Estimating the contribution of everolimus to immunosuppressive efficacy when combined with tacrolimus in liver transplantation: a model-based approach.

Determining the efficacy contribution of an investigational drug as part of a novel combination regimen that also includes a previously untested dose of a standard treatment is challenging, particularly when "placebo control" data (combination regimen minus the investigational drug) is not available for comparison. This situation was encountered in a phase III trial that tested the combination of the investigational drug everolimus with a dose of tacrolimus lower than used in standard liver transplantation therapy. The challenge was addressed by predicting the efficacy of the placebo control from the study data using a pharmacometric-based exposure-response analysis, selected to account for features specific to the transplant setting: systematic change in drug exposure over time and sparse pharmacokinetic sampling. The efficacy contribution of everolimus was then demonstrated by comparing this prediction to the efficacy of the combination regimen. This pharmacometrics-based approach may contribute to characterization of therapeutic agents in real-world settings.

Protein kinase C inhibitor sotrastaurin in de novo liver transplant recipients: a randomized phase II trial.

Efficacy and safety of protein kinase C inhibitor sotrastaurin (STN) with tacrolimus (TAC) was assessed in a 24-month, multicenter, phase II study in de novo liver transplant recipients. A total of 204 patients were randomized (1:1:1:1) to STN 200 mg b.i.d. + standard-exposure TAC (n = 50) or reduced-exposure TAC (n = 52), STN 300 mg b.i.d. + reduced-exposure TAC (n = 50), or mycophenolate mofetil (MMF) 1 g b.i.d. + standard-exposure TAC (control, n = 52); all with steroids. Owing to premature study termination, treatment comparisons were only conducted for Month 6. At Month 6, composite efficacy failure rates (treated biopsy-proven acute rejection episodes of Banff grade ≥1, graft loss, or death) were 25.0%, 16.5%, 20.9% and 15.9% for STN 200 mg + standard TAC, STN 200 mg + reduced TAC, STN 300 mg + reduced TAC and control groups, respectively. Median estimated glomerular filtration rates were 84.0, 83.3, 81.1 and 75.3 mL/min/1.73 m(2), respectively. Gastrointestinal events (constipation, diarrhea, and nausea), infection, and tachycardia were more frequent in STN groups. More patients in STN groups experienced serious adverse events compared with the control group (62.3-70.8% vs. 51.9%). STN-based regimens were associated with a higher efficacy failure rate and higher incidence of adverse events with no significant difference in renal function between the groups.

Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.

Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

Effect of mycophenolate mofetil monotherapy on T-cell functions and inosine monophosphate dehydrogenase activity in patients undergoing a kidney transplantation.

The aim of this study was to assess the effects of 1 g of mycophenolate mofetil (MMF) on T-cell function and inosine monophosphate dehydrogenase (IMPDH) activity among patients undergoing kidney transplantation. Five patients undergoing renal transplantation from a living donor were enrolled in this study. Compared to baseline (before MMF intake), CD25 and CD71 expression were significantly decreased during the first hour following MMF intake. T-cell proliferation and IMPDH activity also decreased dramatically. Thereafter, all biomarker levels increased over time. At 4 hours, CD25 and CD71 levels, as well as IMPDH activity, returned to almost baseline values, whereas T-cell proliferation remained below baseline. Intracytoplasmic IL-2 expression remained unchanged after MMF ingestions. In conclusion, administration of 1 g of MMF was associated with a transient decrease in CD25 expression in addition to a temporary dramatic decrease in both T-cell proliferation and IMPDH activity.

Diabetes mellitus is no independent risk factor for perioperative mortality following hepatic resection.

For patients with concomitant diabetes mellitus an increased perioperative mortality and morbidity in hepatic resections has repeatedly been described. Other studies, however, demonstrated equal outcome data in diabetic and non-diabetic patients. As patient populations were selected for underlying disease, conflicting results may reflect patient selection criteria rather than impact of diabetes mellitus on outcome measures. Therefore, a multivariate analysis in a largely unselected patient population has been performed to determine the independent prognostic value of diabetes mellitus in liver surgery. From a prospective database 633 adult patients undergoing hepatic resection without preceding major abdominal surgery or chemotherapy have been identified. Besides diabetes mellitus, demographic data, variables expressing the functional reserve of the liver, and parameters of surgical technique were analyzed for their impact on mortality and morbidity. 75 patients were diabetic (11.8 %) and 96 hepatic resections (15.2 %) were performed in cirrhotic patients. In the univariate analysis, concomitant diabetes was associated with an increased mortality compared to all non-diabetic patients (10.7 % vs. 5.3 %, p = 0.047). Diabetic patients, however, were also significantly older and presented a higher prevalence of liver cirrhosis. Multivariate modeling finally identified only age, albumin, cirrhosis, extent of surgery, and era of surgery as independent variables with an impact on perioperative mortality. Overall, complications were detected in diabetic and non-diabetic patients with a comparable frequency (44 % vs. 36 %, p = 0.179). Also, the length of in-hospital stay did not significantly differ between both groups (18.5 +/- 1.7 vs. 17.7 +/- 1.0 days, p = 0.119). Rates of postoperative renal impairment, prolonged ascites or pneumonia, however, were higher in diabetics than in other patients. Following established cardiopulmonary and surgical selection criteria, diabetes mellitus is not an independent risk-factor for perioperative mortality in hepatic resections. Although the overall postoperative morbidity was not different in diabetic and non-diabetic patients, a specific pattern of complications has been identified, mandating particular attention in the postoperative course of diabetic patients.

Liver transplantation as ultimate tool to treat portal hypertension.

Portal hypertension is a complication of liver cirrhosis that may itself cause complications such as variceal bleeding, ascites and hepatorenal syndrome. There are several options for symptomatic treatment including drug therapy, endoscopy, transjugular intrahepatic portosystemic shunt (TIPS), and various surgical procedures, notably liver transplantation, the only causal treatment. The indication for liver transplantation has to be defined carefully. Progression of the primary disease, evaluation of comorbidity and overall prognosis have to be considered. Conservative symptomatic treatment is used for bridging purposes until liver transplantation can be provided to cure portal hypertension and the underlying primary disease. Careful timing of the transplantation is necessary as well as reorganization of the waiting lists by introducing new priority systems as the Model for End-Stage Liver Disease (MELD) in order to reduce mortality. Furthermore, living donor liver transplantation and split liver transplantation are methods to enlarge the donor pool, and thus accessibility of transplantation to a greater number of patients. This review evaluates the indication of liver transplantation in the treatment of portal hypertension.

Anti-TNF-alpha therapy for acute rejection in intestinal transplantation.

INTRODUCTION: We present our experience with infliximab rescue therapy for steroid- and OKT3-resistant rejection after intestinal transplantation (ITx). METHODS: Twelve ITx and one multivisceral transplant recipients were immunosuppressed with tacrolimus, rapamycin, daclizumab, steroids (n = 10) or tacrolimus, campath, and steroids (n = 3). RESULTS: In two patients, severe acute rejection did not resolve despite steroid bolus therapy plus 5 to 10 days of OKT3 treatment. Signs of moderate rejection persisted in the distal portions of the grafts. Treatment with infliximab, a chimeric anti-TNF-alpha antibody (four infusions of 3 mg/kg body weight), induced a complete remission of histological and clinical signs of rejection. Two further patients with steroid-resistant rejection received two courses of infliximab (3 mg/kg body weight) as antirejection therapy. All rejection episodes resolved completely. CONCLUSIONS: Infliximab effectively treats steroid and OKT3 resistant acute rejection episodes of intestinal transplantations.

Withdrawal of steroids: a randomized prospective study of prednisone and tacrolimus versus mycophenolate mofetil and tacrolimus in liver transplant recipients with autoimmune hepatitis.

The aim of this study was to evaluate the success of steroid (PRED) withdrawal due to replacement by mycophenolate mofetil (MMF) in orthotopic liver transplant (OLT) recipients with autoimmune hepatitis (AIH). Thirty patients with AIH > 12 months after OLT randomized to receive either PRED and tacrolimus (TAC) or MMF and TAC were followed for 24 months. Withdrawal of steroids showed no difference regarding graft and patient survival. Also we demonstrated significantly lower glucose levels with lower HbA1c and a reduced need for insulin as well as a significantly lower serum cholesterol in the MMF group. Patients without steroids showed a lower incidence of osteopenia. Maintenance therapy in OLT patients with AIH may be performed safely using MMF instead of prednisone.

[Clinical results of intestinal and multivisceral transplantation at the Charité, Berlin. A case series]. / Klinische Ergebnisse der Dünndarm- und Multiviszeraltransplantation an der Berliner Charité - Eine Fallserie -

BACKGROUND AND OBJECTIVE: Intestinal transplantation (ITx) is the only causal therapy of short bowel syndrome (SBS). Long-term survival after ITx has been improved significantly during the last years. The experience with ITx at the Charite, Campus Virchow Klinikum, are described and discussed. PATIENTS AND METHODS: Twelve isolated ITx and one multivisceral transplantation (including stomach, pancreatodudenal complex, small intestine, liver, ascending colon, right kidney, and adrenal gland) were performed. Mean recipient age was 37.7+/-10.6 yrs (median: 35 yrs; range: 27 - 58 yrs; M:F = 8:5). All patients had irreversible SBS (0 - 30 cm residual bowel length; mean: 11.8+/-11.4 cm; median: 13 cm). RESULTS: 6-months and 1-year patient and graft survival were 85 % (11/13) and 77 % (10/13), respectively. Reasons for graft loss and patient death were necrotizing enterocolitis, severe, muromonab-resistent, acute rejection, and graft ischemia due to complex coagulopathy. All other patients had good long-term outcome. They received enteral nutrition at six hours after operation and were persistently off total parenteral nutrition (TPN) by week two after ITx. CONCLUSION: ITx as established in our centre, with 1-year-patient and graft survival rates of 77 %, reflects current international standard. ITx is complementary to conservative and other operative methods of treating SBS. Referral and indication criteria need wider dissemination to prevent life-threatening complications of TPN.

Primary immunosuppression with tacrolimus after liver transplantation: 12-years follow-up.

The early safety and efficacy of tacrolimus after liver transplantation has been shown in two multicenter trials. Herein, we report our single-center long-term follow-up of a randomized controlled trial. As part of a European multicenter trial, 121 patients entered the study at our institution and were randomly assigned to receive either tacrolimus and steroids (n=61) or a quadruple protocol (n=60) using ciclosporin A, steroids, azathioprine, and antithymocyte globulin (ATG). Twelve-year figures of patient survival were 74% in the tacrolimus group and 66% in the cyclosporine-based group. Graft survival after 12 years was 69% in the tacrolimus group compared to 56% in the cyclosporin-based group (not significant, p=0.15). The total rate of graft loss and retransplantation decreased significantly in the tacrolimus arm (p<0.05). De novo malignancies increased significantly in the ciclosporin-based group and dominated as single cause of death beyond 5 years posttransplant. The use of tacrolimus after liver transplantation resulted in a decreased rate of graft loss over the long-term. An increased number of de novo malignancies in the ciclosporin-based group may be attributable to the use of ATG as induction therapy.

[Consensus-recommendations for sirolimus in liver transplantation]. / Konsensusempfehlung zum Einsatz von Sirolimus in der Lebertransplantation.

Sirolimus is an m-TOR inhibitor without renal side effects and potentially protects against the development of malignancy. Due to a higher incidence of complications in two trials and an official warning in the drug information, the use of Sirolimus in liver transplantation is limited. The participants of this consensus meeting had to analyse and evaluate the literature with respect to the potential role of Sirolimus in liver transplantation. This consensus statement follows the scheme normally employed for the presentation of guidelines including the grading of evidence (1a-5) and the extent of recommendation (A-C). Moreover, the consensus included the experience of the authors with respect to the handling of Sirolimus after liver transplantation.

CMV, EBV, HHV6, and HHV7 infections after intestinal transplantation without specific antiviral prophylaxis.

PURPOSE: To analyze the incidence and relevance of viral infections after intestinal transplantation (ITx) without specific antiviral prophylaxis. METHODS: Eleven patients (median age 34 years; range 26 to 58 years) who underwent ITx received no CMV/EBV prophylaxis but rather preemptive treatment. Viral monitoring for CMV or EBV polymerase chain reactions (PCR) in peripheral blood and graft biopsies, for HHV6-, and HHV7-PCR; for adeno-/rotavirus antigen and serology was performed based on clinical indications. RESULTS: Median time under risk was 19 months (range 2 to 39). CMV: The donor (D)-to-recipient (R) status prior to ITx was: D+/R+ (4); D+/R- (3); D-/R- (2); D-/R+ (2). Eight patients showed no positive CMV-PCR. Three episodes of tissue invasive CMV disease occurred in two patients. There were two asymptomatic CMV infections but no episodes of CMV disease. None of the R(-) recipients developed CMV infection or enteritis irrespective of the donor status. EBV: Four patients experienced six episodes of transient significant EBV-viremia. Two patients developed EBV enteritis concurrently with CMV enteritis during acute rejection. There were no PTLD. CMV and EBV enteritis only occurred during or immediately after steroid and OKT3 therapy. None of the patients developed significant HHV6 and HHV7 infection or viremia. There was one episode of adeno- and rotavirus enteritis. CONCLUSIONS: Despite witholding specific antiviral prophylaxis against CMV and EBV, we observed no such infections in 60% to 80% of patients. Donor-recipient matching regarding CMV was not predictive for the occurrence of CMV-related complications. HHV6 and HHV7 have not contributed to posttransplant morbidity.

A dermoid cyst in the greater omentum as a rare epigastric tumor.

A 36-year-old female presented with unspecific epigastric discomfort, without weight loss, night sweat or fever. Ultrasound and computed tomography showed a solid tumor with a diameter of 9 cm in the left upper abdomen, without any connection to the stomach, the pancreas or spleen. Laparoscopy showed a connection to parts of the greater omentum. Two days after laparoscopic resection the patient was discharged from hospital. Histology revealed the rare diagnosis of a dermoid cyst. A possible malignant degeneration of the tumor has to be considered, and therefore the tumor should be resected. Since the operation the patient is asymptomatic and without tumor recurrence.

Right hepatic lobectomy for recurrent cholangitis after combined bile duct and right hepatic artery injury during laparoscopic cholecystectomy: a report of two cases.

BACKGROUND: Bile duct injuries in combination with major vascular injuries may cause serious morbidity and may even require liver resection in some cases. We present two case studies of patients requiring right hepatic lobectomy after bile duct and right hepatic artery injury during laparoscopic cholecystectomy. PATIENTS: Two patients sustained combined major bile duct and hepatic artery injury during laparoscopic cholecystectomy. Surgical management consisted of immediate hepaticojejunostomy with reconstruction of the artery in one patient and hepaticojejunostomy alone in the other patient. In both cases the initial postoperative course was uncomplicated. RESULTS: After 4 and 6 months both patients suffered recurrent cholangitis due to anastomotic stricture. Both developed secondary biliary cirrhosis and required right hepatic lobectomy with left hepaticojejunostomy. The patients remain well 31 months and 4.5 years after surgery. CONCLUSIONS: The outcome of bile duct reconstruction may be worse in the presence of combined biliary and vascular injuries than in patients with an intact blood supply of the bile ducts. We recommend arterial reconstruction when possible in early recognized injuries to prevent late strictures. Short-term follow-up is most important for early recognition of postoperative strictures and to avoid further complications such as secondary biliary cirrhosis.