Urinary soluble CD163 is a putative non-invasive biomarker for primary sclerosing cholangitis.

Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease (IBD). Urinary proteins are emerging as non-invasive diagnostic biomarkers, and here, sCD163 levels were measured in the urine of 18 controls and 63 patients with IBD by enzyme-linked immunosorbent assay. Urinary sCD163 levels did, however, not differentiate IBD patients from controls. Analysis of sCD163 in the serum of 51 of these patients did not show higher levels in IBD. Primary sclerosing cholangitis (PSC) is often associated with IBD, and sCD163 was higher in the urine of the 21 patients and in the serum of the 13 patients with PSC compared to patients with IBD. Of clinical relevance, urinary sCD163 levels were higher in PSC patients compared to those with other chronic liver diseases (n = 16), while serum sCD163 levels were comparable between the two groups. Serum sCD163 of IBD and PSC patients positively correlated with serum C-reactive protein. Serum creatinine and glomerular filtration rate, surrogate markers for renal function, did not significantly correlate with urinary or serum sCD163 levels in IBD or PSC patients. Moreover, urinary sCD163 was not related to fecal calprotectin levels whereas serum sCD163 of IBD patients showed a positive trend. PSC associated with IBD and PSC without underlying IBD had similar levels of urinary sCD163 while serum sCD163 tended to be higher in the latter group. In PSC patients, urinary sCD163 did not correlate with serum aminotransferase levels, gamma glutamyl transferase, alkaline phosphatase, bilirubin or the Model for End Stage Liver Disease score. Ursodeoxycholic acid was prescribed to our PSC patients and fecal levels of ursodeoxycholic acid and its conjugated forms were increased in PSC compared to IBD patients. Otherwise, fecal bile acid levels of IBD and PSC patients were almost identical, and were not correlated with urinary and serum sCD163 in PSC. In summary, our study identified urinary sCD163 as a potential biomarker for PSC.

Unraveling the Role of Reactive Oxygen Species in T Lymphocyte Signaling.

Reactive oxygen species (ROS) are central to inter- and intracellular signaling. Their localized and transient effects are due to their short half-life, especially when generated in controlled amounts. Upon T cell receptor (TCR) activation, regulated ROS signaling is primarily initiated by complexes I and III of the electron transport chain (ETC). Subsequent ROS production triggers the activation of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2), prolonging the oxidative signal. This signal then engages kinase signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway and increases the activity of REDOX-sensitive transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). To limit ROS overproduction and prevent oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant proteins such as superoxide dismutases (SODs) finely regulate signal intensity and are capable of terminating the oxidative signal when needed. Thus, oxidative signals, such as T cell activation, are well-controlled and critical for cellular communication.

Serum Galectin-3 as a Non-Invasive Marker for Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a serious liver disease associated with inflammatory bowel disease (IBD). Galectin-3, an inflammatory and fibrotic molecule, has elevated circulating levels in patients with chronic liver disease and inflammatory bowel disease (IBD). This study aims to clarify whether galectin-3 can differentiate between patients with IBD, PSC, and PSC-IBD. Our study measured serum galectin-3 levels in 38 healthy controls, 55 patients with IBD, and 22 patients with PSC (11 patients had underlying IBD and 11 patients did not), alongside the urinary galectin-3 of these patients and 18 controls. Serum and urinary galectin-3 levels in IBD patients were comparable to those in controls. Among IBD patients, those with high fecal calprotectin, indicating severe disease, exhibited lower serum and elevated urinary galectin-3 levels compared to those with low calprotectin levels. Serum galectin-3 levels were inversely correlated with C-reactive protein levels. PSC patients displayed higher serum and urinary galectin-3 levels than IBD patients, with the highest serum levels observed in PSC patients with coexisting IBD. There was no correlation between serum and urinary galectin-3 levels and laboratory indicators of liver injury in both IBD and PSC patients. In conclusion, this study demonstrates that serum and urinary galectin-3 levels can distinguish IBD from PSC patients, and also reveals higher serum galectin-3 levels in PSC-IBD patients compared to those with isolated PSC.

Critical evaluation of molecular tumour board outcomes following 2 years of clinical practice in a Comprehensive Cancer Centre.

BACKGROUND: Recently, molecular tumour boards (MTBs) have been integrated into the clinical routine. Since their benefit remains debated, we assessed MTB outcomes in the Comprehensive Cancer Center Ostbayern (CCCO) from 2019 to 2021. METHODS AND RESULTS: In total, 251 patients were included. Targeted sequencing was performed with PCR MSI-evaluation and immunohistochemistry for PD-L1, Her2, and mismatch repair enzymes. 125 treatment recommendations were given (49.8%). High-recommendation rates were achieved for intrahepatic cholangiocarcinoma (20/30, 66.7%) and gastric adenocarcinoma (10/16, 62.5%) as opposed to colorectal cancer (9/36, 25.0%) and pancreatic cancer (3/18, 16.7%). MTB therapies were administered in 47 (18.7%) patients, while 53 (21.1%) received alternative treatment regimens. Thus 37.6% of recommended MTB therapies were implemented (47/125 recommendations). The clinical benefit rate (complete + partial + mixed response + stable disease) was 50.0% for MTB and 63.8% for alternative treatments. PFS2/1 ratios were 34.6% and 16.1%, respectively. Significantly improved PFS could be achieved for m1A-tier-evidence-based MTB therapies (median 6.30 months) compared to alternative treatments (median 2.83 months; P = 0.0278). CONCLUSION: The CCCO MTB yielded a considerable recommendation rate, particularly in cholangiocarcinoma patients. The discrepancy between the low-recommendation rates in colorectal and pancreatic cancer suggests the necessity of a weighted prioritisation of entities. High-tier recommendations should be implemented predominantly.

Simulation of Aerosol and Droplet Spread during Upper Airway and Gastrointestinal Endoscopy.

BACKGROUND AND AIMS: Aerosols and droplets are the main vectors in transmission of highly contagious SARS-CoV-2. Invasive diagnostic procedures like upper airway and gastrointestinal endoscopy have been declared as aerosol-generating procedures. Protection of healthcare workers is crucial in times of the COVID-19 pandemic. METHODS: We simulated aerosol and droplet spread during upper airway and gastrointestinal endoscopy with and without physico-mechanical barriers using a simulation model. RESULTS: A clear plastic drape as used for central venous access markedly reduced visualized aerosol and droplet spread during endoscopy. CONCLUSION: A simple and cheap drape has the potential to reduce aerosol and droplet spread during endoscopy. In terms of healthcare worker protection, this may be important particularly in low- or moderate-income countries.

Therapeutic Plasma Exchange in ICU Patients with Acute Hypertriglyceridemia-Induced Pancreatitis Improves Patient Outcomes.

BACKGROUND: Acute severe pancreatitis is associated with high morbidity and mortality. Hypertriglyceridemia is the third most common cause of acute pancreatitis and higher triglyceride levels increase the risk for severe acute pancreatitis. Plasma exchange is an effective treatment method to lower triglycerides. Our study aimed to investigate the efficiency of plasma exchange as a treatment option for acute hypertriglyceridemia-induced pancreatitis (HTGP), the impact on mortality assessed by the SOFA, SAPS II, BISAP Score, Ranson's, and Glasgow-Imrie Criteria, as well as the overall length of stay in hospital and ICU. METHODS: In this retrospective single-center cohort study, triglycerides before and after plasma exchange were compared. SOFA and SAPS II were taken on ICU admission and at discharge. To further characterize the patient cohort, BISAP Score (on admission), Ranson's Criteria (on admission and after 48 h), and the Glasgow-Imrie Criteria (48 h after admission) were calculated. RESULTS: The study included 11 patients (91% male; median age 45 years). Triglycerides were reduced from 4,266 ± 3,560.6 to 842 ± 575.9 mg/dL during plasmapheresis (p < 0.001). The median ICU length of stay was 3 ± 4.2 days. In-hospital mortality was 0%. The SOFA score was significantly reduced from 4 ± 3.4 points on admission to 2 ± 2.1 points at discharge (p = 0.017). Triglycerides and cholesterol decreased from 3,126 ± 3,665 to 531 ± 273 mg/dL (p = 0.003) and from 438 ± 137.9 to 222 ± 59.5 mg/dL (p = 0.028), respectively. The BISAP Score on admission was 3 ± 0.5 points, Ranson's Criteria were 3 ± 1.5 points (48 h after admission, cumulative), and Glasgow-Imrie Criteria 3 ± 1.3 points (48 h after admission). CONCLUSION: Plasmapheresis is an efficient and safe treatment method for ICU patients with acute HTGP and significantly reduces triglycerides. Furthermore, plasmapheresis significantly improves the clinical outcomes of patients with HTGP.

Fecal short chain fatty acids and urinary 3-indoxyl sulfate do not discriminate between patients with Crohn´s disease and ulcerative colitis and are not of diagnostic utility for predicting disease severity.

BACKGROUND: Urinary 3-indoxyl sulfate levels as well as fecal short chain fatty acid (SCFA) concentrations are surrogate markers for gut microbiota diversity. Patients with inflammatory bowel diseases (IBDs) and patients with primary sclerosing cholangitis (PSC), a disease closely associated with IBD, have decreased microbiome diversity. In this paper, the fecal SCFAs propionate, acetate, butyrate and isobutyrate of patients with IBD and patients with PSC-IBD and urinary 3-indoxyl sulfate of IBD patients were determined to study associations with disease etiology and severity. METHODS: SCFA levels in feces of 64 IBD patients and 20 PSC-IBD patients were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Urinary 3-indoxyl sulfate levels of 45 of these IBD patients were analysed by means of reversed-phase liquid chromatography-electrospray ionization-tandem mass spectrometry. Feces of 17 healthy controls and urine of 13 of these controls were analyzed in parallel. These cohorts had comparable sex distribution and age. RESULTS: Urinary 3-indoxyl sulfate concentrations (normalized to urinary creatinine levels) was increased (P = 0.030) and fecal isobutyrate levels (normalized to dry weight of the stool sample) of IBD patients were decreased (P = 0.035) in comparison to healthy controls. None of the analyzed metabolites differed between patients with Crohn´s disease (CD) and patients with ulcerative colitis (UC). Fecal acetate and butyrate positively correlated with fecal calprotectin (P = 0.040 and P = 0.005, respectively) and serum C-reactive protein (P = 0.024 and P = 0.025, respectively) in UC but not CD patients. UC patients with fecal calprotectin levels above 150 µg/g, indicating intestinal inflammatory activity, had higher fecal acetate (P = 0.016), butyrate (P = 0.007) and propionate (P = 0.046) in comparison to patients with fecal calprotectin levels < 50 µg/g. Fecal SCFA levels of PSC-IBD and IBD patients were comparable. CONCLUSIONS: Current findings suggest that analysis of urinary 3-indoxyl-sulfate as well as fecal SCFAs has no diagnostic value for IBD and PSC-IBD diagnosis or monitoring of disease severity.

Altered fecal bile acid composition in active ulcerative colitis.

BACKGROUND: Disturbed bile acid homeostasis associated with a rise of primary and a decline of secondary bile acids is a consistent finding in inflammatory bowel diseases (IBDs). Whether fecal bile acids may emerge as biomarkers for IBD diagnosis and disease severity is less clear. Our study aimed to identify associations of 18 fecal bile acid species with IBD entity and disease activity. METHODS: Stool samples of 62 IBD patients and 17 controls were collected. Eighteen fecal bile acid species were quantified by LC-MS/MS using stable isotope dilution. Lipid levels normalized to a dry weight of the fecal homogenates and ratios of single bile acid species to total bile acid levels were used for calculations. RESULTS: IBD patients exhibited altered primary and secondary bile acid ratios in stool, with notable distinctions between ulcerative colitis (UC) compared to Crohn's disease (CD) and healthy controls. Fecal calprotectin was negatively correlated with glycolithocholic acid (GLCA) and hyodeoxycholic acid (HDCA) in UC. These bile acids were reduced in stool of UC patients with fecal calprotectin levels > 500 µg/g compared to UC patients with low calprotectin levels. Moreover, negative associations of six secondary bile acids with C-reactive protein (CRP) existed in UC. In CD patients, fecal bile acids did not correlate with CRP or fecal calprotectin. Diarrhoea is common in IBD, and UC patients with diarrhoea had reduced deoxycholic acid (DCA), glycine conjugated DCA (GDCA) and lithocholic acid in stool in contrast to patients with normal stool consistency. Fecal bile acid levels were not associated with diarrhoea in CD patients. UC patients treated with mesalazine had increased levels of fecal GDCA whereas no such changes were observed in CD patients. Bile acid levels of CD and UC patients treated with biologicals or corticosteroids did not change. Relative levels of GHDCA (specificity: 79%, sensitivity: 67%) and glycochenodeoxycholic acid (specificity: 74%, sensitivity: 63%) were the most specific to distinguish UC from CD. CONCLUSION: Disrupted fecal bile acid homeostasis is associated with disease severity and disease symptoms in UC but not in CD, potentially aiding in distinguishing IBD subtypes and classifying the pathophysiology of diarrhoea in UC.

[Costs of potentially outpatient endoscopic procedures in cases with a 1-day hospital stay versus a longer stay]. / Kosten potenziell ambulant erbringbarer endoskopischer Leistungen in Fällen mit 1-Tages-Verweildauer gegenüber einer längeren Verweildauer.

INTRODUCTION: The transfer of patient care and medical interventions that was previously provided on an inpatient basis to outpatient settings is a stated goal of health politics. It is unclear to what extent costs of an endoscopic procedure and the disease severity depend on the duration of inpatient treatment. We therefore examined whether endoscopic services for cases with a one-day length of stay (VWD) are comparably expensive to cases with a longer VWD. METHODS: Outpatient services were selected from the DGVS service catalog. Day cases with exactly one such gastroenterological endoscopic (GAEN) service were compared with cases with VWD>1 day regarding their patient clinical complexity levels (PCCL) and mean costs. Data from the DGVS-DRG project with §21-KHEntgG cost data from a total of 57 hospitals from 2018 and 2019 served as the basis. Endoscopic costs were taken from cost center group 8 of the InEK cost matrix and plausibility checked. RESULTS: A total of 122,514 cases with exactly one GAEN service were identified. Statistically equal costs were shown in 30 of 47 service groups. In 10 groups, the cost difference was not relevant (<10%). Cost differences >10% existed only for EGD with variceal therapy, insertion of a self-expanding prosthesis, dilatation/bougienage/exchange with PTC/PTCD in place, non-extensive ERCP, endoscopic ultrasound in the upper gastrointestinal tract, and colonoscopy with submucosal or full thickness resection, or foreign object removal. PCCL differed in all but one group. CONCLUSION: Gastroenterology endoscopy services provided as part of inpatient care but potentially performable on an outpatient basis are predominantly equally expensive for day cases as for patients with a length of stay greater than one day. The disease severity is lower. Calculated §21-KHEntgG cost data thus form a reliable basis for the calculation of appropriate reimbursement for hospital services to be provided as outpatient services under the AOP in the future.

Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases.

OBJECTIVE: Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis with a 1-year mortality of 66%. Bacterial translocation (BT) from the intestine to the mesenteric lymph nodes is crucial for the pathogenesis of SBP. DESIGN: Since BT presupposes a leaky intestinal epithelium, the integrity of mucus and epithelial cell junctions (E-cadherin and occludin) was examined in colonic biopsies from patients with liver cirrhosis and controls. SBP-inducing Escherichia coli (E. coli) and Proteus mirabilis (P. mirabilis) were isolated from ascites of patients with liver cirrhosis and co-cultured with Caco-2 cells to characterise bacteria-to-cell effects. RESULTS: SBP-derived E. coli and P. mirabilis led to a marked reduction of cell-to-cell junctions in a dose-dependent and time-dependent manner. This effect was enhanced by a direct interaction of live bacteria with epithelial cells. Degradation of occludin is mediated via increased ubiquitination by the proteasome. Remarkably, a novel bacterial protease activity is of pivotal importance for the cleavage of E-cadherin. CONCLUSION: Patients with liver cirrhosis show a reduced thickness of colonic mucus, which allows bacteria-to-epithelial cell contact. Intestinal bacteria induce degradation of occludin by exploiting the proteasome of epithelial cells. We identified a novel bacterial protease activity of patient-derived SBP-inducing bacteria, which is responsible for the cleavage of E-cadherin structures. Inhibition of this protease activity leads to stabilisation of cell junctions. Thus, targeting these mechanisms by blocking the ubiquitin-proteasome system and/or the bacterial protease activity might interfere with BT and constitute a novel innovative therapeutic strategy to prevent SBP in patients with liver cirrhosis.

Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol.

The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab + bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase II study is the first trial to evaluate the safety and efficacy of atezolizumab + bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life. Clinical Trial Registration: NCT04224636 (ClinicalTrials.gov).

Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches.

Hereditary diffuse gastric cancer is an autosomal dominant syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is caused by inactivating mutations in the tumor suppressor gene CDH1. Genetic testing technologies have become more efficient over the years, also enabling the discovery of other susceptibility genes for gastric cancer, such as CTNNA1 among the most important genes. The diagnosis of pathogenic variant carriers with an increased risk of developing gastric cancer is a selection process involving a multidisciplinary team. To achieve optimal long-term results, it requires shared decision-making in risk management. In this review, we present a synopsis of the molecular changes and current therapeutic approaches in HDGC based on the current literature.

Diagnostic Accuracy and Therapeutic Efficacy of Digital Single-Operator Cholangioscopy for Biliary Lesions and Stenosis.

BACKGROUND/AIMS: Digital single-operator cholangioscopy (dSOC) has revolutionized bile duct visualization. Interventions like electrohydraulic or laser lithotripsy, inspection of suspicious areas, and targeted biopsies have become possible quick and easy. One main indication for dSOC remains the evaluation of indeterminate biliary strictures. OBJECTIVE AND METHODS: We analyzed 180 consecutive dSOCs procedures performed in a high-volume tertiary center to evaluate sensitivity, specificity as well as positive and negative predictive values (PPV and NPV) for indeterminate strictures. Furthermore, technical success and complications were analyzed. RESULTS: In 92-97%, the region of interest was reached and successfully visualized. In 83-100%, targeted biopsies were obtained from the suspicious area. Only the distal bile duct was less successful with only 84 and 62%, respectively. In general, dSOC procedures were safe. Cholangitis was the main complication. Regarding the diagnostic accuracy of dSOC of indeterminate biliary strictures, we found a sensitivity of 0.87 and specificity of 0.88, over all. Within the whole cohort, the investigators' assessment directly after dSOC had a PPV of 0.63 and a NPV of 0.97. In patients with biliary lesions or stenosis suspicious for malignancy, the dSOC-based visual diagnosis revealed a very high diagnostic accuracy with sensitivity and specificity of 1.0 (95% CI 0.86-1.0) and 0.76 (95% CI 0.56-0.9) with a PPV of 0.77 (95% CI 0.59-0.9) and a high NPV of 1.0 (95% CI 0.85-1.0). CONCLUSIONS: Our study demonstrates that dSOC has a high diagnostic accuracy as well as a favorable safety profile. Therefore, dSOC should be discussed as standard of care during endoscopic retrograde cholangiography for indeterminate biliary lesions.

[Prevention of gastrointestinal cancer]. / Prävention gastrointestinaler Tumore.

Throughout the past decades, considerable progress has been made in the (early) diagnosis and treatment of gastrointestinal cancers. However, the prognosis for advanced stages of gastrointestinal tumors remains limited for many patients and approximately one third of all tumor patients die as a result of gastrointestinal tumors. The prevention and early detection of gastrointestinal tumors is therefore of great importance.For this reason, we summarize the current state of knowledge and recommendations for the primary, secondary and tertiary prevention of esophageal, stomach, pancreas, liver and colorectal cancer in the following.

Accuracy of Different Rapid Urease Tests in Comparison with Histopathology in Patients with Endoscopic Signs of Gastritis.

BACKGROUND AND AIM: According to several guidelines, both invasive and non-invasive tests can be used to detect Helicobacter pylori (H. pylori). Invasive methods include H. pylori culture, histological staining, rapid urease tests (RUTs) and PCR. Non-invasive methods include urease breath test, stool antigen and serum IgG testing. The aim of our study was to compare all commercially available RUTs and histology in Germany. MATERIAL AND METHODS: One hundred fifty patients were enrolled in our study, irrespective of proton pump inhibitors (PPIs) or antibiotic use. If the results of RUTs and histology were diverging, real-time PCR to detect H. pylori DNA was undertaken. RESULTS: We detected no differences in the sensitivity or specificity between the different RUTs. In PPI and/or antibiotic-treated patients, RUTs seemed to be more sensitive for the detection of H. pylori infection compared to histology. In addition to the cheaper price of RUTs, they are also quicker to process. We show that histological staining in patients with signs of gastritis is expensive and not necessary, if there are no additional histological questions besides H. pylori status. CONCLUSIONS: In conclusion, we consider RUTs to be cheap and fast alternatives to histology in patients with endoscopic signs of gastritis, independently of whether PPIs or antibiotic are used. Histological evaluation is expensive, time consuming and may be unnecessary in some cases.

Endoscopic Necrosectomy of Walled-Off Necrosis following Severe Pancreatitis Using a Hot AxiosTM Stent - A Case Series.

BACKGROUND: Walled-off necrosis is a common complication of severe pancreatitis. Guidelines recommend endoscopic transgastric necrosectomy as therapy of choice. Different endoscopic approaches are possible. METHODS: We retrospectively analyzed our series of 9 patients where necrosectomy was performed after application of a lumen-apposing metal stent (LAMS) delivered using a Hot AxiosTM Stent device. RESULTS: In all 9 cases, the walled-off necrosis resolved completely. Necrosectomy was performed through the LAMS (mean: 5.7 times). Endoscopic necrosectomy was repeated every 3rd-7th day using 10- or 15-mm snares. There were no major complications. Especially, no early or delayed bleeding was seen. CONCLUSION: The Hot AxiosTM Stent device is a safe method for necrosectomy of walled-off necrosis. It enables puncture, drainage, and LAMS insertion in a single delivery, followed by several courses of necrosectomy if needed without stent exchange.

Serum Chemerin Does Not Differentiate Colorectal Liver Metastases from Hepatocellular Carcinoma.

The chemoattractant adipokine chemerin is related to the metabolic syndrome, which is a risk factor for different cancers. Recent studies provide evidence that chemerin is an important molecule in colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Serum chemerin is high in CRC patients and low in HCC patients and may serve as a differential diagnostic marker for HCC and liver metastases from CRC. To this end, serum chemerin was measured in 36 patients with CRC metastases, 32 patients with HCC and 49 non-tumor patients by ELISA. Chemerin serum protein levels were, however, similar in the three cohorts. Serum chemerin was higher in hypertensive than normotensive tumor patients but not controls. Cancer patients with hypercholesterolemia or hyperuricemia also had increased serum chemerin. When patients with these comorbidities were excluded from the calculation, chemerin was higher in CRC than HCC patients but did not differ from controls. Chemerin did not correlate with the tumor markers carcinoembryonic antigen, carbohydrate antigen 19-9 and alpha-fetoprotein in both cohorts and was not changed with tumor-node-metastasis stage in HCC. Chemerin was not associated with hepatic fat, liver inflammation and fibrosis. To conclude, systemic chemerin did not discriminate between CRC metastases and HCC. Comorbidities among tumor patients were linked with elevated systemic chemerin.

[Therapeutic regimens using monoclonal antibodies in gastroenterology]. / Therapie mit monoklonalen Antikörpern in der Gastroenterologie.

Therapeutic regimens using monoclonal antibodies have been implemented in clinical daily practice for various gastroenterological diseases, for therapeutic strategies in gastrointestinal (GI) oncology, and infectious diseases of the gastrointestinal tract. The main indications remain the therapy of chronic inflammatory bowel disease and in GI oncology. A new field has opened for targeted therapy with monoclonal antibodies of recurrent Clostridium difficile infection. In the nomenclature of monoclonal antibodies, the endings of the substances indicate the production or degree of "humanization" of the respective antibodies ("umab": fully human, recombinant antibody; "ximab": chimeric antibody with variable murine domain). For chronic inflammatory bowel disease, monoclonal antibodies has been developed to interfere with molecular targets of the inflammatory cascade in the underlying pathogenesis (tumor necrosis factor­α, interleukin-12 and -23; α4ß7-integrins). The development of targeted therapies in the treatment of GI malignancies, monoclonal antibodies has been developed to interfere with substantial pathways of proliferation and apoptosis as well as neoplastic vascularization and neovascularization (e.g., vascular endothelial growth factor [VEGF] and VEGF receptor antibodies, epidermal growth factor receptor antibodies, HER2/neu antibodies). In the current review, we provide a summary of the current applications of monoclonal antibodies in the therapeutic treatment of gastroenterological diseases.

Mucosal Two-Step Pathogenesis in Gastroesophageal Reflux Disease: Repeated Weakly Acidic Stimulation and Activation of Protease-Activated Receptor-2 on Mucosal Interleukin-8 Secretion.

BACKGROUND: Activation of protease-activated receptor-2 (PAR2) is involved in the mucosal immune pathogenesis of gastroesophageal reflux disease (GERD) that is characterized by proinflammatory cytokines such as interleukin-8 (IL-8). PAR2 activation on epithelial cells induces epithelial IL-8 secretion and initiates mucosal inflammation. METHODS: A human primary esophageal epithelial cell model was established to investigate the effects of repeated stimulation with weakly acidic solutions and subsequent PAR2 activation. After creating a monolayer, cells were incubated under weakly acidic conditions for 7 h followed by 17 h at pH 7.4. This short-term exposure was repeated once. After weakly acidic stimulation, PAR2 activation was achieved by a synthetic agonist at pH 7.4. RESULTS: After repeated weakly acidic incubation, PAR2 transcript levels were 3.6-fold upregulated (p = 0.001) and IL-8 transcripts were 2.4-fold enhanced (p = 0.034) compared to nonstimulated controls, while IL-8 protein in the cell pellet and supernatant was not increased. Only the additional PAR2 activation upon pH stimulation led to increased IL-8 secretion into the supernatant. CONCLUSIONS: We propose a 2-step mechanism in which repeated weakly acidic exposure leads to the upregulation of epithelial PAR2 expression. The subsequent activation of upregulated PAR2 contributes to the initiation of mucosal inflammation, which underlies the important role of esophageal epithelium in GERD pathogenesis.