Björn Nashan

Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation

PURPOSE Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics. RESULTS Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (< or = 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. CONCLUSION In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.

Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors.

BACKGROUND Patients suffering from hepatic metastases of neuroendocrine tumors (NET) are potential candidates for orthotopic liver transplantation. Because recurrence rates are high and outcome is variable, prognostic indicators are required. The aim of our study was to identify predictors of long-term survival with a focus on the impact of tumor biology. METHODS We retrospectively analyzed 19 patients who received an orthotopic liver graft for metastatic NET at the Medizinische Hochschule Hannover. Expression of Ki67, E-cadherin, and p53 was studied immunohistochemically in metastases of neuroendocrine tumors of the explanted livers. RESULTS Patients were followed up to 146 months after liver transplantation. Six patients died during follow-up. The resulting 1-, 5-, and 10-year survival rates are 89%, 80%, and 50%, respectively. All deaths during long-term follow-up were tumor-associated. Recurrence was diagnosed in 12 patients between 2 weeks and 48 months after liver transplantation. Three patients are without tumor recurrence more than 8 years after liver transplantation. Survival in the 5 patients with low Ki67 and regular E-cadherin staining was significantly better than in the 12 patients with high Ki67 or aberrant E-cadherin expression (7-year survival 100% vs. 0%, respectively, log rank P=0.007). p53 expression did not significantly improve prognostic accuracy. CONCLUSIONS We conclude that analysis of Ki67 and E-cadherin expression may improve the identification of patients with a favorable prognosis after liver transplantation for metastatic neuroendocrine tumors.

Five-Year Safety and Efficacy of Belatacept in Renal Transplantation

Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept. Seventy-eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving CsA completed the long-term extension period. GFR remained stable in patients who were receiving belatacept for 5 years, and the incidences of death/graft loss or acute rejection were low. The frequencies of serious infections were 16% for belatacept and 27% for CsA, and neoplasms occurred in 12% of each group. No patients who were treated with belatacept and one patient who was treated with CsA developed posttransplantation lymphoproliferative disorder during the follow-up period. Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic analyses showed consistent exposure to belatacept over time. CD86 receptor saturation was higher in patients who were receiving belatacept every 4 weeks (74%) compared with every 8 weeks (56%). In conclusion, this study demonstrated high patient persistence with intravenous belatacept, stable renal function, predictable pharmacokinetics, and good safety with belatacept over 5 years.

Arterial chemoembolization before liver transplantation in patients with hepatocellular carcinoma: marked tumor necrosis, but no survival benefit?

BACKGROUND/AIMS Hepatic artery chemoembolization was introduced in the treatment of patients with unresectable hepatocellular carcinoma waiting for liver transplantation. The rationale for this preoperative treatment was to control tumor growth during the waiting period and to improve long-term survival. This study aimed to investigate whether preoperative chemoembolization not only induces marked tumor necrosis but also has a survival benefit. METHODS In this study 21 patients with hepatocellular carcinoma who underwent pretransplant chemoembolization (group I) were compared with 21 historical control patients (group II) without preoperative chemoembolization in a case-control study. The number of pretransplant chemoembolizations in each patient in group I varied between 1 and 5 with a mean of 2.44+/-1.15. In addition, six patients of this group received preoperative systemic chemotherapy. RESULTS Overall, there were no differences in survival between the groups with and without pretransplant chemoembolization at 1 year (60.8% vs 61.5%) and at 3 years (48.4% vs 53.9%). In group I, three patients developed unexplained severe pneumonia, leading to death very early after liver transplantation. Marked tumor necrosis (>50%) was found in 14 cases in group I. In 6 out of these 14 patients, total tumor necrosis was observed. CONCLUSION Although preoperative chemoembolization or chemotherapy induced marked tumor necrosis, these patients showed no benefit in survival compared to historical controls, and appeared to be at higher risk of developing immediate postoperative infective complications.

Clinical validation studies of neoral C2 monitoring: A review

Although cyclosporine A (CsA) has been the mainstay of immunosuppressive therapy and the subject of intense investigation for more than 20 years, it is only recently that the full potential of the drug has come to be understood. This is primarily owing to two advances: first, the development of an improved microemulsified formulation, Neoral, to improve drug delivery; and second, substantial improvements in the monitoring of CsA, which is the focus of this article. It has been clear for many years that CsA, as a drug with a low therapeutic index, requires individualized monitoring of blood concentration. In the past, standard trough-level (C0) monitoring has been used. Although this method is currently the routine strategy, it became evident after the development of Neoral that the improved bioavailability of the new formulation was not reflected by a change in the trough concentration (1, 2). Subsequent work also showed convincingly that whereas CsA exposure determines the extent of immunosuppression and toxicity, drug exposure did not correlate closely with C0 (3, 4). Interpatient variability in CsA exposure is greatest during the absorption phase (up to 4 hours after a dose of Neoral), and adequate exposure during this absorption phase is critical for CsA efficacy. Neoral C2 monitoring, whereby absorption of CsA is measured by a single sample taken 2 hours postdose, is the result of an extensive program of research into the optimal use of Neoral (5–8). This research has focused on delivery of individualized dosing to achieve minimal rejection with minimal toxicity. The well-documented pharmacokinetic rationale for using C2 to monitor patients receiving Neoral (3, 4, 10–13) has now been borne out by clinical trials that demonstrate a reduced incidence and severity of rejection in de novo patients (14–17) and improvements in safety profile, particularly renal function, in both renal and hepatic maintenance patients (18, 19). This article is a critical review of the most recent clinical evidence for the use of Neoral C2 monitoring as a management tool in different transplant populations. THE RATIONALE FOR NEORAL C2 MONITORING

Long-term outcome of liver transplantation for autoimmune hepatitis

Abstract:  Background:  Liver transplantation is the final therapeutic option for about 10% of patients with autoimmune hepatitis (AIH) who do not respond to medical therapy. The aim of this study was to evaluate the long‐term outcome in serologically defined subgroups of AIH after transplantation.

Persistence Of Donor Lymphocytes In Liver Allograft Recipients

Occasional cases of graft-versus-host disease after liver transplantation indicate a transfer of donor lymphocytes by human liver grafts. However, little is known about the usual fate and potential function of passenger lymphocytes in clinical liver transplantation. In this study, we have analyzed liver graft recipients for the presence of donor lymphocytes in the early course after transplantation. The presence of such cells in blood, the graft, and, occasionally, the skin was studied by the use of mAb to polymorphic HLA class I determinants and double-staining techniques in flow cytometry and immunocytology. The findings were compared with the clinical courses and with the results of routine graft biopsies. Within the first week after transplantation, in all 16 patients, between 1% and 24% donor lymphocytes (T, NK, and B cells) were detectable in blood, and in 14 of 22 patients (64%), between 2% and 23% donor T cells were found in the graft. After more than 2 weeks, donor cells were still present in blood in 2 of 14 patients at very low numbers. The presence of donor lymphocytes in the graft was associated with intragraft immune activation in 5 of 15 patients, but no clinical rejection occurred in these cases; mild graft-versus-host disease was observed in one patient. These findings demonstrate that donor lymphocytes regularly persist in liver-grafted patients for some time; this transient mixed lymphoid chimerism is only rarely associated with clinical graft-versus-host disease and some evidence even suggests that these donor-derived lymphocytes may exert beneficial immunomodulatory properties.

Results of 3-year phase III clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation

BACKGROUND Daclizumab (Zenapax, Roche Pharmaceuticals), a humanized monoclonal antibody directed against the alpha chain of the interleukin 2 receptor, has been shown to reduce the incidence of acute rejection at 6 months after renal transplantation in two phase III clinical trials. This report presents the combined 1- and 3-year outcomes of kidney transplant recipients who participated in these two phase III clinical trials. METHODS Data from two multicenter, randomized, placebo-controlled trials were evaluated with regard to graft survival, patient survival, incidence of malignancies (including lymphoma), renal function (serum creatinine and glomerular filtration rate [GFR]), and current maintenance immunosuppressive regimen. In addition, the impact of acute rejection and acute rejection requiring treatment with antilymphocyte therapy upon 3-year graft survival was evaluated. Daclizumab was compared to placebo on a background of cyclosporine (CsA), azathioprine, and corticosteroids (triple therapy, TT) or CsA and corticosteroids (double therapy, DT). RESULTS Treatment with daclizumab in the pooled analysis demonstrated a significant reduction in the incidence of biopsy-proven acute rejection episodes at 12 months posttransplant (43% vs. 28%, P<0.001). The 3-year graft survival was not significantly different between placebo and daclizumab-treated patients in the TT trial (83% vs. 84%) or in the DT trial (78% vs. 82%). Pooled patient survival was excellent in both placebo- (91%) and daclizumab- (93%) treated patients. The incidence of malignancies or posttransplant lymphoproliferative disorder (PTLD) in placebo- versus daclizumab-treated groups was comparable in both clinical trials. Renal function was similar between placebo- and daclizumab-treated groups in both the TT and DT trials. The occurrence of delayed graft function, acute rejection requiring antilymphocyte therapy at 6 months, and acute rejection at 12 months posttransplant were associated with decreased graft survival rates at 3 years posttransplant. CONCLUSIONS The beneficial effect of daclizumab prophylaxis upon the incidence of acute rejection after renal transplant with TT or with DT was not associated with adverse clinical sequelae, including the development of PTLD, at 3 years posttransplant. There was no beneficial effect of daclizumab on graft survival at 3 years, but the trial was inadequately powered to detect this. Both studies showed excellent graft and patient survival at 3 years.

Improvement of acute and chronic renal dysfunction in liver transplant patients after substitution of calcineurin inhibitors by mycophenolate mofetil.

BACKGROUND Renal dysfunction caused by treatment with the calcineurin inhibitors (CNI) is a major problem in the long-term course after liver transplantation. PATIENTS In 22 liver graft recipients with renal dysfunction and stable graft function between 3 weeks and 12 years after transplantation, CNI were substituted by MMF at a final dose of 1.5-3 g/day between October 1996 and October 1998. METHODS In a prospective non-randomized study, the development of renal function, the side effects of MMF medication, and the stability of liver function were analyzed for a mean follow-up of 15 months. Results. (1) MMF was withdrawn in four patients for major side effects between 1 and 7 months after study entry; eight patients had minor side effects. (2) Six months after study entry, renal function had improved in 17 of the 22 study patients; mean serum creatinine +/-SD (micromol/L) was 201+/-77 at entry and 153+/-65 after 3 months (P<0.001). (3) Improvement occurred in 11 of 15 patients with creatinine elevation > or =12 months and in 6 of 6 patients with creatinine elevation < or =6 months. (4) One patient developed transient liver dysfunction and a second required retransplantation for progressive cholestasis but without signs of rejection. CONCLUSIONS In patients who undergo liver transplantation, substitution of CNI by MMF leads to improvement of acute as well as chronic renal dysfunction in most cases. Side effects of MMF may be limiting in some patients, and the immunological consequences remain to be studied.

Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature.

&NA; Surgical complications, including events such as lymphocele and urological complications that affect wound healing, are reported with an incidence of 15% to 32% after kidney transplantation. The experience of the surgeon and comorbidities play an important role in determining the risk of such complications occurring. Since the introduction of the inosine 5′-monophosphate dehydrogenase inhibitors (mycophenolate mofetil) to the immunosuppressive armamentarium, replacing the antimetabolite prodrug azathioprine, reports have associated certain forms of wound healing complications (wound dehiscence, impaired healing, lymphocele, and incisional hernia) with the use of these agents. When mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) became available, these findings were observed increasingly, particularly in direct comparisons with inosine 5′-monophosphate dehydrogenase inhibitors. The purpose of this article was to review the reported incidence of wound healing complications from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo kidney transplantation and the information available from the U.S. Food and Drug Administration database. The clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors’ discretion. This review summarizes these studies to consider whether modern mTOR inhibitor–based immunosuppressive regimens exert and affect wound healing after kidney transplantation.