Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Liver transplantation for hepatocellular carcinoma--is there a risk of recurrence caused by intraoperative blood salvage autotransfusion?

BACKGROUND/AIMS: The use of intraoperative blood salvage autotransfusion (IBSA) during surgical approaches may contribute to tumour cell dissemination. Therefore, IBSA should be avoided in cases of malignancy. However, the risks of IBSA might be acceptable in liver transplantation (LT) for selected small hepatocellular carcinoma (HCC). METHODS: In total, 136 recipients of LT with histologically proven HCC in the explanted liver were included in this analysis. With regard to tumour recurrence, 40 patients receiving IBSA despite HCC (IBSA group) were compared to 96 patients without IBSA (non-IBSA group). RESULTS: Milan criteria as assessed in the explanted liver were fulfilled in 24 of 40 IBSA patients and 58 of 96 non-IBSA patients (p = 0.85). Five of 40 patients in the IBSA group and 18 of 96 patients in the non-IBSA group experienced tumour recurrence (p = 0.29). In spite the theoretical risk of tumour cell dissemination, the recurrence rate was not increased in the IBSA group. CONCLUSION: Our results indicate that IBSA does not modify the risk of HCC recurrence. Therefore, in highly selected HCC patients undergoing LT, the use of IBSA appears to be justified.

Tacrolimus effects and side effects after liver transplantation: is there a difference between immediate and extended release?

BACKGROUND: Immunosuppressive therapy after orthotopic liver transplantation (OLT) requires a high degree of patient compliance to guarantee safety and avoid side effects. In 2007, prolonged-release tacrolimus was launched in Europe to improve compliance. In this prospective observational crossover single-center trial, we analyzed effects and side effects of prolonged-release tacrolimus in OLT patients. METHODS: LT patients at our center were included if they were older than l8 years of age, had had the procedure at least 6 months prior, and were outpatients currently on twice-daily tacrolimus. Patients were observed for 6 months before switching to once-daily tacrolimus. Patient history, clinical examination, and laboratory examinations were recorded on inclusion as well as after 3, 6, 9, 12, and 18 months. RESULTS: The rates of rejection, hypertension, hypercholesterolemia, and diabetes mellitus were compared during twice-daily and once-daily tacrolimus. Similarly, laboratory parameters were identical during both periods with the exception of glycated hemoglobin, which was significantly elevated under once-daily tacrolimus (P = .00l). CONCLUSION: Converting patients to extended-release tacrolimus with was safe in terms of rejection, hypertension, and hypercholesterolemia as well as renal and liver functions. Further investigations concerning pharmacokinetics and glucose metabolism will be needed to evaluate prolonged-release tacrolimus.

Comparative analysis of in situ versus ex situ perfusion on micro circulation in liver procurement--an experimental trial in a porcine model.

INTRODUCTION: The Achilles heel of liver transplantation remains the biliary system. The crucial step for liver preservation is effective rinsing and perfusion of the peribiliary plexus (PBP). Due to the physiology of the vascular tree, it seems almost impossible to achieve the necessary physiologic ranges of pressure and flow by the in situ perfusion technique. We investigated the role of additional ex situ perfusion via the hepatic artery in this animal model. MATERIALS AND METHODS: Fifteen German Landrace pigs underwent standardized multiorgan procurement. In situ perfusion and additional ex situ perfusion were performed consecutively. Meanwhile the external pressure applied to the perfusion system was increased stepwise. To visualize the effects on the liver parenchyma and PBP, we administered colored microparticles (MPs; 10 µm). Frozen sections of the explanted liver were studied histologically by quantitative evaluation of the MPs. RESULTS: Ex situ perfusion was able to build up significantly higher values of pressure (P < .001) and flow (P < .001) than in situ perfusion. Those of ex situ perfusion reached physiological levels under application of an external pressure of 200 mm Hg. Considering the liver parenchyma, significantly higher amounts of MPs originating from ex situ perfusion were evident (P < .001) and PBP (P < .001). CONCLUSION: MPs provide an appropriate tool to determine organ perfusion quantitatively in experimental models. Considering flow, pressure, and microcirculation, we consider that additional ex situ perfusion of the liver is more effective than in situ perfusion.

Ten years of simultaneous pancreas-kidney transplantation: a retrospective single-center analysis of prospectively obtained data.

INTRODUCTION: Simultaneous pancreas-kidney transplantation (SPK) is a standardized and life-saving procedure for a patient suffering from both insulin-dependent diabetes mellitus type 1 (IDDM 1) and end-stage diabetic nephropathy. To expand the donor pool and to determine the influence of the preprocurement pancreas suitability scoring system (P-PASS) on pancreas graft survival we retrospectively analyzed our data on SPK. PATIENTS AND METHODS: From 1999 to 2010 we performed 55 SPKs, using systemic-enteric drainage as surgical approach. The immunosuppressive therapy was induced with basiliximab; maintenance therapy was based on tacrolimus, mycophenolate mofetil, and steroids. Data were prospectively obtained, analyzed, and correlated to the P-PASS. RESULTS: The overall 10-year patient survival rate was 78% with a 10-year pancreas survival rate of 53%. Three patients needed retransplantation of SPK and 6 patients needed singular pancreas retransplantation. Seventeen patients showed acute rejection episodes and 14 patients suffered from cytomegalovirus (CMV) infections. We compared 43 patients receiving organs from an "ideal" donor (P-PASS <17) with 12 patients receiving grafts from "marginal" donors (P-PASS ≥17). Neither P-PASS nor donor age demonstrated significant influence on pancreas graft survival. However, the body mass index (BMI) of the donor showed a negative tendency (P = .059). CONCLUSION: The P-PASS showed no significant prediction of pancreas graft survival. In view of our data, expansion of the German donor pool is possible. A multicenter study of SPK using "marginal" pancreas grafts is mandatory to define a realistic "cut-off" value for P-PASS.

Organ recipients suffering from undifferentiated neuroendocrine small-cell carcinoma of donor origin: a case report.

BACKGROUND: Transmission of donor-derived cancer by organ transplantation is rare, but the risk has been increasing due to the aging donor pool. Undifferentiated neuroendocrine small-cell carcinoma is an aggressive tumor with the tendency to spread. Herein we have demonstrated different approaches to treat organ recipients with transmitted tumors. METHODS AND RESULTS: Grafts were retrieved from a decreased donor without any history of previous diseases. Autopsy was not performed after donation. The recipient of the liver graft presented with suspected nodules on routine abdominal ultrasound. After computed tomography (CT) scan, biopsy confirmed the diagnosis of a small-cell carcinoma. Donor origin was unequivocally identified by DNA fingerprinting. Despite chemotherapy the patient died 7 months after orthotopic liver transplantation (OLT). All involved transplantation centers were informed immediately following diagnosis. The male kidney recipient underwent detailed diagnostic work-up to exclude tumor transmission. One year after transplantation, liver metastases caused by a histologically proven small-cell carcinoma from the same donor were apparent. Chemotherapy was immediately started and the graft was removed. Despite continued treatment the tumor progressed and the patient died after repeated intestinal complications. The pathological examination of the explanted second kidney graft did not show any tumor infiltration. CONCLUSION: Therapeutic regimens in recipients suffering from donor-derived carcinoma differ depending on the transplanted organ. Graft removal of non-life-sustaining organs and discontinuation of immunosuppressive medication should result in complete tumor rejection. Minimizing the risk of tumor transmission, a CT scan might be advisable in donors of more advanced age.

[The solid pseudopapillary tumor (SPT)--a rare neoplasm of the pancreas]. / Der solid pseudopapilläre Pankreastumor (SPT)--eine seltene Raumforderung der Bauchspeicheldrüse.

BACKGROUND: In general, the rare SPT is a tumour of low malignancy predominantly affecting young women. The outcome after radical resection is favourable. In exceptional cases the tumour presents as solid pseudopapillary carcinoma (SPC) with typical malignant features and even metastases. Unresectable liver metastases can be treated with RFA, TACE or chemotherapy. METHODS: We retrospectively reviewed the surgical approach, immunohistochemistry and clinical outcome in five female patients (1998--2007). RESULTS: The mean age was 16 years (range: 13-47 years). For radical tumour removal a pancreato-duodenectomy (n = 3), a distal pancreatectomy (n = 1) and an enucleation (n = 1) were performed. We encountered a mean tumour diameter of 8 cm (range: 6-15 cm), an angioinvasion (3/5) and a lymphatic infiltration (1/5). After 30 to 101 months follow-up four patients were free of recurrence. Chemotherapy has resulted in a survival of over 98 months in a case of SPC with liver metastases. CONCLUSION: SPT is a tumour of low malignancy. Radical resection is recommended for long-term recurrence-free survival. Chemotherapy may prolong survival in SPC with unresectable metastases.

Flow and pressure during liver preservation under ex situ and in situ perfusion with University of Wisconsin solution and histidine-tryptophan-ketoglutarate solution.

Effective preservation of liver grafts is the first essential step for successful liver transplantation. Insufficient perfusion leads to ischemic-type biliary lesions after transplantation. Perfusion of the graft can be performed either in situ or ex situ, with gravity flow or pressure-controlled. Mainly University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions are used widespread in clinical liver transplantation. Due to a persistent lack of data, we performed this systematic investigation of in situ and ex situ perfusion of liver grafts with HTK (low-viscous) and UW (high-viscous) solutions at different pressure steps on the perfusion solution (gravity flow, 50, 100, 150, and 200 mm Hg). End points were perfusion flow and pressure in the hepatic artery. A pig model was used with n = 8 pigs randomized to each (HTK and UW) group. In situ perfusion was ineffective for both solutions at any pressure on the perfusate bag. Ex situ perfusion showed significantly improved flow and pressure in the hepatic artery and, therefore, was highly effective. No major differences between HTK and UW solutions could be detected. Therefore, an additional ex situ perfusion of the hepatic artery should be mandatory in every liver procurement.