Andreas Pascher

Brain Death Activates Donor Organs and Is Associated with a Worse I/R Injury After Liver Transplantation

The majority of transplants are derived from donors who suffered from brain injury. There is evidence that brain death causes inflammatory changes in the donor. To define the impact of brain death, we evaluated the gene expression of cytokines in human brain dead and ideal living donors and compared these data to organ function following transplantation.

Bile duct complications after liver transplantation

Complications involving the biliary tract after orthotopic liver transplantation (OLT) have been a common problem since the early beginning of this technique. Biliary complications have been reported to occur at a relatively constant rate of approximately 10–15% of all deceased donor full size OLTs. There is a wide range of potential biliary complications which can occur after OLT. Their incidence varies according to the type of graft, type of donor, and the type of biliary anastomosis performed. The spectrum of biliary complications has changed over the past decade because of the establishment of split liver, reduced‐size, and living donor liver transplantation. Apart from technical developments, novel diagnostic methods have been introduced and evaluated in OLT, the most prominent being magnetic resonance imaging (MRI). Treatment modalities have also changed over the past years towards a primarily nonoperative, endoscopy‐based strategy, leaving the surgical intervention for lesions which otherwise are not curable. The management of biliary complications after OLT requires a multidisciplinary approach. Conservative, interventional, and endoscopic treatment options have to be weighed up against surgical re‐intervention. In the following the spectrum of specific bile duct complications after OLT and their treatment options will be reviewed.

Methylprednisolone therapy in deceased donors reduces inflammation in the donor liver and improves outcome after liver transplantation: a prospective randomized controlled trial.

Objective:To investigate potential beneficial effects of donor treatment with methylprednisolone on organ function and outcome after liver transplantation. Summary Background Data:It is proven experimentally and clinically that the brain death of the donor leads to increased levels of inflammatory cytokines and is followed by an intensified ischemia/reperfusion injury after organ transplantation. In experiments, donor treatment with steroids successfully diminished these effects and led to better organ function after transplantation. Methods:To investigate whether methylprednisolone treatment of the deceased donor is applicable to attenuate brain death-associated damage in clinical liver transplantation we conducted a prospective randomized treatment-versus-control study in 100 deceased donors. Donor treatment (n = 50) consisted of 250 mg methylprednisolone at the time of consent for organ donation and a subsequent infusion of 100 mg/h until recovery of organs. A liver biopsy was taken immediately after laparotomy and blood samples were obtained after brain death diagnosis and before organ recovery. Cytokines were assessed by real-time reverse transcriptase-polymerase chain reaction. Soluble serum cytokines were measured by cytometric bead array system. Results:After methylprednisolone treatment, steroid plasma levels were significantly higher (P < 0.05), and a significant decrease in soluble interleukins, monocyte chemotactic protein-1, interleukin-2, interleukin-6, tumor necrosis factor-&agr;, and inducible protein-10 was observed. Methylprednisolone treatment resulted in a significant downregulation of intercellular adhesion molecule-1, tumor necrosis factor-&agr;, major histocompatibility complex class II, Fas-ligand, inducible protein-10, and CD68 intragraft mRNA expression. Significantly ameliorated ischemia/reperfusion injury in the posttransplant course was accompanied by a decreased incidence of acute rejection. Conclusions:Our present study verifies the protective effect of methylprednisolone treatment in deceased donor liver transplantation, suggesting it as a potential therapeutical approach.

ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms : colorectal neuroendocrine neoplasms

ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms : colorectal neuroendocrine neoplasms

Incidence of and risk factors for ischemic-type biliary lesions following orthotopic liver transplantation.

Ischemic‐type biliary lesions (ITBL) account for a major part of patients’ morbidity and mortality after orthotopic liver transplantation (OLT). The exact origin of this type of biliary complication remains unknown. This study retrospectively evaluated 1843 patients. Patients with primary sclerosing cholangitis were excluded from this study. The diagnosis of ITBL was established only when all other causes of destruction of the biliary tree were ruled out. Donor age (P = 0.028) and cold ischemic time (CIT) (P = 0.002) were found to be significant risk factors for the development of ITBL. Organs that were perfused with University of Wisconsin (UW) solution developed ITBL significantly more often than Histidine–Tryptophan–Ketoglutarate (HTK)‐perfused organs (P = 0.036). The same applied to organs harvested externally and shipped to our center versus those that were procured locally by our harvest teams (P < 0.001). Pressure perfusion via the hepatic artery significantly reduced the risk of ITBL (P = 0.001). The only recipient factor that showed a significant influence was Child‐Pugh score status C (P = 0.021). Immunologic factors had no significant impact on ITBL. The clinical consequences of this study for our institution have been the strict limitation of CIT to <10 h and the exclusive use of HTK solution. We further advocate that all organ procurement teams perform pressure perfusion on harvested organs.

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.

Age and immune response in organ transplantation.

The immune system undergoes a complex and continuous remodeling as the result of aging. These changes have a major impact on allorecognition and alloresponse. In addition, immunosuppression in the elderly is challenging as a consequence of an increased incidence of associated comorbidities and altered pharmacokinetics. Both advanced donor and recipient age should be considered independent risk factors for poor patient and graft survival rates, albeit acting in a synergistic manner. Consequently, modifications of the immune system because of aging may request an age-adapted allocation and immunosuppression in parallel with close patient monitoring. Interventions to selectively target changes associated with the senescence process seem to be promising therapeutic strategies to improve transplantation outcome. Here, we are going to review the immunologic changes associated with the aging process relevant for transplantation and their impact on immunosuppressive protocols, organ allocation policies, and transplantation outcome.

Impact of Multiphase 68Ga-DOTATOC-PET/CT on therapy management in patients with neuroendocrine tumors.

Aim: Retrospective evaluation of the impact of integrated positron emission tomography/computed tomography (PET/CT) using 68Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide (68Ga-DOTATOC) on the therapeutic management of patients with neuroendocrine tumors (NET). Methods: The 68Ga-DOTATOC-PET/CT data of 66 patients (31 male, 35 female; age: 29–79, mean age: 56 years) with known or suspected NET were included. Imaging data (PET and triple-phase contrast-enhanced CT) were evaluated in consensus by two readers for the visualization of NET manifestations. Combined PET/CT, clinical and imaging follow-up as well as histopathology (if available) served as the reference standard. In order to assess the impact of the respective submodalities on the therapeutic strategy chosen, the results were compared to the treatment decision made by the interdisciplinary NET tumor board of our institution. Results: Two of the initial 66 patients included did not suffer from NET according to further immunohistopathological examination. In 50 of the remaining 64 (78%) NET patients, a total of 181 NET manifestations were detected by PET/CT. 59/181 (32.6%) were detected by one submodality only (CT 17.1%, PET 15.5%, p for comparison of both = 0.459). Combined PET/CT reading had an impact on the therapeutic management in 24 of 64 (38%) NET patients: primary resection (n = 5), curative lymph node resection (n = 1), initiation/switch of chemotherapy (CTx) due to progressive disease (n = 10), no surgery due to systemic disease (n = 2), radiopeptide receptor therapy instead of CTx (n = 1), additional bisphosphonate therapy (n = 4), and hepatic brachytherapy (n = 1). In 12 of 24 (50%) of these patients, relevant findings were detected by a single submodality only: CT (n = 5), PET (n = 7); p for comparison = 0.774). Conclusion:68Ga-DOTATOC-PET/CT influences therapeutic management in about one third of patients examined. CT and PET are comparably sensitive, deliver complementary information and equally contribute to therapeutic decision-making. Thus, despite the merits of the PET modality, the CT component must not be neglected and an optimized multiphase CT protocol is recommended.

Liver Transplantation for Neuroendocrine Tumors in Europe—Results and Trends in Patient Selection A 213-Case European Liver Transplant Registry Study

Objective:The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. Background:LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. Methods:This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1–149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. Results:Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. Conclusions:LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

Renal function, efficacy, and safety of sirolimus and mycophenolate mofetil after short-term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: one-year analysis of a randomized multicenter trial.

Background. De novo sirolimus in calcineurin inhibitor-free regimens, although potentially useful to improve early renal function, are complicated by various drug-related side effects. Methods. We report a prospective open-label, multicenter, randomized trial to evaluate early conversion from a CsA-based to a sirolimus (SRL)-based regimen 10 to 24 days after renal transplantation. Of the 196 patients, 141 patients with a low-to-moderate immunological risk were eligible to be converted to SRL or to continue CsA. All patients received antithymocyte globulin-F single-bolus induction, mycophenolate mofetil, and steroids. Results. The primary endpoint, renal function determined by S-creatinine and estimated glomerular filtration rate calculated by Nankivell formula at 12 months was significantly better in the SRL group (1.51±0.59 vs. 1.87±0.98 mg/dL or 64.5±25.2 vs. 53.4±18.0 mL/min/1.73 m2). Patient survival, graft survival, and incidence of biopsy-proven acute rejection after conversion were not statistically different. Drug discontinuations were significantly higher in the SRL group (36.2% vs. 19.7%). Significantly, more patients in the SRL group reported acne, aphtous, and temporary hyperlipidemia, whereas cytomegalovirus viremia was significantly decreased (7.3% vs. 28.2%). Conclusions. Early conversion to a calcineurin inhibitor-free regimen with SRL in combination with mycophenolate mofetil may be a useful strategy to improve renal function. The identification of appropriate candidates and safe management of SRL-related adverse events will be a key to avoid the high rate of dropouts, which currently limit the broad applicability of this protocol.