D Wildner

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis

Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.

Dynamic contrast-enhanced ultrasound (DCE-US) for the characterization of hepatocellular carcinoma and cholangiocellular carcinoma.

PURPOSE In a prospective study, we compared the different perfusion kinetics of HCC and ICC using dynamic contrast-enhanced ultrasound (DCE-US). MATERIALS AND METHODS Patients with proven HCC and ICC were included. Three-minute video clips of CEUS examinations (CPS - low MI mode) after a bolus injection of 1.2 ml SonoVue were recorded and analyzed with quantification software (VueBox). Parameters for the arterial contrast enhancement [rise time (RT), time-to-peak (TTP)] towards portal venous contrast enhancement [mean transit time (local) (mTTl) and fall time (FT)] were quantified. Furthermore, contrast wash-out after peak enhancement (PE) (40 s, 80 s, 100 s and 120 s after PE) was compared between HCC and ICC. RESULTS 43 patients with proven HCC (n = 23 HCC; cirrhosis n = 16) and ICC (n = 20 ICC; Cirrhosis n = 6) were examined. No statistical difference of the arterial DCEUS parameters was found between HCC and ICC. Contrast enhancement of the portal venous and late phases showed significantly lower values in the ICC group indicating early wash-out of the contrast agent: mTTl (p = 0.0209): HCC 118.4 s (SD± 88.4); ICC 64.8 s (SD± 49.7). FT (p = 0.0433): HCC 42.5 s (SD± 27.7); ICC 27.7 s (SD± 16.2). The percental loss of intensity at a definite time point after PE was significantly higher in ICC than in HCC lesions. CONCLUSION DCE-US is able to detect and quantify differences in perfusion kinetics between HCC and ICC. Whereas arterial contrast enhancement patterns may overlap between HCC and ICC, a timed characterization of wash-out kinetics may offer an additional tool to characterize HCC and ICC. The presence of a rapid loss of signal intensity in the early portal venous phase is significantly higher in ICC than in HCC lesions.

Multispectral Optoacoustic Tomography for Assessment of Crohn’s Disease Activity

A preliminary study suggests that intestinal-wall assessment by means of noninvasive multispectral optoacoustic tomography may distinguish remission from active disease in patients with Crohn’s disease.

CEUS in hepatocellular carcinoma and intrahepatic cholangiocellular carcinoma in 320 patients - early or late washout matters: a subanalysis of the DEGUM multicenter trial.

PURPOSE The aim of the study was the comparison of tumor vascularization and contrast enhancement in contrast-enhanced ultrasound (CEUS) for the characterization of hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC). We present data of the subpopulations HCC and ICC examined in the DEGUM multicenter trial for the characterization of focal liver lesions in clinical practice. MATERIALS AND METHODS Based on the data of the DEGUM multicenter trial (1349 patients), all patients with histologically proven HCC (n = 278) and ICC (n = 42) were analyzed. The vascularity pattern and contrast enhancement pattern during the arterial, portal-venous and late phase were compared. RESULTS An underlying liver cirrhosis was found in 214/278 patients with HCC (76.9 %) and 7/42 patients with ICC (16.7 %). In CEUS, HCC showed a global arterial hyperenhancement compared to ICC (HCC: tumor center: 60.3 %; tumor periphery: 75 %; ICC: tumor center: 16.7 %; tumor periphery: 40.5 %). ICC showed an initial contrast enhancement primarily at the tumor periphery (ICC: 85.7 % vs. HCC: 61 %) followed by an early portal-venous contrast washout in the tumor center (ICC: 85.8 % vs. HCC: 49.8 %) and tumor periphery (ICC: 66.7 % vs. HCC: 32.6 %). HCC showed a delayed contrast washout (late phase hypoenhancement: HCC: 75 % vs. ICC: 92.9 %). CONCLUSION ICCs are rare in cirrhotic livers. CEUS can demonstrate differences in the vascularization patterns between HCC and ICC. HCC showed an arterial global hyperenhancement and delayed contrast washout in the late phase. ICCs are characterized by an arterial contrast enhancement at the tumor periphery with early contrast washout of the vascularized parts of the lesions in the portal-venous and late phase.

Confocal laser endomicroscopy for the differential diagnosis of ulcerative colitis and Crohn’s disease: a pilot study

BACKGROUND AND STUDY AIM The differential diagnosis of ulcerative colitis from Crohns disease is of pivotal importance for the management of inflammatory bowel diseases, as both entities involve specific therapeutic management strategies. Confocal laser endomicroscopy (CLE) allows on-demand, in vivo characterization of architectural and cellular details during endoscopy. The aim of this study was to assess the efficacy of CLE to differentiate between ulcerative colitis and Crohns disease. PATIENTS AND METHODS This was a prospective study involving consecutive patients with a well-established diagnosis of ulcerative colitis or Crohns disease who underwent colonoscopy with fluorescein-aided confocal imaging. RESULTS Overall, 79 patients were included (40 Crohns disease, 39 ulcerative colitis). CLE findings in patients with Crohns disease, showed significantly more discontinuous inflammation (87.5 % vs. 5.1 %), focal cryptitis (75.0 % vs. 12.8 %), and discontinuous crypt architectural abnormality (87.5 % vs. 10.3 %) than in ulcerative colitis (P < 0.0001). Conversely, ulcerative colitis was associated with severe, widespread crypt distortion (87.2 % vs. 17.5 % in Crohns disease), decreased crypt density (79.5 % vs. 22.5 %), and frankly irregular surface (89.7 % vs. 17.5 %; P < 0.0001 for all comparisons). Statistically significant differences were not seen for heavy, diffuse lamina propria cell increase or mucin preservation. No granulomas were visible. Based on these findings, a CLE scoring system was developed that revealed excellent accuracy (93.7 %) when compared with the historical clinical diagnosis and the histopathological gold standard. CONCLUSIONS CLE could visualize several disease-specific microscopic features, which are conventionally used in standard histopathology to differentiate between ulcerative colitis and Crohns disease. However, because of the limited penetration depth of CLE, submucosal details or granulomas were not visible. The new scoring system may allow in vivo diagnosis of ulcerative colitis or Crohns disease. Trial registered at ClinicalTrials.gov: NCT 02238665.

Early response to anti-tumoral treatment in hepatocellular carcinoma--can quantitative contrast-enhanced ultrasound predict outcome?

PURPOSE In order to detect an early response to anti-angiogenic therapy, this study aims at analyzing specific effects of a sorafenib-based regime on intra-tumoral D-CEUS flow parameters of patients with HCC. MATERIALS AND METHODS Videos of the arterial phase were captured before initiation of a therapy with sorafenib and 1 and 3 months after (n = 9). Patients receiving a non-anti-angiogenic therapy (TACE, n = 10) served as a comparison group. Cross-sectional imaging was performed at the same time points and patients were followed up for 1 year. RESULTS In the responder group (RE), the absolute (percentage) TTP was 11.28 s ± 2.03 s (1.00) before treatment, 13.60 s ± 1.52 s (1.53 ± 0.08) after one month (p = 0.0405), and 16.17 s ± 2.35 s (1.46 ± 0.07) after three months of treatment (p = 0.0071). The TTP increased significantly in the RE group as early as 1 month after initiation of sorafenib compared to the non-responder group. There were no significant differences in the non-responder group or between the NR and the TACE group at any time point. D-CEUS values from all sorafenib-treated patients showed good accordance with RECICL (response evaluation criteria in cancer of the liver) criteria (R2 = 0.7154, p = 0.0001). CONCLUSIONS Quantitative CEUS reveals variations of dynamic parameters of blood flow during anti-tumoral therapy in liver cancer patients. Further investigations and clinical trails have to confirm that the TTP is a promising parameter in the prediction of early response to sorafenib-based therapy.

Description of a new, endoscopic technique to remove the over-the-scope-clip in an ex vivo porcine model (with video)

BACKGROUND Various studies have demonstrated the usefulness of the over-the-scope-clip (OTSC) to treat perforations, anastomotic leaks, and fistulae. Endoscopic removal of the OTSC was previously described in a series of 3 patients by using the Nd:YAG laser. OBJECTIVE To evaluate a new endoscopic technique to remove the OTSC. DESIGN Prospective, single-arm, pilot study in an ex vivo porcine model. INTERVENTIONS Perforations were created by using a surgical scalpel and a blunt trocar. Then they were endoscopically closed with the OTSC. Next, the OTSC was removed under endoscopic control by inserting a 0.035-inch straight hydrophilic tip guidewire into the oval hole on the side of the OTSC jaw. Afterward, the OTSC clip was removed by pulling on the wire. RESULTS Fifteen perforations were closed: with the OTSC. In all of the cases, the endoscopic closure of the defects was feasible and effective. Successful visualization of the oval hole of the OTSC was possible in 12 cases (80%), and guidewire cannulation was possible in all of these 12 cases (100%). Advancement of the guidewire through the OTSC and then the lumen of the stomach was accomplished in 8 cases (53.3%). In all of the cases with successful cannulation of the orifice, removal of the OTSC was managed safely. The result was an overall success rate of 53.3% (8 of 15 cases). LIMITATIONS Ex vivo porcine model. CONCLUSIONS Guidewire removal is a new and feasible technique to remove the OTSC. Future studies should refine the technique to enhance visualization and cannulation of the oval hole of the OTSC.

Multispectral Optoacoustic Tomography in Crohn’s Disease: Noninvasive Imaging of Disease Activity

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Impact of Acoustic Radiation Force Impulse Imaging in Clinical Practice of Patients after Orthotopic Liver Transplantation

Background Acoustic radiation force impulse (ARFI) elastography is a reliable diagnostic device for quantitative non-invasive assessment of liver fibrosis in patients with chronic liver disease. The aim of our prospective study was to evaluate the impact of ARFI in patients after orthotopic liver transplantation (OLT). Therefore, we compared ARFI shear wave velocities with clinical features, non-invasive markers, and the histology of patients following OLT. Material/Methods Post-transplant patients underwent a clinical examination and blood samples were taken. B-mode and Doppler ultrasound (US) of the portal vein and the hepatic artery were performed. Subsequently, a minimum of 10 valid ARFI values were measured in the left and right liver lobe. Liver biopsy was performed if indicated. Results Between May 2012 and May 2014, 58 Patients after OLT were included in the prospective study. Laboratory markers and aspartate aminotransferase-to-platelet ratio index (APRI) correlated with ARFI values (r=0.44, p<0.001). The histological (n=22) fibrosis score (Ludwig) was significantly correlated with the ARFI of the biopsy site (r=0.55, p=0.008). The mean shear-wave velocities were significantly increased in advanced fibrosis (F≤2 1.57±0.57 m/s; F≥3 2.85±0.66 m/s; p<0.001), obstructive cholestasis and active viral hepatitis. The area under the receiver operating characteristic (AUROC) curves for the accuracy of ARFI were 74% (F≥1), 73% (F≥2), 93% (F≥3), and 80% (=F4). Conclusions ARFI elastography correlates well with laboratory values and with noninvasive and invasive markers of fibrosis in patients after OLT. In this regard, elevated ARFI-velocities should be interpreted with caution in the context of obstructive cholestasis and active viral disease.

Liver Stiffness Assessed by Acoustic Radiation Force Impulse (ARFI) Technology Is Considerably Increased in Patients with Cholestasis

PURPOSE To explore the impact of cholestasis on liver stiffness assessed by acoustic radiation force impulse (ARFI) technology. MATERIALS AND METHODS Over a period of four months, patients with sonographic cholestasis and increased cholestatic blood values (Bilirubin, γGT, AP > 2 times ULN) scheduled for endoscopic therapy were recruited. Exclusion criteria were: known liver disease; signs of cirrhosis at ultrasound (irregular liver veins and/or surface); heart insufficiency (NYHA III-VI). ARFI (Siemens S2000), ultrasound and blood examinations were performed before and in a subgroup after successful biliary drainage. RESULTS In total, 21 patients with cholestasis were included in the study. ARFI measurements were above the cut-off for cirrhosis (1.8  m/s) in all patients with a mean of 2.91  m/s ± 0.89  m/s without a history or signs of cirrhosis. Bilirubin, γGT and AP were elevated on average to 9.7 ± 5.3  mg/dl, 1192 ± 960  U/l and 730 ± 389  U/l. A subgroup of 10 patients was measured after successful drainage. ARFI measurements declined in all patients of that subgroup on average by 0.76  m/s at a mean time interval of 4.5 days (p < 0.001). CONCLUSION Cholestasis significantly increases liver stiffness assessed by ARFI. Therefore, it is important to exclude profound cholestasis when using ARFI for evaluating patients for liver fibrosis.