Liver transplantation as a therapeutic option for hepatocellular carcinoma

Better outcomes of the patients receiving liver transplantation for viral hepatitis and hepatocellular carcinoma (HCC) are achieved by improved patient selection and perioperative treatment with antiviral agents including lamivudine, ribavirin and interferon. Patient selection is accomplished by high-quality imaging as well as exclusion of patients with large tumors, obvious extrahepatic disease or macroscopic vascular invasion. Using such criteria, a 5-year survival of 92% has been reached in the Queensland Liver Transplant Service on a small number of highly selected patients with HCC. The treatment algorithm of Makuuchi has guided us in recommending resection, estimating to what extent the liver resection can be performed safely, and timing liver transplantation when it is the only option. Adult-to-adult living-donor liver transplantation is being performed safely in many centers worldwide. The transplantation of liver from living donors to HCC patients, when standard criteria for the likelihood of good outcomes are fulfilled, will increase in Japan in the near future. Copyright (C) 2002 S. Karger AG, Basel.

A Pilot Randomized Trial Comparing CD-34Selected Versus Unmanipulated Hemopoietic Stem Cell Transplantation for Severe, Refractory Rheumatoid Arthritis

Objective. Evidence from animal studies, case reports, and phase I studies suggests that hemopoietic stem cell transplantation (HSCT) can be effective in the treatment of rheumatoid arthritis (RA). It is unclear, however, if depletion of T cells in the stem cell product infused after high-dose chemotherapy is beneficial in prolonging responses by reducing the number of infused autoreactive T cells. This pilot multicenter, randomized trial was undertaken to obtain feasibility data on whether CD34 selection (as a form of T cell depletion) of an autologous stem cell graft is of benefit in the HSCT procedure in patients with severe, refractory RA. Methods. Thirty-three patients with severe RA who had been treated unsuccessfully with methotrexate and at least 1 other disease-modifying agent were enrolled in the trial. The patients received high-dose immunosuppressive treatment with 200 mg/kg cyclophosphamide followed by an infusion of autologous stem cells that were CD34 selected or unmanipulated. Safety, efficacy (based on American College of Rheumatology [ACR] response criteria), and time to recurrence of disease were assessed on a monthly basis for up to 12 months. Results. All patients were living at the end of the study, with no major unexpected toxicities. Overall, on an intent-to-treat basis, ACR 20% response (ACR20) was achieved in 70% of the patients. An ACR70 response was attained in 27.7% of the 18 patients who had received CD34-selected cells and 53.3% of the 15 who had received unmanipulated cells (P = 0.20). The median time to disease recurrence was 147 days in the CD34-selected cell group and 201 days in the unmanipulated cell group (P = 0.28). There was no relationship between CD4 lymphopenia and response, but 72% of rheumatoid factor (RF)-positive patients had an increase in RF titer prior to recurrence of disease. Conclusion. HSCT can be performed safely in patients with RA, and initial results indicate significant responses in patients with severe, treatment-resistant disease. Similar outcomes were observed in patients undergoing HSCT with unmanipulated cells and those receiving CD34-selected cells. Larger studies are needed to confirm these findings.

Total energy expenditure and body composition changes following peripheral blood stem cell transplantation and participation in an exercise programme

The purpose of this investigation was to assess changes in total energy expenditure (TEE), body weight (BW) and body composition following a peripheral blood stem cell transplant and following participation in a 3-month duration, moderate-intensity, mixed-type exercise programme. The doubly labelled and singly labelled water methods were used to measure TEE and total body water (TBW). Body weight and TBW were then used to calculate percentage body fat (%BF), and fat and fat-free mass (FFM). TEE and body composition measures were assessed pretransplant (PI), immediately post-transplant (PII) and 3 months post-PII (PIII). Following PII, 12 patients were divided equally into a control group (CG) or exercise intervention group (EG). While there was no change in TEE between pre- and post-transplant, BW (P

The influence of viral genotypes and rejection episodes on the recurrence of hepatitis C after liver transplantation

Purpose. The aim of this study was to report the influence of hepatitis C virus (HCV) genotype and rejection episodes on the outcome of orthotopic liver transplantation (OLT), hepatitis recurrence, and progression to graft cirrhosis after OLT. Methods. Fifty-three patients who all had undergone OLT for end-stage liver cirrhosis were selected for this study. Hepatitis C genotype was determined. Recurrent hepatitis and rejection were diagnosed based on elevated liver function tests and a liver biopsy. Results. The patients were followed up for a mean of 51.9 +/- 34.3 months. The cumulative survival rate was no different in OLT for hepatitis C and OLT for all other liver diseases. After OLT, serum HCV RNA was detected in 93%. Histological recurrence occurred in 85% of all patients. The 1-, 3-, and 5-year recurrence rates were 48%, 77%, and 85%, respectively. Of the 41 patients with recurrent hepatitis C, 4 (10%) had cirrhosis, 18 (44%) had hepatitis with fibrosis, and 91 (46%) had hepatitis without fibrosis at the end of follow-up. A total of 32% of the patients were infected by HCV genotype 1b and 68% by other HCV genotypes. The recurrence rates were significantly higher in patients infected with genotype 1b than in those with other genotypes (p = 0.04). Twenty of 48 patients (42%) experienced acute rejection. There was a strong association between the number of rejection episodes and the incidence of HCV-related cirrhosis (p < 0.01). Conclusion. Our findings showed the genotype 1b to result in a higher recurrence rate after OLT. On the other hand, rejection episodes were associated with a more rapid progression to graft cirrhosis.

Toward better outcomes with tacrolimus therapy: Population pharmacokinetics and individualized dosage prediction in adult liver transplantation

Patient outcomes in transplantation would improve if dosing of immunosuppressive agents was individualized. The aim of this study is to develop a population pharmacokinetic model of tacrolimus in adult liver transplant recipients and test this model in individualizing therapy. Population analysis was performed on data from 68 patients. Estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F) using the nonlinear mixed effects model program (NONMEM). Factors screened for influence on these parameters were weight, age, sex, transplant type, biliary reconstructive procedure, postoperative day, days of therapy, liver function test results, creatinine clearance, hematocrit, corticosteroid dose, and interacting drugs. The predictive performance of the developed model was evaluated through Bayesian forecasting in an independent cohort of 36 patients. No linear correlation existed between tacrolimus dosage and trough concentration (r(2) = 0.005). Mean individual Bayesian estimates for CL/F and V/F were 26.5 8.2 (SD) L/hr and 399 +/- 185 L, respectively. CL/F was greater in patients with normal liver function. V/F increased with patient weight. CL/F decreased with increasing hematocrit. Based on the derived model, a 70-kg patient with an aspartate aminotransferase (AST) level less than 70 U/L would require a tacrolimus dose of 4.7 mg twice daily to achieve a steady-state trough concentration of 10 ng/mL. A 50-kg patient with an AST level greater than 70 U/L would require a dose of 2.6 mg. Marked interindividual variability (43% to 93%) and residual random error (3.3 ng/mL) were observed. Predictions made using the final model were reasonably nonbiased (0.56 ng/mL), but imprecise (4.8 ng/mL). Pharmacokinetic information obtained will assist in tacrolimus dosing; however, further investigation into reasons for the pharmacokinetic variability of tacrolimus is required.

Donor pretreatment with progenipoietin-1 is superior to granulocyte colony-stimulating factor in preventing graft-versus-host disease after allogeneic stem cell transplantation

The granulocyte colony-stimulating factor (G-CSF) and Fit-3 receptor agonist progenipoietin-1 (ProGP-1) has potent effects on dendritic cell (DC) expansion and may be an alternative to G-CSF for the mobilization of stem cells for allogeneic stem cell transplantation (SCT). We studied the ability of stem cell grafts mobilized with this agent to induce graft-versus-host disease (GVHD) to minor and major histocompatibility antigens in the well-described B6 --> B6D2F1 SCT model. ProGP-1, G-CSIF, or control diluent was administered to donor B6 mice. ProGP-1 expanded all cell lineages in the spleen, and unseparated splenocytes from these animals produced large amounts of interleukin 10 (IL-10) and transforming growth factor beta (TGFbeta) whereas the expression of T-cell adhesion molecules was diminished. Transplantation survival was 0%, 50%, and 90% in recipients of control-, G-CSF-, and ProGP-1-treated allogeneic donor splenocytes, respectively (P < .0001). Donor pretreatment with ProGP-1 allowed a 4-fold escalation in T-cell dose over that possible with G-CSF. Donor CD4 T cells from allogeneic SCT recipients of ProGP-1 splenocytes demonstrated an anergic response to host antigen, and cytokine production (interferon gamma [IFNγ], IL-4, and IL-10) was also reduced while CD8 T-cell cytotoxicity to host antigens remained intact. Neither CD11c(hi) DCs nor CD11c(dim)/B220(hi) DCs from ProGP-1-treated animals conferred protection from GVHD when added to control spleen. Conversely, when equal numbers of purified T cells from control-, G-CSF-, or ProGP-1-treated allogeneic donors were added to allogeneic T-cell-depleted control spleen, survival at day 60 was 0%, 15%, and 90%, respectively (P < .0001). The improved survival in recipients of ProGP-1 T cells was associated with reductions in systemic tumor necrosis factor alpha generation and GVHD of the gastrointestinal tract. We conclude that donor pretreatment with ProGP-1 is superior to G-CSIF for the prevention of GVHD after allogeneic SCT, primarily due to incremental affects on T-cell phenotype and function