Publications by authors named "Volker Schmitz"

87 Publications

[Postoperative dumping-syndrome with relevant impairment of glucose homeostasis - relief by continuous glucose monitoring and individual therapy with GLP-1 receptor agonists].

Z Gastroenterol 2021 Jun 15;59(6):556-559. Epub 2021 Jun 15.

Innere Medizin, Krankenhaus St. Marienwörth, Bad Kreuznach, Germany.

Dumping syndromes are a common side effect after partial or total gastric resection. The symptoms may be diverse, with vasomotoric reactions, collapse tendencies and digestive disorders (early dumping) as well as blood sugar derailment as a result of too fast absorption of glucose (late dumping).Entrenched therapy concepts, including personalized nutritional concepts and the use of medication as octreotide or diazoxide, will not always lead to the desired results. It is then, that individual therapy concepts have to be found to restore the patient's quality of life, as shown in this case study.
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http://dx.doi.org/10.1055/a-1324-4136DOI Listing
June 2021

Urinary Biomarkers α-GST and π-GST for Evaluation and Monitoring in Living and Deceased Donor Kidney Grafts.

J Clin Med 2019 Nov 7;8(11). Epub 2019 Nov 7.

Department of General, Visceral and Transplantation Surgery, Universitätsklinikum Münster, 48189 Münter, Germany.

The aim of this study was to analyze the value of urine α- and π-GST in monitoring and predicting kidney graft function following transplantation. In addition, urine samples from corresponding organ donors was analyzed and compared with graft function after organ donation from brain-dead and living donors. Urine samples from brain-dead ( = 30) and living related ( = 50) donors and their corresponding recipients were analyzed before and after kidney transplantation. Urine α- and π-GST values were measured. Kidney recipients were grouped into patients with acute graft rejection (AGR), calcineurin inhibitor toxicity (CNI), and delayed graft function (DGF), and compared to those with unimpaired graft function. Urinary π-GST revealed significant differences in deceased kidney donor recipients with episodes of AGR or DGF at day one after transplantation ( = 0.0023 and = 0.036, respectively). High π-GST values at postoperative day 1 (cutoff: >21.4 ng/mg urine creatinine (uCrea) or >18.3 ng/mg uCrea for AGR or DGF, respectively) distinguished between rejection and no rejection (sensitivity, 100%; specificity, 66.6%) as well as between DGF and normal-functioning grafts (sensitivity, 100%; specificity, 62.6%). In living donor recipients, urine levels of α- and π-GST were about 10 times lower than in deceased donor recipients. In deceased donors with impaired graft function in corresponding recipients, urinary α- and π-GST were elevated. α-GST values >33.97 ng/mg uCrea were indicative of AGR with a sensitivity and specificity of 77.7% and 100%, respectively. In deceased donor kidney transplantation, evaluation of urinary α- and π-GST seems to predict different events that deteriorate graft function. To elucidate the potential advantages of such biomarkers, further analysis is warranted.
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http://dx.doi.org/10.3390/jcm8111899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912502PMC
November 2019

Acute sedation-associated complications in GI endoscopy (ProSed 2 Study): results from the prospective multicentre electronic registry of sedation-associated complications.

Gut 2019 03 3;68(3):445-452. Epub 2018 Jan 3.

Gastroenterologie, Kreiskrankenhaus Dormagen, Dormagen, Germany.

Objectives: Sedation has been established for GI endoscopic procedures in most countries, but it is also associated with an added risk of complications. Reported complication rates are variable due to different study methodologies and often limited sample size.

Designs: Acute sedation-associated complications were prospectively recorded in an electronic endoscopy documentation in 39 study centres between December 2011 and August 2014 (median inclusion period 24 months). The sedation regimen was decided by each study centre.

Results: A total of 368 206 endoscopies was recorded; 11% without sedation. Propofol was the dominant drug used (62% only, 22.5% in combination with midazolam). Of the sedated patients, 38 (0.01%) suffered a major complication, and overall mortality was 0.005% (n=15); minor complications occurred in 0.3%. Multivariate analysis showed the following independent risk factors for all complications: American Society of Anesthesiologists class >2 (OR 2.29) and type and duration of endoscopy. Of the sedation regimens, propofol monosedation had the lowest rate (OR 0.75) compared with midazolam (reference) and combinations (OR 1.0-1.5). Compared with primary care hospitals, tertiary referral centres had higher complication rates (OR 1.61). Notably, compared with sedation by a two-person endoscopy team (endoscopist/assistant; 53.5% of all procedures), adding another person for sedation (nurse, physician) was associated with higher complication rates (ORs 1.40-4.46), probably due to higher complexity of procedures not evident in the multivariate analysis.

Conclusions: This large multicentre registry study confirmed that severe acute sedation-related complications are rare during GI endoscopy with a very low mortality. The data are useful for planning risk factor-adapted sedation management to further prevent sedation-associated complications in selected patients.

Trial Registration Number: DRKS00007768; Pre-results.
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http://dx.doi.org/10.1136/gutjnl-2015-311037DOI Listing
March 2019

Delayed gastric emptying following pancreatoduodenectomy with alimentary reconstruction according to Roux-en-Y or Billroth-II.

BMC Surg 2017 Mar 20;17(1):24. Epub 2017 Mar 20.

Department of Surgery, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.

Background: Delayed gastric emptying (DGE) remains the most frequent complication following pancreatoduodenectomy (PD) with published incidences as high as 61%. The present study investigates the impact of bowel reconstruction techniques on DGE following classic PD (Whipple-Kausch procedure) with pancreatogastrostomy (PG).

Methods: We included 168 consecutive patients who underwent PD with PG with either Billroth II type (BII, n = 78) or Roux-en-Y type reconstruction (ReY, n = 90) between 2004 and 2015. Excluded were patients with conventional single loop reconstruction after pylorus preserving procedures. DGE was classified according to the 2007 International Study Group of Pancreatic Surgery definition. Patients were analyzed regarding severity of DGE, morbidity and mortality, length of hospital stay and demographic factors.

Results: No difference was observed between BII and ReY regarding frequency of DGE. Overall rate for clinically relevant DGE was 30% (ReY) and 26% (BII). BII and ReY did not differ in terms of demographics, morbidity or mortality. DGE significantly prolongs ICU (four vs. two days) and hospital stay (20.5 vs. 14.5 days). Risk factors for DGE development are advanced age, retrocolic reconstruction, postoperative hemorrhage and major complications.

Conclusions: The occurrence of DGE can not be influenced by the type of alimentary reconstruction (ReY vs. BII) following classic PD with PG. Old age and major complications could be identified as important risk factors in multivariate analysis.

Trial Registration: German Clinical Trials Register (DRKS) DRKS00011860 . Registered 14 March 2017.
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http://dx.doi.org/10.1186/s12893-017-0226-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359898PMC
March 2017

Gender Matches in Liver Transplant Allocation: Matched and Mismatched Male-Female Donor-Recipient Combinations; Long-term Follow-up of More Than 2000 Patients at a Single Center.

Exp Clin Transplant 2016 Apr;14(2):184-90

From the Department of General, Visceral, and Transplantation Surgery, Charité, Campus Virchow Klinikum, Berlin, Germany; and the Department of General, Visceral, and Transplantation Surgery, University Hospital of RWTH, Aachen, Germany.

Objectives: The influence of donor-recipient sex mismatches on long-term graft survival after liver transplant is controversial. In this study, our aim was to characterize the differences in long-term graft outcome after liver transplant in more than 2000 cases with special regard to sex match and mismatch.

Materials And Methods: In this retrospective, single center study of 2144 adult primary liver transplant recipients (median follow-up of 92 months), we analyzed specific long-term graft survival and the effect of different donor and recipient sex combinations (Kaplan-Meier, multivariate regression).

Results: In the 15-year follow-up, female recipients (58.6%) had significantly better graft survival than male recipients did (51.6%, P = .031). Matched and mismatched male-female combinations revealed significant differences (P = .003): a male donor-female recipient combination showed the best 15-year graft survival (61.1%), and a female donor-male recipient combination showed the worst graft survival (48.6%), whereas male-male (53.3%) and female-female combinations (55.6%) were not significantly different (P = .967). Donor age (P ≤ .0001), body mass index (P = .021), female sex (P = .015), Eurotransplant Donor Risk Index > 1.4 (P ≤ .001), recipients' age (P < .0001), indication for liver transplant (P < .0001), and kidney function (P = .003) significantly affected graft survival. In the multivariate analysis model, a Eurotransplant Donor Risk Index > 1.4 and impaired kidney function at liver transplant again emerged as significant negative predictors. Female donors and male recipients showed significantly more unfavorable characteristics concerning long-term graft survival.

Conclusions: The impressive long-term graft survival benefit of male donor-female recipient versus female donor-male recipient and of male donor-female recipient versus matched groups (male-male, female-female) in liver transplant may be caused by significant differences in donor quality and recipient characteristics and may not be related to sex itself.
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April 2016

Colonoscopy detects significantly more flat adenomas than 3-tesla magnetic resonance colonography: a pilot trial.

Endosc Int Open 2016 Feb 28;4(2):E164-9. Epub 2016 Jan 28.

Department of Radiology, University Hospital of Bonn, Bonn, Germany.

Background And Study Aims: Colorectal cancer (CRC) is one of the most common cancers worldwide, and several efforts have been made to reduce its occurrence or severity. Although colonoscopy is considered the gold standard in CRC prevention, it has its disadvantages: missed lesions, bleeding, and perforation. Furthermore, a high number of patients undergo this procedure even though no polyps are detected. Therefore, an initial screening examination may be warranted. Our aim was to compare the adenoma detection rate of magnetic resonance colonography (MRC) with that of optical colonoscopy.

Patients And Methods: A total of 25 patients with an intermediate risk for CRC (17 men, 8 women; mean age 57.6, standard deviation 11) underwent MRC with a 3.0-tesla magnet, followed by colonoscopy. The endoscopist was initially blinded to the results of MRC and unblinded immediately after examining the distal rectum. Following endoscopic excision, the size, anatomical localization, and appearance of all polyps were described according to the Paris classification.

Results: A total of 93 lesions were detected during colonoscopy. These included a malignant infiltration of the transverse colon due to gastric cancer in 1 patient, 28 adenomas in 10 patients, 19 hyperplastic polyps in 9 patients, and 45 non-neoplastic lesions. In 5 patients, no lesion was detected. MRC detected significantly fewer lesions: 1 adenoma (P = 0.001) and 1 hyperplastic polyp (P = 0.004). The malignant infiltration was seen with both modalities. Of the 28 adenomas, 23 (82 %) were 5 mm or smaller; only 4 adenomas 10 mm or larger (14 %) were detected.

Conclusion: MRC does not detect adenomas sufficiently independently of the location of the lesion. Even advanced lesions were missed. Therefore, colonoscopy should still be considered the current gold standard, even for diagnostic purposes.
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http://dx.doi.org/10.1055/s-0041-111501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751010PMC
February 2016

Eurotransplant donor-risk-index and recipient factors: influence on long-term outcome after liver transplantation - A large single-center experience.

Clin Transplant 2016 May 16;30(5):508-17. Epub 2016 Mar 16.

Department of General, Visceral- and Transplantation Surgery, Charité, Berlin, Germany.

The organ shortage has led to increased use of marginal organs. The Eurotransplant Donor-Risk-Index (ET-DRI) was established to estimate outcome after Liver Transplantation (LT). Currently, data on impact of ET-DRI on long-term outcome for different indications and recipient conditions are missing. Retrospective, single-center analysis of long-term graft survival (GS) of 1767 adult primary LTs according to indication, labMELDcategory (1: ≤18; 2: >18-25; 3: >25-35; 4: >35), and ET-DRI. Mean ET-DRI in our cohort was 1.63 (±0.43). One-, 10, and 15-yr GS was 83.5%, 63.3%, and 54.8%. Long-term GS was significantly influenced by ET-DRI. Accordingly, four ET-DRI categories were defined and analyzed with respect to underlying disease. Significant impact of these categories was observed for: Alcohol, cholestatic/autoimmune diseases (CD/AIH), and HCV, but not for HCC, HBV, cryptogenic cirrhosis, and acute liver failure. labMELD categories showed no significant influence on graft, but on patient survival. Matching ET-DRI categories with labMELD revealed significant differences in long-term GS for labMELDcategories 1, 2, and 3, but not 4. In multivariate analysis, HCV combined with ET-DRI > 2 and labMELDcategory 3 combined with ET-DRI > 2 emerged as negative predictors. To achieve excellent long-term graft survival, higher risk organs (ET-DRI > 1.4) should be used restrictively for patients with CD/AIH or HCV. Organs with ET-DRI > 2 should be avoided in patients with a labMELD of >25-35.
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http://dx.doi.org/10.1111/ctr.12714DOI Listing
May 2016

Iloprost donor treatment reduces ischemia-reperfusion injury in an isolated extracorporeal pig liver perfusion model.

Exp Clin Transplant 2015 Feb;13(1):51-61

From the Transplant Surgery Charité Humboldt-University, Berlin, Germany.

Objectives: Iloprost has the potential to protect the liver transplant graft before and during cold ischemia. We studied iloprost administration during organ procurement and reperfusion in an extracorporeal pig liver perfusion model.

Materials And Methods: German Landrace pigs (n = 7/group; 22-26 kg each) were used as donors. Preservation was performed by aortic perfusion with 2 L Bretschneiders' Histidine-Tryptophan-Ketoglutarate solution HTK and cold ischemia time (4°C) 20 hours followed by normothermic extracorporeal perfusion for 8 hours. Untreated controls (1) were compared to iloprost (2) donor bolus-treatment (1 μg/kg body weight), (3) addition of iloprost to Bretschneiders' Histidine-Tryptophan-Ketoglutarate solution HTK (0.0125 μg/mL), (4) continuous infusion during reperfusion (2 ng/kg/min), and (5) combined treatment (2) and (4).

Results: Iloprost donor treatment led to significantly higher bile production. Addition of iloprost to the preservation solution significantly improved hepatic artery perfusion and was accompanied by improvements of microcirculation and bile production. Iloprost reperfusion treatment alone significantly improved bile production. Enzyme levels were positively affected by all treatment regimens. Combined use of iloprost before and after ischemia improved hepatic artery flow and microcirculation and showed significantly lower hypoxia staining versus controls.

Conclusions: Iloprost donor treatment and use of iloprost in the preservation solution significantly improved graft perfusion and function. The effects of graft treatment seemed greater before than after reperfusion. Combined treatment did not reveal a synergistic advantage.
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February 2015

Cardiovascular risk and events after liver transplantation. Experiences from 313 consecutive transplants with a follow-up of 20 years.

Clin Transplant 2015 Apr;29(4):343-50

Department of General-, Visceral- and Transplantation Surgery, Charité, Berlin, Germany.

Cardiovascular diseases (CVD) are the third leading cause of late death after liver transplantation (LT). The old PROCAM score was described in males (aged 35-65 yr) to estimate cardiovascular events after LT. New PROCAM is now available to estimate risks for cardiovascular events in both genders and for a wider age range (25-75 yr). We tested old and new PROCAM in long-term follow-up (10 and 20 yr) and described CVD risk factors, kidney function, and immunosuppression over two decades. A retrospective study of 313 consecutive LTs was conducted. At 10 (T2) and 20 (T3) yr, patients were screened for cardiovascular events, and for T1 (0.5 yr) and T2, CVD risk factors were recorded and old and new PROCAM calculated. PROCAM estimates were compared with observed events. CVD risk factors increased significantly over time and kidney function decreased. Between T1 and T2 in males, fewer events were observed (o) than estimated (e) (males: o: 3 vs. e: 6.05-9.88; females o: 2 vs. e: 1.35-4.21). For both genders, new PROCAM was appropriate between T2 and T3 (males o: 8; e: 4.5-8.57; females o: 2; e: 1.2-4.46). New PROCAM sufficiently estimates cardiovascular risk after LT, while overestimation in T1-T2 may be due to strict surveillance.
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http://dx.doi.org/10.1111/ctr.12520DOI Listing
April 2015

The author reply.

Authors:
Volker Schmitz

Hepatobiliary Pancreat Dis Int 2014 Oct;13(5):555-6

Department of General, Visceral and Transplantation Surgery, Charite, Campus Virchow, Berlin 13353, Germany.

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October 2014

Response to preoperative chemotherapy predicts survival in patients undergoing hepatectomy for liver metastases from gastric and esophageal cancer.

J Gastrointest Surg 2014 Nov 27;18(11):1974-86. Epub 2014 Aug 27.

Department of General, Visceral and Transplant Surgery, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany,

Background: The role of hepatectomy for patients with liver metastases from gastric and esophageal cancer (GELM) is not well defined. The present study examined the morbidity, mortality, and long-term survivals after liver resection for GELM.

Methods: Clinicopathological data of patients who underwent hepatectomy for GELM between 1995 and 2012 at two European high-volume hepatobiliary centers were assessed, and predictors of overall survival (OS) were identified. In addition, the impact of preoperative chemotherapy for GELM on OS was evaluated.

Results: Forty-seven patients underwent hepatectomy for GELM. The primary tumor was located in the stomach, cardia, and distal esophagus in 27, 16, and 4 cases, respectively. Twenty patients received preoperative chemotherapy before hepatectomy. After a median follow-up time of 76 months, 1-, 3-, and 5-year OS rates were 70, 37, and 24%, respectively. Postoperative morbidity and mortality rates were 32 and 4%, respectively. Outcomes were comparable between the two centers. Preoperative chemotherapy for GELM (5-year OS: 45 vs 9%, P = .005) and the lack of posthepatectomy complications (5-year OS: 34 vs 0%, P < .0001) were significantly associated with improved OS in univariate and multivariate analyses. When stratifying OS by radiologic response of GELM to preoperative chemotherapy, patients with progressive disease despite preoperative treatment had significantly worse OS (5-year OS: 0 vs 70%, P = .045).

Conclusion: For selected patients with GELM, liver resection is safe and should be regarded as a potentially curative approach. A multimodal treatment strategy including systemic therapy may provide better patient selection resulting in prolonged survival in patients with GELM undergoing hepatectomy.
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http://dx.doi.org/10.1007/s11605-014-2623-0DOI Listing
November 2014

Different cava reconstruction techniques in liver transplantation: piggyback versus cava resection.

Hepatobiliary Pancreat Dis Int 2014 Jun;13(3):242-9

Department of General, Visceral and Transplantation Surgery, Charite, Campus Virchow, Berlin, Germany.

Background: Originally, cava reconstruction (CR) in liver transplantation meant complete resection and reinsertion of the donor cava. Alternatively, preservation of the recipients inferior vena cava (IVC) with side-to-side anastomosis (known as "piggyback") can be performed. Here, partial clamping maintains blood flow of the IVC, which may improve cardiovascular stability, reduce blood loss and stabilize kidney function. The aim of this study was to compare both techniques with particular focus on kidney function.

Methods: A series of 414 patients who had had adult liver transplantations (2006-2009) were included. Among them, 176 (42.5%) patients had piggyback and 238 had classical CR operation, 112 (27.1%) of the patients underwent CR accompanied with veno-venous bypass (CR-B) and 126 (30.4%) without a bypass. The choice of either technique was based on the surgeons' individual preference. Kidney function [serum creatinine, calculated glomerular filtration rate (GFR), RIFLE stages] was assessed over 14 days.

Results: Lab-MELD scores were significantly higher in CR-B (22.5+/-11.0) than in CR (17.3+/-9.0) and piggyback (18.8+/-10.0) (P=0.008). Unexpectedly, the incidences of arterial stenoses (P=0.045) and biliary leaks (P=0.042) were significantly increased in piggyback. Preoperative serum creatinine levels were the highest in CR-B [1.45+/-1.17 vs 1.25+/-0.85 (piggyback) and 1.13+/-0.60 mg/dL (CR); P=0.033]. Although a worsening of postoperative kidney function was observed among all groups, this was most pronounced in CR-B [creatinine day 14: 1.67+/-1.40 vs 1.35+/-0.96 (piggyback) and 1.45+/-1.03 mg/dL (CR); P=0.102]. Accordingly, the proportion of patients displaying RIFLE stages ≥2 was the highest in CR/CR-B (26%/19%) when compared to piggyback (18%).

Conclusions: Piggyback revealed a shorter warm ischemic time, a reduced blood loss, and a decreased risk of acute kidney failure. Thus, piggyback is a useful technique, which should be applied in standard procedures. When piggyback is unfeasible, cava replacement, which displayed a lower incidence of vascular and biliary complications in our study, remains as a safe alternative.
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http://dx.doi.org/10.1016/s1499-3872(14)60250-2DOI Listing
June 2014

Plasmid transfer of plasminogen K1-5 reduces subcutaneous hepatoma growth by affecting inflammatory factors.

Biomed Res Int 2014 8;2014:656527. Epub 2014 May 8.

Department of Inner Medicine I, University of Hospital Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.

There is evidence that plasminogen K1-5 (PlgK1-5) directly affects tumour cells and inflammation. Therefore, we analysed if PlgK1-5 has immediate effects on hepatoma cells and inflammatory factors in vitro and in vivo. In vitro, effects of plasmid encoding PlgK1-5 (pK1-5) on Hepa129, Hepa1-6, and HuH7 cell viability, apoptosis, and proliferation as well as VEGF and TNF-alpha expression and STAT3-phosphorylation were investigated. In vivo, tumour growth, proliferation, vessel density, and effects on vascular endothelial growth factor (VEGF) and tumour necrosis factor alpha (TNF-alpha) expression were examined following treatment with pK1-5. In vivo, pK1-5 halved cell viability; cell death was increased by up to 15% compared to the corresponding controls. Proliferation was not affected. VEGF, TNF-alpha, and STAT3-phosphorylation were affected following treatment with pK1-5. In vivo, ten days after treatment initiation, pK1-5 reduced subcutaneous tumour growth by 32% and mitosis by up to 77% compared to the controls. Vessel density was reduced by 50%. TNF-alpha levels in tumour and liver tissue were increased, whereas VEGF levels in tumours and livers were reduced after pK1-5 treatment. Taken together, plasmid gene transfer of PlgK1-5 inhibits hepatoma (cell) growth not only by reducing vessel density but also by inducing apoptosis, inhibiting proliferation, and triggering inflammation.
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http://dx.doi.org/10.1155/2014/656527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034484PMC
September 2015

Mycophenolate mofetil enhances the negative effects of sirolimus and tacrolimus on rat kidney cell metabolism.

PLoS One 2014 30;9(1):e86202. Epub 2014 Jan 30.

Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America.

Background And Purpose: Mycophenolate mofetil (MMF) per se is not known to have negative effects on the kidney. MMF alone or in combination with sirolimus, can be the basis of calcineurin inhibitor (CNI)-free, kidney sparing drug protocols. However, long-term outcomes in patients on MMF/SRL seem to be inferior to those treated with regimens that include the CNI tacrolimus (TAC) due to an increased risk of allo-immune reactions. Interestingly, potential enhancement of the negative effects of SRL and TAC on the kidney by MMF has never been considered.

Experimental Approach: It was our aim to study the effects of TAC, SRL and MMF alone and evaluate their interactions when combined on the rat kidney. For this purpose we used a comprehensive molecular marker approach including measurements of urinary 8-isoprostane concentrations (oxidative stress marker) and changes of urinary metabolite patterns ((1)H-NMR spectroscopy) and comparing these markers to renal function (glomerular filtration rate (GFR)) and morphologic alterations (histology).

Key Results: While MMF alone did not impact GFR, its interaction with SRL and TAC led to a significant decrease of rats' renal function. The decline went in parallel with a significant increase in urinary isoprostane concentrations and an enhancement of negative effects on urinary metabolite patterns.

Conclusions: In broad summary, the present study showed that MMF may enhance the negative effects of TAC on kidney function and may even display nephrotoxic properties when combined with SRL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086202PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907404PMC
December 2014

The conservative and interventional treatment of the complications of liver cirrhosis: Part 2 of a series on liver cirrhosis.

Dtsch Arztebl Int 2013 Feb 22;110(8):126-32, I. Epub 2013 Feb 22.

Department of Internal Medicine I at the University Hospital of Bonn, Bonn, Germany.

Background: It is estimated that 1 million persons in Germany suffer from hepatic cirrhosis, which is the final stage of chronic inflammation of the liver. Cirrhosis has multiple causes, all of which lead to structural changes of the liver and to portal hypertension. The main complications of cirrhosis arise in turn: These include bleeding from collateral veins, ascites, hepatocellular carcinoma, encephalopathy, and infection leading to organ failure.

Methods: We present the treatment of the main complications of liver cirrhosis with reference to the relevant literature (phase II and III trials, meta-analyses, and reviews).

Results: Endoscopic treatment (ligation) is used for the primary and secondary prophylaxis of variceal bleeding. Drugs to lower portal pressure (e.g., beta-blockers) are an established means of preventing initial or recurrent variceal bleeding over the long term. Vasoconstrictors such as terlipressin are mainly used to treat acute hemorrhage and type 1 hepatorenal syndrome. The main treatment of ascites is with spironolactone, in combination with a loop diuretic where indicated. A shunt (TIPS) is used to treat severe or repeat variceal hemorrhage or refractory ascites. Antibiotics play a well-established role in the treatment of acute hemorrhage, in the treatment and prevention of spontaneous bacterial peritonitis, and in the treatment of encephalopathy. The treatment of hepatocellular carcinoma depends on its extent of spread and on the degree of decompensation of cirrhosis.

Conclusion: For most of the main complications of liver cirrhosis, there are treatments that have been well-tested in randomized trials. Liver transplantation should also be considered in every case.
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http://dx.doi.org/10.3238/arztebl.2013.0126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594709PMC
February 2013

Development and validation of an LC-MS/MS assay for the quantification of the trans-methylation pathway intermediates S-adenosylmethionine and S-adenosylhomocysteine in human plasma.

Clin Chim Acta 2013 Jun 13;421:91-7. Epub 2013 Mar 13.

Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045-7503, United States.

Background: Although increased levels of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) have been implicated as markers for renal and vascular dysfunction, until now there have been no studies investigating their association with clinical post-transplant events such as organ rejection and immunosuppressant nephrotoxicity.

Methods: A newly developed and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of SAM and SAH in human EDTA plasma was used for a clinical proof-of-concept pilot study. Retrospective analysis was performed using samples from a longitudinal clinical study following de novo kidney transplant patients for the first year (n=16).

Results: The ranges of reliable response were 8 to 1024 nmol/l for SAM and 16 to 1024 nmol/l for SAH. The inter-day accuracies were 96.7-103.9% and 97.9-99.3% for SAM and SAH, respectively. Inter-day imprecisions were 8.1-9.1% and 8.4-9.8%. The total assay run time was 5 min. SAM and SAH concentrations were significantly elevated in renal transplant patients preceding documented acute rejection and nephrotoxicity events when compared to healthy controls (n=8) as well as transplant patients void of allograft dysfunction (n=8).

Conclusion: The LC-MS/MS assay will provide the basis for further large-scale clinical studies to explore these thiol metabolites as molecular markers for the management of renal transplant patients.
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http://dx.doi.org/10.1016/j.cca.2013.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033670PMC
June 2013

Toxic damage increases angiogenesis and metastasis in fibrotic livers via PECAM-1.

Biomed Res Int 2014 6;2014:712893. Epub 2014 Mar 6.

Department of Inner Medicine, University Hospital Bonn, Sigmund-Freud-Straße 25, 53107 Bonn, Germany ; Krankenhaus Marienwörth, Mühlenstraße 39, 55543 Bad Kreuznach, Germany.

Excessive ethanol consumption is one of the main causes of liver fibrosis. However, direct effects of ethanol exposure on endothelial cells and their contribution to fibrogenesis and metastasis were not investigated. Therefore we analysed whether ethanol directly affects endothelial cells and if this plays a role during fibrogenesis and metastasis in the liver. Murine and human endothelial cells were exposed to ethanol for up to 72 hours. In vitro, effects on VEGF, HIF-1alpha, PECAM-1, and endothelial cell functions were analysed. In vivo, effects of continuous liver damage on blood vessel formation and metastasis were analysed by PECAM-1 immunohistochemistry. Ethanol increased HIF-1alpha and VEGF levels in murine and human endothelial cells. This resulted in enhanced intracellular signal transduction, and PECAM-1 expression as well as tube formation and wound healing. In vivo, toxic liver damage increased angiogenesis during fibrogenesis. Metastasis was also enhanced in fibrotic livers and located to PECAM-1 positive blood vessels compared to nonfibrotic mice. In conclusion, ethanol had strong effects on endothelial cells, which--at least in part--led to a profibrotic and prometastatic environment mediated by PECAM-1. Blockade of increased PECAM-1 expression could be a promising tool to inhibit fibrogenesis and metastasis in the liver.
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http://dx.doi.org/10.1155/2014/712893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964781PMC
October 2015

Association of socio-economic status and stage of pancreatic cancer at time of surgery in a German setting.

Hepatogastroenterology 2012 Nov-Dec;59(120):2614-7

Department of Surgery, University of Bonn Medical Center, Bonn, Germany.

Background/aims: Curative resection has been proven to be one of the most important factors determining outcome in pancreatic cancer patients. Advanced stage of pancreatic cancer at diagnosis is strongly associated with a low socioeconomic status (SES), and patients from affluent areas have better cancer survival than patients from deprived areas. We tested, in our population of pancreatic cancer patients, the hypothesis that surrogates representing a lower SES or demographic factors (DGF) linked to rural areas are associated with a more advanced disease stage at presentation.

Methodology: Between 1989 and 2008, patients with pancreatic adenocarcinoma and pancreaticoduodenectomy were identified from our pancreatic resection database. DGF, SES surrogates and tumor stage were obtained from patients' files together with pathology reports, a residents' registration office questionnaire and telephone interviews with patients and family members.

Results: Follow-up was completed in 117 patients. There were no significant differences regarding tumor stage (local size and lymph node metastases), or the likelihood of negative resection margins in relation to the patients' DGF or any surrogate parameters for SES. Furthermore, comparison of two different treatment periods showed no significant advances regarding secondary cancer prevention within 20 years.

Conclusions: Longer waiting times for appointments combined with less sensitive imaging techniques and consecutive later referral to a cancer specialist are likely to be associated with inferior quality of medical results. Therefore, a lively debate is currently underway in Germany concerning the harmonization of reimbursement modes for statutory and private health insurance. Our data with no negative correlation of low SES or unfavorable DGF and disease stage at time of presentation or the likelihood for a curative resection, do not promote the universal accusation of health care disparities solely based on economic issues in Germany.
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http://dx.doi.org/10.5754/hge10334DOI Listing
March 2013

Everolimus and sirolimus in combination with cyclosporine have different effects on renal metabolism in the rat.

PLoS One 2012 31;7(10):e48063. Epub 2012 Oct 31.

iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA.

Enhancement of calcineurin inhibitor nephrotoxicity by sirolimus (SRL) is limiting the clinical use of this drug combination. We compared the dose-dependent effects of the structurally related everolimus (EVL) and sirolimus (SRL) alone, and in combination with cyclosporine (CsA), on the rat kidney. Lewis rats were treated by oral gavage for 28 days using a checkerboard dosing format (0, 3.0, 6.0 and 10.0 CsA and 0, 0.5, 1.5 and 3.0 mg/kg/day SRL or EVL, n = 4/dose combination). After 28 days, oxidative stress, energy charge, kidney histologies, glomerular filtration rates, and concentrations of the immunosuppressants were measured along with (1)H-magnetic resonance spectroscopy (MRS) and gas chromatography- mass spectrometry profiles of cellular metabolites in urine. The combination of CsA with SRL led to higher urinary glucose concentrations and decreased levels of urinary Krebs cycle metabolites when compared to controls, suggesting that CsA+SRL negatively impacted proximal tubule metabolism. Unsupervised principal component analysis of MRS spectra distinguished unique urine metabolite patterns of rats treated with CsA+SRL from those treated with CsA+EVL and the controls. SRL, but not EVL blood concentrations were inversely correlated with urine Krebs cycle metabolite concentrations. Interestingly, the higher the EVL concentration, the closer urine metabolite patterns resembled those of controls, while in contrast, the combination of the highest doses of CsA+SRL showed the most significant differences in metabolite patterns. Surprisingly in this rat model, EVL and SRL in combination with CsA had different effects on kidney biochemistry, suggesting that further exploration of EVL in combination with low dose calcineurin inhibitors may be of potential benefit.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048063PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485290PMC
April 2013

Low-salt diet and cyclosporine nephrotoxicity: changes in kidney cell metabolism.

J Proteome Res 2012 Nov 11;11(11):5135-44. Epub 2012 Oct 11.

Department of Anesthesiology, University of Colorado, Aurora, Colorado, USA.

Cyclosporine (CsA) is a highly effective immunosuppressant used in patients after transplantation; however, its use is limited by nephrotoxicity. Salt depletion is known to enhance CsA-induced nephrotoxicity in the rat, but the underlying molecular mechanisms are not completely understood. The goal of our study was to identify the molecular effects of salt depletion alone and in combination with CsA on the kidney using a proteo-metabolomic strategy. Rats (n = 6) were assigned to four study groups: (1) normal controls, (2) low-salt fed controls, (3) 10 mg/kg/d CsA for 28 days on a normal diet, (4) 10 mg/kg/d CsA for 28 days on low-salt diet. Low-salt diet redirected kidney energy metabolism toward mitochondria as indicated by a higher energy charge than in normal-fed controls. Low-salt diet alone reduced phospho-AKT and phospho-STAT3 levels and changed the expression of ion transporters PDZK1 and CLIC1. CsA induced macro- and microvesicular tubular epithelial vacuolization and reduced energy charge, changes that were more significant in low-salt fed animals, probably because of their more pronounced dependence on mitochondria. Here, CsA increased phospho-JAK2 and phospho-STAT3 levels and reduced the phospho-IKKγ and p65 proteins, thus activating NF-κB signaling. Decreased expression of lactate transport regulator CD147 and phospho-AKT was also observed after CsA exposure in low-salt rats, indicating a decrease in glycolysis. In summary, our study suggests a key role for PDZK1, CD147, JAK/STAT, and AKT signaling in CsA-induced nephrotoxicity and proposes mechanistic explanations on why rats fed a low-salt diet have higher sensitivity to CsA.
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http://dx.doi.org/10.1021/pr300260eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831655PMC
November 2012

Detection of IGF2BP3, HOXB7, and NEK2 mRNA expression in brush cytology specimens as a new diagnostic tool in patients with biliary strictures.

PLoS One 2012 7;7(8):e42141. Epub 2012 Aug 7.

Department of Internal Medicine 1, University of Bonn, Bonn, Germany.

Introduction: It is a challenging task to distinguish between benign and malignant lesions in patients with biliary strictures. Here we analyze whether determination of target gene mRNA levels in intraductal brush cytology specimens may be used to improve the diagnosis of bile duct carcinoma.

Materials And Methods: Brush cytology specimens from 119 patients with biliary strictures (malignant: n = 72; benign: n = 47) were analyzed in a retrospective cohort study. mRNA of IGF-II mRNA-binding protein 3 (IGF2BP3), homeobox B7 (HOXB7), Forkhead box M1 (FOXM1), kinesin family member 2C (KIF2C) and serine/threonine kinase NEK2 was determined by semi-quantitative RT-PCR using the ΔCt method.

Results: IGF2BP3 (p<0.0001), HOXB7 (p<0.0001), and NEK2 (p<0.0001) mRNA expression levels were significantly increased in patients with cholangiocarcinoma or pancreatic cancer. Median ΔCt values differed by 3.5 cycles (IGF2BP3), 2.8 cycles (HOXB7) and 1.3 cycles (NEK2) corresponding to 11-fold, 7-fold and 2.5-fold increased mRNA levels in malignant versus benign samples. Sensitivity to detect biliary cancer was 76.4% for IGF2BP3 (80.9% specificity); 72.2% for HOXB7 (78.7% specificity) and 65.3% for NEK2 (72.3% specificity), whereas routine cytology reached only 43.1% sensitivity (85.4% specificity). Diagnostic precision was further improved, when all three molecular markers were assessed in combination (77.8% sensitivity, 87.2% specificity) and achieved 87.5% sensitivity and 87.2% specificity when molecular markers were combined with routine cytology.

Conclusions: Our data suggest that measuring IGF2BP3, HOXB7 and NEK2 mRNA levels by RT-PCR in addition to cytology has the potential to improve detection of malignant biliary disorders from brush cytology specimens.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042141PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413695PMC
January 2013

Anti-tumoural effects of PlgK1-5 are directly linked to reduced ICAM expression, resulting in hepatoma cell apoptosis.

Int J Colorectal Dis 2012 Aug 28;27(8):1029-38. Epub 2012 Mar 28.

Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.

Purpose: Angiostatin and angiostatin-like molecules are known as anti-angiogenic factors, which inhibit endothelial cell functions resulting in reduced tumour growth. Recent data indicate that these molecules, especially PlgK1-5, directly affect tumour cells, which could explain the strong anti-tumoural effects of PlgK1-5. Therefore, we have analysed whether PlgK1-5 alters tumour cell functions and expression levels of cell adhesion molecules in murine and human hepatoma cells in vitro and in vivo.

Methods: First, effects on tumour growth, proliferation and apoptosis were investigated in vivo in a subcutaneous tumour model. In vitro, effects of PlgK1-5 on tumour cell apoptosis, clonal expansion, migration, corresponding ICAM expression and intracellular signal transduction in murine Hepa129 and human HuH7 hepatoma cells have been analysed.

Results: In vivo, subcutaneous tumour growth was reduced by 75% in PlgK1-5-treated animals compared to the controls. This was accompanied by increased tumour cell apoptosis (up to 33%) and decreased tumour cell proliferation (by up to 21%). In vitro, PlgK1-5 induced apoptosis in hepatoma cells, corresponding to increased caspase-8 cleavage and reduced AKT phosphorylation. Migration and clonal expansion was also diminished in PlgK1-5-treated Hepa129, corresponding to decreased ICAM expression levels.

Conclusions: Here, we show that PlgK1-5 directly affects tumour cells by decreasing cell adhesion resulting-at least partly-in apoptosis. This is mediated by altered intracellular signal transduction and by activation of the caspase cascade. These findings further underscore the potential therapeutic role of PlgK1-5 in the treatment of HCC.
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http://dx.doi.org/10.1007/s00384-012-1418-6DOI Listing
August 2012

Transforming growth factor-β1-gene polymorphism in the development of kidney disease after liver transplantation.

Transplantation 2012 Mar;93(5):555-60

General, Visceral and Transplantation Surgery, Charité Campus Virchow, Berlin, Germany.

Background: The development of kidney dysfunction is one of the most important after liver transplantation (LT). Genetic variants of pathogenetically relevant cytokines may influence the development and course of the disease. The aim of our study was to evaluate the role of transforming growth factor-β1 (TGF-β1) polymorphism in this context.

Methods: Four hundred eighty-six liver graft recipients were genotyped for TGF-β1 codon 25 (guanine → cytosine, G → C) by polymerase chain reaction. Renal function before and after LT was characterized by estimation of glomerular filtration rate (GFR) using four-parameter-modification of diet in renal disease formula on defined dates. GFR was compared among TGF-β1-genotype groups of the entire cohort within the median observation period of 7 years. For the assessment of renal function recovery after LT, patients were divided into three groups by GFR difference (ΔGFR = ± 10 mL/min).

Results: Mean pretransplant GFR differed significantly among TGF-β1-genotype groups (GG: 85.0 mL/min vs. GC/CC: 75.3 mL/min; P=0.016). The significance disappeared in the follow-up period. Although GG genotype demonstrated higher mean GFR levels, patients with GC/CC genotype tended to improve kidney function compared with GG genotype (P=0.013). Interestingly, lower mean GFR rates were observed among female compared with male recipients before (P=0.002), separately at all dates and cumulatively after LT (P<0.001).

Conclusions: Genetic variants of one of the most important cytokine TGF-β1 at codon 25 may have an impact on kidney function, suggesting an unfavorable effect of C allele in pretransplant setting and serve as marker for the recovery of renal function after LT. The identification of further confounders seems to be promising.
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http://dx.doi.org/10.1097/TP.0b013e318242be0bDOI Listing
March 2012

Apoptotic potency of angiostatic compounds in the treatment of cancer.

Curr Pharm Biotechnol 2012 Sep;13(11):2283-9

Department of Inner Medicine I, University Hospital Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany.

When tumours outgrow their vascular supply, they become hypoxic because of nutrient deficiency. This increases the expression and secretion of proangiogenic factors, like vascular endothelial growth factor (VEGF), leading to the activation of endothelial cells. The activated endothelial cells migrate, proliferate and form new blood vessels, resulting in increased tumour growth. This process is called tumour angiogenesis. Inhibiting tumour angiogenesis and therefore tumour growth is a well known concept in the treatment of cancer, such as hepatocellular carcinoma (HCC). This can be done by endogenous angiogenesis inhibitors, like angiostatin and its derivates. These are known to affect endothelial cell functions including the induction of apoptosis. The impact of these angiostatic factors on the cell is manifold. This also applies for so called small molecules, which affect tyrosine kinases such as receptors or intracellular signal transduction proteins. Other approaches, like monoclonal antibodies, target a single molecule, mainly VEGF, to inhibit receptor binding and downstream signal transduction. Gene silencing, mainly via RNA interference (RNAi) intervenes on RNAlevel, leading to reduced gene expression and protein secretion. Due to intense research in this field, there is rising evidence that also tumour cells themselves are influenced by angiostatic treatment approaches and the underlying molecular mechanisms are more and more revealed. Here we give a (short) review regarding the pro-apoptotic potency of antiangiogenic compounds like angiostatic molecules, sequestering antibodies, small molecules and RNAi approaches targeting endothelial and tumour cell survival to inhibit angiogenesis and tumour growth.
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http://dx.doi.org/10.2174/138920112802502024DOI Listing
September 2012

Combination of hypoxia and RNA-interference targeting VEGF induces apoptosis in hepatoma cells via autocrine mechanisms.

Curr Pharm Biotechnol 2012 Sep;13(11):2290-8

Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, Bonn/Germany.

Control of VEGF signaling is an intense objective of pre-clinical and clinical studies in HCC disease with steadily increasing clinical application. Despite its emerging role, several aspects of anti-VEGF based treatments are poorly investigated, like the impact on tumor cells themselves, such as the effect on intracellular signaling and apoptosis induction in hepatoma cells. Effects of siRNA-VEGF on VEGF, VEGF-receptor expression and VEGF-A signaling such as AKT and JNK phosphorylation were determined under normoxic or hypoxic conditions in murine hepatoma cells. Apoptosis induction was analyzed by SubG1-fraction, JC1-staining and caspase-8 activation. VEGF receptor expression was analysed by semiquantitative real time PCR. Independent of oxygen status, siRNA-VEGF reduced VEGF levels resulting in decreased AKT and increased JNK phosphorylation in Hepa129 cells. The VEGF-receptors neuropilin-1 (Nrp1) and neuropilin-2 (Nrp2) were downregulated following siRNA-VEGF treatment or hypoxia induction respectively. Functionally, hypoxia significantly increased the apoptosis rate (as analyzed by SubG1-fraction, JC1-staining and JNKphosphorylation) which was further stimulated by siRNA-VEGF treatment. Our data indicate that antitumoral efficacy of an anti-VEGF based treatment with siRNA is partly based on negative autocrine feedback mechanisms which are even enhanced under hypoxic conditions. This observation helps to understand why antitumoral efficacy can be maintained despite of counteracting stimulation of tumoral VEGF secretion due to hypoxia. The direct impact on tumor cells further underscores the attractiveness of an anti-VEGF based siRNA treatment.
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http://dx.doi.org/10.2174/138920112802502088DOI Listing
September 2012

Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells.

J Hepatol 2011 Oct 18;55(4):828-37. Epub 2011 Feb 18.

Center for Applied Medical Research (CIMA), Spain.

Background & Aims: Cell therapy has been used to attenuate liver injury. Here we evaluated whether genetic engineering of either bone marrow-derived mononuclear cells (MNC) or endothelial progenitor cells (EPC) many enhance their hepatoprotective properties.

Methods: Mice with ConA-induced hepatitis or with lethal fulminant hepatitis resulting from administration of an adenovirus encoding CD40L (AdCD40L) received an intra-splenic injection of saline or 2 × 10(6) unmodified MNC or EPC or the same cells transduced ex vivo with an adenovirus expressing luciferase (MNCLUC and EPCLUC) or encoding the hepatoprotective cytokine cardiotrophin-1 (CT-1) (MNCCT-1 and EPCCT-1). We analyzed the extent of liver damage, the intensity of inflammatory reaction, and animal survival.

Results: Luciferase immunohistochemistry showed that after injection into the spleen, the engineered cells migrated efficiently to the damaged liver. In mice with ConA hepatitis EPCCT-1, but not other forms of cell therapy, significantly decreased serum transaminases and induced more intense histological improvement than other treatments. This superior therapeutic effect was associated with upregulation of cytoprotective molecules including IGF-I and EGF, lower expression of proinflammatory cytokines, IL-1b and TNFα, and decreased granzyme B levels. In AdCD40L-induced lethal fulminant hepatitis, EPCCT-1 also exceeded other cell therapies in attenuating the expression of proinflammatory mediators and hepatic injury enabling 35.7% survival while mortality was 100% in the other treatment groups.

Conclusions: Genetic engineering of EPC to overexpress CT-1 enhances the hepatoprotective properties of EPC and constitutes a therapy that deserves consideration for acute liver failure.
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http://dx.doi.org/10.1016/j.jhep.2011.01.036DOI Listing
October 2011

Biomarkers of immunosuppressant organ toxicity after transplantation: status, concepts and misconceptions.

Expert Opin Drug Metab Toxicol 2011 Feb;7(2):175-200

University of Colorado, Department of Anesthesiology, 1999 North Fitzsimons Parkway, Bioscience East, Suite 100, Aurora, CO 80045-7503, USA.

Introduction: A major challenge in transplantation is improving long-term organ transplant and patient survival. Immunosuppressants protect the transplant organ from alloimmune reactions, but sometimes also exhibit limiting side effects. The key to improving long-term outcome following transplantation is the selection of the correct immunosuppressive regimen for an individual patient for minimizing toxicity while maintaining immunosuppressive efficacy.

Areas Covered: Proteomics and metabolomics have the potential to develop sensitive and specific diagnostic tools for monitoring early changes in cell signal transduction, regulation and biochemical pathways. Here, we review the steps required for the development of molecular markers from discovery, mechanistic and clinical qualification to regulatory approval, and present a critical discussion of the current status of molecular marker development as relevant for the management and individualization of immunosuppressive drug regimens.

Expert Opinion: Although metabolomics and proteomics-based studies have yielded several candidate molecular markers, most published studies are poorly designed, statistically underpowered and/or often have not gone beyond the discovery stage. Most molecular marker candidates are still at an early stage. Due to the high complexity of and the resources required for diagnostic marker development, initiatives and consortia organized and supported by funding agencies and regulatory agencies will be critical.
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http://dx.doi.org/10.1517/17425255.2011.544249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079351PMC
February 2011

Role of hypoxia-inducible transcription factor 1alpha for progression and chemosensitivity of murine hepatocellular carcinoma.

J Mol Med (Berl) 2010 Aug 12;88(8):817-27. Epub 2010 Apr 12.

Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.

Hepatocellular carcinoma (HCC) is a hypervascularized tumor entity with association of arterial vessel density with poor prognosis. The hypoxia-inducible transcription factor HIF-1alpha represents a pivotal regulator of angiogenesis and is thought to determine the angiogenic nature of HCC. However, the precise role of HIF-1alpha during the pathogenesis of HCC remains elusive. We established a functional inactivation of HIF-1alpha in vitro and in vivo via RNAi and Cre/loxP-mediated recombination, respectively, to determine HIF-1alpha's role for tumor growth and chemosensitivity in transgenic and orthotopic murine HCC models. HIF-1alpha-deficient HCC cells displayed significantly reduced anchorage-independent growth and enhanced sensitivity toward etoposide, while basic cellular proliferation was unaffected. Analysis of gross tumor growth failed to detect reduced growth of HIF-1alpha-deficient tumors in the orthotopic and the transgenic HCC model, respectively. In line with the in vitro data, treatment of HIF-1alpha-deficient tumors with etoposide resulted in greater antiproliferative efficacy when compared to wild-type mice. Taken together, our study does not support a pivotal role of HIF-1alpha for tumor growth and angiogenesis in two murine HCC models. However, our data point toward a significant function of HIF-1alpha in determining chemosensitivity of HCC and therefore warrant validation of HIF-1alpha-inhibitors as adjuvant therapeutic agents in clinical studies of human HCC.
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http://dx.doi.org/10.1007/s00109-010-0623-4DOI Listing
August 2010

The influence of storage temperature during machine perfusion on preservation quality of marginal donor livers.

Cryobiology 2010 Jun 15;60(3):337-43. Epub 2010 Mar 15.

Clinic for General, Visceral and Transplantation Surgery, Charité Campus Virchow-Klinikum, University Medicine Berlin, Germany.

Background: Although non-heart-beating donors have the potential to increase the number of available organs, the livers are used very seldom because of the risk of primary non-function. There is evidence that machine perfusion is able to improve the preservation of marginal organs, and therefore we evaluated in our study the influence of the perfusate temperature during oxygenated machine perfusion on the graft quality.

Methods: Livers from male Wistar rats were harvested after 60-min warm ischemia induced by cardiac arrest. The portal vein was cannulated and the liver flushed with Lifor (Lifeblood Medical, Inc.) organ preservation solution for oxygenated machine perfusion (MP) at 4, 12 or 21 degrees C. Other livers were flushed with HTK and stored at 4 degrees C by conventional cold storage (4 degrees C-CS). Furthermore two groups with either warm ischemic damage only or without any ischemic damage serve as control groups. After 6h of either machine perfusion or cold storage all livers were normothermic reperfused with Krebs-Henseleit buffer, and functional as well as structural data were analyzed.

Results: Contrary to livers stored by static cold storage, machine perfused livers showed independently of the perfusate temperature a significantly decreased enzyme release of hepatic transaminases (ALT) during isolated reperfusion. Increasing the machine perfusion temperature to 21 degrees C resulted in a marked reduction of portal venous resistance and an increased bile production.

Conclusions: Oxygenated machine perfusion improves viability of livers after prolonged warm ischemic damage. Elevated perfusion temperature of 21 degrees C reconstitutes the hepatic functional capacity better than perfusion at 4 or 12 degrees C.
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http://dx.doi.org/10.1016/j.cryobiol.2010.03.005DOI Listing
June 2010
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