Jan Martinek

10.1055/a-2718-4945 In the above-mentioned article the Graphical abstract has been corrected. This was corrected in the online version on November 25, 2025. Article published online: 25 November 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Gastroparesis is predominantly caused by diabetes mellitus or vagal nerve injury post-surgery. About 30% of patients develop gastroparesis after esophagectomy with gastric pull-through. Standard treatments often fail, and endoscopic pyloromyotomy (G-POEM) has shown promising results. This study aimed to assess the efficacy and safety of G-POEM in patients with refractory gastroparesis after esophagectomy. A multicenter retrospective cohort study was conducted across 18 expert centers. Patients who underwent G-POEM for refractory gastroparesis following esophagectomy from August 2014 to December 2023 were included. Inclusion criteria were confirmed gastroparesis by scintigraphy, a mean Gastroparesis Cardinal Symptom Index (GCSI) of at least 1.0, and a minimum of 6 months of follow-up. The primary outcome was treatment success at 6 months, defined as a ≥50% decrease in the GCSI score. Of 113 G-POEM procedures, 108 patients (median age 65 years; 75% men) met the inclusion criteria. The primary indication for esophagectomy was adenocarcinoma (75.5%). At 6 months, 63.5% (95%CI 54.1%–72.0%) achieved clinical success, with the mean GCSI significantly decreased to 1.2 (95%CI 1.0–1.4) from 2.9 (95%CI 2.7–3.1) preprocedure. Minor adverse events occurred in 2.8% of cases. Long-term follow-up showed sustained efficacy with success rates of 54.9% and 66.1% at 12 and 24 months, respectively. G-POEM appears to be a safe and effective treatment for refractory gastroparesis in post-esophagectomy patients, achieving significant symptom relief in the majority of patients. Future prospective studies are necessary to further validate these findings and explore predictive factors for treatment success.

Background: Idiopathic achalasia (IA) is characterised by the degeneration of neurons in the myenteric plexus leading to an irreversible impaired oesophageal function. Although immune-mediated mechanisms have been proposed, the underlying aetiopathology of IA remains poorly understood. Objective: This study aimed to uncover the genetic risk architecture of IA. Design: We carried out the first genome-wide association study (GWAS) on 4602 European patients with IA and 10 766 ethnically-matched controls. Results: A single nucleotide polymorphism (SNP) in HLA-DQB1 leading to an 8-amino acid insertion on the protein level conferred strongest IA risk (PQGPPPAG: p=3.27×10 ^–68 , OR=2.45). Conditional analyses within the HLA locus revealed a complex genetic risk architecture. Three additional amino acid positions showed independent IA association (Omnibus p−8 ). These refer to positions 41 and 130 in HLA-DQα1, position 45 in HLA-DQβ1 and position 86 in HLA-DRβ1. Together, these findings highlight the pivotal role of class II HLA genetic variation in IA pathogenesis. Outside HLA, three independent variants showed IA association (p−8 ). One leads to an amino acid substitution with functional effect in PTPN22. Another risk variant leads to a downregulated expression of TNFSF8 , TNFSF15 and TNC in immune cells. The third risk SNP is located near ZNF365 , but the exact underlying cellular mechanism remains unknown. Beyond the single marker level, polygenic risk scores revealed that patients with IA can be stratified based on their genetic risk. In addition, IA shows a shared aetiopathology with Crohn’s disease (r _g =0.335). Integrating GWAS and single-cell RNA-sequencing data from the myenteric plexus showed that the memory T-cell type FOS ⁺ Tc4 ⁺ CD8 ⁺ plays a central role in IA development (p=2.50×10 ⁻¹⁹ ). Conclusion: This GWAS led to the identification of SNPs, cellular mechanisms and cell types that are involved in IA aetiopathology.

Gastroparesis is a serious condition with complex pathophysiology. Treatment of gastroparesis might be a real challenge because there is no universal therapy suitable for all patients. Invasive approaches should never be applied as first-line treatments, and management of patients with gastroparesis should start with dietary measures, pharmacotherapy (a wide range of medications such as prokinetics, neuromodulators, and antiemetics are available) and alternative approaches such as hypnotherapy. Pylorospasm – or more accurately, pyloric muscle that does not function correctly during digestion – is considered an important pathophysiological factor responsible for the development of gastroparesis. As a result, increasing attention is being paid to therapies targeting the pylorus, which aim to relieve its presumed spasm. Endoscopic pyloromyotomy (G-POEM) is currently the most studied pylorus-targeted therapy, achieving clinical success in about 50%–75% of cases. It means that about two-thirds of patients experience symptomatic relief (however, no cure) but approximately one-third of patients remain without adequate clinical improvement. G-POEM (in contrast to gastric electrical stimulation) also accelerates gastric emptying. However, there is no correlation between clinical effect and improvement in gastric emptying. Two randomized trials showed superiority of G-POEM over sham procedure or botulinum toxin injection [1] [2]. These studies proved that pylorospasm is partially responsible for symptoms in about two-thirds of patients with gastroparesis. In this issue of Endoscopy, Farooq et al. report on a large prospective study on whether assessment of pyloric function using functional intraluminal imaging probe (FLIP) may predict symptomatic response to G-POEM [3]. Overall treatment success was achieved in 71.1% of the patients at 6 months. The authors obtained FLIP values prior to and immediately after G-POEM and then at 6 months. Responders had significantly lower baseline distensibility index (DI, at 40 mL filling volume) compared with non-responders (7.10 [SD 2.75] vs. 9.24 [3.14] mm²/mmHg; P = 0.002), and a baseline DI value below 7.35 mm²/mmHg predicted clinical success with 81% specificity. DI increased in all patients immediately after the procedure, but at 6 months, increased DI value remained only in responders while in non-responders, DI decreased to values measured at baseline. The authors suggest that “recurrent” pylorospasm due to less compliant pylorus – maybe because of fibrosis – may be responsible. However, when looking at absolute DI values at 6 months, they were very similar between responders and non-responders (10.44 [SD 4.4] vs. 9.68 [SD 4.7]). Finally, the authors found that clinical success after G-POEM and FLIP values were in no way influenced by previous botulinum toxin injection. Botulotoxin toxin injection has been used in several centers to select patients with gastroparesis for G-POEM. However, the recent study is in line with the recommendation of several societies (European Society of Gastrointestinal Endoscopy, American Society for Gastrointestinal Endoscopy, and American Gastroenterological Association) not to recommend botulinum toxin as a selection tool for G-POEM [4]. Other studies have also analyzed impedance planimetry in patients undergoing G-POEM, but the results are conflicting and inconsistent. The problem is that several cutoff values of DI or cross-sectional area have been suggested to predict clinical success or failure. The studies are only consistent in terms of increased values of both DI and cross-sectional area after G-POEM. For example, Vosoughi et al. found a cutoff post-G-POEM cross-sectional area of >154 mm² to predict 1-year clinical success [5]. In a randomized study, post G-POEM DI values >13 mm²/mmHg were associated with clinical success [1]. These results are consistent with the logical assumption that the more the pylorus is relaxed, the greater is the therapeutic success. However, a real predictor should be available before, not after the procedure. In terms of impedance planimetry, two studies reported such a predictor. Jacques et al. identified a distensibility threshold of 9.2 mm²/mmHg before the G-POEM that predicted a clinical response with 100% specificity and 72.2% sensitivity [6]. In the present study, which is more robust in terms of patient number and the inclusion of three systematic planimetry measurements, the authors identified a pre-G-POEM distensibility threshold of 7.35 mm²/mmHg as a predictor of clinical success [3]. However, due to low sensitivity (60.6%) and negative predictive value (46.7%), it is obvious that should these thresholds be used in clinical practice, many potential responders would be missed. Should impedance planimetry (FLIP) be performed systematically before and after G-POEM? The measurement before G-POEM should be a standard part of the preoperative assessment, as well as distensibility measurement after the procedure, especially in non-responders. Patients should be provided with information about the possible probability of treatment success based on the measured values. If performed during the procedure, it may also help to guide sufficient myotomy even if most endoscopists recognize it without the measurement. Post-procedure impedance planimetry measurement may identify those with a recurrent/residual pylorospasm who might benefit from repeat G-POEM. But should FLIP be used for patient selection? At present, patients not fulfilling the present cutoff planimetry values (e.g. high baseline DI) should not be denied G-POEM. Therefore, FLIP itself should not be used for patient selection because the predictive values are not accurate enough. The fundamental question is whether we really need predictors of clinical success/failure of endoscopic pyloromyotomy. If predictors are reliable enough, their usefulness would not be in doubt. However, if the prediction is not strong enough? We should also keep in mind that endoscopic pyloromyotomy is a very safe procedure. If it does not have good clinical effect, it does not harm the patients. Moreover, as already mentioned, all treatment modalities in gastroparesis have limited efficacy. For example, electrical stimulation is effective in about 60% of patients and reliable predictors of efficacy are not well established [7]. Finally, several studies identified different predictors based on clinical or other aspects related to gastroparesis. These include presence or absence of specific symptoms (less nausea, more fullness and bloating), severity of symptoms, severity of gastric retention rate on gastric scintigraphy, etiology of gastroparesis etc. [8]. As with FLIP, there is significant inconsistency in what may predict treatment success/failure. Such inconsistency likely reflects the complexity of gastroparesis as a disease. It is obvious that gastroparesis is not only about the pylorus, and endoscopists should keep this in mind. Article published online: 22 July 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

1 A POEM equipment checklist should be used before commencing the procedure to ensure the availability and proper functioning of all necessary materials. 2 A thorough esophageal cleansing before mucosal incision is mandatory. There should be no residual dietary liquid or food in the lumen. 3 Use at least 5–10 mL of lifting agent, which should be injected using a needle at the desired point where the mucosotomy will commence. 4 To create the mucosotomy, the first incision should be made at the site of previous injection with the fewest possible taps on the electrosurgical unit using a cutting mode, with the knife tip at 45–80° to the mucosal surface. 5 After adequate submucosal injection (through a needle or knife), the incision should be extended by 1.5–2 cm in the longitudinal axis from cranial to caudal, in the planned direction of the tunnel. 6 Dissection within the tunnel should be performed using sequential injection of saline and chromic dye (if available using the knife jet function) and dissection with the knife. Pushing the endoscope forward gently against the advancing submucosa–muscularis propria interface is important to facilitate mucosal tunneling. 7 The myotomy should be performed in a cranial to caudal manner, starting 2 cm or more below the caudal extent of the mucosotomy site. 8 ESGE recommends that the myotomy should be extended 2–3 cm distal to the gastroesophageal junction to allow complete disruption of the lower esophageal sphincter. 9 ESGE recommends that POEM can be performed on either the anterior (1–2 o’clock in supine position) or posterior (5–6 o’clock) side. 10 ESGE recommends that the myotomy length should be tailored to the disease being treated, with evidence favoring short esophageal-side myotomy if indicated because of decreased adverse events and procedure times. 11 ESGE recommends the use of through-the-scope clips for mucosal closure owing to their high efficacy and availability, and lower price compared with other closure methods. 12 Mucosal injury during POEM should be proactively sought during the procedure and particularly before completion. Mucosal injury can be represented on a spectrum from whitening of the overlying mucosa to a full-thickness perforation. 13 ESGE recommends performing POEM using low flow CO₂ insufflation. 14 In the absence of adverse events, resume fluids on day 1, soft diet on day 3, and normal diet on day 7 post-POEM. 15 ESGE recommends against the routine use of standard or computed tomography fluoroscopic esophagrams after POEM in asymptomatic patients. ^‡ joint first co-authorship. ^* joint senior authors. Article published online: 28 May 2025 © 2025. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Main Recommendations: Peroral endoscopic myotomy (POEM) is an advanced endoscopic procedure that has become a first-line treatment for esophageal achalasia and other esophageal spastic disorders. Structured training is essential to optimize the outcomes of this technique. The European Society of Gastrointestinal Endoscopy (ESGE) has recognized the need to formalize and enhance training in POEM. This Position Statement presents the results of a systematic review of the literature and a formal Delphi process, providing recommendations for an optimal training program in POEM that aims to produce endoscopists competent in this procedure. In a separate document (POEM curriculum Part II), we provide technical guidance on how to perform the POEM procedure based on the best available evidence. 1 POEM trainees should acquire a comprehensive theoretical knowledge of achalasia and other esophageal motility disorders that encompasses pathophysiology, diagnostic tool proficiency, clinical outcome assessment, potential adverse events, and periprocedural management. 2 Experience in advanced endoscopic procedures (endoscopic mucosal resection and/or endoscopic submucosal dissection [ESD]) is encouraged as a beneficial prerequisite for POEM training. 3 ESGE suggests that POEM trainees without ESD experience should perform an indicative minimum number of 20 cases on ex vivo or animal models before advancing to human POEM cases with an experienced trainer. 4 ESGE recommends that the trainee should observe an indicative minimum number of 20 live cases at expert centers before starting to perform POEM in humans. 5 The trainee should undertake an indicative minimum number of 10 cases under expert supervision for the initial human POEM procedures, ensuring that trainees can complete all POEM steps independently. 6 ESGE recommends avoiding complex POEM cases during the early training phase. 7 POEM competence should reflect the technical success rate, both the short- and long-term clinical success rates, and the rate of true adverse events. 8 A POEM center should maintain a prospective registry of all procedures performed, including patient work-up and outcomes, procedural techniques, and adverse events.

Background/Objectives: Tacrine is a centrally active non-competitive reversible acetylcholinesterase inhibitor. It also exerts antagonising activity against N-methyl-D-aspartate receptors. Tacrine was approved for the treatment of Alzheimer’s disease in 1993, but was withdrawn from clinical use in 2013 because of its hepatotoxicity and gastrointestinal side effects. Nevertheless, tacrine is currently facing a renewed wave of interest primarily due to several new tacrine-incorporated hybrids and derivates. There were two specific aims for this study: firstly, to explain the mechanisms of the adverse action of tacrine, as a distinctive example of a highly effective acetylcholinesterase inhibitor; and secondly to check whether luminal impedance planimetry is feasible for preclinical testing of possible side effects of compounds potentially toxic to the gastrointestinal tract. Methods: Six experimental pigs were used as the animal model in this study. Five major parameters were evaluated: luminal pressure (mmHg), estimated diameter (mm), cross-sectional area (mm²), distensibility (mm²/mmHg), and zone compliance (mm³/mmHg). All measurements were performed before and 360 min after intragastric administration of 200 mg tacrine (at the porcine tacrine T_max). Results: This study consistently demonstrated an increase in luminal pressure (a directly measured indicator) for the particular balloon filling volumes used, and inversely a reciprocal decrease in the other parameters after tacrine administration. Conclusions: Endoscopic luminal impedance planimetry is a feasible method to evaluate functional response of the lower oesophageal sphincter to tacrine in experimental pigs. Tacrine did not compromise the function of the lower oesophageal sphincter either toward oesophageal spasms or, in contrast, decreased competence of the lower oesophageal sphincter.

Background Peroral endoscopic myotomy (POEM) is nowadays a standard method for treatment of achalasia; nevertheless, it remains an invasive intervention with corresponding risk of adverse events (AEs). The classification and grading of AEs are still a matter of discussion. The aim of our retrospective study was to assess the occurrence of all “undesirable” events and “true” adverse events in patients undergoing POEM and to compare the outcomes when either Clavien–Dindo classification (CDC) or American Society of Gastrointestinal Endoscopy (ASGE) lexicon classification applied. Methods This was a retrospective analysis of prospectively managed database of all patients who had undergone POEM between December 2012 and August 2018. We assessed the pre-, peri-, and early-postoperative (up to patient’s discharge) undesirable events (including those not fulfilling criteria for AEs) and “true” AEs according the definition in either of the classifications. Results A total of 231 patients have successfully undergone 244 POEM procedures (13 × re-POEM). Twenty-nine procedures (11.9%) passed uneventfully, while in 215 procedures (88.1%), a total of 440 undesirable events occurred. The CDC identified 27 AEs (17 minor, 10 major) occurring in 23/244 (9.4%) procedures. The ASGE lexicon identified identical 27 AEs (21 mild or moderate, 6 severe or fatal) resulting in the severity distribution of AEs being the only difference between the two classifications. Only the absence of previous treatment was found to be a risk factor [p = 0.047, OR with 95% CI: 4.55 (1.02; 20.25)] in the combined logistic regression model. Conclusion Undesirable events are common in patients undergoing POEM but the incidence of true AEs is low according to both classifications. Severe adverse events are infrequent irrespective of the classification applied. CDC may be more appropriate than ASGE lexicon for classifying POEM-related AEs given a surgical nature of this procedure. Graphical abstract