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ZusammenfassungIn jüngster Zeit wurden in der Therapie der eosinophilen Ösophagitis (EoE) und insbesondere im Bereich der topischen Corticosteroide erhebliche Fortschritte erreicht. Neue EoE-spezifische Darreichungsformen wurden entwickelt und haben in Form der orodispersiblen Budesonid-Tablette zu der ersten in Deutschland und anderen europäischen und außereuropäischen Ländern zugelassenen Therapie der EoE bei Erwachsenen geführt. In den USA steht eine EoE-spezifische orale Budesonid-Suspension kurz vor der Zulassung. Dagegen bleibt die wissenschaftliche Datenlage zur Wirksamkeit von Protonenpumpeninhibtoren weiterhin limitiert. Auch im Bereich der Biologika konnten nach langer Zeit Substanzen identifiziert werden, die erstmals in Phase 2 sehr vielversprechende Ergebnisse gezeigt haben und sich derzeit in klinischen Prüfungen der Phase 3 befinden. In diesem Artikel sollen die aktuellen Fortschritte und Perspektiven in der Therapie der EoE dargestellt und diskutiert werden.

Background: A novel budesonide orodispersible tablet (BOT) has been proven effective in adult patients with active eosinophilic oesophagitis (EoE) in a 6-week placebo-controlled trial (EOS-1). Aims: To report the efficacy of an open-label induction treatment with BOT in a large prospective cohort of EoE patients within the EOS-2 study. Methods: Patients with clinico-histological active EoE were treated with BOT 1 mg BID for 6 weeks. The primary endpoint was clinico-histological remission (≤2 points on numerical rating scales [0–10] each for dysphagia and odynophagia, and peak eosinophil count

Background and Aims Direct endoscopic necrosectomy (DEN) of walled-off pancreatic necrosis (WOPN) lacks dedicated instruments and requires repetitive and cumbersome procedures. This study evaluated the safety and efficacy of a new powered endoscopic debridement (PED) system designed to simultaneously resect and remove solid debris within WOPN. Methods This was a single-arm, prospective, multicenter, international device trial conducted from November 2018 to August 2019 at 10 sites. Patients with WOPN ≥6 cm and ≤22 cm and with >30% solid debris were enrolled. The primary endpoint was safety through 21 days after the last DEN procedure. Efficacy outcomes included clearance of necrosis, procedural time, adequacy of debridement, number of procedures until resolution, hospital stay duration, and quality of life. Results Thirty patients (mean age, 55 years; 60% men) underwent DEN with no device-related adverse events. Of 30 patients, 15 (50%) achieved complete debridement in 1 session and 20 (67%) achieved complete debridement within 2 or fewer sessions. A median of 1.5 interventions (range, 1-7) were required. Median hospital stay was 10 days (interquartile range, 22). There was an overall reduction of 91% in percent necrosis within WOPN from baseline to follow-up and 85% in collection volume. Baseline WOPN volume was positively correlated with the total number of interventions (ρ = .363, P = .049). Conclusions The new PED system seems to be a safe and effective treatment tool for WOPN, resulting in fewer interventions and lower hospital duration when compared with published data on using conventional instruments. Randomized controlled trials comparing the PED system with conventional DEN are needed. (Clinical trial registration number: NCT03694210 .)

Background Motorized spiral enteroscopy (MSE) has been shown to be safe and effective for deep enteroscopy in studies performed at expert centers with limited numbers of patients without previous abdominal surgery. This study aimed to investigate the safety, efficacy, and learning curve associated with MSE in a real-life scenario, with the inclusion of patients after abdominal surgery and with altered anatomy. Methods Patients with indications for deep enteroscopy were enrolled in a prospective observational multicenter study. The primary objective was the serious adverse event (SAE) rate; secondary objectives were the diagnostic and therapeutic yield, procedural success, time, and insertion depth. Data analysis was subdivided into training and core (post-training) study phases at centers with different levels of MSE experience. Results 298 patients (120 women; median age 68, range 19–92) were enrolled. In the post-training phase, 21.5 % (n = 54) had previous abdominal surgery, 10.0 % (n = 25) had surgically altered anatomy. Overall, SAEs occurred in 2.3 % (7/298; 95 %CI 0.9 %–4.8 %). The SAE rate was 2.0 % (5/251) in the core group and 4.3 % (2/47) in the training group, and was not increased after abdominal surgery (1.9 %). Total enteroscopy was achieved in half of the patients (n = 42) undergoing planned total enteroscopy. In 295/337 procedures (87.5 %), the anatomical region of interest could be reached. Conclusions This prospective multicenter study showed that MSE was feasible and safe in a large cohort of patients in a real-life setting, after a short learning curve. MSE was shown to be feasible in postsurgical patients, including those with altered anatomy, without an increase in the SAE rate.

Background & Aims: There are no studies or recommendations on optimal monitoring strategies for patients with eosinophilic esophagitis (EoE). Our objective was to develop guidance on how to monitor patients with EoE in routine clinical practice, on the basis of available clinical evidence and expert opinion. Methods: A multidisciplinary, international group of EoE experts identified the following important 3 questions during several consensus meetings: why, by what means, and when to monitor patients with EoE. A steering committee was named, and 3 teams were formed to review literature and to formulate statements for each topic. In a Delphi survey, a level of agreement of ?75% was defined as threshold value for acceptance. In a final conference, results were presented, critical points and comments on the statements were discussed, and statements were rephrased/rewritten if necessary. Results: Eighteen EoE experts (14 adult and pediatric gastroenterologists, 2 pathologists and 2 allergists) with a median of 21.7 years in clinical practice, mostly academic or university-based, completed the Delphi survey, which included 11 statements and a proposed algorithm for monitoring patients with EoE. Each statement attained ?75% agreement. Participants discussed and debated mostly about the statement concerning surveillance intervals for EoE patients with stable disease. Conclusions: It was concluded that effective maintenance treatment probably reduces the development of EoE complications, and regular, structured, and, under certain conditions, individualized clinical follow-up is recommended to assess disease activity while opening a window to monitoring side effects, adjusting therapy, and encouraging adherence to treatment. Follow-up should comprise symptom assessment and periodic or repeated endoscopy with histological assessment in specific EoE settings.

The Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS) collaborators are a group of more than 70 gastroenterologists, pathologists, allergists, researchers, dietitians, psychologists, and methodologists who convened in a series of in-person and virtual meetings between 2018 and 2020 with the aim of developing a core outcome set (COS) for use in therapeutic studies of pharmacologic and dietary therapies for the treatment of eosinophilic esophagitis (EoE). Given heterogeneity in reported outcomes and uncertainties regarding the most appropriate end points for use in both randomized controlled trials (RCTs) and observational studies involving EoE patients, the EoE experts launched the COREOS exercise in 2018 to standardize outcome definitions using methods established by the Core Outcome Measures in Effectiveness Trials (COMET) initiative.1,2 The COS was developed using a multiphase approach, which is summarized in Figure 1. In the first phase, systematic reviews of the literature and patient engagement surveys were conducted to identify candidate outcomes that have been previously measured and are important to patients with EoE. Next, this information was used to build a framework of different outcome domains, and working groups for each domain were assembled to review the literature for relevant end points.3–6 The relative importance of these domains was categorized in a Delphi survey as core, important, and research agenda domains, and discussed in a moderated in-person meeting on May 17, 2019 at Digestive Disease Week (San Diego, CA). In phase 3, a comprehensive list of outcome measures within each of the core domains was evaluated by the COREOS collaborators in a 2-round Delphi survey and, finally, outcomes were ratified in a virtual meeting on December 8, 2020. In this meeting summary, we highlight the major points of discussion that occurred during the development of the EoE COS.

Main RecommendationsThe European Society of Gastrointestinal Endoscopy (ESGE) has recognized the need to formalize and enhance training in endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS). This manuscript represents the outcome of a formal Delphi process resulting in an official Position Statement of the ESGE and provides a framework to develop and maintain skills in ERCP and EUS. This curriculum is set out in terms of the prerequisites prior to training; recommended steps of training to a defined syllabus; the quality of training; and how competence should be defined and evidenced before independent practice. 1 Trainees should be competent in gastroscopy prior to commencing training. Formal training courses and the use of simulation in training are recommended. 2 Trainees should keep a contemporaneous logbook of their procedures, including key performance indicators and the degree of independence. Structured formative assessment is encouraged to enhance feedback. There should be a summative assessment process prior to commencing independent practice to ensure there is robust evidence of competence. This evidence should include a review of a trainee’s procedure volume and current performance measures. A period of mentoring is strongly recommended in the early stages of independent practice. 3 Specifically for ERCP, all trainees should be competent up to Schutz level 2 complexity (management of distal biliary strictures and stones > 10 mm), with advanced ERCP requiring a further period of training. Prior to independent practice, ESGE recommends that a trainee can evidence a procedure volume of > 300 cases, a native papilla cannulation rate of ≥ 80 % (90 % after a period of mentored independent practice), complete stones clearance of ≥ 85 %, and successful stenting of distal biliary strictures of ≥ 90 % (90 % and 95 % respectively after a mentored period of independent practice). 4 The progression of EUS training and competence attainment should start from diagnostic EUS and then proceed to basic therapeutic EUS, and finally to advanced therapeutic EUS. Before independent practice, ESGE recommends that a trainee can evidence a procedure volume of > 250 cases (75 fine-needle aspirations/biopsies [FNA/FNBs]), satisfactory visualization of key anatomical landmarks in ≥ 90 % of cases, and an FNA/FNB accuracy rate of ≥ 85 %. ESGE recognizes the often inadequate quality of the evidence and the need for further studies pertaining to training in advanced endoscopy, particularly in relation to therapeutic EUS.

Endoscopic treatment of pancreatic necrosis can be challenging and time-consuming because sticky necrotic debris is sometimes difficult to remove. The over-the-scope-grasper, a new tool that has recently become available for this purpose, might also be useful for other indications. However, clinical data on the efficacy and safety of this new device are lacking.To evaluate the technical success and safety of the device in a multicenter setting.The over-the-scope-grasper was used in nine selected endoscopic centers between November 2020 and October 2021 for appropriate indications. Overall, 56 procedures were included in the study. We retrospectively evaluated procedural parameters of all endoscopic interventions using a predefined questionnaire, with special respect to technical success, indications, duration of intervention, type of sedation, and complications. In the case of pancreatic necrosectomy, the access route, stent type, number of necrosis pieces removed, and clinical handling were also recorded.A total of 56 procedures were performed, with an overall technical success rate of 98%. Most of the procedures were endoscopic pancreatic necrosectomies (33 transgastric, 4 transduodenal). In 70% of the procedures, access to the necrotic cavity was established with a lumen apposing metal stent. The technical success of pancreatic necrosectomy was 97%, with a mean of 8 pieces (range, 2-25 pieces) of necrosis removed in a mean procedure time of 59 min (range, 15-120 min). In addition, the device has been used to remove blood clots (These first multicenter data demonstrate that the over-the-scope-grasper is a promising device for endoscopic pancreatic necrosectomy, which is also appropriate for removing foreign bodies and blood clots, or cleaning insufficiency cavities prior to endoluminal vacuum therapy.

In patients with altered upper gastrointestinal anatomy, conventional endoscopic retrograde cholangiography is often not possible and different techniques, like enteroscopy-assisted or percutaneous approaches are required. Aim of this study was to analyze success and complication rates of these techniques in a large collective of patients in the daily clinical practice in a pre-endosonographic biliary drainage era. Patients with altered upper gastrointestinal anatomy with biliary interventions between March 1st, 2006, and June 30th, 2014 in four tertiary endoscopic centers in Munich, Germany were retrospectively analyzed. At least one endoscopic-assisted biliary intervention was successful in 234/411 patients (56.9%)—in 192 patients in the first, in 34 patients in the second and in 8 patients in the third attempt. Success rates for Billroth-II/Whipple-/Roux-en-Y reconstruction were 70.5%/56.7%/49.5%. Complication rates for these reconstructions were 9.3%/6.5%/6.3%, the overall complication rate was 7.1%. Success rates were highest in patients with Billroth-II reconstruction where use of a duodenoscope was possible, complication rates were also highest in this scenario. Success rates were lowest in longer-limb anatomy like Roux-en-Y reconstruction. Percutaneous biliary drainages (PTBD) were inserted 268 times with substantially higher success (90.7%) as well as complication rates (11.6%) compared to the endoscopic approach. Compared to patients treated endoscopically, patients with PTBD had a lower performance status, more severe cholestasis and a significant higher rate of malignant underlying disease. In patients with altered upper gastrointestinal anatomy, success rates of endoscopic-assisted biliary interventions are lower compared to PTBD. Still, due to the beneficial complication rates of the endoscopic approach, this technique should be preferred whenever possible and in selected patients who still need to be defined in detail, repeated endoscopic attempts are useful to help achieve the desired result.

Background Endoscopic vacuum therapy (EVT) has emerged as a novel treatment option for upper gastrointestinal wall defects. The basic principle of action of EVT entails evacuation of secretions, removal of wound debris, and containment of the defect. Furthermore, there is increasing evidence that EVT reduces interstitial edema, increases oxygen saturation, and promotes tissue granulation and microcirculation. Various devices, such as macroporous polyurethane sponge systems or open-pore film drains, have been developed for specific indications. Depending on the individual situation, EVT devices can be placed in- or outside the intestinal lumen, as a stand-alone procedure, or in combination with surgical, radiological, and other endoscopic interventions. Purpose The aim of this narrative review is to describe the current spectrum of EVT in the upper gastrointestinal tract and to assess and summarize the related scientific literature. Conclusions There is growing evidence that the efficacy of EVT for upper GI leakages exceeds that of other interventional treatment modalities such as self-expanding metal stents, clips, or simple drainages. Owing to the promising results and the excellent risk profile, EVT has become the therapy of choice for perforations and anastomotic leakages of the upper gastrointestinal tract in many centers of expertise. In addition, recent clinical research suggests that preemptive use of EVT after high-risk upper gastrointestinal resections may play an important role in reducing postoperative morbidity.

Background and study aims Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) with lumen-apposing metal stents (LAMS) appears to be a promising intervention in management of gastroduodenal out obstruction (GOO), particularly for patients for whom surgery is high risk or in a palliative setting. This study aimed to evaluate the technical feasibility, procedure-associated adverse events (AEs), and clinical outcome of direct “free hand” EUS-GE. Patients and methods This retrospective two-center study included patients who underwent direct “free hand” EUS-GE (April 2017 to March 2021) investigating technical success (correctly placed LAMS), clinical outcome (successful oral nutrition), and management of procedure-associated AEs. “Free hand” was defined as the use of the electrocautery enhanced stent delivery system alone without additional guidewire-assistance for EUS-GE creation. Results Forty-five patients (58 % women/42 % men; mean age 65 years) with malignant (n = 39), benign (n = 4) or unclear (n = 2) GOO underwent direct “free hand” EUS-GE. The technical success rate was 98 % (44/45). Of the patients, 95% (42/44) had less vomiting and increased ability to tolerate oral food intake after the intervention. In one patient, a second EUS-GE was necessary to achieve sufficient clinical improvement. Procedure-associated AEs were observed in 24 % (11/45) of cases including stent misplacement (n = 7), leakage (n = 1), development of a gastrojejunocolic fistula (n = 1), and bleeding (n = 2), which could be all managed endoscopically. Conclusions Direct EUS-GE has a favorable risk-benefit profile for patients with GOO, showing high technical success rates, manageable AEs, and rapid symptom relief.

Background Malignant tumors of the esophagus are the sixth leading cause of cancer-related deaths worldwide. Postoperative leakage of the esophago-gastrostomy leads to mediastinal sepsis, which is still associated with a high morbidity and mortality rate. The aim of this study was to describe the endoscopic view of the different severity grades of an anastomotic leakage. MethodsPatients Between June 2016 and September 2018, 144 patients were operated upon in the Department of Surgery, University of Munich, Germany. Among these patients, 34 (23.6%) presented with a leakage of the anastomosis. EndoscopyIn this retrospective analysis the focus is to describe different patterns of leakage of the anastomosis. Results We studied 34 patients in whom post-esophagectomy leakage of the anastomosis was detected and treated with an endoluminal vacuum sponge system. The leakage healed in 26 of 29 patients (success rate 89.7%). With increasing severity of leakage, the treatment time and the in-hospital mortality correspondingly increased. Furthermore, the incidence of development of a fistula to the tracheobronchial system increased with higher grades of leakage. ConclusionsExact descriptions of leakage are necessary to compare the cases and to prove post-treatment improvement. This is, to our knowledge, the first publication to present a leakage grading score in patients after esophagectomy including reconstruction with a gastric tube. This new grading system needs to be tested in further analyses, with special focus on prospective analysis.

Background Malignant tumors of the esophagus are the sixth leading cause of cancer-related deaths worldwide. Postoperative leakage of the esophago-gastrostomy leads to mediastinal sepsis, which is still associated with a high morbidity and mortality rate. The aim of this study was to describe the endoscopic view of the different severity grades of an anastomotic leakage. Methods Patients Between June 2016 and September 2018, 144 patients were operated upon in the Department of Surgery, University of Munich, Germany. Among these patients, 34 (23.6%) presented with a leakage of the anastomosis. Endoscopy In this retrospective analysis, the focus is to describe different patterns of leakage of the anastomosis. Results We studied 34 patients in whom post-esophagectomy leakage of the anastomosis was detected and treated with an endoluminal vacuum sponge system. The leakage healed in 26 of 29 patients (success rate 89.7%). With the increasing severity of leakage, the treatment time and the in-hospital mortality correspondingly increased. Furthermore, the incidence of the development of a fistula to the tracheobronchial system increased with higher grades of leakage. Conclusions Exact descriptions of leakage are necessary to compare the cases and to prove post-treatment improvement. This is, to our knowledge, the first publication to present a leakage grading score in patients after esophagectomy including reconstruction with a gastric tube. This new grading system needs to be tested in further analyses, with a special focus on prospective analysis.

In recent years significant progress has been made in the treatment of eosinophilic esophagitis (EoE), especially in the area of topical corticosteroids. Novel EoE-specific formulations have been developed and first approvals have been obtained for induction and maintenance of remission in adult EoE patients with the orodispersible budesonide tablet in Germany and other European and non-EU countries. A novel budesonide oral suspension is currently under priority review by the FDA for first approval in the U.S. In contrast, the scientific evidence on the efficacy of proton pump inhibitors remains limited. Moreover, new biologicals have been identified which showed promising results in phase 2 trials and are now being studied in phase 3. This article aims to summarize and discuss recent advances and perspectives in the treatment of EoE.In jüngster Zeit wurden in der Therapie der eosinophilen Ösophagitis (EoE) und insbesondere im Bereich der topischen Corticosteroide erhebliche Fortschritte erreicht. Neue EoE-spezifische Darreichungsformen wurden entwickelt und haben in Form der orodispersiblen Budesonid-Tablette zu der ersten in Deutschland und anderen europäischen und außereuropäischen Ländern zugelassenen Therapie der EoE bei Erwachsenen geführt. In den USA steht eine EoE-spezifische orale Budesonid-Suspension kurz vor der Zulassung. Dagegen bleibt die wissenschaftliche Datenlage zur Wirksamkeit von Protonenpumpeninhibtoren weiterhin limitiert. Auch im Bereich der Biologika konnten nach langer Zeit Substanzen identifiziert werden, die erstmals in Phase 2 sehr vielversprechende Ergebnisse gezeigt haben und sich derzeit in klinischen Prüfungen der Phase 3 befinden. In diesem Artikel sollen die aktuellen Fortschritte und Perspektiven in der Therapie der EoE dargestellt und diskutiert werden.

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

Background Cellular Dissociation Grade (CDG) composed of tumour budding and cell nest size has been shown to independently predict prognosis in pre-therapeutic biopsies and primary resections of oesophageal squamous cell carcinoma (ESCC). Here, we aimed to evaluate the prognostic impact of CDG in ESCC after neoadjuvant therapy. Methods We evaluated cell nest size and tumour budding activity in 122 post-neoadjuvant ESCC resections, correlated the results with tumour regression groups and patient survival and compared the results with data from primary resected cases as well as pre-therapeutic biopsies. Results CDG remained stable when results from pre-therapeutic biopsies and post-therapeutic resections from the same patient were compared. CDG was associated with therapy response and a strong predictor of overall, disease-specific (DSS) and disease-free (DFS) survival in univariate analysis and—besides metastasis—remained the only significant survival predictor for DSS and DFS in multivariate analysis. Multivariate DFS hazard ratios reached 3.3 for CDG-G2 and 4.9 for CDG-G3 neoplasms compared with CDG-G1 carcinomas (p = 0.016). Conclusions CDG is the only morphology-based grading algorithm published to date, which in concert with regression grading, is able to contribute relevant prognostic information in the post-neoadjuvant setting of ESCC.

ZUSAMMENFASSUNGDas Pankreaskarzinom weist eine weltweit steigende Inzidenz auf, wobei die Gründe hierfür bis dato nicht bekannt sind. Die NCCN-Leitlinie von 2017 empfiehlt zur Diagnose und Beurteilung der Resektabilität des pankreatischen duktalen Adenokarzinoms (PDAC) die Computertomografie (CT) als primäre Bildgebung. Bei fehlendem Nachweis und Verdacht eines Tumors wird die Magnetresonanztomografie (MRT) zur Abklärung kleiner Tumoren sowie zur Diagnostik einer eventuellen Lebermetastasierung empfohlen. Durch den Einsatz von neoadjuvanten Chemotherapieregimes konnte die Anzahl der insgesamt resezierbaren Tumoren deutlich gesteigert und somit auch die Prognose dramatisch verbessert werden. Inzwischen sind neue Therapiekonzepte etabliert, die zu einer signifikanten Verbesserung der Prognose beim inoperablen Pankreaskarzinom in der palliativen Situation geführt haben. Im Rahmen der Erkrankung mit einem Pankreaskarzinom kann es zu einer Verlegung der Gallenwege und konsekutiv zu Cholestase und Cholangitis kommen. In einem solchen Fall sollte, sofern möglich, der Galleabfluss wiederhergestellt werden. Eine adäquate Therapieoption stellt hierbei die Durchführung einer ERCP mit Stentanlage dar. Auch bei Obstruktion des Duodenums ist eine endoskopische Stentanlage zur Wiederherstellung der Passage eine Option.

Eosinophilic esophagitis (EoE) is an increasingly recognized immune-mediated esophageal disease and a common cause for dysphagia and food bolus obstruction. The aim of this study was to evaluate the current clinical management of EoE among adult gastroenterologists in Germany. We performed a cross-sectional study of 1393 adult gastroenterologists using a questionnaire containing 22 questions to general, diagnostic, and therapeutic aspects of EoE. The self-administered online survey was conducted between November 2017 and February 2018. Data capture and analysis was performed using SurveyMonkey. The overall responder rate was 29.6 %. More than half of the responders (54.9 %) felt to observe a significant increase of EoE patients. The EREFS score was mostly either unknown (44.3 %) or not routinely used (52.2 %). If EoE was suspected, most responders obtained multiple esophageal biopsies (n = 3 - 4: 35.7 %; n 4: 61.6 %). The preferred primary treatment was proton pump inhibitors (PPI) in 37.2 % and topical steroids in 35.0 % of responders. PPI regimens were highly diverse, with only half of responders using high-dose PPI regimens. Allergy testing was often initiated (always 25.4 %, sometimes 48.9 %). The most common dietary therapy was 6-food elimination diet (52 %), followed by allergy test-directed diets (16 %) and 2-food elimination diet (16.5 %). The majority of responders indicated a need for long-term treatment (i. e., 23 % of responders in 50 % their patients and 47.7 % of responders in 25 - 50 % of their patients). Among gastroenterologists in Germany, substantial variation in the adherence to published EoE guidelines appears to exist. This indicates the need for intensified education and national guidelines in order to optimize and harmonize the clinical management of EoE patients. Die eosinophile Ösophagitis (EoE) ist eine zunehmend häufig erkannte, immunvermittelte Erkrankung der Speiseröhre und eine der häufigsten Ursachen für Dysphagie und Bolusobstruktionen. Ziel dieser Umfrage war es, das gegenwärtige klinische Management der EoE unter Gastroenterologen in Deutschland zu untersuchen. Wir führten eine Querschnittsstudie unter 1393 Gastroenterologen (bng, ALGK) mittels eines Fragebogens durch, der 22 Fragen zu allgemeinen, diagnostischen und therapeutischen Aspekten der EoE enthielt. Die online-Umfrage erfolgte zwischen November 2017 und Februar 2018. Die Daten wurden mittels SurveyMonkey erfasst und analysiert. Die Responderrate betrug 29,6 %. Mehr als die Hälfte der Responder (54,9 %) gaben an, eine signifikante Zunahme von EoE-Patienten zu beobachten. Der EREFS-Score war in der Mehrzahl entweder unbekannt (44,3 %) oder wird in der Routine nicht verwendet (52,2 %). Bei Verdacht auf EoE entnahmen die Mehrzahl multiple Ösophagusbiopsien (n = 3 – 4: 35,7 %, n 4: 61,6 %). Die bevorzugte Initialtherapie waren PPI (37,2 %) oder topische Steroide (35 %). Die PPI-Regime waren sehr divers. Nur in der Hälfte der Fälle wurde eine hochdosierte PPI-Therapie durchgeführt. Eine Allergietestung wurde häufig veranlasst (immer: 25,4 %, manchmal: 48,9 %). Die häufigste dietätische Therapie war die 6-Food-Eliminationsdiät (52 %), gefolgt von der Allergietest-gesteuerten Diät (16 %) und der 2-Food-Eliminationsdiät (16 %). Die Mehrzahl der Responder sahen die Notwendigkeit einer Langzeittherapie (in 50 % der Patienten: 23 %, in 25 – 50 % der Patienten: 47,7 %). Unter Gastroenterologen in Deutschland gibt es eine substantielle Variation in der Adhärenz zu publizierten Leitlinien der EoE. Dieser Befund unterstreicht die Notwendigkeit einer intensiveren Fortbildung und einer nationalen Leitlinie, um eine Optimierung und Harmonisierung in der klinischen Versorgung von EoE-Patienten sicherzustellen.

Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway, creating an urgent need for novel therapeutic targets. To unbiasedly find MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found that protein arginine N-methyltransferase 5 (PRMT5) inhibitors triggered an MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirmed the increased efficacy of PRMT5 inhibitors in MYC-deregulated PDACs. Although inhibition of PRMT5 was inducing DNA damage and arresting PDAC cells in the G2/M phase of the cell cycle, apoptotic cell death was executed predominantly in cells with high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor-sensitive subtype. Our work suggests developing PRMT5 inhibitor-based therapies for PDAC.

BACKGROUND: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments. OBJECTIVE: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE. METHODS: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists. RESULTS: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life. CONCLUSIONS: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:149 issue:2 pages:659-670 ispartof: location:United States status: published

Background & Aims: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder. Swallowed topical-acting corticosteroids are effective in bringing active EoE into remission. However, it is not clear whether these drugs are effective for long-term maintenance of remission. Methods: We performed a double-blind trial to compare the efficacy and safety of 2 dosages of a budesonide orodispersible tablet (BOT) vs placebo in maintaining remission of EoE. Maintenance of remission was defined as absence of clinical and histologic relapse and no premature withdrawal for any reason. Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given BOT 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks. Results: At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo). Median time to relapse in the placebo group was 87 days. The frequency of adverse events was similar in the BOT and placebo groups. Morning serum levels of cortisol were in the normal range at baseline and did not significantly change during treatment. Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment. Conclusions: In a phase 3 trial, up to 48 weeks of treatment with BOT (0.5 mg or 1.0 mg twice daily) was superior to placebo in maintaining remission of EoE. Both dosages were equally effective and well tolerated. EudraCT number; 2014-001485-99; ClinicalTrials.gov number, NCT02434029.

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with poor survival rates as almost all patients develop resistance towards chemotherapy and molecular-informed targeted therapies are reserved to a few. Here, we aim to establish a longitudinal precision oncology platform with a multi-dimensional characterization of PDAC biopsies including genomic, transcriptomic as well as functional analyses to identify and exploit treatment-induced vulnerabilities. In order to investigate adaptive processes of tumors under treatment we aimed to generate PDAC patient-derived organoids (PDOs) and 2D cell lines before and after chemotherapy. Therefore, we enrolled a patient with borderline resectable PDAC who received neoadjuvant FOLFIRINOX. Endoscopic fine needle (pre-FFX) and surgical biopsies (post-FFX) were used to generate PDOs and 2D cells. Whole exome sequencing (WES) and RNA sequencing data of the pre-FFX and post-FFX organoids were compared in order to evaluate the genetic landscape and PDAC subtypes. 2D cells were subjected to an unbiased automated drug screening of 415 compounds to investigate FFX-induced vulnerabilities. Top targets were validated manually in the 2D cells and organoids. Although transcriptional subtyping classified both PDOs as classical PDAC, gene set enrichment analysis (GSEA) revealed a reduced pathway activation linked to the basal-like phenotype such as KRAS signaling in the post-FFX organoids. WES did not show major differences in the genetic landscape of the tumor pre- and post-FFX induction suggesting a plasticity process rather than a clonal selection during chemotherapy. Importantly, post-FFX cells exhibited an increased sensitivity in the unbiased drug screening towards MEK and EGFR inhibition compared to pre-FFX cells. 2D cells and organoids were treated with different MEK inhibitors (MEKi) for validation and post-FFX cells showed a highly increased response compared to the treatment-naïve cells, as well. Interestingly, when placed into the context of a panel of 15 primary PDAC cell lines the pre-FFX cells cluster with highly MEKi resistant PDAC cells whereas post-FFX cells belong to the most sensitive cell lines. In sum, integrating functional layers into personalized medicine allowed us to identify chemotherapy-induced vulnerabilities as potent targeted therapy options in PDAC. Thus, this longitudinal precision oncology platform harbors a unique opportunity to understand adaptive processes in tumor evolution and/or treatment-imposed pressure in PDAC patients. Citation Format: Katja Peschke, Hannah Jakubowski, Arlett Schäfer, Carlo Maurer, Sebastian Lange, Felix Orben, Raquel Bernad, Felix Harder, Matthias Eiber, Rupert Öllinger, Melissa Schlitter, Wilko Weichert, Veit Phillip, Christoph Schlag, Roland Schmid, Rickmer Braren, Bo Kong, Ekin Demir, Helmut Friess, Roland Rad, Dieter Saur, Günter Schneider, Maximilian Reichert. Longitudinal precision oncology platform to identify chemotherapy-induced vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-070.