Falk Rauchfuss

A Randomized, Controlled Study to Assess the Conversion From Calcineurin-Inhibitors to Everolimus After Liver Transplantation—PROTECT

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal‐sparing alternative. In this randomized 1‐year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post‐LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft‐Gault formula (−2.9 mL/min in favor of EVR, 95%‐CI: [−10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (−7.8 mL/min, 95%‐CI: [−14.366; −1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy‐proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI‐based to EVR‐based immunosuppression proved to be a safe alternative post‐LTx that deserves further investigation in terms of nephroprotection.

New methods for clinical pathways—Business Process Modeling Notation (BPMN) and Tangible Business Process Modeling (t.BPM)

PurposeClinical pathways (CP) are nowadays used in numerous institutions, but their real impact is still a matter of debate. The optimal design of a clinical pathway remains unclear and is mainly determined by the expectations of the individual institution. The purpose of the here described pilot project was the development of two CP (colon and rectum carcinoma) according to Business Process Modeling Notation (BPMN) and Tangible Business Process Modeling (t.BPM).MethodsBPMN is an established standard for business process modelling in industry and economy. It is, in the broadest sense, a computer programme which enables the description and a relatively easy graphical imaging of complex processes. t.BPM is a modular construction system of the BPMN symbols which enables the creation of an outline or raw model, e.g. by placing the symbols on a spread-out paper sheet. The thus created outline can then be transferred to the computer and further modified as required. CP for the treatment of colon and rectal cancer have been developed with support of an external IT coach.ResultsThe pathway was developed in an interdisciplinary and interprofessional manner (55 man-days over 15 working days). During this time, necessary interviews with medical, nursing and administrative staffs were conducted as well. Both pathways were developed parallel. Subsequent analysis was focussed on feasibility, expenditure, clarity and suitability for daily clinical practice. The familiarization with BPMN was relatively quick and intuitive. The use of t.BPM enabled the pragmatic, effective and results-directed creation of outlines for the CP. The development of both CP was finished from the diagnostic evaluation to the adjuvant/neoadjuvant therapy and rehabilitation phase. The integration of checklists, guidelines and important medical or other documents is easily accomplished. A direct integration into the hospital computer system is currently not possible for technical reasons.ConclusionBPMN and t.BPM are sufficiently suitable for the planned modelling and imaging of CP. The application in medicine is new, and transfer from the industrial process management is in principle possible. BPMN-CP may be used for teaching and training, patient information and quality management. The graphical image is clearly structured and appealing. Even though the efficiency in the creation of BPMN-CP increases markedly after the training phase, high amounts of manpower and time are required. The most sensible and consequent application of a BPMN-CP would be the direct integration into the hospital computer system. The integration of a modelling language, such as BPMN, into the hospital computer systems could be a very sensible approach for the development of new hospital information systems in the future.

Everolimus and Early Calcineurin Inhibitor Withdrawal: 3-Year Results From a Randomized Trial in Liver Transplantation

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open‐label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI‐based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft‐Gault) at month 11 postrandomization. A 24‐month extension phase followed 81/114 (71.1%) of eligible patients to month 35 postrandomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] −1.3, 21.5 mL/min, p = 0.082) in favor of CNI‐free versus CNI using Cockcroft‐Gault, 9.4 mL/min/1.73 m2 (95% CI −0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four‐variable) and 9.5 mL/min/1.73 m2 (95% CI −1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI‐free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy‐proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI‐free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus‐based CNI‐free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Epidemiological Pattern of Hepatitis B and Hepatitis C as Etiological Agents for Hepatocellular Carcinoma in Iran and Worldwide

Context Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections constitute a major global health problem. About 60,000 and 350,000 deaths occur as the results of HBV and HCV infections, respectively. Chronic hepatitis B and C infections are leading causes of cirrhosis and hepatocellular carcinoma (HCC) which are considered as the third cancer-associated cause of deaths worldwide. Iran suffers from the same problem but to a lesser extent as it is considered as a low endemic area for HBV and HCV infections and also as a low incidence area of HCC. This study was conducted to assess and provide a clear picture about epidemiology of HBV and HCV infections in Iran and worldwide, with the consequence on HCC distribution all over the world including Iran, and to analyze current literature regarding the modes of transmission and risk factors of HBV and HCV infections. Evidence Acquisition In this review, we performed electronic and manual searches on available databases such as MEDLINE, PubMed, Ovid, Embase, and the Iranian databases such as IranMedex. We also performed a Google search to find related articles. Results HBV and HCV infections are the most common risk factors of hepatocellular carcinoma. The epidemiology of HCC usually follows that of HBV and HCV infections. With the introduction of HBV national vaccine in Iran and worldwide, there is a noticeable effect on reduction in HBV prevalence in most countries, and we expect that HCV will replace HBV as a major risk factor of HCC in Iran and worldwide. Alcohol plays a minor role as a risk factor for cirrhosis and HCC in Iran, Asia, and Africa, despite its noticeable role in Europe and the USA. Conclusions Vaccination against HBV remains the most effective approach against HBV infection with consequence decrease in HBV-related HCC. There is a need to improve the awareness about epidemiology of HBV and HCV infections, modes of transmission, and their complications, specifically HCC among population.

Albumin Dialysis in Liver Failure: Comparison of Molecular Adsorbent Recirculating System and Single Pass Albumin Dialysis—A Retrospective Analysis

Despite improvement in critical care, liver failure is still associated with high mortality. Therapeutic concepts are aimed at restoring endogenous liver function or to bridge the time to liver transplantation. In addition to standard medical treatment, extracorporeal liver support with albumin dialysis is used for this purpose. The aim of this study was to analyze the efficacy of single pass albumin dialysis (SPAD) in comparison to the molecular adsorbent recirculating system (MARS) in patients treated at our university hospital intensive care unit between July 2004 and August 2008. In this retrospective analysis we studied patients presenting with liver failure who were treated with albumin dialysis. Laboratory parameters, daily health scoring, the number of transfusions, and mortality were recorded. The (paired) t‐test, Mann–Whitney U‐test, and Wilcoxon test were used for statistical analysis. In all, 163 albumin dialysis treatments, 126 with MARS and 37 with SPAD, in 57 patients were performed. MARS resulted in a significant decrease in bilirubin (−38 ± 66.5 µmol/L from a baseline of 301 ± 154.6 µmol/L), γ‐glutamyltransferase (γ‐GT), alanine aminotransferase, creatinine, and urea. SPAD resulted in a significant decrease in bilirubin (−41 ± 111.2 µmol/L from a baseline of 354 ± 189.4 µmol/L) and γ‐GT, while lactate levels increased. No differences in the need for blood transfusion, health scoring, or mortality between the two treatment modalities were detected. This retrospective analysis suggests equal efficacy of MARS and SPAD; however, prospective assessment to further define the role of SPAD in the treatment of acute or acute‐on‐chronic liver failure is needed.

Waiting time, not donor-risk-index, is a major determinant for beneficial outcome after liver transplantation in high-MELD patients

BACKGROUND Due to the increasing donor shortage, patients undergo liver transplantation actually mostly with high MELD-scores. In this study, we analyze high-MELD patients who underwent liver transplantation at a german single center. MATERIAL AND METHODS Since implementation of the MELD-score within the Eurotransplant region (December 2006) up to May 2011, 45 patients with a lab-MELD-score ≥ 36 underwent liver transplantation at our center. We correlated the 1-year-survival with donor data (especially the donor risk index, DRI), the time interval from reaching a lab-MELD-score ≥ 36 up to liver transplantation and the recipients state prior transplantation. RESULTS The overall 1-year-survival in our cohort is 68,8%. Waiting time of survivors was significantly shorter compared to non-survivors (MedianSurvivors: 2 days vs. MedianNon-survivors: 4 days; p=0.049). DRI showed no significant differences between both groups. Furthermore, the recipients state prior transplantation (dialysis, mechanical ventilation, catecholamines) showed no significant association with the outcome. CONCLUSIONS The outcome after liver transplantation in high-MELD patients is worse compared to that of patients with a marked lower MELD-score. Especially the time interval between reaching a lab-MELD score ≥ 36 to the transplantation is a major determinant for survival. Since the DRI is not associated with a worsened outcome, transplantation centers should accept even marginal organs for high-MELD patients to keep the waiting time as short as possible.

Liver Transplantation Utilizing Old Donor Organs: A German Single-Center Experience

INTRODUCTION Due to the current profound lack of suitable donor organs, transplant centers are increasingly forced to accept so-called marginal organs. One criterion for marginal donors is the donor age >65 years. We have presented herein the impact of higher donor age on graft and patient survival. PATIENTS AND METHODS Since 2004, 230 liver transplantations have been performed at our center, including 54 donor organs (23.5%) from individuals >65 years of age. We performed a retrospective analysis of recipient and graft survivals. RESULTS The overall 1-year mortality was 22.2% (12/54) among recipients of organs from older donors versus 19.5% among recipients whose donors were <65 years. When donor organs were grouped according to age, the 1-year mortality in patients receiving organs from donors aged 65-69 years was 30% (6/20); 70-74 years, 29.4% (5/17); and donors >75 years, 5.9% (1/17). There was no significant correlation between mortality rate and the number of additional criteria of a marginal donor organ. DISCUSSION The current lack of donor organs forces transplant centers to accept organs from older individuals; increasingly older patients are being recruited for the donor pool. Our results showed that older organs may be transplanted with acceptable outcomes. This observation was consistent with data from the current literature. It should be emphasized, however, that caution is advised when considering the acceptance of older organs for patients with hepatitis C-related cirrhosis.

Long-term follow-up of five yr shows superior renal function with everolimus plus early calcineurin inhibitor withdrawal in the PROTECT randomized liver transplantation study

The 12‐month (M) PROTECT study showed that de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI)‐based immunosuppression to a CNI‐free everolimus (EVR)‐based regimen showed numerically better renal function. Here, we present the five‐yr follow‐up data.

Sustained liver regeneration after portal vein embolization – A human molecular pilot study

BACKGROUND Portal vein embolization is a treatment option to achieve a sufficient future remnant liver volume for patients with central liver tumours requiring an extended resection with an extensive parenchymal loss. However, molecular mechanisms of this intervention are up to now poorly understood. The objective of this prospective pilot study was the characterization of molecular events leading to late hypertrophy of the non-embolized liver tissue in the human liver. METHODS Liver tissue of ten patients was collected before and intraoperatively more than one month after embolization. Investigation of molecular features was performed by pangenomic chips, polymerase chain reaction, immunostaining of proliferation marker Ki-67 and immunofluorescence measurements. RESULTS Significantly elevated genes hint towards angiogenesis and signalling by insulin-like growth factor and associated binding proteins. Increased transcript levels of activator protein 1 complex members like c-jun were reflecting potential molecular events of liver growth after embolization. Immunofluorescence data confirmed a predominant upregulation of β-catenin and c-jun (p<0.1) supported by Ki-67 (p<0.05) in the non-embolized liver. In silico analysis of transcriptomic dysplasia and hepatocellular carcinoma data showed divergent signatures compared to embolization. CONCLUSIONS Our findings indicate a sustained regeneration after portal vein embolization reflected in hyperplasia and angiogenesis in the human liver and provide novel molecular mechanisms of interlobe crosstalk.

Implantation of the Liver During Reperfusion of the Heart in Combined Heart-Liver Transplantation: Own Experience and Review of the Literature

BACKGROUND There are only a few reports about combined heart-liver transplantations. The surgical techniques differ widely, ranging from sequential implantation of the organs to simultaneous transplantations. We report our experience with simultaneous, combined heart-liver transplantations without using a veno-venous bypass demonstrating that this is a feasible surgical technique. METHODS Since 2005, we performed 4 combined heart-liver transplantations by implanting the liver during the reperfusion period of the newly implanted heart. We retrospectively reviewed patient clinical data and outcomes. RESULTS The mean operative time was 534 ± 247 minutes and the ischemia times for heart and liver were 190 ± 72 minutes (cold ischemia time for the heart), 98 ± 96 minutes (warm ischemia time for the heart), 349 ± 101 minutes (cold ischemia time for the liver), and 36.25 ± 3.5 minutes (warm ischemia time for the liver). Three patients were discharged from the hospital after an uneventful clinical course. One patient died due to multi-organ failure during the intensive care unit stay on the 23rd postoperative day. CONCLUSION We suggest that combined, simultaneous heart-liver transplantation without veno-venous bypass is a feasible surgical technique.