Jürgen Siebler

Assessment of Crohn's disease activity by confocal laser endomicroscopy

Background: Confocal laser endomicroscopy (CLE) allows microscopic imaging within the mucosal layer of the gut during ongoing endoscopy. Different studies have addressed the potential of CLE for in vivo diagnosis of ulcerative colitis and microscopic colitis. However, there are no data on the utility of CLE for in vivo diagnosis of Crohns disease (CD). The aim was to assess the clinical utility of CLE in patients with CD and to determine whether disease activity can be graded using CLE. Methods: Consecutive patients with and without CD were enrolled. The colonic mucosa was examined by standard white‐light endoscopy followed by CLE. The features seen on CLE were compared between CD patients and controls. Results: In all, 76 patients with CD were screened, of whom 54 patients were included in the present study. Eighteen patients without inflammatory bowel disease (IBD) served as controls. A significantly higher proportion of patients with active CD had increased colonic crypt tortuosity, enlarged crypt lumen, microerosions, augmented vascularization, and increased cellular infiltrates within the lamina propria. In quiescent CD, a significant increase in crypt and goblet cell number was detected compared with controls. Based on our findings, we propose a Crohns Disease Endomicroscopic Activity Score (CDEAS) for assessing CD activity in vivo. Conclusions: CLE has the potential to significantly improve diagnosis of CD compared with standard endoscopy. These findings should be evaluated in future prospective trials to assess the value of this newly developed CLE score for prediction of disease course and therapeutic responses. (Inflamm Bowel Dis 2012;)

Review article: in vivo imaging by endocytoscopy.

Aliment Pharmacol Ther 2011; 33: 1183–1193

Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo.

BACKGROUND & AIMS Apoptosis is crucially involved in acute and chronic liver injury, including viral, cholestatic, toxic, and metabolic liver disease. Additionally, dysregulation of apoptosis signaling pathways has been implicated in hepatocarcinogenesis. The most prominent members of the apoptosis-mediating tumor necrosis factor receptor superfamily are the TNF-R1 (CD120a) and the CD95 (Apo-1/Fas) receptor. Although extensively studied, the intracellular signaling events in hepatocytes are only incompletely understood. METHODS To examine the role of the caspase-8 homolog cellular FLICE-inhibitory protein (c-FLIP) in liver injury, we generated mice with hepatocyte specific deletion of c-FLIP. Three models of acute liver injury were employed: the agonistic anti-CD95 antibody Jo2, d-galactosamine and LPS (GalN/LPS), and concanavalin A. RESULTS Conditional ablation of c-FLIP in hepatocytes augmented liver injury and cell death in all three models of liver injury. CD95- and GalN/LPS-induced liver injury was ameliorated by a pancaspase inhibitor, while ConA-induced injury was unaffected by caspase inhibition. Augmented activation of the MAPK JNK was observed in parallel to liver injury in c-FLIP knockout mice in all injury models; however, inhibition of JNK only affected TNF- and ConA-mediated injury. CONCLUSIONS In summary, c-FLIP is a central regulator of cell death in hepatocytes, involving increased activation of caspases and the MAPK JNK.

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.

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.

Complete Long-Term Remission of an Inflammatory Pseudotumor under Corticosteroid Therapy

Inflammatory pseudotumors (IPT) form a group of etiologically, histologically, and biologically heterogeneous tumefactive lesions that are histologically characterized by prominent inflammatory infiltrates. IPT has been described in various organs including the lungs, bladder, liver, spleen, heart, and others. It may mimic a malignant tumor clinically and radiologically. We report a case of a 26-year-old woman with an ALK1-negative IPT (7 cm in maximal diameter) mainly located in the 12th right back muscles, surrounding a fractured rib. Histologically, the tumor consisted of an inflammatory infiltrate composed predominantly of diffusely distributed lymphoplasmacytic cells and stromal fibroblasts associated with focal obliterative phlebitis. Conservative steroid treatment resulted in complete remission and the patient remained disease-free for more than 1 year later. To our knowledge this is the first report of IPT involving the skeletal back muscle and complete resolution under corticosteroid treatment.

Prospective Evaluation of Acoustic Radiation Force Impulse (ARFI) Elastography and High-Frequency B-Mode Ultrasound in Compensated Patients for the Diagnosis of Liver Fibrosis/Cirrhosis in Comparison to Mini-Laparoscopic Biopsy

PURPOSE Ultrasound is a well-established noninvasive test for assessing patients with liver disease. This study aims to prospectively compare ultrasound to the new technique elastography (ARFI) for the assessment of liver fibrosis/cirrhosis. MATERIALS AND METHODS High-frequency B-mode ultrasound (liver surface/vein irregularity, liver homogeneity, spleen size), ARFI quantification, mini-laparoscopic liver evaluation including biopsy were prospectively obtained in compensated patients scheduled for liver biopsy. For the diagnosis of cirrhosis, a combined gold standard (cirrhosis at histology and/or at macroscopic liver evaluation) was used. RESULTS Out of 157 patients, 35 patients were diagnosed cirrhotic. Ultrasound (combination of liver vein and/or surface irregularity) showed no significant difference compared to ARFI quantification for the diagnosis of significant liver fibrosis (Ishak> = 3) and cirrhosis. Diagnosis of cirrhosis had a sensitivity/specificity/PPV/NPV of 83 %(± 12) / 82 %(± 7) / 57 %(± 14) / 94 %(± 4), respectively, with ultrasound and 86 %(± 12) / 81 %(± 7) / 57 %(± 13) / 95 %(± 4), respectively, with ARFI quantification. The sensitivity/specificity/PPV/NPV for the detection of significant fibrosis were 68 %(± 13) / 86 %(± 7) / 71 %(± 13) / 84 %(± 7), respectively, for ultrasound and 70 %(± 12) / 84 %(± 7) / 69 %(± 12) / 84 %(± 7), respectively, for ARFI quantification. CONCLUSION ARFI elastography and high-frequency B-mode ultrasound show similar and good results for the diagnosis of compensated liver cirrhosis and high-grade fibrosis. A key benefit of both methods is the high NPV suggesting them as noninvasive exclusion tests.

Palliative first-line therapy with weekly high-dose 5-fluorouracil and sodium folinic acid as a 24-hour infusion (AIO regimen) combined with weekly irinotecan in patients with metastatic adenocarcinoma of the stomach or esophagogastric junction followed by secondary metastatic resection after downsizing

Summary Background The aim of this retrospective study was to evaluate the efficacy and safety of weekly high-dose 5-fluorouracil (5-FU)/folinic acid (FA) as 24-h infusion (AIO regimen) plus irinotecan in patients with histologically proven metastatic gastroesophageal adenocarcinoma (UICC stage IV). Material/Methods From 08/1999 to 12/2008, 76 registered, previously untreated patients were evaluable. Treatment regimen: irinotecan (80 mg/m2) as 1-h infusion followed by 5-FU (2000 mg/m2) combined with FA (500 mg/m2) as 24-h infusion (d1, 8, 15, 22, 29, 36, qd 57). Results Median age: 59 years; male/female: 74%/26%; ECOG ≤1: 83%; response: CR: 1%, PR: 16%, SD: 61%, PD: 17%, not evaluable in terms of response: 5%; tumor control: 78%; median OS: 11.2 months; median time-to-progression: 5.3 months; 1-year survival rate: 49%; 2-year survival rate: 17%; no evidence of disease: 6.6%; higher grade toxicities (grade 3/4): anemia: 7%, leucopenia: 1%, ascites: 3%, nausea: 3%, infections: 12%, vomiting: 9%, GI bleeding of the primary tumor: 4%, diarrhea: 17%, thromboembolic events: 4%; secondary metastatic resection after downsizing: 16 patients (21%), R-classification of secondary resections: R0/R1/R2: 81%/6%/13%, median survival of the 16 patients with secondary resection: 23.7 months. Conclusions Combined 5-FU/FA as 24-h infusion plus irinotecan may be considered as an active palliative first-line treatment accompanied by tolerable toxicity; thus offering an alternative to cisplatin-based treatment regimens. Thanks to efficient interdisciplinary teamwork, secondary metastatic resections could be performed in 16 patients. In total, the patients who had undergone secondary resection had a median survival of 23.7 months, whereas the median survival of patients without secondary resection was 10.1 months (p≤0.001).

Efficacy and Safety of Irinotecan-Based Chemotherapy for Advanced Colorectal Cancer outside Clinical Trials: An Observational Study

Background: This prospective observational study in typical community-based outpatient clinics evaluated the efficacy and toxicity of weekly and biweekly irinotecan-based chemotherapies and their compatibility depending on age. Methods: 601 patients with advanced or metastatic colorectal cancer receiving first-, second-, or third-line irinotecanbased therapy were regularly analyzed for response and toxicity until the end of therapy. Results: The median age was 65 (28–87) years, approximately one-third of the patients were ≥70 years old. Of all patients, 405 were treated weekly and 68 biweekly. Median overall survival (OS) for first-line therapy was 26.5 months for the <70-year-old patients and 19.4 months for the ≥70-year-old patients. Toxicities were moderate in all groups. Tumor growth control rates (TCR) and median time to progression (TTP) were marginally better for patients <70 years old. Median TTP was 9.9 months in first-line therapy, 9.8 months after adjuvant therapy, 7.7 months in second-line, and 6.4 months in third-line therapy. Conclusions: Toxicity and response data from this observational study clearly confirm the positive results from previous clinical studies and show a slight ad-vantage in efficacy for the <70-year-old patients.

Granulomatous Lung Disease Requiring Mechanical Ventilation Induced by a Single Application of Oxaliplatin-Based Chemotherapy for Colorectal Cancer: A Case Report

Combined chemotherapeutic regimens in conjunction with oxaliplatin are considered safe and effective treatment options in the clinical management of metastatic colorectal cancer. A 62-year-old male patient with a metastatic rectal carcinoma developed a pulmonary reaction after the first application of the combined standard chemotherapy regimen (5-fluorouracil and sodium folinic acid as a 24 h infusion and oxaliplatin). Following the first dose of chemotherapy, the patient developed acute dyspnoea and fever. A computerised scan of the chest revealed bilateral pulmonary patchy consolidation. Despite high-dose empiric antibiotic and antimycotic treatment, no clinical improvement was seen. The patients condition deteriorated, and he required invasive mechanical ventilation. Diagnostic thoracoscopic wedge resections were performed for further diagnosis. The histological workup revealed distinct granulomatous inflammation, but no microbial pathogens were to be found. Thereupon, a drug-induced reaction to chemotherapy was suspected and high-dose steroid treatment initiated. Subsequently, the patients respiratory condition improved and he was extubated. The present case exemplifies the rare course of a bilateral pneumonia-like, drug-induced granulomatous reaction following a single application of oxaliplatin. In addition to the known side effects of oxaliplatin-containing combination chemotherapy, unexpected serious adverse events in the form of pulmonary toxicities should also be taken into account.