H. Bektas

The Donor-Risk-Index, ECD-Score and D-MELD-Score all fail to predict short-term outcome after liver transplantation with acceptable sensitivity and specificity

BACKGROUND Expansion of the donor pool by the use of grafts with extended donor criteria reduces waiting list mortality with an increased risk for graft and patient survival after liver transplantation. This study investigates the ability of the Donor-Risk-Index (DRI), the Extended-Criteria-Donor-Score (ECD-score) and the D-MELD-score to predict early outcome after liver transplantation. MATERIAL/METHODS 291 consecutive adult liver transplants (01.01.2007-31.12.2010) were analysed in a single centre study with ongoing data collection. Primary study endpoints were 30-day mortality, 3-month mortality, 3-month patient and graft survival and the necessity of acute retransplantation within 30 days. For the primary study endpoints ROC-curve analysis was performed to calculate the sensitivity, specificity, and overall model correctness of the Donor-Risk-Index (DRI), Extended-Criteria-Donor-Score (ECD-score) and the D-MELD-Score as predictive models. Cut-off values were selected with the best Youden index. RESULTS ROC-curve analysis showed areas under the curve (AUROCs) <0.7 for the DRI, the ECD-Score and the D-MELD-Score as models for the prediction of 30-day mortality, 3-month mortality, 3-month patient survival, 3-month graft survival as well as the necessity of acute retransplantation within 30 days after transplantation with unacceptable low levels of overall model correctness (<62%) and specificity (<56%). CONCLUSIONS The DRI, the ECD-Score and the D-MELD-Score all fail to predict short-term outcome after liver transplantation with acceptable overall model correctness in a current European transplant setting.

A multicentre, randomized clinical trial comparing the Veriset™ haemostatic patch with fibrin sealant for the management of bleeding during hepatic surgery

BACKGROUND Bleeding during hepatic surgery is associated with prolonged hospitalization and increased morbidity and mortality. The Veriset™ haemostatic patch is a topical haemostat comprised of an absorbable backing made of oxidized cellulose and self-adhesive hydrogel components. It is designed to achieve haemostasis quickly and adhere to tissues without fixation. METHODS A prospective, randomized, multicentre, single-blinded study (n = 50) was performed to compare the use of a Veriset™ haemostatic patch with a fibrin sealant patch (TachoSil(®) ) (control) in the management of diffuse bleeding after hepatic surgery. Patients were randomized following the confirmation of diffuse bleeding requiring the use of a topical haemostat. Time to haemostasis was assessed at preset intervals until haemostasis was achieved. RESULTS Both groups were similar in comorbidities and procedural techniques. The median time to haemostasis in the group using the Veriset™ haemostatic patch was 1.0 min compared with 3.0 min in the control group (P < 0.001; 3-min minimum application time for the control patch). This result was independent of bleeding severity and surface area. Both products had similar safety profiles and no statistical differences were observed in the occurrence of adverse or device-related events. CONCLUSIONS Regardless of bleeding severity or surface area, the Veriset™ haemostatic patch achieved haemostasis in this setting significantly faster than the control device in patients undergoing hepatic resection. It was safe and easy to handle in open hepatic surgery.

Langzeit-Outcome nach Lebertransplantation

Liver transplantation has been reported to reach excellent results for selected indications. We analysed the results of liver transplantation in our centre over a period of 23 years, with a total of 2,114 consecutive liver transplants in 1,773 patients (eras I-III 5.5 years each, era IV 6.5 years). Overall 20-year survival after liver transplantation was 29.8%. The most frequent leading causes of death were infections of various origins (30%), tumour recurrence (14.2%), and pneumonia (8.4%). The most frequent leading causes for graft loss were infection of various origins (19.6%), initial nonfunction of the graft (14.6%), and tumour recurrence (9.6%). Both long-term patient and graft survival were significantly better after primary liver transplantation than after first retransplantation (P<0.001). Patient and graft long-term survival improved significantly across all four consecutive eras (P<0.001). In era IV, the most recent, 5-year patient survival reached 96% for PBC, 89.4% for PSC, 78.5% for biliary atresia, 70% for acute liver failure, 69.1% for HBV-related cirrhosis, 61.3% for hepatocellular carcinoma, and 56% for HCV-related cirrhosis.

Inhibition of Autophagic Flux by Salinomycin Results in Anti-Cancer Effect in Hepatocellular Carcinoma Cells

Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0–10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

Value of the SOFA score as a predictive model for short-term survival in high-risk liver transplant recipients with a pre-transplant labMELD score ≥30

IntroductionThe Sequential Organ Failure Assessment (SOFA) score has been applied for the prediction of survival in critically ill patients. We analysed the value of the SOFA score for the prediction of short-term survival after liver transplantation in high-risk liver transplant recipients with a labMELD score ≥30.Patients and methodsWe conducted a retrospective single-centre analysis including 88 consecutive liver transplants in adults between January 1, 2007 and December 31, 2010 with a pre-transplant labMELD score ≥30. The SOFA score was assessed preoperatively, directly after transplantation and on post-operative days (PODs) 1–10. Combined and living-related liver transplants were excluded. Receiver operating characteristic (ROC) curve analysis with the Hosmer–Lemeshow test and application of the Brier score were used to calculate sensitivity, specificity, overall model correctness and calibration. Cutoff values were selected with the best Youden index.ResultsROC curve analysis showed areas under the curve (AUROCs) >0.8 for the SOFA score on PODs 1–10 for the prediction of hospital mortality, 30-day mortality and 3-month mortality with Hosmer–Lemeshow test results that confirmed good model calibration (p > 0.05). The Brier score demonstrated an accuracy of prediction (<0.25) of hospital mortality, 30-day mortality and 3-month mortality for the SOFA scores on PODs 4–9 indicating superior accuracy on PODs 7 and 8 with cutoff values for the SOFA score between 16.5 and 18.5. The pre-transplant SOFA score failed to reach AUROCs >0.7 (0.603–0.663) for the prediction of short-term survival.ConclusionsOur results confirm the usefulness of the SOFA score in high-risk liver recipients during the early post-operative course, especially on PODs 7–8 for the prediction of hospital mortality, 30-day mortality and 3-month mortality and may be useful to predict futile early acute retransplantation.

Expression and cell-specific and membrane-specific localization of NHE-3 in the human and guinea pig upper gastrointestinal tract.

Abstract. Na+/H+ exchangers (NHEs) are vital transmembrane transport proteins mediating the electroneutral exchange of Na+ and H+ ions in mammalian cells. In the epithelium of the lower intestine, the isoform NHE-3 is apparently involved in Na+ absorption; however, its presence and cellular localization in the duodenum and particularly in the stomach remain largely unclear. Therefore, we studied the human and guinea pig stomach and duodenum for the expression, regional and mucosal distribution pattern, and membrane-specific localization of NHE-3. Reverse transcription/polymerase chain reaction analyses revealed strong expression of NHE-3 in the stomach and duodenum, where it was identified as a 85-kDa immunoreactive protein by Western blotting experiments. Whereas NHE-3 was localized to the basolateral membrane of surface mucous cells of the stomach, it was exclusively confined to the brush border membrane of epithelial cells in the duodenum. We conclude that the basolateral NHE-3 in the stomach protects the mucosa by secreting protons that diffuse into the mucous cells. In the duodenum, the localization of NHE-3 to the apical membrane of enterocytes suggests a resorptive function by directional Na+ transport. These findings indicate that NHE-3 may be involved in various segment-specific functions in the upper gastrointestinal tract.

Surgical treatment for intrahepatic cholangiocarcinoma in Europe : a single center experience

Intrahepatic cholangiocarcinoma is the second most common primary liver tumor. The aim of this study was to analyze retrospectively the outcome of surgical treatment and prognostic factors. Clinical, histopathological and treatment data of 221 patients treated from 1995 to 2010 at our institution were investigated. Univariate and multivariate analysis of the patients data was performed. Patients after R0 and R1 resection presented an overall survival of 67% and 54.5% after 1 year and 40% and 36.4% after 3 years, respectively. The survival of patients without resection of the tumor was dismal with 26% and 3.4% after 1 and 3 years, respectively. Survival after resection was not statistically different in cases with R0 versus R1 resection (P = 0.639, log rank). Univariate Cox regression revealed that higher T stages are a significant hazard for survival (P = 0.048, hazard ratio (HR): 1.211, 95% confidence interval (CI): 1.002–2.465). Patients with tumor recurrence had a significantly inferior long‐term survival when compared to patients without recurrence (P < 0.001, log rank). Presence of lymph node metastasis (N1) was an independent prognostic factor for survival after resection in risk‐adjusted multivariate Cox regression (P < 0.001, HR: 2.577, 95% CI: 1.742–3.813). Adjuvant chemotherapy did not improve patient survival significantly (P = 0.550, log rank). Surgical resection is still the best treatment option for intrahepatic cholangiocarcinoma regarding the patients long‐term survival. R0 and R1 resection enable both better survival rates when compared to surgical exploration without resection. T status, N status, and tumor recurrence seem to be the most important prognostic factors after resection.

Insulin dependence and pancreatic enzyme replacement therapy are independent prognostic factors for long-term survival after operation for chronic pancreatitis.

BACKGROUND This retrospective, single-center, observational study on postoperative long-term results aims to define yet unknown factors for long-term outcome after operation for chronic pancreatitis. PATIENTS AND METHODS We analyzed 147 consecutive patients operated for chronic pancreatitis from 2000 to 2011. Mean follow-up was 5.3 years (range, 1 month to 12.7 years). Complete long-term survival data were provided by the German citizen registration authorities for all patients. A quality-of-life questionnaire was sent to surviving patients after a mean follow-up of 5.7 years. RESULTS Surgical principles were resection (n = 86; 59%), decompression (n = 29; 20%), and hybrid procedures (n = 32; 21%). No significant influences of different surgical principles and operative procedures on survival, long-term quality of life and pain control could be detected. Overall 30-day mortality was 2.7%, 1-year survival 95.9%, and 3-year survival 90.8%. Multivariate Cox regression analysis revealed that only postoperative insulin dependence at the time of hospital discharge (P = .027; Exp(B) = 2.111; 95% confidence interval [CI], 1.089-4.090) and the absence of pancreas enzyme replacement therapy at the time of hospital discharge (P = .039; Exp(B) = 2.102; 95% CI, 1.037-4.262) were significant, independent risk factors for survival with significant hazard ratios for long-term survival. Long-term improvement in quality of life was reported by 55 of 76 long-term survivors (73%). CONCLUSION Pancreatic enzyme replacement should be standard treatment after surgery for chronic pancreatitis at the time of hospital discharge, even when no clinical signs of exocrine pancreatic failure exist. This study underlines the potential importance of early operative intervention in chronic pancreatitis before irreversible endocrine dysfunction is present.

Helicobacter hepaticus Induces an Inflammatory Response in Primary Human Hepatocytes

Helicobacter hepaticus can lead to chronic hepatitis and hepatocellular carcinoma in certain strains of mice. Until now the pathogenic role of Helicobacter species on human liver tissue is still not clarified though Helicobacter species identification in human liver cancer was successful in case controlled studies. Therefore we established an in vitro model to investigate the interaction of primary human hepatocytes (PHH) with Helicobacter hepaticus. Successful co-culturing of PHH with Helicobacter hepaticus was confirmed by visualization of motile bacteria by two-photon-microscopy. Isolated human monocytes were stimulated with PHH conditioned media. Changes in mRNA expression of acute phase cytokines and proteins in PHH and stimulated monocytes were determined by Real-time PCR. Furthermore, cytokines and proteins were analyzed in PHH culture supernatants by ELISA. Co-cultivation with Helicobacter hepaticus induced mRNA expression of Interleukin-1 beta (IL-1β), Tumor necrosis factor-alpha, Interleukin-8 (IL-8) and Monocyte chemotactic protein-1 (MCP-1) in PHH (p<0.05) resulting in a corresponding increase of IL-8 and MCP-1 concentrations in PHH supernatants (p<0.05). IL-8 and IL-1β mRNA expression was induced in monocytes stimulated with Helicobacter hepaticus infected PHH conditioned media (p<0.05). An increase of Cyclooxygenase-2 mRNA expression was observed, with a concomitant increase of prostaglandin E2 concentration in PHH supernatants at 24 and 48 h (p<0.05). In contrast, at day 7 of co-culture, no persistent elevation of cytokine mRNA could be detected. High expression of intercellular adhesion molecule-1 on PHH cell membranes after co-culture was shown by two-photon-microscopy and confirmed by flow-cytomety. Finally, expression of Cytochrome P450 3A4 and albumin mRNA were downregulated, indicating an impairment of hepatocyte synthesis function by Helicobacter hepaticus presence. This is the first in vitro model demonstrating a pathogenic effect of a Helicobacter spp. on human liver cells, resulting in an inflammatory response with increased synthesis of inflammatory mediators and consecutive monocyte activation.

Erweiterte Spenderkriterien der Bundesärztekammer

INTRODUCTION Expansion of the donor pool by the use of grafts with extended donor criteria reduces waiting list mortality with an increased risk for graft and patient survival after liver transplantation. The ability of the number of fulfilled extended donor criteria as currently defined by the German Medical Association (BÄK-Score) to predict early outcome is unclear. PATIENTS A total of 291 consecutive adult liver transplantations (01.01.2007-31.12.2010) in 257 adult recipients were analyzed. METHODS Primary study endpoints were 30 day mortality, 3 month mortality, 3 month patient and graft survival and the necessity of acute retransplantation within 30 days. For primary study endpoints a ROC curve analysis was performed to calculate sensitivity, specificity and overall model correctness of the BÄK score as a predictive model. Further methods included Kaplan-Meier estimates, log-rank tests, Cox regression analysis, logistic regression analysis and χ(2)-tests. RESULTS The number of extended donor criteria fulfilled had no statistically significant influence on the primary study endpoints (p > 0.05) or on patient survival (p > 0.05). ROC curve analysis revealed areas under the curve ≤ 0.561 for the prediction of primary study endpoints (overall model correctness < 58%, sensitivity < 52%). CONCLUSIONS The number of fulfilled extended donor criteria as currently defined by the German Medical Association is unable to predict early outcome after liver transplantation.