Microenvironmental Determinants of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) belongs to the most lethal solid tumors in humans. A histological hallmark feature of PDAC is the pronounced tumor microenvironment (TME) that dynamically evolves during tumor progression. The TME consists of different non-neoplastic cells such as cancer-associated fibroblasts, immune cells, endothelial cells, and neurons. Furthermore, abundant extracellular matrix components such as collagen and hyaluronic acid as well as matricellular proteins create a highly dynamic and hypovascular TME with multiple biochemical and physical interactions among the various cellular and acellular components that promote tumor progression and therapeutic resistance. In recent years, intensive research efforts have resulted in a significantly improved understanding of the biology and pathophysiology of the TME in PDAC, and novel stroma-targeted approaches are emerging that may help to improve the devastating prognosis of PDAC patients. However, none of anti-stromal therapies has been approved in patients so far, and there is still a large discrepancy between multiple successful preclinical results and subsequent failure in clinical trials. Furthermore, recent findings suggest that parts of the TME may also possess tumor-restraining properties rendering tailored therapies even more challenging.

An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.

Gut microbiota predicts severity and reveals novel metabolic signatures in acute pancreatitis.

OBJECTIVE: Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP (Pancreatitis-Microbiome As Predictor of Severity; P-MAPS) early at hospital admission. DESIGN: Buccal and rectal microbial swabs were collected from 424 patients with AP within 72 hours of hospital admission in 15 European centres. All samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore Technologies. Primary endpoint was the association of the orointestinal microbiome with the revised Atlanta classification (RAC). Secondary endpoints were mortality, length of hospital stay and severity (organ failure >48 hours and/or occurrence of pancreatic collections requiring intervention) as post hoc analysis. Multivariate analysis was conducted from normalised microbial and corresponding clinical data to build classifiers for predicting severity. For functional profiling, gene set enrichment analysis (GSEA) was performed and normalised enrichment scores calculated. RESULTS: After data processing, 411 buccal and 391 rectal samples were analysed. The intestinal microbiome significantly differed for the RAC (Bray-Curtis, p value=0.009), mortality (Bray-Curtis, p value 0.006), length of hospital stay (Bray-Curtis, p=0.009) and severity (Bray-Curtis, p value=0.008). A classifier for severity with 16 different species and systemic inflammatory response syndrome achieved an area under the receiving operating characteristic (AUROC) of 85%, a positive predictive value of 67% and a negative predictive value of 94% outperforming established severity scores. GSEA revealed functional pathway units suggesting elevated short-chain fatty acid (SCFA) production in severe AP. CONCLUSIONS: The orointestinal microbiome predicts clinical hallmark features of AP, and SCFAs may be used for future diagnostic and therapeutic concepts. TRIAL REGISTRATION NUMBER: NCT04777812.

The four seasons of pancreatitis - Etiology of acute pancreatitis during the course of the year.

BACKGROUND/OBJECTIVES: Whether seasonality is a factor that influences the incidence of acute pancreatitis (AP) is an under-investigated area. If seasonal incidence peaks can be detected, specifically with regard to biliary pancreatitis, has so far been answered in contradictory ways in the literature. METHODS: All AP cases from two tertiary German referral centers were identified between 2016 and 2022 based on ICD-10 discharge codes. The χ2 test for goodness of fit was applied to test significant differences in monthly and seasonal distributions of AP admissions. RESULTS: In total, 3597 AP cases were included. We observed significantly more idiopathic and biliary cases in May to July (p-values 0.041 and 0.027, respectively). Furthermore, most drug-induced APs were identified during the winter months (p-value 0.006). Moreover, there was a significant peak of alcohol-induced pancreatitis in summer and fall (p-value 0.038). CONCLUSIONS: Our data indicate a seasonal impact on AP incidences for certain etiologies.

Dynamics of intestinal and intratumoral microbiome signatures in genetically engineered mice and human pancreatic ductal adenocarcinoma.

BACKGROUND: Emerging evidence has recently revealed a prominent role of the microbiome in pancreatic ductal adenocarcinoma (PDAC). However, while most observations were made in patients, mouse models still require a precise characterization of their disease-related microbiome to employ them for mechanistic and interventional preclinical studies. METHODS: To investigate the fecal and tumoral microbiome of LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) and control (CTRL) mice, Oxford Nanopore sequencing was applied. Feces were collected from 10 KPC mice and 10 CTRLs at 3 timepoints (6 weeks, 12 weeks, and when tumor-bearing (KPC) or 6 months (CTRL), respectively). Metagenomic sequencing was performed on feces DNA. KPC tumor and healthy pancreas DNA samples were subjected to 16S rRNA gene sequencing. Bacterial marker components were detected in KPC tumor tissue over time by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). RESULTS: Murine fecal samples showed a significantly different microbiome compared to age-matched healthy CTRLs regarding beta diversity (p = 0.001, R2 = 0.2-0.25 for Bray-Curtis). Adjusted human PDAC classifiers predicted disease status from feces of KPC mice achieving area under the receiver operating characteristic (AUROC) values of 80%. Furthermore, KPC tumors harbored significantly more bacterial components than healthy pancreas. Also the microbial composition differs significantly between KPC tumors and healthy pancreas tissue (p = 0.042 for Bray-Curtis). Microbiota found highly abundant in human PDAC samples were considerably more abundant in KPC tumors as compared to healthy pancreas samples (p-value <0.001). CONCLUSION: KPC fecal samples show similarities with the microbial composition of stool samples from human PDAC patients.

Endoscopic mucosal resection and endoscopic submucosal dissection with an external additional working channel (EMR+ and ESD+) are equivalent to using a double-channel endoscope: a systematic evaluation in a porcine ex vivo model.

BACKGROUND AND AIMS: With an external additional working channel (AWC) endoscopic mucosal resection (EMR) as well as endoscopic submucosal dissection (ESD) can be extended to techniques termed "EMR+" and "ESD+." These novel techniques are systematically compared to EMR and ESD under the use of a double-channel endoscope (DC). METHODS: Our trial was conducted prospectively in a pre-clinical porcine animal model (EASIE-R simulator) with standardized gastric lesions measuring 3 or 4 cm. RESULTS: EMR+ and EMR DC showed both good results for 3 cm lesions with no adverse events and an en bloc resection rate of 73.33% (EMR+) and 60.00% (EMR DC, p = 0.70). They came to their limits in 4 cm lesions with muscularis damages of 20.00% (EMR+), 13.33% (EMR DC, p ≥ 0.99) and decreasing en bloc resection rates of 60.00% (EMR+) and 46.67% (EMR DC, p = 0.72). ESD+ and ESD DC were both reliable concerning en bloc resection rates (100% in all groups) and adverse events (0.00% in 3 cm lesions, 12.50% muscularis damages in both ESD+ and ESD DC in 4 cm lesions). Resection time was slightly shorter in all groups with the AWC compared to DC although only reaching significance in 3 cm ESD lesions (p < 0.05*). CONCLUSIONS: With the AWC, a standard endoscope can easily be transformed to double-channel functionality. We could show that EMR+ and ESD+ are non-inferior to EMR and ESD under the use of a double-channel endoscope. Consequently, the AWC presents an affordable alternative to a double-channel endoscope for both EMR and ESD.

[Acute necrotizing pancreatitis with hemorrhagic shock in secondary splenic rupture: a case report and literature review]. / Akute nekrotisierende Pankreatitis mit hämorrhagischem Schock bei sekundärer Milzruptur: Ein Fallbericht und Literaturübersicht.

Atraumatic splenic rupture is a rare complication of acute and chronic pancreatitis. It arises due to its anatomical proximity to the pancreas, for instance, due to erosion of large pseudocysts or walled-of-necrosis (WON).Following we describe the case of a 62-year-old woman who presented for further diagnostics and treatment of acute pancreatitis with the development of large walled-of necrosis (WON) in the pancreatic corpus and tail. During the course, the patient developed a hemorrhagic shock. An emergency computer tomography (CT) of the abdomen revealed a ruptured spleen with a large capsular hematoma with no evidence of active bleeding. In contrast to previous published case reports, our treatment was exclusively minimal-invasive: by radiological guided embolization of the splenic artery and by endosonographic guided implantation of a lumen apposing metal stent (LAMS). The splenic hematoma was spontaneously regressive without secondary drainage.

NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease. DESIGN: NFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor (Alb-cre, NFATc1c.a . and NFATc1Δ/Δ ). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo. RESULTS: NFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration. CONCLUSION: NFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH.

[Chronic pancreatitis: update diagnostic and therapeutic concepts]. / Chronische Pankreatitis: Update Diagnostik und Therapie.

INTRODUCTION: Chronic pancreatitis (CP) is a frequent cause for hospitalization and is associated with impaired quality of life and reduced overall survival. The German Society for Gastroenterology (DGVS) has recently completed the S3-Guideline "Pancreatitis" that summarizes key findings on epidemiology, diagnostic and therapeutic concepts for acute and chronic pancreatitis. Here, we recapitulate the most relevant findings for clinicians regarding CP. RESULTS: The most common cause of CP is chronic alcohol abuse, other causes are hereditary pancreatitis, autoimmune pancreatitis, hyperparathyroidism and idiopathic forms. Apart from the classical hereditary pancreatitis (PRSS1 mutation), a number of genetic associations have been discovered over the last years that are associated with an increased risk to develop idiopathic CP. The conservative management of CP is focused on the appropriate management of exocrine and endocrine insufficiency, and the prevention and treatment of secondary complications such as osteoporosis, vitamin deficiencies and malnutrition. Local complications (bile duct stenosis, duodenal stenosis, pseudocysts and chronic pain) should be managed in multidisciplinary teams in specialized pancreas centres with expert surgeons, radiologists and gastroenterologists. Infected or symptomatic pseudocysts should be primarily addressed by endoscopic drainage. In contrast, patients with chronic pain, dilated pancreas duct and opioid use should be considered for early surgical intervention. CONCLUSION: Chronic pancreatitis is associated with increased morbidity and mortality and often leads to hospital admissions. The clinical management of complex patients with local complications requires an interdisciplinary approach to tailor available therapeutic modalities depending on the stage of the disease and pre-existing comorbidities.

Liver metastasis mimicking a liver cyst of a thymoma in a 38-year-old immunocompromised patient.

Cystic liver lesions (CLL) are common and, in the majority of cases, benign. However, the range of differential diagnoses of CLL is wide. A combination of medical history, blood test results, and imaging can help find the correct diagnosis. We report the case of a 38-year-old immunocompromised female patient with a history of thymectomy and postoperative radiation 3 years prior due to thymoma. Subsequently, the patient was referred to our department for clarification of a cystic liver lesion. During short-term follow-up, the lesion increased in size, and due to the contrast agent behavior in the ultrasound and MRI examination, the suspicion of a biliary cystadenocarcinoma was considered.Furthermore, imaging showed several subcentimetric liver lesions of unknown dignity. Finally, pericystectomy and atypical partial liver resection was performed. Histology revealed a cystic metastasis of the malignant B3 thymoma and a cavernous hemangioma. Liver metastases of a thymoma are rare, and this is the first case of a cystic liver metastasis of a thymoma. The presented case illustrates that in the management of CLLs beside imaging techniques, the medical history with previous conditions should be considered, especially in past malignancies.

Frequency of synchronous malignant liver lesions initially detected by ultrasound in patients with newly diagnosed underlying non-hematologic malignant disease: a retrospective study in 434 patients.

INTRODUCTION: This study described the frequency of malignant synchronous focal liver lesions (FLLs) in patients with newly diagnosed non-hematologic malignant disease. METHODS: From June 2013 to January 2017, 434 patients with synchronous FLLs and newly diagnosed underlying malignant disease were included in the study. The diagnosis of the FLLs was made by histology and/or contrast-enhanced imaging. The final medical report was used for analysis in the study. RESULTS: Of the 434 liver lesions, 258 (59.4%) were malignant and 176 (40.6%) benign. All malignant lesions were metastases. The benign liver lesions were comprised of 93 cysts (21.4%), 52 hemangiomas (12.0%), 20 focal fatty sparing (4.6%), 4 focal nodular hyperplasia (0.9%), 3 unspecified benign lesions (0.7%), 2 regenerative nodules (0.5%), 1 calcification (0.2%), and 1 adenoma (0.2%). Diseases with the highest percentage frequency of synchronous malignant FLLs were cholangiocarcinoma with 86.7%, neuroendocrine tumor with 72.7%, and pancreatic carcinoma with 72.0%. Gastric carcinoma (33.3%), breast carcinoma (44.4%), and urothelial cell carcinoma (45.5%) were the diseases with the lowest percentage frequency of synchronous malignant FLLs. CONCLUSION: In total, the frequency of malignant synchronous FLLs in newly diagnosed non-hematologic malignant disease was 59.4%. In particular, cholangiocarcinoma, neuroendocrine tumor, and pancreatic carcinoma were the diseases with the highest rate of synchronous malignant FLLs.

Pathological gallbladder wall thickening is associated with advanced chronic liver disease and independent of serum albumin.

PURPOSE: Increased gallbladder wall thickness (GBWT) is a common finding. Reported causes include advanced chronic liver disease (ACLD), ascites and hypalbuminemia. GBWT is a marker for the prediction of esophageal varices. It remains unclear which of these factors is the decisive driver of GBWT. We aim to investigate whether there is a predominant factor associated with the GBWT. METHODS: We enrolled 258 patients with ascites, hypalbuminemia and/or ACLD and 98 healthy volunteers that underwent abdominal ultrasound. Differences of mean GBWT in subgroups of patients with ACLD, ascites, and/or hypalbuminemia were analyzed. Correlation between various parameters and GBWT were calculated using multiple regression analysis. RESULTS: GBWT in patients with ACLD + ascites + hypalbuminemia (n = 59; 5.70 ± 2.05 mm) was pathologically increased compared to patients with hypalbuminemia + ascites without ACLD (n = 36; 2.14 ± 0.66 mm; p < .001) and to patients with only hypalbuminemia (n = 76; 2.02 ± 0.80 mm; p < .001). GBWT of patients with ACLD + hypalbuminemia (n = 30; 3.42 ± 1.52 mm) and with ACLD and normal albumin level were not different (n = 46; 3.10 ± 1.62 mm; p > .999). Significant correlation was seen between GBWT and ACLD (r = .53; p < .001) and ascites (r = .51; p < .001) but not albumin level (r = .04; p = .510). CONCLUSION: We demonstrate that ACLD is predominantly associated with GBWT. In contrast to the current literature, serum albumin level appears not to be associated with pathological GBWT.

[Acute Diseases of the Esophagus - Esophagitis]. / Akute Erkrankungen des Ösophagus ­ Ösophagitis.

Acute Diseases of the Esopagus - Esophagitis Abstract. Inflammation of the esophagus can be caused by various conditions including gastroesophageal reflux (GERD), immunosuppression, infections, allergens, or distinct medications. GERD will be covered in a separate article. Clinical symptoms include heartburn, retrosternal pain, dysphagia, or fetor ex ore. Bleeding, strictures, or stenoses can occur as local complications. Besides a detailed medical history, diagnostic tools are usually an accurate physical examination and flexible endoscopy including histological and microbiological sampling. Immunosuppressive drugs, HIV, malignancies, and chronic alcohol abuse are often associated with candida esophagitis which is typically treated with fluconazole. History of allergies is especially relevant for eosinophilic esophagitis (EoE) which mostly affects young patients and can be treated with topical steroids. A rare but important differential diagnosis to EoE is esophageal lichen planus.

[State of the Art Diagnostics of the Esophagus]. / State of the Art Diagnostik des Ösophagus.

State of the Art Diagnostics of the Esophagus Abstract. Modern diagnostics of the esophagus is highly technical. It mainly includes endoscopic, radiological, nuclear medicine, functional and electrochemical examinations. Diagnostic tools for esophageal disorders involve esophagogastroduodenoscopies with chromoendoscopy, manometric and pH-impedance catheters as well as radiological techniques, such as CT, MRI or PET-CTs. The patient's history including the main clinical symptoms such as heartburn or dysphagia, and the physical examination will determine the choice and order of subsequent examinations. The esophagogastroduodenoscopy is one of the most important diagnostic tools and has a very low complication rate. During esophagogastroduodenoscopy biopsies, chromoendoscopy or therapeutic interventions can be performed. Endosonography is essential for the staging of esophageal cancer and accuracy can be improved by endosonographically guided biopsies. A CT scan completes the tumor staging and is essential to search for metastases. For motility disorders high resolution manometry is the gold standard which can be supplemented with esophagus barium swallow exams. pH-impedance catheters can be used for diagnosis of reflux. MRI swallow exams are predominantly applied in clinical studies but may be more frequently used in the future.

Management of Severe Acute Pancreatitis: An Update.

BACKGROUND: Severe acute pancreatitis (AP) continues to be a serious gastrointestinal disease with relevant morbidity and mortality. SUMMARY: Successful clinical management requires close interdisciplinary cooperation and coordination from experienced gastroenterologists, intensive care physicians, surgeons, and radiologists. While the early phase of the disease is characterized by intensive care aspects that focus primarily on treatment of organ failure, later complications are characterized especially by (infected) necrotic collections. Here, we discuss current clinical standards and developments for conservative and interventional management of patients with severe AP. Key messages: Early targeted fluid therapy within the first 48 h is critical to improve the outcome of severe AP. Thoracic epidural analgesia may have prognostically beneficial effects due to suspected anti-inflammatory effects and increased perfusion of splanchnic vessels. Enteral feeding should be started early during severe AP. Persistent organ failure (>48 h) is the strongest predictor of poor prognosis, and local complications such as infected walled-off necrosis should be primarily treated by minimally invasive endoscopic step-up approaches that are usually superior to surgical therapy options.

Endoscopic submucosal dissection with an additional working channel (ESD+): a novel technique to improve procedure time and safety of ESD.

BACKGROUND AND AIMS: A new external additional working channel (AWC) was recently introduced by which endoscopic submucosal dissection (ESD) can be converted to a technique termed "ESD+ ". We aim to systematically evaluate this novel technique in flat gastric lesions and compare it to classical ESD. METHODS: The study was prospectively conducted in a pre-clinical ex vivo animal model (EASIE-R simulator) with porcine stomachs. Prior to intervention, we set standardized lesions measuring 3 cm or 4 cm in antegrade as well as in retrograde positions. RESULTS: Overall, 64 procedures were performed by an experienced endoscopist. Both techniques were reliable and showed en bloc resection rates of 100%. Overall, ESD+ reduced time of procedure compared to ESD (24.5 vs. 32.5 min, p = 0.025*). Particularly, ESD+ was significantly faster in retrograde lesions with a median of 22.5 vs. 34.0 min in 3 cm retrograde lesions (p = 0.002*) and 34.5 vs. 41.0 min (p = 0.011*) in 4 cm retrograde lesions. There were 0 perforations with both techniques. In ESD+ , 1 muscularis damage occurred (3.13%) compared to 6 muscularis damages with ESD (18.75%, p = 0.045*). CONCLUSIONS: By its grasp-and-mobilize technique, ESD+ allows potentially faster and safer resections of flat gastric lesions compared to conventional ESD in an ex vivo porcine model. The potential advantages of ESD+ in terms of procedure time may be particularly relevant for difficult lesions in retrograde positions.

Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma - A Prospective Multicenter DEGUM Study.

BACKGROUND: This prospective multicenter study funded by the DEGUM assesses the diagnostic accuracy of standardized contrast-enhanced ultrasound (CEUS) for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. METHODS: Patients at high risk for HCC with a histologically proven focal liver lesion on B-mode ultrasound were recruited prospectively in a multicenter approach. Clinical and imaging data were entered via online entry forms. The diagnostic accuracies for the noninvasive diagnosis of HCC were compared for the conventional interpretation of standardized CEUS at the time of the examination (= CEUS on-site) and the two CEUS algorithms ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) and CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System). RESULTS: 321 patients were recruited in 43 centers; 299 (93.1 %) had liver cirrhosis. The diagnosis according to histology was HCC in 256 cases, and intrahepatic cholangiocarcinoma (iCCA) in 23 cases. In the subgroup of cirrhotic patients (n = 299), the highest sensitivity for the diagnosis of HCC was achieved with the CEUS algorithm ESCULAP (94.2 %) and CEUS on-site (90.9 %). The lowest sensitivity was reached with the CEUS LI-RADS algorithm (64 %; p < 0.001). However, the specificity of CEUS LI-RADS (78.9 %) was superior to that of ESCULAP (50.9 %) and CEUS on-site (64.9 %; p < 0.001). At the same time, the negative predictive value (NPV) of CEUS LI-RADS was significantly inferior to that of ESCULAP (34.1 % vs. 67.4 %; p < 0.001) and CEUS on-site (62.7 %; p < 0.001). The positive predictive values of all modalities were high (around 90 %), with the best results seen for CEUS LI-RADS and CEUS on-site. CONCLUSION: This is the first multicenter, prospective comparison of standardized CEUS and the recently developed CEUS-based algorithms in histologically proven liver lesions in cirrhotic patients. Our results reaffirm the excellent diagnostic accuracy of CEUS for the noninvasive diagnosis of HCC in high-risk patients. However, on-site diagnosis by an experienced examiner achieves an almost equal diagnostic accuracy compared to CEUS-based diagnostic algorithms.

Testing of Helicobacter pylori by Endoscopic Biopsy: The Clinical Dilemma of Suppressive Conditions.

BACKGROUND AND AIMS: Testing for Helicobacter pylori is frequently conducted during esophagogastroduodenoscopy (EGD). Suppressive conditions such as the intake of proton-pump inhibitors (PPIs), preceded antibiotic treatment or recent upper gastrointestinal bleeding impair H. pylori test quality. The aim of our study was to evaluate the frequency and pattern of H. pylori suppressive conditions in a large patient collective undergoing elective EGD in a German university hospital. METHODS: The trial was performed as a single-center study. Only elective EGD from inpatients and outpatients were included. Prior to endoscopy, H. pylori suppressive conditions were collected using a standardized questionnaire. If H. pylori testing was indicated according to the guidelines, always both histology and helicobacter urease test were performed in analogy to the Sydney classification. RESULTS: One thousand six hundred and thirty-one patients were included (median 61 years, 36.0% outpatients, 64.0% inpatients). Overall, 76.5% of patients were under H. pylori suppressive conditions. The main suppressive condition was the intake of PPIs (70.7%). In 819 (50.2%) of all included cases, H. pylori testing was performed. The following were the results: 17.3% (142) had a positive H. pylori testing and 82.7% (677) were negative. Of those with negative result, 70.0% were tested under suppressive conditions. CONCLUSION: Guidelines recommend H. pylori testing under non-suppressive conditions. However, this does not always meet the clinical practice. Our data show that de facto, many patients undergoing elective EGD are tested for H. pylori under suppressive conditions coming along with a higher risk of potentially false negative results. Particularly, concerning this issue, further research is needed to improve and clarify everyday clinical practice.

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.