Nico Schäfer

Orthotopic liver transplantation in human immunodeficiency virus (HIV)‐positive patients: Outcome of 7 patients from the Bonn cohort

The outcome and clinical features of 7 HIV‐positive patients who were liver transplanted at Bonn University in the era of highly active antiretroviral therapy (HAART) between 1997 and 2004, analyzed by retrospective chart review, are reported. Reasons for orthotopic liver transplantation (OLT) were end‐stage liver disease due to chronic hepatitis C (n = 4) or hepatitis B (n = 1) or acute liver failure due to fulminant hepatitis B (n = 2). Immunosuppression was based on cyclosporine A and prednisone. HAART was reinitiated 1 month after transplantation, and immunosuppression was carefully adapted to account for drug‐drug interactions between cyclosporine A and protease inihibitors. Prednisone was withdrawn 5 months (median) after OLT when immunosuppression had been reliably established in the presence of HAART. One patient died 95 days after OLT due intrathoracic hemorrhage, whereas 6 patients were alive at a median of 24 months. A single episode of acute rejection was observed. The spectrum of postoperative complications was no different from HIV‐negative patients apart from Kaposis sarcoma and multicentric Castlemans disease in a single patient. Recurrent hepatitis B infection was efficiently prevented, whereas hepatitis C reinfection occurred in all 4 patients who had preexisting hepatitis C. Earlier reports on fatal courses of recurrent hepatitis C infection, high rates of organ rejection, and HAART‐related liver toxicity were not observed in our patients. In conclusion, even though preliminary, our data suggest that outcomes after liver transplantation of HIV‐infected patients can be improved. (Liver Transpl 2005;11:1515–1521.)

Operative Re-intervention Following Pancreatic Head Resection: Indications and Outcome

BackgroundThis study analyzed indication and outcome regarding operative re-intervention following pancreatoduodenectomy (PD) and pancreatogastrostomy (PG) with special emphasis on complications related to redo surgery.Patients and MethodsTwo hundred eighty-five patients who underwent PD with PG between 1989 and 2008 were identified from a pancreatic resection database and indications for repeat surgery were registered. Patients with and without reoperation were analyzed with regard to gender, age, underlying disease, length of hospital stay, mortality rate, and postoperative complications.ResultsThirty-one patients (11%) underwent operative reintervention. Early intra-abdominal extraluminal postoperative bleeding was the main cause for redo surgery followed by abdominal abscesses. Thirteen percent of patients with and 1.9% without secondary surgery died during the postoperative course. Forty-five percent of reoperated patients had to undergo at least one more operation resulting in doubling of the length of hospital stay. There was no correlation between patients’ gender, age, and underlying disease and the need for operative reintervention. However, redo surgery was associated with higher incidence of delayed gastric emptying, pancreatic fistula and bleeding, and non-surgery related complication. Intra-abdominal bleeding and abscesses, insufficiencies of bilio-digestive and gut anastomosis, wound infections, and pancreatitis were observed significantly more often in patients with secondary surgery.ConclusionsComplications after pancreatic resection that require operative re-intervention are associated with a notably increased mortality, ranging between 13% and 60%. Apart from the surgeon’s experience in selecting patients and his/her personal technical skills in performing a pancreaticoduodenectomy, timely anticipation and determined management of postoperative complications is essential for improving the outcome of this operation.

Hemin induction of HO-1 protects against LPS-induced septic ileus

BACKGROUND Heme oxygenase (HO-1) protects against inflammation. In this study, we investigated the protective function of hemin-induced HO-1 against lipopolysaccharide (LPS)-induced ileus. METHODS Rats received LPS intraperitoneally 24 h after intraperitoneal hemin pretreatment or placebo. We also injected zinc protoporphyrin (ZnPP, 3rd group), an inhibitor of HO-1, intraperitoneally 2 h before LPS administration. To assess intestinal muscle function, we examined muscularis strip contractility in an organ bath and measured gastrointestinal transit in vivo. We investigated inflammation within the muscularis using polymerase chain reaction (interleukin [IL]-6, inducible nitric oxide synthase (iNOS), HO-1 and IL-10) 6 and 24 h after LPS. RESULTS Hemin significantly improved in vitro intestinal muscularis contractility (P < 0.001). In addition, hemin prevented LPS-induced dysmotility in vivo (gastrointestinal transit, geometric center: 8.39 ± 0.33 versus 5.68 ± 0.44; P < 0.001). In Zinc protoporphyrin (ZnPP)-treated animals, both parameters were significantly decreased compared with the hemin group. Messenger RNA expression demonstrated a significant reduction in IL-6 (6 h, hemin: 127.6 ± 36.7 versus LPS: 14,431 ± 5407; 24 h: 1.58 ± 0.39 versus 11.15 ± 2.59; P < 0.01) and iNOS (6 h: 2516 ± 985 versus 50,771 ± 13,321; 24 h: 55.11 ± 10.55 versus 257.1 ± 43.18; P < 0.001) in hemin-treated animals. Anti-inflammatory HO-1 messenger RNA levels (6 h, hemin: 116.3 ± 18.55 versus LPS: 26.02 ± 3.64; 24 h: 18.46 ± 2.69 versus 2.80 ± 0.32; P < 0.001) were increased. There was no significant difference in IL-10 levels at 6 and 24 h. ZnPP reversed the anti-inflammatory hemin effects. CONCLUSIONS Hemin induction of HO-1 diminishes LPS-induced sepsis. Heme oxygenase-1 has a central role in preventing sepsis-induced ileus. This benefit is reversed by HO-1 inhibition with ZnPP.

Meloxicam, a COX-2 inhibitor, ameliorates ischemia/reperfusion injury in non-heart-beating donor livers.

Background/Aims: Chronic organ donor shortage has led to the consideration to expand the donor pool with livers from non-heart-beating donors (NHBD), although a higher risk of graft dys- or nonfunction is associated with these livers. We examined the effects of selective cyclooxygenase-2 (COX-2) inhibition on hepatic warm ischemia (WI) reperfusion (I/R) injury of NHBD. Methods: Male Wistar rats were used as donors and meloxicam (5 mg/kg body weight) was administered into the preservation solution. Livers were excised after 60 min of WI in situ, flushed and preserved for 24 h at 4°C. Reperfusion was carried out in vitro at a constant flow for 45 min. During reperfusion (5, 15, 30 and 45 min), enzyme release of alanine aminotransferase and glutamate lactate dehydrogenase were measured as well as portal venous pressure, bile production and oxygen consumption. The production of malondialdehyde was quantified and TUNEL staining was performed. Quantitative PCR analyzed COX-2 mRNA. COX-2 immunohistochemistry and TxB2 detection completed the measurements. Results: Meloxicam treatment led to better functional recovery concerning liver enzyme release, vascular resistance and metabolic activity over time in all animals. Oxidative stress and apoptosis were considerably reduced. Conclusion: Cold storage using meloxicam resulted in significantly better integrity and function of livers retrieved from NHBD. Selective COX-2 inhibition is a new therapeutic approach achieving improved preservation of grafts from NHBD.

DNA Methylation of PITX2 and PANCR Is Prognostic for Overall Survival in Patients with Resected Adenocarcinomas of the Biliary Tract.

Biliary tract cancers (BTC) are rare but highly aggressive malignant epithelial tumors. In order to improve the outcome in this lethal disease, novel biomarkers for diagnosis, prognosis, and therapy response prediction are urgently needed. DNA promoter methylation of PITX2 variants (PITX2ab, PITX2c) and intragenic methylation of the PITX2 adjacent non-coding RNA (PANCR) were investigated by methylations-specific qPCR assays in formalin-fixed paraffin-embedded tissue from 80 patients after resection for BTC. Results were correlated with clinicopathologic data and outcome. PITX2 variants and PANCR showed significant hypermethylation in tumor vs. normal adjacent tissue (p < 0.001 and p = 0.015), respectively. In survival analysis, dichotomized DNA methylation of variant PITX2c and PANCR were significantly associated with overall survival (OS). Patients with high tumor methylation levels of PITX2c had a shorter OS compared to patients with low methylation (12 vs. 40 months OS; HR 2.48 [1.38–4.48], p = 0.002). In contrast, PANCR hypermethylation was associated with prolonged survival (25 vs. 19 months OS; HR 0.54 [0.30–0.94], p = 0.015) and qualified as an independent prognostic factor on multivariate analysis. The biomarkers investigated in this study may help to identify BTC subpopulations at risk for worse survival. Further studies are needed to evaluate if PITX2 might be a clinically useful biomarker for an optimized and individualized treatment.

Clinical Management of Chronic Portal/Mesenteric Vein Thrombosis: The Surgeon's Point of View

Background: Bleeding from esophageal varices is a life-threatening complication of chronic portal hypertension (PH), occuring in 15% of patients with a mortality rate between 20 and 35%. Methods: Based on a literature review and personal experience in the therapy of PH, we recommend a therapy strategy for the secondary prophylaxis of variceal bleeding in PH. Results: The main causes for PH in western countries are alcoholic/viral liver cirrhosis and extrahepatic portal/mesenteric vein occlusion, mainly caused by myeloproliferative neoplasms or hypercoagulability syndromes. The primary therapy is medical; however, when recurrent bleeding occurs, a definitive therapy is required. In the case of parenchymal decompensation, liver transplantation is the causal therapy, but in case of good hepatic reserve or without underlying liver disease, a portal decompressive therapy is necessary. Transjugular intrahepatic portosystemic shunt has achieved a widespread acceptance, although evidence is comparable with or better for surgical shunting procedures in patients with good liver function. The type of surgical shunt should be chosen depending on the patent veins of the portovenous system and the personal expertise. Conclusion: The therapy decision should be based on liver function, morphology of the portovenous system, and imminent liver transplantation and should be made by an interdisciplinary team of gastroenterologists, interventional radiologists, and visceral surgeons.

Iatrogenic Extracellular Matrix Disruption as a Local Trigger for Postoperative Ileus

BACKGROUND Active matrix metallopeptidase 9 (MMP-9) disruption of the extracellular matrix (ECM) plays an important role in inflammatory disorders. In this study, we investigated the inflammatory role of MMP-9 and the ECM breakdown product hyaluronan as a trigger for the postoperative intestinal inflammatory response of postoperative ileus. METHODS We performed a standardized intestinal surgical manipulation on rats to produce ileus assessed by the oral non-digestible fluorescein isothiocyanate-dextran transit assay. We studied isolated intestinal muscularis extracts for mRNA expressions of interleukin 6 (IL-6), MMP-9 and CD44. We quantified peritoneal MMP-9 activity using zymography, and quantified peritoneal fluid and serum for hyaluronan and tissue inhibitor of metalloproteinase 1 levels by enzyme-linked immunosorbent assay (ELISA). We cultured peritoneal macrophages and exposed them to peritoneal fluid or synthetic hyaluronan for ELISA analysis of IL-6 and macrophage inflammatory protein-1α. RESULTS Transit was significantly delayed after surgical manipulation, and extracts of the isolated jejunal and colonic muscularis demonstrated a significant induction of IL-6, MMP-9, and CD44 mRNAs compared with controls. Zymography confirmed significant MMP-9 activity in peritoneal fluid compared with controls. Enzyme-linked immunosorbent assay measurements showed a significant up-regulation in hyaluronan and tissue inhibitor of metalloproteinase 1 in the peritoneal fluid and serum. In addition, ELISA and reverse transcriptase-polymerase chain reaction measurements of peritoneal macrophages stimulated with postsurgical peritoneal fluid and synthetic hyaluronan resulted in higher expressions of IL-6 and macrophage inflammatory protein-1α in the macrophage supernatant. CONCLUSIONS Our results confirm that MMP-9 disruption in the ECM with hyaluronan release and muscularis CD44 receptor induction has the potential to trigger muscularis proinflammatory cascades that cause postoperative ileus. Matrix metallopeptidase 9 inhibition may be a novel therapeutic approach to limit postoperative ileus.

Akute und chronische Thrombosen des Pfortadersystems

ZusammenfassungThrombosen des Pfortadersystems entstehen meist aufgrund einer Kombination einer systemischen Hyperkoagulabilität (Verminderung inhibitorischer Gerinnungsfaktoren, myeloproliferative Erkrankungen) und eines lokalen Faktors (Trauma, Kompression, Inflammation).Bei akuten Thrombosen konnten in den letzten Jahren durch die CT- und Ultraschalldiagnostik eine frühere Erkennung, durch die moderne Gerinnungsdiagnostik neue Einsichten in die Pathophysiologie und durch die interventionelle Therapie eine bessere Prognose des venösen Mesenterialinfarktes erzielt werden.Je nach klinischem Verlauf, der durch Lokalisation und Ausdehnung der Thrombose bestimmt wird, kommen neben der obligatorischen Antikoagulation transhepatische Lyseverfahren, interventionelle oder operative Thrombektomie oder bei hämorrhagischer Infarzierung eine Darmresektion mit Second-look-Operation in Frage.Bei chronischen Thrombosen des Pfortadersystems ist die Symptomatik durch Varizenblutungen, Folgen der Splenomegalie, seltener durch pseudosklerosierende Cholangitis und bei Kindern durch Wachstumsretardierung geprägt.Beim Versagen der endoskopischen Varizentherapie sollten frühzeitig dekomprimierende Shuntverfahren erwogen werden. Durch Shuntanlagen lassen sich eine dauerhafte Reduktion des Blutungsrisikos und die Möglichkeit einer effektiven Antikoagulation erreichen. Bei extrahepatischen Pfortaderthrombosen kommen wegen der guten Langzeitergebnisse splenorenale und mesokavale Shunts ohne Verwendung von Prothesen bevorzugt in Frage.AbstractThe cause of thrombosis of the portal system is multifactorial, often exhibiting a combined etiology of systemic thrombophilia (deficiency of inhibitory coagulation factors, myeloproliferative disease) and local factors (trauma, compression, decreased portal flow, inflammation).The prognosis of acute venous mesenteric thrombosis (AMT) has improved during the last decade due to better imaging by CT and Doppler ultrasound, understanding of the pathophysiology of genetic and acquired coagulation disorders, and more aggressive interventions to restore the patency of the mesenteric veins.In AMT, the extent of thrombosis and clinical conditions dictate whether anticoagulation alone, transhepatic lysis, interventional or surgical thrombectomy, or bowel resection with second-look procedures are appropriate treatment modalities.Chronic thrombosis of the portal system is characterized by a long asymptomatic latency and sequelae of portal hypertension, such as variceal hemorrhage, hypersplenism, pseudosclerosing cholangitis, or growth retardation in children.If endoscopic therapy fails to control variceal bleeding portosystemic shunt surgery offers an effective therapy which leads to freedom from recurrent bleeding and repeated endoscopies for many years and improves hypersplenism without deteriorating liver function or encephalopathy. Gastroesophageal devascularization and other direct variceal ablative procedures should be restricted to treat endoscopic therapy failures without shuntable portal tributaries.

Cyclooxygenase Inhibitors as a New Therapeutic Strategy in Small Bowel Transplantation.

Background The long-term outcome of intestinal transplantations is still not favorable, which is partly due to the intestinal susceptibility to ischemia. There are several indications that the inflammatory response to ischemia-reperfusion injury is mediated by cyclooxygenases and that their inhibition may be associated with improved organ function. The aim of this study was to analyze if cyclooxygenase (COX) inhibitors could improve the early posttransplant outcome after orthotopic small bowel transplantation. Methods Small bowel transplantation was performed between rats to test the impact of nonselective (Piroxicam), preferential (Meloxicam), and selective COX-2 inhibitors (Parecoxib). The donor intestines were either perfused and stored with inhibitor or had inhibitor administered intravenously after transplantation. Results Using COX inhibitors, a sequential increase of posttransplantation intestinal integrity could be shown, with Parecoxib the least effective and Meloxicam the most effective treatment. These differences were in line with the downregulation of COX-2 activity by the inhibitors. Functionally, the same tendency could be seen in diminished expression of proinflammatory molecules, decreased leucocyte inflammation, and significantly improved graft microcirculation. In most cases, the intravenous administration was more effective. However, the COX inhibitors used were shown to cause relevant hepatotoxicity under nearly all conditions, but particularly under intravenous administration. Only Meloxicam in histidine-tryptophan-ketoglutarate was demonstrated to be a safe drug without hepatotoxic side effects. Conclusions The activity of COX contributes to ischemia-reperfusion injury after intestinal transplantation. In this comparative study, the administration of the preferential COX-2 inhibitor Meloxicam via histidine-tryptophan-ketoglutarate showed the best graft-protective attributes and the lowest hepatotoxic side effects.

Recombinant HLA-G as Tolerogenic Immunomodulant in Experimental Small Bowel Transplantation.

The non-classical MHC I paralogue HLA-G is expressed by cytotrophoblast cells and implicated with fetomaternal tolerance by downregulating the maternal adaptive and innate immune response against the fetus. HLA-G expression correlates with favorable graft outcome in humans and recently promising immunosuppressive effects of therapeutic HLA-G in experimental transplantation (skin allograft acceptance) were shown. Consequently, we examined this novel therapeutic approach in solid organ transplantation. In this study, therapeutic recombinant HLA-G5 was evaluated for the first time in a solid organ model of acute rejection (ACR) after orthotopic intestinal transplantation (ITX). Allogenic ITX was performed in rats (Brown Norway to Lewis) with and without HLA-G treatment. It was found that HLA-G treatment significantly reduced histologically proven ACR at both an early and late postoperative timepoint (POD 4/7), concomitant to a functionally preserved graft contractility at POD 7. Interestingly, graft infiltration by myeloperoxidase+ cells was significantly reduced at POD7 by HLA-G treatment. Moreover, HLA-G treatment showed an effect on the allogenic T-cell immune response as assessed by flow cytometry: The influx of recipient-derived CD8+ T-cells into the graft mesenteric lymphnodes at POD7 was significantly reduced while CD4+ populations were not affected. As a potential mechanism of action, an induction of T-reg populations in the mesenteric lymphnodes was postulated, but flow cytometric analysis of classical CD4+/CD25+/FoxP3+Treg-cells showed no significant alteration by HLA-G treatment. The novel therapeutic approach using recombinant HLA-G5 reported herein demonstrates a significant immunosuppressive effect in this model of allogenic experimental intestinal transplantation. This effect may be mediated via inhibition of recipient-derived CD8+ T-cell populations either directly or by induction of non-classical Treg populations.