: POEMNet's overall phase identification accuracy was 87.6% (95% CI 87.4-87.9%). When evaluated on a per-phase basis, the model performed well, with mean unweighted and prevalence-weighted F1 scores of 0.766 and 0.875, respectively. The model performed best with longer phases, with 70.6% accuracy for phases that had a duration under 5 min and 88.3% accuracy for longer phases., Discussion: A deep-learning-based approach to CV, previously successful in laparoscopic video phase identification, translates well to endoscopic procedures. With continued refinements, AI could contribute to intra-operative decision-support systems and post-operative risk prediction.

Objectives: High‐resolution manometry (HRM) and esophagography are used for achalasia diagnosis; however, achalasia phenotypes combining esophageal motility and morphology are unknown. Moreover, predicting treatment outcomes of peroral endoscopic myotomy (POEM) in treatment‐naïve patients remains an unmet need. Methods: In this multicenter cohort study, we included 1824 treatment‐naïve patients diagnosed with achalasia. In total, 1778 patients underwent POEM. Clustering by machine learning was conducted to identify achalasia phenotypes using patients' demographic data, including age, sex, disease duration, body mass index, and HRM/esophagography findings. Machine learning models were developed to predict persistent symptoms (Eckardt score ≥3) and reflux esophagitis (RE) (Los Angeles grades A–D) after POEM. Results: Machine learning identified three achalasia phenotypes: phenotype 1, type I achalasia with a dilated esophagus (n = 676; 37.0%); phenotype 2, type II achalasia with a dilated esophagus (n = 203; 11.1%); and phenotype 3, late‐onset type I–III achalasia with a nondilated esophagus (n = 619, 33.9%). Types I and II achalasia in phenotypes 1 and 2 exhibited different clinical characteristics from those in phenotype 3, implying different pathophysiologies within the same HRM diagnosis. A predictive model for persistent symptoms exhibited an area under the curve of 0.70. Pre‐POEM Eckardt score ≥6 was the greatest contributing factor for persistent symptoms. The area under the curve for post‐POEM RE was 0.61. Conclusion: Achalasia phenotypes combining esophageal motility and morphology indicated multiple disease pathophysiologies. Machine learning helped develop an optimal risk stratification model for persistent symptoms with novel insights into treatment resistance factors. [ABSTRACT FROM AUTHOR]