Rapid point-of-care detection of SARS-CoV-2 infection in exhaled breath using ion mobility spectrometry: a pilot study.

BACKGROUND: An effective testing strategy is essential for pandemic control of the novel Coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Breath gas analysis can expand the available toolbox for diagnostic tests by using a rapid, cost-beneficial, high-throughput point-of-care test. We conducted a bi-center clinical pilot study in Germany to evaluate breath gas analysis using multi-capillary column ion mobility spectrometry (MCC-IMS) to detect SARS-CoV-2 infection. METHODS: Between September 23, 2020, and June 11, 2021, breath gas measurements were performed on 380 patients (SARS-CoV-2 real-time polymerase chain reaction (PCR) positive: 186; PCR negative: 194) presenting to the emergency department (ED) with respiratory symptoms. RESULTS: Breath gas analysis using MCC-IMS identified 110 peaks; 54 showed statistically significant differences in peak intensity between the SARS-CoV-2 PCR-negative and PCR-positive groups. A decision tree analysis classification resulted in a sensitivity of 83% and specificity of 86%, but limited robustness to dataset changes. Modest values for the sensitivity (74%) and specificity (52%) were obtained using linear discriminant analysis. A systematic search for peaks led to a sensitivity of 77% and specificity of 67%; however, validation by transferability to other data is questionable. CONCLUSIONS: Despite identifying several peaks by MCC-IMS with significant differences in peak intensity between PCR-negative and PCR-positive samples, finding a classification system that allows reliable differentiation between the two groups proved to be difficult. However, with some modifications to the setup, breath gas analysis using MCC-IMS may be a useful diagnostic toolbox for SARS-CoV-2 infection. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov on September 21, 2020 (NCT04556318; Study-ID: HC-N-H-2004).

Adjunctive Hydrocortisone Improves Hemodynamics in Critically Ill Patients with Septic Shock: An Observational Study Using Transpulmonary Thermodilution.

Introduction: Septic shock is associated with high mortality and hemodynamic impairment. The use of corticoids is a common therapeutic tool in critically ill patients. However, data on the mechanisms and prognostic ability of hemodynamic improvement by adjunctive steroids are rare. This study primarily aimed to evaluate short-term effects of hydrocortisone therapy on catecholamine requirement and hemodynamics derived from transpulmonary thermodilution (TPTD) in 30 critically ill patients with septic shock and a 28 days mortality rate of 50%. Methods: Hydrocortisone was administered with an intravenous bolus of 200 mg, followed by a continuous infusion of 200 mg per 24 h. Hemodynamic assessment was performed immediately before as well as 2, 8, 16, and 24 h after the initiation of corticoids. For primary endpoint analysis, we evaluated the impact of hydrocortisone on vasopressor dependency index (VDI) and cardiac power index (CPI). Results: Adjunctive hydrocortisone induced significant decreases of VDI from 0.41 (0.29-0.49) mmHg-1 at baseline to 0.35 (0.25-0.46) after 2 h (P < .001), 0.24 (0.12-0.35) after 8 h (P < .001), 0.18 (0.09-0.24) after 16 h (P < .001) and 0.11 (0.06-0.20) mmHg-1 after 24 h (P < .001). In parallel, we found an improvement in CPI from 0.63 (0.50-0.83) W/m2 at baseline to 0.68 (0.54-0.85) after 2 h (P = .208), 0.71 (0.60-0.90) after 8 h (P = .033), 0.82 (0.6-0.98) after 16 h (P = .004) and 0.90 (0.67-1.07) W/m2 after 24 h (P < .001). Our analyses revealed a significant reduction in noradrenaline requirement in parallel with a moderate increase in mean arterial pressure, systemic vascular resistance index, and cardiac index. As a secondary endpoint, our results showed a significant decrease in lung water parameters. Moreover, changes in CPI (ΔCPI) and VDI (ΔVDI) after 24 h of hydrocortisone therapy revealed accurate prognostic ability to predict 28 days mortality (AUC = 0.802 vs 0.769). Conclusion: Adjunctive hydrocortisone leads to a rapid decrease in catecholamine requirement and a substantial circulatory improvement in critically ill patients with septic shock.

[First case description of contagious ovine digital dermatitis in Switzerland]. / Erstbeschreibung der Krankheit «Kontagiöse ovine digitale Dermatitis¼ in der Schweiz.

INTRODUCTION: Contagious ovine digital dermatitis (CODD) is an emerging infectious foot disease in sheep. To date, CODD has been described in Great Britain, Ireland, Sweden and Germany and now in Switzerland for the first time. Unlike foot rot, the CODD lesions do not spread from the interdigital space, but usually begin at the dorsal/abaxial coronary band. The changes can spread to the hoof wall and the sole and finally can lead to exungulation, similar to foot rot. Treponema spp. are often found in CODD lesions analogous to digital dermatitis (Mortellaro's disease) in cattle. Involvement of Dichelobacter nodosus (D. nodosus) is considered a risk factor, but the presence of the bacterium is not mandatory. In February 2022, ulcerative lesions in the dorso-axial coronary band area were noticed on both claws of the left forelimb in an ewe. Histology of the biopsy showed hyperkeratosis and erosion with exocytosis and crust formation. Treponema spp. PCR and fluorescence in situ hybridization (FISH) were positive for Treponema phylotype 1 (PT1). In addition, D. nodosus and Porphyromonas levii could be detected in the biopsy using PCR. A single local application of chlortetracycline spray led to clinical healing within two weeks, no recurrence was seen within the following two months. Three control sheep, which were kept together with the diseased sheep, did not show any clinical signs of CODD. Treponema spp could not be found in interdigital and coronary band biopsies by PCR or FISH. This is the first description of CODD in Switzerland and aims to sensitize veterinarians to CODD as a differential diagnosis for foot diseases in sheep.

INTRODUCTION: La dermatite digitale contagieuse ovine (contagious ovine digital dermatitis; CODD) est une maladie infectieuse des onglons des moutons d'importance croissante. À ce jour, la CODD a été décrite en Grande-Bretagne, Irlande, Suède et Allemagne, et maintenant pour la première fois également en Suisse. Au contraire du piétain, les lésions de CODD ne s'étendent pas à partir de l'espace interdigité, mais elles commencent en général au bord coronaire dorsal/abaxial. De là, les lésions peuvent s'étendre à la corne de la paroi et à la sole, ce qui peut finalement conduire à une perte complète de la boite cornée de l'onglon, comme en cas de piétain. En analogie à la dermatite digitale (maladie de Mortellaro) chez les bovins, des tréponèmes sont souvent mis en évidence dans les lésions de CODD. La présence de Dichelobacter nodosus (D. nodosus) est considérée comme un facteur de risque, mais elle n'est pas indispensable au développement de la CODD. Des lésions ulcératives dans la région du bord coronaire dorso-axial des deux onglons antérieurs d'une brebis ont été remarqués en février 2022. L'examen histologique de la biopsie de la lésion de CODD a montré une hyperkératose ainsi que des érosions avec de l'exocytose et la formation de croûtes. Aussi bien la PCR pour les Treponema spp. que l'hybridisation in-situ à fluorescence (FISH) étaient positives pour Treponema Phylotype 1 (PT1). De plus, D. nodosus et Porphyromonas levii ont été mis en évidence dans la biopsie. Une application locale unique de spray à la tétracycline après le prélèvement de la biopsie a conduit à une guérison clinique en deux semaines, et aucune récidive n'a été observée dans le deux mois suivants. Trois moutons de boucherie qui étaient détenus avec la brebis malade mais ne présentaient pas de lésions de CODD ont servi de contrôles négatifs. Des Treponema spp. n'ont été mis en évidence chez ces animaux, ni dans des biopsies du bord coronaire ni dans celles de l'espace interdigité. Cette étude représente la première description de la CODD en Suisse et est destinée à sensibiliser la profession vétérinaire à la CODD comme diagnostic différentel en cas de maladies des onglons chez les moutons.

Clinical characteristics and outcome of patients with enterococcal liver abscess.

Epidemiology of bacteria isolated from pyogenic liver abscesses change, and an increase in enterococci has been reported in European hospitals. The aim of this study was to investigate the clinical characteristics and outcome of enterococcal PLA. We performed a retrospective analysis of patients with microbiologically confirmed PLA at three German university centers. Indicators of enterococcal PLA were determined using binary logistic regression, and survival analysis was performed using Kaplan-Meier statistics and Cox regression analysis. Enterococci were isolated in 51/133 (38%) patients with PLA. Patients with enterococcal PLA had smaller abscess diameter (4.8 vs. 6.7 cm, p = 0.03) than patients with non-enterococcal PLA, but had more frequent polymicrobial culture results. In univariate logistic regression analysis, alcohol abuse (OR 3.94, 95% CI 1.24-12.49, p = 0.02), hepatobiliary malignancies (OR 3.90, 95% CI 1.86-8.18, p < 0.001) and cirrhosis (OR 6.36, 95% CI 1.27-31.96, p = 0.02) were associated with enterococcal PLA. Patients with enterococcal PLA had a higher mortality than patients with non-enterococcal PLA (hazard ratio 2.92; 95% confidence interval 1.09-7.80; p = 0.03), which remained elevated even after excluding patients with hepatobiliary malignancies, cirrhosis, and transplant recipients in a sensitivity analysis. The increased mortality was associated with non-fecal enterococci but not in patients with Enterococcus faecalis. In this retrospective, multicenter study, enterococcal PLA was common and indicated an increased risk of mortality, underscoring the need for close clinical monitoring and appropriate treatment protocols in these patients.

A proof of concept study for the differentiation of SARS-CoV-2, hCoV-NL63, and IAV-H1N1 in vitro cultures using ion mobility spectrometry.

Rapid, high-throughput diagnostic tests are essential to decelerate the spread of the novel coronavirus disease 2019 (COVID-19) pandemic. While RT-PCR tests performed in centralized laboratories remain the gold standard, rapid point-of-care antigen tests might provide faster results. However, they are associated with markedly reduced sensitivity. Bedside breath gas analysis of volatile organic compounds detected by ion mobility spectrometry (IMS) may enable a quick and sensitive point-of-care testing alternative. In this proof-of-concept study, we investigated whether gas analysis by IMS can discriminate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from other respiratory viruses in an experimental set-up. Repeated gas analyses of air samples collected from the headspace of virus-infected in vitro cultures were performed for 5 days. A three-step decision tree using the intensities of four spectrometry peaks correlating to unidentified volatile organic compounds allowed the correct classification of SARS-CoV-2, human coronavirus-NL63, and influenza A virus H1N1 without misassignment when the calculation was performed with data 3 days post infection. The forward selection assignment model allowed the identification of SARS-CoV-2 with high sensitivity and specificity, with only one of 231 measurements (0.43%) being misclassified. Thus, volatile organic compound analysis by IMS allows highly accurate differentiation of SARS-CoV-2 from other respiratory viruses in an experimental set-up, supporting further research and evaluation in clinical studies.

A rare case of perivascular epithelioid cell tumor (PEComa) of the pancreas diagnosed by endoscopic ultrasound.

A 49-year-old woman consulted her general practitioner (GP) regarding epigastric pain that she had experienced for 2 months. Physical examination and laboratory results were unremarkable. An abdominal ultrasound indicated a solid pancreatic tumor, which was confirmed on subsequent CT and MRI. Endoscopic ultrasound (EUS) showed a well-defined heterogeneous, predominantly hypoechoic mass in the pancreatic body, so a neuroendocrine tumor (NET) was suspected. However, EUS-guided fine-needle aspiration (EUS-FNA) was performed and based on (immuno-)histochemical findings, the extremely rare diagnosis of a perivascular epithelioid cell tumor (PEComa) of the pancreas was made. Due to the malignant potential of pancreatic PEComas, laparoscopic left-sided pancreatectomy was performed. We present a case diagnosed by preoperative EUS-FNA highlighting the clinical and endosonographic features which help to distinguish it from its most important differential diagnosis, neuroendocrine tumors (NETs) of the pancreas.

Changes in gut microbial metagenomic pathways associated with clinical outcomes after the elimination of malabsorbed sugars in an IBS cohort.

Specific diets to manage sugar malabsorption are reported to reduce clinical symptoms of irritable bowel syndrome (IBS). However, the effects of diets for malabsorbed sugars on gut microbiota signatures have not been studied, and associations with clinical outcomes in IBS have not been characterized. 22 IBS patients positively tested for either lactose-, fructose-, sorbitol- or combined malabsorptions were subjected to 2-weeks sugar elimination and subsequent 4-weeks re-introduction. 7 IBS patients tested negative for sugar malabsorption were used as controls. Nutrition and clinical symptoms were recorded throughout the study. Fecal samples were serially collected for 16S rRNA amplicon and shotgun-metagenome sequencing. Dietary intervention supervised by nutrition counseling reduced IBS symptoms during the elimination and tolerance phases. Varying clinical response rates were observed between subjects, and used to dichotomize our cohort into visual analogue scale (VAS) responders and non-responders. Alpha -and beta-diversity analyzes revealed only minor differences regarding 16S rRNA-based fecal microbiota compositions between responder and non-responder patients during baseline or tolerance phase. In shotgun-metagenome analyzes, however, we analyzed microbial metabolic pathways and found significant differences in pathways encoding starch degradation and complex amino acid biosynthesis at baseline between IBS controls and malabsorbers, and notably, between diet responder and non-responders. Faecalibacterium prausnitzii, Ruminococcus spp. and Bifidobacterium longum largely informed these metabolic pathways. Our study demonstrates that diet interventions for specific, malabsorbed carbohydrates reshaped the metagenomic composition of the gut microbiota, with a small community of bacterial taxa contributing to these changes rather than a single species.

A retrospective clinical and microbial analysis of 32 patients with bilomas.

BACKGROUND: Bilomas are defined collections of bile fluids mainly caused by iatrogenic injuries of the bile duct system. Owing to the infrequency of this disease, studies addressing bilomas are rare. METHODS: By using an endoscopic database, this retrospective study identified 32 patients with bilomas treated between 2004 to 2015, in order to analyse aetiology, clinical presentation, spectrum of pathogens, and resolution rate of bilomas. RESULTS: 65.6% of the study population (21/32) developed bilomas after surgery and 21.9% (7/32) after endoscopic retrograde cholangiography (ERC). Icterus, fever, and abdominal pain were the leading symptoms. 93.9% (46/49) of microbiological bile cultures revealed a positive microbiology. The predominant microorganisms were the group of Enterobacteriaceae (43.0%, 52/121), followed by Enterococcus spp. (32.2%, 39/121), and Candida spp. (9.1%, 11/121). Multiresistant bacteria like Enterobacteriaceae were isolated from one quarter of all patients. Single or multimodal treatment resulted in an overall complication rate of 4.8% (9/188). Clinical follow-up analysis showed a complete resolution rate of 78.3% for interventional therapy and 80% in the non-interventional group. CONCLUSIONS: Pathogen spectrum of bilomas mainly comprises the group of Enterobacteriacae and Enterococcus spp., with a high proportion of multiresistant bacteria. Different interventional approaches are available for biloma drainage, which seem to be safe and effective for most patients. TRIAL REGISTRATION: German Clinical Trials Register DRKS00015208 , retrospectively registered.

[Retrieval of a migrated plastic stent in a 51-year-old man]. / Bergung eines migrierten Doppel-Pigtail-Stents bei einem 51-jährigen Patienten.

BACKGROUND: Endosonographically guided transgastric drainage is the first-line interventional therapy of walled-off necrosis and symptomatic pancreatic pseudocysts in necrotizing pancreatitis. Plastic stents or lumen apposing metal stents are commonly used. A possible complication of endoscopic therapy is stent migration. CASE REPORT: We report upon a 51-year-old man who presented with acute necrotizing pancreatitis. Transgastric necrosectomy was performed and 5 transmural double-pigtail stents (DPS) were left in situ to drain the residual retroperitoneal cavity. The patient recovered and 4 stents were endoscopically removed 5 weeks later on an outpatient basis, whereas the fifth stent was suspected to have passed spontaneously via the natural route. The asymptomatic patient presented 3 months later for follow-up computed tomography. The necrosis had healed but one DPS was seen beyond the gastric wall near the kidney. Transmural access to the stent could be achieved by an endosonographically guided puncture toward the proximal portion of the stent followed by placement of a hydrophilic guidewire alongside the stent. A new gastrostomy was created by using a 6F cystotome followed by wire-guided dilation with a 12 mm balloon. The stent could then be grasped with transmurally inserted rat-tooth forceps and repositioned across the gastrostomy site. The patient was given prophylactic antibiotics. After removal of the stent, the patient could be discharged. CONCLUSION: Herein, we present the successful endosonographically guided transmural removal of a retroperitoneally migrated plastic stent. Of note, in our patient we had to rely completely on endosonography and radiography for localization and targeting of the stent, since the former necrotic cavity had meanwhile completely healed.

First description of spontaneous fungal peritonitis caused by Fusarium solani in a critically ill patient with liver cirrhosis.

Fusarium spp., common soil moulds, are emerging fungal pathogens in immunocompromised subjects. We report the first case of Fusarium solani peritonitis in a patient with liver cirrhosis. Because of the high morbidity and mortality associated with fusariosis, an aggressive approach to treatment as well as identification of the species and drug susceptibilities is warranted.

Endoscopic rendez-vous reconstruction of complete biliary obstruction.

BACKGROUND AND STUDY AIMS: Complete biliary strictures normally require surgical intervention. We describe an alternative, minimally invasive endoscopic/percutaneous rendez-vous technique for the reconstruction of complete benign biliary strictures. PATIENTS AND METHODS: Complete biliary strictures were reconstructed in four patients using a rendez-vous percutaneous-endoscopic or percutaneous-percutaneous route guided by fluoroscopic and visual (transillumination) control. RESULTS: All four patients were treated successfully and safely with the rendez-vous technique. Complications were caused by the preliminary creation, dilatation and maturation of the percutaneous tract. CONCLUSION: This technique may offer a good alternative to surgical bilio-enteric anastomosis in experienced hands. The long term course of the patients treated remains to be seen.

Assessment of volume status and fluid responsiveness in the emergency department: a systematic approach.

When treating acutely ill patients in the emergency department (ED), the successful management of a variety of medical conditions, such as sepsis, acute kidney injury, and pancreatitis, is highly dependent on the correct assessment and optimization of a patient's intravascular volume status. Therefore, it is crucial that the ED physician knows and uses available means to assess intravascular volume status to adequately guide fluid therapy. This review focuses on techniques for volume status assessment that are available in the ED including basic clinical and laboratory findings, apparatus-based tests such as sonography and chest x-ray, and functional tests to evaluate fluid responsiveness. Furthermore, we provide an outlook on promising innovative, noninvasive technologies that might be used for advanced hemodynamic monitoring in the ED.

Esophageal bougination: a novel ex vivo endoscopic training model correlated with clinical data.

BACKGROUND: Esophageal bougination is a worldwide standard endoscopic procedure. Clinical methods and recommendations are based on clinical experiences only. Mechanical properties have never been described. Aim of the study was to establish a realistic ex vivo training model. Therefore, detailed assessment of relevant mechanical features of esophageal bougination should be evaluated ex vivo and in patient setting and correlated against. PATIENTS AND METHODS: A three-step concept was used to evaluate mechanical properties at stenosis level. First, insertion forces were evaluated in an ex vivo linear single stenosis model during steady mechanical insertion. Second, adding friction and properties of the pharynx and upper esophagus, the model was integrated in an artificial endoscopic training model (ELITE training model). Third, in vivo measurements were taken to correlate ex vivo data with parameters of a realistic patient setting. RESULTS: With the presented setup, we were able to assess insertion force and pressure levels in an artificial stricture using different sizes of commercially available standard bougies. In all models, there was a relevant increase in insertion force with higher stricture pressure levels. Insertion force levels in the ELITE model show higher levels compared to the linear stenosis model. Having regard to the maximum forces in patients, there is also a constant increase in mean insertion force according to higher bougie sizes, but lower forces were measured as in the ELITE model. DISCUSSION: The applied models are suitable to appraise mechanical properties of esophageal bougination in an ex vivo model and patient setting. Forces could be constituted reliable, significant increase was documented according to stenosis level and results were comparable to patient data. This was comparable to patient data. Further clinical evaluation in different kinds of stenosis is necessary.

HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer.

Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.

Short-term effects and adverse events of endoscopically applied radiofrequency ablation appear to be comparable with photodynamic therapy in hilar cholangiocarcinoma.

BACKGROUND AND STUDY AIMS: Radiofrequency ablation (RFA) is a new endoscopic palliation therapy for malignant biliary obstruction. The aim of this study was to compare the short-term effects of biliary drainage and adverse events of this technique with the standard of endoscopical treatment of hilar cholangiocarcinoma, photodynamic therapy (PDT). PATIENTS AND METHODS: We retrospectively and since December 2012 prospectively investigated the efficacy and adverse events of RFA in patients with hilar cholangiocarcinoma in two tertiary referral centers between November 2011 and January 2013. The approach of the study was prospective, but because of the large amount of retrospectively included patients, the design of the study is overall retrospective. A group of 20 patients treated with PDT between April 2005 and May 2011 served as a historical control. RESULTS: Fourteen patients received 31 biliary RFAs and 20 patients received 36 PDTs. Within the RFA group, a significant decrease (p = 0.046) of the bilirubin level was seen 14 days after the first RFA (3.3 ± 3.9 (mg/dl) versus 2.3 ± 2.6 (mg/dl)). In the PDT group no significant decrease (p = 0.67) of the bilirubin level was obtained (4.1 ± 6.9 (mg/dl) versus 3.5 ± 5.3 (mg/dl)). In the PDT group (13/20, 65%) a significantly higher number of premature stent replacements (<3 months) after the first intervention was noticed in comparison with the RFA group (four of 14, 29%) (p < 0.01). Between the first and fifth procedure, post-interventional adverse events tend to occur more frequently in patients with PDT (eight of 20, 40%) than with RFA (three of 14, 21%) (p = 0.277). CONCLUSIONS: Looking at the short-term effects, we conclude that RFA may present a therapeutic alternative to PDT for palliative treatment of malignant biliary obstruction because of its simple feasibility and moderate adverse event rate. To provide a definitive evaluation of the long-term effects and of overall median survival, a controlled trial with PDT must follow.

Gastrointestinal stromal tumor as entry port for S. intermedius causing bacteremia and multiple liver abscesses. Case report and review of literature.

We report a case of a previously healthy 52-year-old man who presented with fever and liver lesions suspicious for metastatic disease, which proved subsequently to be abscesses. Further workup revealed a gastrointestinal stromal tumor (GIST) in the gastric corpus as entry port to Streptococcus intermedius-associated bacteremia and liver abscesses. After antibiotic treatment and surgical resection of the tumor, the patient recovered well. This unusual case indicates that gastrointestinal stromal tumors can remain undetected until they cause a life threatening infection. A review of recent literature pertaining to GIST and liver abscesses follows.

High-resolution manometry in patients with eosinophilic esophagitis under topical steroid therapy-a prospective observational study (HIMEOS-study).

BACKGROUND: In eosinophilic esophagitis (EoE), dysphagia, which might reflect esophageal dysmotility, is the most common symptom. High-resolution manometry (HRM) has become widely accepted for evaluating esophageal motility disorders, but to date has been sparsely examined in EoE patients, particularly under therapy. The aim of this study was to evaluate HRM in symptomatic EoE-patients under topical steroid treatment. METHODS: In this prospective observational study, symptomatic EoE patients received HRM-examinations before and after 8 weeks of topical steroid treatment with budesonide. All HRM-abnormalities were assessed and interpreted according to the Chicago classification. The primary endpoint was the influence of topical steroid treatment on the intrabolus pressure (IBP). Clinical symptoms, endoscopic findings and histological esophageal eosinophilic load were also reported. KEY RESULTS: Twenty symptomatic EoE patients were included. Overall success of budesonide therapy was 85% regarding complete histologic remission and 80% regarding complete clinical remission. High-resolution manometry showed abnormal esophageal motility in 35% of patients at baseline, which was resolved after therapy in 86% of these patients. Most frequent HRM-findings were early pan-esophageal pressurizations and weak persitalsis. There was no significant reduction of the IBP under therapy (before: 12.5 ± 4.9 mmHg, after: 10.9 ± 2.9 mmHg; p = 0.119). CONCLUSIONS & INFERENCES: Although dysphagia is the leading symptom of EoE, HRM is able to identify esophageal motility disorders in only some EoE patients. Observed motility disorders resolve after successful treatment in almost all of these patients. Intrabolus pressure does not seem an optimal parameter for the monitoring of successful treatment response in EoE patients.

Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells.

Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D)-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras(G12D)-driven carcinogenesis in the pancreas.