tacrolimus and Carcinoma--Hepatocellular

Liver transplantation has been widely accepted as an effective intervention for end-stage liver diseases and early hepatocellular carcinomas. However, a variety of postoperative complications and adverse reactions have baffled medical staff and patients. Currently, transplantation monitoring relies primarily on nonspecific biochemical tests, whereas diagnosis of multiple complications depends on invasive pathological examination. Therefore, a noninvasive monitoring method with high selectivity and specificity is desperately needed. This review summarized the potential of endogenous small-molecule metabolites as biomarkers for assessing graft function, ischemia-reperfusion injury and liver rejection. Exogenous metabolites, mainly those immunosuppressive agents with high intra- and inter-individual variability, were also discussed for transplantation monitoring.

Topics: Biomarkers; Carcinoma, Hepatocellular; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Metabolome; Mycophenolic Acid; Postoperative Complications; Prognosis; Reperfusion Injury; Tacrolimus

Calcineurin-inhibitor immunosuppressants (tacrolimus and ciclosporin) have been associated with an exposure-related increase in tumour recurrence following liver transplantation for hepatocellular carcinoma (HCC). Conversely, mechanistic target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) have been suggested to reduce recurrence rates and improve survival in this patient group.. To clarify the potential benefit of mTOR-inhibitors in HCC transplant patients by comparing recurrence and survival outcomes with calcineurin-inhibitor-based immunosuppression.. A systematic review and meta-analysis was performed. The inclusion criteria were observational or interventional studies reporting the effect of early-initiated (<6 months post-transplant) mTOR-inhibitor-based immunosuppression on survival or tumour recurrence in patients transplanted with HCC, compared to a control of calcineurin-inhibitor-based therapy.. Meta-analysis demonstrated that compared with calcineurin-inhibitor controls, recurrence-free-survival was significantly increased with mTOR-inhibitor-based therapy at 1-year (Risk-Ratio (RR): 1.09, 95% CI: 1.01-1.18) and 3-years (RR: 1.1, 95% CI: 1.01-1.21) post-transplant, with a nonsignificant increase at 5-years (RR: 1.15, 95% CI: 0.99-1.35). Overall survival was improved at 1-year (RR: 1.07, 95% CI: 1.02-1.12), 3-years (RR: 1.1, 95% CI: 1.02-1.19), and 5-years (RR: 1.18, 95% CI: 1.08-1.29). Recurrence-rate was lower in the mTOR-inhibitor arm (RR: 0.67, 95% CI: 0.56-0.82), with no significant increase in acute rejection (RR: 1.1, 95% CI: 0.94-1.28).. mTOR-inhibitor-based immunosuppression may be a preferable option in patients transplanted with HCC. It improves recurrence-free-survival over at least three years and reduces the recurrence rate compared with standard calcineurin-inhibitor-based therapy, with no significant increase in the rate of acute rejection. Future research should clarify the effect in higher vs lower risk cohorts.

Topics: Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Everolimus; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Neoplasm Recurrence, Local; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

The development of immunosuppression has significantly affected the development of liver transplantation and has helped to switch from the experimental method to a standard treatment of life threatening liver conditions. Tacrolimus is the basic immunosuppressant for patients after a liver transplant and thanks to its prolonged-release dosage form, which due to its simplicity and reliability of use, replaces tacrolimus twice daily early after the transplant and in the longterm administration, will apparently, for a while, defend its position. Other widely used medicines include mycophenolic acid and mTOR inhibitors, sirolimus and everolimus. The induction with antilymphocyte antibodies is used in less than 10% of liver recipients. Only a few new immunosuppresants in this century have passed later stages of clinical studies; the last 2 medicines registered for patients after liver transplantation include Advagraf (Astellas) and Certican (Novartis). Personalised immunosuppression should respect at least the following basic clinical situations: recipients renal function, hepatitis C virus infection, and hepatocellular carcinoma as the liver transplant indication. The results of immunotolerance bio-marker research are necessary for a more successful conduct of protocols minimising immunosuppression and leading to immunotolerance, especially under the efforts of complete withdrawal of immunosupression.

Topics: Antilymphocyte Serum; Carcinoma, Hepatocellular; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Failure; Liver Neoplasms; Liver Transplantation; Mycophenolic Acid; Reproducibility of Results; Sirolimus; Tacrolimus

Interdigitating dendritic cell sarcoma is an extremely rare neoplasm derived from professional antigen presenting cells. We report an unusual case of such a tumor occurring in a 61-year-old woman who had undergone orthotopic liver transplantation for stage IVA2 primary hepatocellular carcinoma with a raised preoperative α-fetoprotein level, followed by tacrolimus-based immunosuppressive therapy. During her subsequent management, the tacrolimus blood levels ranged from 7.9 ng/mL to 16.1 ng/mL. Physical examination revealed bilateral neck and left axillary lymphadenopathy. No evidence of either chronic hepatitis B virus or Epstein-Barr virus could be detected in serum. An excisional biopsy of a right neck lymph node was performed. Microscopically, the normal architecture was diffusely effaced by a proliferation of spindled to ovoid cells arrayed in a fascicular, ill-defined whorled pattern and small lymphocytes were admixed in varying numbers with the tumor cells. Immunohistochemical studies showed that the tumor cells were positive for S100 protein, vimentin and CD68. Based on these findings, the case was diagnosed as an interdigitating dendritic cell sarcoma. The patient unfortunately had no response to 2 cycles of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), and died of wide spread disease 6 months after the original biopsy. We propose that tacrolimus-based immunosuppression was associated with the development of interdigitating dendritic cell sarcoma after liver transplantation in this case.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cyclophosphamide; Dendritic Cell Sarcoma, Interdigitating; Doxorubicin; Fatal Outcome; Female; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Lymph Nodes; Middle Aged; Prednisone; Tacrolimus; Vincristine

As newer immunosuppressive regimens have steadily reduced the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant malignancy has become an important cause of mortality. In fact, it is expected that cancer will surpass cardiovascular complications as the leading cause of death in transplant patients within the next 2 decades. An understanding of the underlying pathobiology and how to minimize cancer risks in transplant recipients are essential. The etiology of posttransplant malignancy is believed to be multifactorial and likely involves impaired immunosurveillance of neoplastic cells as well as depressed antiviral immune activity with a number of common posttransplant malignancies being viral-related. Although calcineurin inhibitors and azathioprine have been linked with posttransplant malignancies, newer agents such as mycophenolate mofetil and sirolimus have not and indeed may have antitumor properties. Long-term data are needed to determine if the use of these agents will ultimately lower the mortality due to malignancy for transplant recipients.

Topics: Azathioprine; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Hepatitis, Viral, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Neoplasms; Sirolimus; Skin Neoplasms; Tacrolimus; Transplantation Immunology; Transplantation, Homologous

Clinical liver transplantation became an established therapy of end-stage liver disease since the first at least medium-term successful liver transplantation in 1967. Clinical studies have played a major part in improving peri- and postoperative therapy in liver transplantation. In this article clinical studies of major impact are presented. Main topics are studies dealing with immunosuppressants, improvements in surgical techniques, viral infections and tumor diseases. Controlled randomized multicentric studies are rare; most of the studies are unicentric. Further studies in the fields of reducing side effects of immunosuppression, the introduction of monoclonal antibodies and improvement of the therapy of viral hepatitis would be helpful. These studies should be controlled, randomized and multicentric.

Topics: Carcinoma, Hepatocellular; Cyclosporine; Cytomegalovirus Infections; Double-Blind Method; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Multicenter Studies as Topic; Postoperative Complications; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Tacrolimus

We investigate whether low-dose rapamycin is effective in preventing hepatocellular carcinoma (HCC) growth and treating HCC after tumor development in transgenic mice.. We established transgenic mice with HCC induced by activated HrasG12V and p53 suppression. Transgenic mice were randomly assigned to five experimental groups: negative control, positive control, tacrolimus only, rapamycin only, and tacrolimus plus rapamycin. The mice were further divided into two groups according to time to commencement of immunosuppressant treatment: de novo treatment and post-tumor development.. In the de novo treatment group, marked suppression of tumor growth was observed in the rapamycin only group. In the post-tumor development group, the rapamycin only group displayed no significant suppression of tumor growth, compared to the positive control group. In T lymphocyte subset analysis, the numbers of CD4. Low-dose rapamycin might be effective to prevent HCC growth, but may be ineffective as a treatment option after HCC development.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Liver Neoplasms; Mice; Mice, Transgenic; Sirolimus; Tacrolimus

BACKGROUND The study objective was to evaluate the effect of everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared with a standard TAC (sTAC) regimen on hepatocellular carcinoma (HCC) recurrence in de novo living-donor liver transplantation recipients (LDLTRs) with primary HCC at liver transplantation through 5 years after transplantation. MATERIAL AND METHODS In this multicenter, non-interventional study, LDLTRs with primary HCC, who were previously randomized to either everolimus plus reduced tacrolimus (EVR+rTAC) or standard tacrolimus (sTAC), and who completed the 2-year core H2307 study, were followed up. Data were collected retrospectively (end of core to the start of follow-up study), and prospectively (during the 3-year follow-up study). RESULTS Of 117 LDLTRs with HCC at LT in the core H2307 study (EVR+rTAC, N=56; sTAC, N=61), 86 patients (EVR+rTAC, N=41; sTAC, N=45) entered the follow-up study. Overall HCC recurrence was lower but statistically non-significant in the EVR+rTAC group (3.6% vs 11.5% in sTAC; P=0.136) at 5 years after LT. There was no graft loss or chronic rejection. Acute rejection and death were comparable between treatment groups. Higher mean estimated glomerular filtration rate in the EVR+rTAC group (76.8 vs 65.8 mL/min/1.73 m² in sTAC) was maintained up to 5 years. Reported adverse events were numerically lower in the EVR+rTAC group (41.0% vs 53.5% sTAC) but not statistically significant. CONCLUSIONS Although statistically not significant, early EVR initiation reduced HCC recurrence, with comparable efficacy and safety, and better long-term renal function, than that of sTAC treatment.

Topics: Carcinoma, Hepatocellular; Everolimus; Follow-Up Studies; Humans; Liver Neoplasms; Liver Transplantation; Living Donors; Retrospective Studies; Tacrolimus

HBV-specific T-cell receptor (HBV-TCR) engineered T cells have the potential for treating HCC relapses after liver transplantation, but their efficacy can be hampered by the concomitant immunosuppressive treatment required to prevent graft rejection. Our aim is to molecularly engineer TCR-T cells that could retain their polyfunctionality in such patients while minimizing the associated risk of organ rejection.. We first analyzed how immunosuppressive drugs can interfere with the in vivo function of TCR-T cells in liver transplanted patients with HBV-HCC recurrence receiving HBV-TCR T cells and in vitro in the presence of clinically relevant concentrations of immunosuppressive tacrolimus (TAC) and mycophenolate mofetil (MMF). Immunosuppressive Drug Resistant Armored TCR-T cells of desired specificity (HBV or Epstein-Barr virus) were then engineered by concomitantly electroporating mRNA encoding specific TCRs and mutated variants of calcineurin B (CnB) and inosine-5'-monophosphate dehydrogenase (IMPDH), and their function was assessed through intracellular cytokine staining and cytotoxicity assays in the presence of TAC and MMF. Liver transplanted HBV-HCC patients receiving different immunosuppressant drugs exhibited varying levels of activated (CD39. We engineered TCR-T cells of desired specificities that transiently escape the immunosuppressive effects of TAC and MMF. This finding has important clinical applications for the treatment of HBV-HCC relapses and other pathologies occurring in organ transplanted patients.

Topics: Carcinoma, Hepatocellular; Coculture Techniques; Drug Resistance; Graft Rejection; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Immunotherapy, Adoptive; Liver; Liver Neoplasms; Liver Transplantation; Mycophenolic Acid; Neoplasm Recurrence, Local; Protein Engineering; Receptors, Antigen, T-Cell; T-Lymphocytes; Tacrolimus

To evaluate the safety and efficacy of steroid-minimization therapy in liver transplantation (LT) recipients with hepatitis B virus-related diseases in China.. From March 2000 to June 2007, 502 adult LT recipients, mostly with hepatitis B (HBV)-related diseases, were enrolled in our study. Four study groups were setup according to the steroid-minimization protocols: tacrolimus (TAC) with 6 months steroids withdrawal (6M SW), TAC with 3 months SW (3M SW), TAC with 14 days SW (14d SW), and TAC with basiliximab induction and steroids avoidance (Bas SA). All patients were followed up for at least 36 months after LT.. There were no significant differences in the overall 3-year survival rates of the patients and graft, and chronic rejection among the four groups (P = 0.092, P = 0.113 and P = 0.684, respectively). There was also no difference in acute rejection within 12 months after LT (P = 0.514). The 3-year recurrence rates of HBV infection and hepatocellular carcinoma (HCC) after LT were significantly different among all the groups (lowest in TAC/Bas SA group; P = 0.037 and P = 0.029, respectively). The overall incidence of infection was significantly higher in the 6M SW group (62.2% vs 56.1% in 3M SW, 30.5% in 14d SW, 20.5% in Bas SA; P < 0.01). By the end of the 3-year follow-up, more than 90% of the surviving patients could safely receive TAC monotherapy.. Bas SA immunosuppressive protocol can be achieved safely in LT and reduce HBV infection and HCC recurrence and side effects of steroids after LT.

Topics: Adult; Antibodies, Monoclonal; Bacterial Infections; Basiliximab; Carcinoma, Hepatocellular; Chi-Square Distribution; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Neoplasm Recurrence, Local; Recombinant Fusion Proteins; Recurrence; Statistics, Nonparametric; Survival Rate; Tacrolimus

Choice of calcineurin inhibitor may be a contributing factor to deteriorating patient and graft survival following liver transplantation for hepatitis C virus (HCV). In our multicenter, open-label LIS2T study, de novo liver transplant patients stratified by HCV status were randomized to cyclosporine or tacrolimus. Follow-up data were obtained in an observational study of 95 patients. Mean follow-up was 34 and 37 months, respectively, for cyclosporine-treated (n = 47) and tacrolimus-treated (n = 48) patients. In patients not receiving antiviral therapy, 22 of 31 given cyclosporine (72%) and 24 of 29 given tacrolimus (83%) had biochemical recurrence of HCV. In 68 patients with at least one biopsy, histological evidence of HCV-related hepatitis was present in 27 of 31 (87%) cyclosporine-treated patients and 37 of 37 (100%) tacrolimus-treated patients (P = .02, chi-square test). Three-year actuarial risk of fibrosis stage 2 was 66% with cyclosporine and 90% with tacrolimus; for fibrosis stage 3 or 4 it was 46% and 80%, respectively. Three graft losses were attributed to HCV recurrence in cyclosporine-treated patients and six in tacrolimus-treated patients. Tacrolimus may be associated with increased risk of histological HCV disease recurrence compared to cyclosporine.

Topics: Adult; Carcinoma, Hepatocellular; Cyclosporine; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Recurrence; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC). Recurrence of HCC after LT occurs in 10% to 20% of cases. Preclinical studies to evaluate immune checkpoint inhibitors in conjunction with immunosuppressant treatment in transplant recipients have been lacking. Here, we evaluated the efficacy, safety, and mechanism of programmed cell death-1 (PD1) blockade under tacrolimus treatment in transplant recipients.. We used a murine allogeneic skin transplantation model and murine syngeneic subcutaneous and orthotopic HCC models and measured the tumor volume and the change in tumor-infiltrating lymphocytes under PD1 blockade and tacrolimus treatment.. Tacrolimus treatment prolonged allograft survival in the allogeneic transplantation model and enhanced tumor growth in both subcutaneous and orthotopic HCC models. PD1 blockade suppressed tumor growth and lung metastasis in correlation with the number of infiltrating CD8 + T cells. Under tacrolimus treatment, PD1 blockade still resulted in an antitumor effect accompanied by a significant increase in tumor-infiltrating CD8 + T cells, natural killer cells, dendritic cells, and natural killer T cells. Tacrolimus treatment rescued the acceleration of transplant rejection induced by PD1 blockade in the allogeneic transplantation model.. Our data suggest that treatment with high-dose tacrolimus in conjunction with PD1 blockade has an antitumor effect and reduces transplant rejection in mouse models of allograft skin transplantation and HCC. Thus, these results suggest that a clinical trial of PD1 inhibitors for HCC in LT merits consideration.

Topics: Animals; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Immunosuppressive Agents; Immunotherapy; Liver Neoplasms; Mice; Tacrolimus

We aimed to compare the adherence to immunosuppressive medication use in patients who underwent liver transplantation (LT) due to hepatocellular carcinoma (HCC) and non-HCC reasons.. The study population was determined as 242 patients with HCC and 1290 patients with non-HCC who had LT performed in our institute between March 2002 and November 2021; all these patients were contacted by phone in March 2022. The sample size was calculated using the MedCalc software program, and the number of patients required in each group was determined as 111 patients. Furthermore, we used the sample.int function, a random integer generator in the R (version 4.1.2) software program. Whereas demographic and clinical parameters were determined as independent variables, the immunosuppressive medication adherence scale (IMAS) score was determined as a dependent variable. Patients were evaluated by the IMAS. This 11-item IMAS scale evaluates the lowest compliance score as 11 and the highest as 55.. Out of a total number of 221 patients, 161 (72%) were men and 60 (27.1%) were women, with a median age of 58 years (IQR: 14); one patient in the non-HCC group was excluded due to lack of data. Among the HCC and non-HCC groups, significant differences were found in terms of the variables of age (P = .003), IMAS score (P < .001), sex (P = .001), working status (P = .004), chronic diseases (P = .008), tacrolimus alone (P < .001), tacrolimus plus everolimus (P < .001), and often medication changes (P < .001). A statistically significant correlation was found between the IMAS score and whether the patients had HCC (P < .001) and frequently changing immunosuppressive drugs (P = .023).. This study showed that patients with frequent drug changes or non-HCC etiology had better adherence to immunosuppressive drug use.

Topics: Adolescent; Carcinoma, Hepatocellular; Case-Control Studies; Female; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Medication Adherence; Neoplasm Recurrence, Local; Tacrolimus

The clinical effects of tacrolimus (TAC) exposure on hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) remain unclear. In this retrospective single centric study, 512 patients who underwent LT for HCC were divided into four groups according to cumulative exposure to tacrolimus (CET) during 3 months after LT: conventional (n = 218), aggressive minimization (n = 32), minimization (n = 161), and high exposure (n = 101). Impact of CET on HCC recurrence and death were analyzed. Compared with the conventional group, the other three CET groups showed a similar risk of HCC recurrence. The aggressive minimization group showed a higher risk [hazard ratio (HR) 5.64, P < 0.001] and the high exposure group showed a marginal risk (HR 1.67, P = 0.081) of overall death compared to the conventional group. CET during 3 months was not associated with HCC recurrence in the matched cohort and various subgroups. TAC minimization is not effective to prevent HCC recurrence but could result in higher mortality in LT recipients.

Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Liver Transplantation; Retrospective Studies; Tacrolimus

Cancer is the leading cause of death after liver transplantation (LT). This multicenter case-control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05-1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14-1.99]), smoking habit (HR = 1.96 [95% CI 1.42-2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19-1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.

Topics: Carcinoma, Hepatocellular; Humans; Incidence; Liver Neoplasms; Liver Transplantation; Male; Neoplasm Recurrence, Local; Retrospective Studies; Risk Factors; Tacrolimus

Tacrolimus is the mainstay of immunosuppression in liver transplantation to prevent rejection. However, the clinical use of tacrolimus is complicated by its narrow therapeutic window and significant intra-patient variability (IPV). High tacrolimus IPV is associated with overexposure and adverse effects, including malignancy. The effects of tacrolimus IPV in liver transplant recipients with and without hepatocellular carcinoma (HCC) are unknown. We investigated the association between tacrolimus IPV and transplant outcomes in 636 liver transplant patients. Tacrolimus IPV was determined by calculating the coefficient of variance (CV) of outpatient tacrolimus trough levels from 3 to 12 months after transplantation. High tacrolimus IPV was defined as CV > 30%. Patients were grouped according to tacrolimus IPV and HCC status. Among 636 liver transplant patients, 349 had HCC and 287 had no HCC. Overall survival in HCC patients was significantly reduced with high tacrolimus IPV (P < 0.001), whereas survival of non-HCC patients was not associated with tacrolimus IPV. Multivariable analysis confirmed the independent association between high tacrolimus IPV and overall mortality in HCC patients (HR, 3.010; 95% CI, 1.084-4.918). HCC recurred in 59 patients (16.9%) post-transplantation. After adjusting for donor/recipient factors, immunosuppression, and tumor characteristics, high tacrolimus IPV was independently associated with an increased risk of HCC recurrence (HR, 2.196; 95% CI, 1.272-3.791). High tacrolimus IPV was associated with significantly increased risks of overall mortality and HCC recurrence in liver transplant recipients with HCC.

Topics: Carcinoma, Hepatocellular; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Retrospective Studies; Risk Factors; Tacrolimus

Tacrolimus is a calcineurin inhibitor widely used for immunological disorders. However, there is significant controversy regarding its effect on the liver. The present study was conducted to evaluate the anticancer effects of tacrolimus on an induced murine hepatocellular carcinoma (HCC) model and its possible hepatotoxicity at standard therapeutic doses.. Fifty-four male mice were divided into five groups: a control healthy group, control HCC group, tacrolimus-treated group, doxorubicin (DOXO)-treated group, and combined tacrolimus- and DOXO-treated group. The activity of liver enzymes, including alkaline phosphatase, gamma- glutamyl transferase, lactate dehydrogenase, alanine transaminase, and aspartate transaminase, was determined. Serum vascular endothelial growth factor (VEGF) was measured using an enzyme- linked immunosorbent assay. A quantitative real time- polymerase chain reaction (qRTPCR) was conducted to measure the expression of proliferating cell nuclear antigen (PCNA), Bax, and p53 mRNA. Immunohistochemical staining for cyclin D1 and VEGF was performed.. Mice that received combined treatment with tacrolimus and DOXO exhibited the best improvement in all parameters when compared with the groups that received DOXO or tacrolimus alone (p < 0.001).. The combination of DOXO and tacrolimus was more effective in the management of HCC compared with either agent alone. This improvement was detected by the reduction of liver enzymes and the improvement of the histopathological profile. The involved mechanisms included significant apoptosis induction demonstrated by upregulation of bax along with a reduction in angiogenesis demonstrated by downregulation of VEGF. This was accompanied by inhibition of cell cycle progression mediated by upregulated p53 and downregulated PCNA and cyclin D1.

Topics: Animals; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Cyclin D1; Doxorubicin; Liver Neoplasms; Male; Mice; Proliferating Cell Nuclear Antigen; Tacrolimus; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A

Topics: Carcinoma, Hepatocellular; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma, Primary Effusion; Male; Middle Aged; Pleural Effusion; Stomach Ulcer; Tacrolimus

Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24.. EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, -1.0%; 95% confidence interval, -5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (-8.37 versus -13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (-12.82 versus -17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels.. EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.

Topics: Adult; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Randomized Controlled Trials as Topic; Recurrence; Tacrolimus; Time Factors; Treatment Outcome

Topics: Anastomosis, Surgical; Carcinoma, Hepatocellular; Disease Progression; Fatal Outcome; Female; Hematoma; Hepatic Artery; Humans; Immunosuppressive Agents; Liver Neoplasms; Middle Aged; Patient Readmission; Peritoneal Cavity; Postoperative Care; Reoperation; Risk Assessment; Rupture, Spontaneous; Sirolimus; Tacrolimus; Tomography, X-Ray Computed

Liver transplantation (LT) is currently considered an important method in treating hepatocellular carcinoma (HCC) and an alternative treatment for other liver malignancies. Here, we demonstrated that the graft-versus-tumor (GVT) effect exists in allogeneic liver transplantation (allo LT). Recipient-derived T cells played a critical role in the GVT process of allo LT, as demonstrated by extensive infiltration and significant activation of recipient T cells in the tumor after surgery. Moreover, this process was related to donor-derived T/B cells by improving the immune microenvironment in the tumor, as demonstrated by elevated levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-6, IL-16, chemokine (C-X-C motif) ligand 10 (CXCL10), and CXCL11 and decreased levels of IL-10 and IL-4 at tumor sites. Additionally, tacrolimus (FK506) treatment inhibited the GVT effect on allo LT. Donor liver-derived T/B cells infiltrate extrahepatic tumors to trigger a strong T-cell-mediated immune response and thus improve the tumor immune microenvironment.

Topics: Allografts; Animals; Carcinoma, Hepatocellular; Cytokines; Disease Models, Animal; Graft vs Tumor Effect; Humans; Immunosuppressive Agents; Isoantigens; Liver; Liver Neoplasms; Liver Transplantation; Male; Mice; T-Lymphocytes; Tacrolimus; Transplantation, Homologous; Tumor Microenvironment

Patients after orthopic liver transplantation (OLT) are at risk of developing graft dysfunction. Sphingolipids (SL's) have been identified to play a pivotal role in the regulation of hepatocellular apoptosis, inflammation and immunity. We aimed to investigate the serum SL profile in a prospective real-world cohort of post-OLT patients. From October 2015 until July 2016, 149 well-characterized post-OLT patients were analyzed. SL's were assessed in serum probes via Liquid Chromatography/Tandem Mass Spectrometry. Twenty-nine (20%) patients had a biopsy proven graft rejection with decreased C20-ceramide (Cer) (

Topics: Adult; Aged; Carcinoma, Hepatocellular; Ceramides; Cross-Sectional Studies; Female; Graft Rejection; Humans; Liver; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus; Young Adult

Topics: Allografts; Biopsy; Carcinoma, Hepatocellular; Cholestasis; Cyclosporine; Graft Rejection; Hepatitis; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Tacrolimus; Ultrasonography, Doppler

The role of sorafenib in patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been rarely studied. The aim of this study was to evaluate the efficacy of sorafenib in post-LT era.. Consecutive patients with post-transplant HCC recurrence not eligible to resection or locoregional therapy were included. Patients receiving best supportive care (BSC) until 2007 were compared with those treated by sorafenib thereafter.. Of a total of 65 patients, 20 patients received BSC and 45 received sorafenib. Clinical characteristics were similar between two groups except that sorafenib group received tacrolimus and mammalian target-of-rapamycin inhibitors more frequently than BSC group. Treatment with sorafenib conferred a survival advantage as compared with BSC for survival after recurrence (median, 14.2 vs. 6.8 months;. Sorafenib may be beneficial in patients with post-transplant HCC recurrence.

Topics: alpha-Fetoproteins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Sorafenib; Tacrolimus; TOR Serine-Threonine Kinases

Orthotopic liver transplantation (OLT) improves the prognosis of patients with hepatocellular carcinoma (HCC). Moreover, the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis. However, studies correlating the complement system with tacrolimus metabolism after OLT are scarce. In this study, the role of single nucleotide polymorphisms (SNPs) associated with the sixth complement component (C6) in tacrolimus metabolism was investigated during the early stages of liver transplantation.. The study enrolled 135 adult patients treated with OLT for HCC between August 2011 and October 2013. Ten SNPs in C6 gene and rs776746 in cytochrome P450 3A5 (CYP3A5) gene were investigated. The tacrolimus levels were monitored daily during 4 weeks after transplantation.. Both donor and recipient CYP3A5 rs776746 allele A were correlated with decreased concentration/dose (C/D) ratios. Recipient C6 rs9200 allele G and donor C6 rs10052999 homozygotes were correlated with lower C/D ratios. Recipient CYP3A5 rs776746 allele A (yielded median tacrolimus C/D ratios of 225.90 at week 1 and 123.61 at week 2), C6 rs9200 allele G (exhibited median tacrolimus C/D ratios of 211.31 at week 1, 110.23 at week 2, and 99.88 at week 3), and donor CYP3A5 rs776746 allele A (exhibited median C/D ratios of 210.82 at week 1, 111.06 at week 2, 77.49 at week 3, and 85.60 at week 4) and C6 rs10052999 homozygote (exhibited median C/D ratios of 167.59 at week 2, 157.99 at week 3, and 155.36 at week 4) were associated with rapid tacrolimus metabolism. With increasing number of these alleles, patients were found to have lower tacrolimus C/D ratios at various time points during the 4 weeks after transplantation. In multiple linear regression analysis, recipient C6 rs9200 group (AA vs. GG/GA) was found to be related to tacrolimus metabolism at weeks 1, 2, and 3 (P = 0.005, P = 0.045, and P = 0.033, respectively), whereas donor C6 rs10052999 group (CC/TT vs. TC) was demonstrated to be correlated with tacrolimus metabolism only at week 4 (P = 0.001).. Recipient C6 gene rs9200 polymorphism and donor C6 gene rs10052999 polymorphism are new genetic loci that affect tacrolimus metabolism in patients with HCC after OLT.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Tacrolimus

We aimed to evaluate the efficacy and safety of an immunosuppressive regimen without steroids after liver transplantation (LT) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).. Sixty-six HCC patients who underwent an immunosuppressive regimen without steroids after LT were enrolled in the steroid-free group. The preoperative characteristics and postoperative outcomes of these patients were compared with those of 132 HCC recipients who were placed on an immunosuppressive regimen using steroids (steroid group). The incidence of acute rejection, HBV recurrence, infection, and new-onset diabetes mellitus and the overall and tumor-free survival rates were compared between the two groups.. Differences were not observed in the 1-year (83.3% vs 97.0%, p=0.067), 3-year (65.4% vs 75.8%, p=0.067) or 5-year (56.3% vs 70.7%, p=0.067) patient survival rates or in the 1-year (62.1% vs 72.7%, p=0.067), 3-year (49.8% vs 63.6%, p=0.067) or 5-year (48.6% vs 63.6%, p=0.067) tumor-free survival rates between the two groups, respectively. In the steroid-free group, the patients who fulfilled the Milan criteria had higher overall and tumor-free survival rates than those in the steroid group (p<0.001). The prevalence of HBV recurrence (3.0% vs 13.6%, p=0.02) was significantly lower in the steroid-free group compared with the steroid group.. After LT, an immunosuppressive regimen without steroids could be a safe and feasible treatment for HBVrelated HCC patients, thus resulting in the reduction of HBV recurrence. Based on the observed survival rates, patients who fulfill the Milan criteria may derive benefits from teroidfree immunosuppression.

Topics: Antibodies, Monoclonal; Basiliximab; Carcinoma, Hepatocellular; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucocorticoids; Hepatitis B; Hepatitis B virus; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Postoperative Period; Prednisolone; Recombinant Fusion Proteins; Tacrolimus; Treatment Outcome

Drug adherence is one of the most important factors determining graft and patient survivals after liver transplantation. A systematic pharmaceutical educational approach has been implemented to improve adherence in immunosuppressive drugs therapy at Siriraj Hospital.. This study was a single-center cross-sectional study of liver transplant patients who received pharmaceutical care from transplant pharmacists. The clinical pharmacy services, including medication review to emphasize patients' knowledge and awareness of immunosuppressive and general drug therapies with the use of various tools, were used to educate the patients. Drug-related problems (DRPs) and pre- and post-transplantation educational tests (divided into 3 parts: immunosuppressants [12 points], drug monitoring [6 points], and general drugs [2 points]) were analyzed.. From October 2012 to September 2014, a total of 50 liver transplant recipients (86 visits) were enrolled. After the systematic pharmaceutical educational program, the average total score of post-transplantation educational test improved from 3.48 to 13.30 (P < .001). Likewise, the mean scores of all 3 parts significantly increased (part I: 2.28 vs 8.18 [P < .001]; part II: 0.75 vs 3.63 (P < .001); and part III: 0.46 vs 1.50 [P < .001]). The incidences of major DRPs, nonadherence, and adverse drug reactions were 8%, 4%, and 2%, respectively.. A systematic pharmaceutical educational approach can significantly improve patients' knowledge and awareness concerning immunosuppressive drug usage.

Topics: Adult; Carcinoma, Hepatocellular; Cross-Sectional Studies; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; End Stage Liver Disease; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Medication Adherence; Middle Aged; Mycophenolic Acid; Patient Education as Topic; Pharmaceutical Services; Risk Factors; Tacrolimus

The once-daily prolonged-release formulation of tacrolimus has been recently related with significant graft and patient mid-term survival advantages; however, practical information on the de novo administration after liver transplantation and longterm outcomes is currently lacking. This study is a 5-year retrospective analysis of a single-center cohort of liver transplant recipients treated de novo with once-daily tacrolimus (April 2008/August 2011). The study cohort consisted of 160 patients, including 23 with pretransplant renal dysfunction, with a median follow-up of 57.6 months (interquartile range, 46.6-69.0). Tacrolimus target trough levels were 5-10 ng/mL during the first 3 months after transplant, reducing progressively to <7 ng/mL after the first posttransplant year. Once-daily tacrolimus was withdrawn in 35 (21.8%) patients during follow-up, mostly due to renal dysfunction and/or metabolic syndrome. The biopsy-proven acute rejection rate was 12.5% with no cases of steroid-resistant rejection. The cumulative incidence of de novo diabetes, hypertension, and dyslipidemia were 16.9%, 31.2%, and 6.5%, respectively. Hepatocellular carcinoma recurrence rate was 2.8%. Renal function remained stable after the sixth month after transplant with a mean estimated glomerular filtration rate of 77.7 ± 19.6 mL/minute/1.73 m(2) at 5 years. None of our patients developed chronic kidney disease stage 4 or 5. Patient survival at 1, 3, and 5 years was 96.3%, 91.9%, and 88.3%, respectively. Overall survival of patients with Model for End-Stage Liver Disease (MELD) score > 25 points was not significantly different. In conclusion, our study suggests that immunosuppression based on de novo once-daily tacrolimus is feasible in routine clinical practice, showing favorable outcomes and outstanding longterm survival even in patients with high MELD scores. Liver Transplantation 22 1391-1400 2016 AASLD.

Topics: Adult; Aged; Biopsy; Carcinoma, Hepatocellular; Drug Administration Schedule; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Prospective Studies; Retrospective Studies; Tacrolimus; Treatment Outcome

We report a case of a 27-year-old man diagnosed with the infection of HBV delta in the 8th month of life. The treatment complied with evidence-based medical guidelines, comprising neoadiuvant chemotherapy and surgery. Liver transplantation from a deceased donor followed by chemotherapy was performed when the patient was 16 years 9 months of age because of recurrent HCC tumor. The patient qualified for immunosuppressive treatment (rapamycin, tacrolimus), lamivudine, anti-HBs globulin intravascular infusion, and anti-HBV vaccination as a prophylaxis against reinfection with HBV. In conclusion, this case demonstrates the importance of a postoperative follow-up of patients with HCC, even years after liver transplantation.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B; Hepatitis B virus; Humans; Immunosuppressive Agents; Lamivudine; Liver Neoplasms; Liver Transplantation; Male; Neoplasm Recurrence, Local; Recurrence; Tacrolimus; Tissue Donors; Treatment Outcome

Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with potential portal hypertension and/or bilirubinemia, but without vascular-associated diseases. The patients are receiving immunosuppressive therapy to reduce graft rejection, but differential side effects have been related to calcineurin and mTOR inhibitor administration regarding tumor recurrence and nephrotoxicity. The in vitro studies showed that Tacrolimus exerted a more potent pro-apoptotic effect than Everolimus (Huh 7>Hep 3B>HepG2), being sirolimus only active in Hep3B cell line. Tacrolimus and Everolimus exerted potent antiproliferative properties in Huh 7 and Hep3B in which cells Sirolimus was inactive. Interestingly, Tacrolimus- and Everolimus-dependent G0/G1 cell accumulation occurred as a consequence of drastic reduction in S, as well as in S and G2+M phases, respectively. The in vivo studies support data on the more effective antitumoral properties of Everolimus, eventual risk of pro-angiogenic tumoral properties and nephrotoxicity of Tacrolimus, and pro-proliferative properties of Sirolimus in tumors developed in nude mice.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Everolimus; Fibrosis; Humans; Immunosuppressive Agents; Kidney; Liver Neoplasms; Male; Mice; Neovascularization, Pathologic; Tacrolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

HBV-DNA integration frequently occurs in HBV-related hepatocellular carcinoma (HCC), but whether HBV antigens are expressed in HCC cells and can be targeted by immune therapeutic strategies remains controversial. Here, we first characterized HBV antigen expression in HCC metastases, occurring in a patient who had undergone liver transplantation for HBV-related HCC. We then deployed for the first time in HCC autologous T cells, genetically modified to express an HBsAg specific T cell receptor, as therapy against chemoresistant extrahepatic metastases. We confirmed that HBV antigens were expressed in HCC metastases (but not in the donor liver) and demonstrated that tumour cells were recognized in vivo by lymphocytes, engineered to express an HBV-specific T cell receptor (TCR). Gene-modified T cells survived, expanded and mediated a reduction in HBsAg levels without exacerbation of liver inflammation or other toxicity. Whilst clinical efficacy was not established in this subject with end-stage metastatic disease, we confirm the feasibility of providing autologous TCR-redirected therapy against HCC and advocate this strategy as a novel therapeutic opportunity in hepatitis B-associated malignancies.

Topics: Aged; Carcinoma, Hepatocellular; Fatal Outcome; Follow-Up Studies; Hepatitis B Surface Antigens; Humans; Immunosuppressive Agents; Immunotherapy; Liver Neoplasms; Male; Neoplasm Metastasis; Receptors, Antigen, T-Cell; Tacrolimus

Topics: Carcinoma, Hepatocellular; Hepatitis B Surface Antigens; Humans; Immunotherapy; Liver Neoplasms; Male; Receptors, Antigen, T-Cell; Tacrolimus

Topics: Carcinoma, Hepatocellular; Hepatitis B Surface Antigens; Humans; Immunotherapy; Liver Neoplasms; Male; Receptors, Antigen, T-Cell; Tacrolimus

Tacrolimus is prescribed to prevent allograft rejection in pediatric liver transplant recipients; however, its metabolism through the cytochrome P-450 enzyme system presents a multitude of challenges in regard to drug interactions. Here, we describe four children (ages 1.4-8.7 yr) who acutely developed supra-therapeutic serum tacrolimus trough concentrations, despite standard dosing, while on concomitant nicardipine therapy following liver transplantation. Even though tacrolimus regimens were altered (dosage reductions and held doses), serum tacrolimus concentrations remained elevated. Resolution of high tacrolimus concentrations was achieved only after the discontinuation of nicardipine. Following the termination of nicardipine, all children eventually required dosage increases in their tacrolimus regimens to re-achieve target serum concentrations. We conclude that concomitant use of tacrolimus and nicardipine can result in high tacrolimus concentrations due to the inhibition of cytochrome p450 enzymes responsible for the metabolism of tacrolimus. We encourage clinicians to consider alternative antihypertensive options in children on tacrolimus therapy. If nicardipine therapy is necessary, we recommend a 50% reduction in tacrolimus dose and daily serum concentration monitoring.

Topics: Alagille Syndrome; Antihypertensive Agents; Biliary Atresia; Carcinoma, Hepatocellular; Child; Child, Preschool; Cholestasis, Intrahepatic; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Liver Neoplasms; Liver Transplantation; Male; Nicardipine; Reoperation; Tacrolimus

We describe an observational, retrospective study that included patients who underwent a liver transplantation (LT) for hepatocellular carcinoma (HCC) in our center between 2004 and 2012.. Clinical variables were recorded for donors and recipients as diagnosis and treatment, immunosuppressive therapy, toxicity, graft dysfunction, recurrence, and exitus. Fifty-eight patients were analyzed. The mean age was 57 ± 8 years. The viral etiology of HCC was 50% (n = 29), alcoholic 26% (n = 15), and others, 24% (n = 14). Regarding initial immunosuppressive strategy (IS), 51 patients (87.9%) were treated with standard regimen with corticosteroids (CS) and tacrolimus (TA), compared with 7 patients with impaired renal function (12.1%) who underwent a delayed therapy with calcineurin inhibitors (CNI) + mycophenolate mophetil (MMF) + CS. Concomitant use of anti-CD25 monoclonal antibodies was less than 10%. Regarding maintenance, 43 patients (74.1%) were treated with MMF + CNI versus 15 treated only with TA (25.9%).. Recurrence of HCC was approximately 12%: 7 patients (2 hepatic only, 5 also extra-hepatic). Exitus was established in 19 patients (32.75%); only 3 patients (5.17%) were attributable to HCC. Bivariate studies were conducted according to the initial IS (standard regimen versus delayed therapy) and maintenance therapy (MMF + TA versus TA alone), with no differences in any of them in recurrence, treatment toxicity, graft rejection, and dysfunction.. In our experience with the IS, we found no differences in the development of recurrent disease, treatment toxicity, development of graft dysfunction, or rejection. We believe that individualized immunosuppressive therapy in these patients is safe and effective.

Topics: Adrenal Cortex Hormones; Aged; Antibodies, Monoclonal; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Female; Graft Rejection; Graft Survival; Hospitals, University; Humans; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Renal Insufficiency; Retrospective Studies; Tacrolimus

Topics: Blindness, Cortical; Blood Group Incompatibility; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Confusion; Drug Substitution; Drug Therapy, Combination; Emergencies; Everolimus; Graft Rejection; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Photopheresis; Plasmapheresis; Sirolimus; Syndrome; Tacrolimus

Hepatocellular carcinoma is the fifth most common cancer worldwide and shows a complex clinical course, poor response to pharmacological treatment, and a severe prognosis. Thus, the aim of this study was to investigate whether tacrolimus (FK506) has synergistic antitumor effects with doxorubicin on two human hepatocellular carcinoma cell lines, Huh7 and HepG2. Cell viability was analyzed by Sulforhodamine B assay and synergic effect was evaluated by the software CalcuSyn. Cell apoptosis was evaluated using Annexin V and Dead Cell assay. Apoptosis-related protein PARP-1 cleaved and autophagy-related protein expressions (Beclin-1 and LC3B) were measured by western blotting analysis. Cytokines concentration in cellular supernatants after treatments was studied by Bio-Plex assay. Interestingly the formulation with doxorubicin and tacrolimus induced higher cytotoxicity level on tumor cells than single treatment. Moreover, our results showed that the mechanisms involved were (i) a strong cell apoptosis induction, (ii) contemporaneous decrease of autophagy activation, understood as prosurvival process, and (iii) downregulation of proinflammatory cytokines. In conclusion, future studies could relate to the doxorubicin/tacrolimus combination effects in mice models bearing HCC in order to see if this formulation could be useful in HCC treatment.

Topics: Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Hep G2 Cells; Humans; Immunosuppressive Agents; Liver Neoplasms; Tacrolimus

The aim of our study was to elucidate the effect of tacrolimus (FK506) and of C-X-C chemokine receptor type 4 (CXCR4), which is a receptor specific to the stromal cell-derived factor-1α (SDF‑1α), on growth and metastasis of hepatocellular carcinoma (HCC). Following treatment with different concentrations of FK506, AMD3100 or normal saline (NS), the proliferation of Morris rat hepatoma 3924A (MH3924A) cells was measured by the MTT assay, the expression of CXCR4 was analyzed with immunohistochemistry, and the morphological changes and the invasiveness of cells were studied with a transwell assay and under a scanning electron microscope, respectively. In addition, August Copenhagen Irish rat models implanted with tumor were used to examine the pathological changes and invasiveness of tumor in vivo, the expression of CXCR4 in tumor tissues and the expression of SDF‑1α in the adjacent tissues to the HCC ones, using immunohistochemistry. In vitro, FK506 (100‑1,000 µg/l) significantly promoted the proliferation of MH3924A cells (P<0.01), and increased the expression of CXCR4 in MH3924A cells, albeit with no significance (P>0.05). By contrast, AMD3100 had no effect on the proliferation of MH3924A cells, but significantly reduced the expression of CXCR4 (P<0.05). The invasiveness of MH3924A cells was significantly (P<0.01) enhanced following treatment with FK506, SDF‑1α, FK506 + AMD3100, FK506 + SDF‑1α or FK506 + AMD3100 + SDF‑1α. In vivo, tumor weight (P=0.041), lymph node metastasis (P=0.002), the number of pulmonary nodules (P=0.012), the expression of CXCR4 in tumor tissues (P=0.048) and that of SDF‑1α in adjacent tissues (P=0.026) were significantly different between the FK506-treated and the NS group. Our results suggest that FK506 promotes the proliferation of MH3924A cells and the expression of CXCR4 and SDF‑1α in vivo. Therefore, inhibiting the formation of the CXCR4/SDF‑1α complex may partly reduce the promoting effect of FK506 on HCC.

Topics: Animals; Benzylamines; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CXCL12; Cyclams; Disease Models, Animal; Heterocyclic Compounds; Immunohistochemistry; Immunosuppressive Agents; Liver Neoplasms; Lymphatic Metastasis; Rats; Receptors, CXCR4; Tacrolimus

To evaluate the influence of sirolimus on the long-term survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC).. Clinic data of 165 consecutive patients who underwent OLT for HCC from February 2005 to March 2012 was analyzed retrospectively. Among them, 94 patients were treated with a sirolimus-based immunosuppressive protocol after OLT, while the other 71 patients with a FK506-based protocol. Postoperative survival time, survival, disease-free survival (DFS) and tumor recurrence rates between the two groups were compared.. The 2 groups were comparable in all clinicopathologic parameters. The sirolimus-based group had higher patient survival rates than the control group at 1-year (87% vs. 97%, P = 0.03), 2-year (80% vs. 88%), 3-year (76% vs. 85%) and 5-year (63% vs. 75%). The 1-year, 2-year, 3-year and 5-year recurrence rates were 12% vs. 3%, 17% vs. 9%, 21% vs. 9% (P = 0.04) and 31% vs. 16% (P = 0.03). Early and mid-HCC (I - II stage) of 131 cases (control group 61 cases, sirolimus-based group of 70 patients). The 1-year, 2-year, 3-year and 5-year survival rates were 90% vs. 97% , 80% vs. 90%, 78% vs. 86% and 65% vs. 82% (P = 0.04) and recurrence rates were 10% vs. 3%, 16% vs. 8%, 18% vs. 8% and 29% vs. 11% (P = 0.01).. The sirolimus-based immunosuppressive protocol reduce long-term postoperative recurrence rate and improve the survival rate of patients after OLT for HCC significantly (especially early-mid HCC).

Topics: Adult; Carcinoma, Hepatocellular; Female; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Sirolimus; Survival Rate; Tacrolimus

Topics: Aged; Alcoholism; Biopsy; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Hepatitis C; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Time Factors

We report our experience with a 61-year-old patient with alcoholic and hepatitis C cirrhosis who underwent liver transplantation. On the 3rd postoperative day he presented a mediastinitis secondary to esophageal perforation produced by a Linton tube. An esophagectomy with jejunostomy was performed. Tacrolimus granules for oral suspension (Modigraf) were administered through the jejunostomy. This case report highlights the use of Modigraf and the absence of secondary effects. We observed biochemical parameters during the jejunostomy period. We discuss the administration strategy applied and whether tacrolimus granules for oral suspension by jejunostomy affect the bioavailability and its side effects.

Topics: Administration, Oral; Biological Availability; Carcinoma, Hepatocellular; Chemistry, Pharmaceutical; Esophageal Perforation; Esophagectomy; Hepatitis C; Humans; Immunosuppressive Agents; Jejunostomy; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Neoplasms; Liver Transplantation; Male; Mediastinitis; Middle Aged; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Topics: Anti-HIV Agents; Carcinoma, Hepatocellular; Cyclohexanes; Drug Interactions; Hepatitis B; HIV Infections; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Maraviroc; Middle Aged; Plasma; Tacrolimus; Treatment Outcome; Triazoles

Recurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenable to surgical approaches is associated with poor outcome.. Retrospective evaluation of the safety and efficacy of sorafenib in patients with post-transplant hepatocellular carcinoma recurrence.. Patients with post-transplant hepatocellular carcinoma recurrence were treated with sorafenib. Adverse events were assessed using National Cancer Institute Common Toxicity Criteria of AEs version 3.0, tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours.. First-line therapy after recurrence was surgery (n=6), radiation therapy (n=1), chemotherapy (n=1), and sorafenib (n=3). Finally, 11 patients were treated with sorafenib. Nine patients (82%) received an additionally targeted therapy with sirolimus as part of their immunosuppressive regimen. Most common grade 3 adverse events included diarrhoea (46%), hand-foot skin reaction (27%), nausea, fatigue, and leucopoenia (all 18%). Sorafenib had to be discontinued in two patients due to adverse events and six additional patients required a dose adjustment. No deterioration of liver graft function occurred. Median time to progression was 4.1 months; however, patients were treated with ongoing sorafenib in case of clinical benefit (median 8.9 months). Median overall survival after initiation of sorafenib treatment was 20.1 months.. Sorafenib in combination with immunosuppression including sirolimus may be administered to patients with post-transplant hepatocellular carcinoma recurrence with acceptable toxicity and without deterioration of liver graft function.

Topics: Adult; Aged; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Hepatocellular; Female; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Niacinamide; Phenylurea Compounds; Pyridines; Retrospective Studies; Sirolimus; Sorafenib; Tacrolimus

Steroids have been the mainstay of immunosuppressive regimen in liver transplantation. However, the use of steroids is associated with various post-transplant complications. This study evaluated the efficacy and safety of reduced immunosuppressive regimen with steroids (steroid elimination within 24 hours post-transplant) in a cohort of Chinese liver transplant recipients.. Seventy-six patients in line with the selection criteria were enrolled in this prospective study. All patients received anti-IL-2 receptor antibody induction and tacrolimus-based maintenance therapy. The recipients were divided into two groups according to the duration of steroid use: 40 transplant in a 3-month withdrawal group and the remaining 36 in a 24-hour elimination group. Recipient survival, post-operative infections, biopsy-proven acute rejection and steroid-resistant acute rejection, non-healing wound, recurrence of hepatitis B virus (HBV) and hepatocellular carcinoma (HCC), de novo diabetes, hyperlipidemia and hypertension were assessed in the two groups.. There was no significant difference in patient survival, incidence of acute rejection episodes and hyperlipidemia, and recurrence of HBV and HCC between the two groups. However, the incidence rates of post-transplant infection, non-healing wound, de novo diabetes and hypertension were significantly lower in the 24-hour elimination group than in the 3-month withdrawal group (all P values <0.05).. Under anti-IL-2 receptor antibody induction and tacrolimus-based maintainance, steroid elimination within 24 hours post-transplant is associated with reduced steroid-related complications without increasing the risk of rejection.

Topics: Antibodies, Anti-Idiotypic; Carcinoma, Hepatocellular; China; Follow-Up Studies; Graft Rejection; Hepatitis B; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Prospective Studies; Receptors, Interleukin-2; Recurrence; Steroids; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome; Withholding Treatment

We present the case of a liver transplant recipient with alcoholic liver cirrhosis and early-stage hepatocellular carcinoma who developed biopsy-proven acute steroid-resistant rejection 3 months after liver transplantation. After the failure of immunosuppressive therapy with intravenous boluses of 6-methyl-prednisolone and switching of the immunosuppressive regimen to tacrolimus plus mycophenolate mofetil, two doses of intravenous basiliximab were administered four days apart. Clinical, analytical, and biopsy-proven histological response was complete. No basiliximab-related adverse events were detected. Basiliximab may represent an alternative in liver transplantation immunosuppression to treat acute steroid-resistant rejection, without increasing the incidence of infections, neoplasms, or other adverse events, as shown by this case.

Topics: Acute Disease; Antibodies, Monoclonal; Basiliximab; Carcinoma, Hepatocellular; Cyclosporine; Drug Resistance; Graft Rejection; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Function Tests; Liver Neoplasms; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Pregnenediones; Receptors, Interleukin-2; Recombinant Fusion Proteins; Tacrolimus

Highly effective antiretroviral therapy in the last decade has increased the survival rates of HIV-positive patients, yielding a greater number of HIV patients suffering from liver-related disease. Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD) associated or not with hepatocellular carcinoma (HCC).. From June 2003 to September 2010, 23 patients underwent cadaveric donor LT for ESLD at our institution. Inclusion criteria followed the Italian Protocol for LT in HIV-positive patients. Immunosuppressive regimens were based on cyclosporine or tacrolimus, eventually switched to Rapamycin.. The median CD4 T-cell count was 275/mmc (range=119-924). All patients were affected by ESLD, which was associated with HCC in 14 cases. Ten patients were within the Milan criteria and four patients exceeded them but were within the San Francisco criteria. Conversion from calcineurin inhibitors (CNI) to rapamycin occurred in ten cases. Hepatitis C virus (HCV) recurrence occurred in 13/21 HCV-positive patients. Acute cellular rejection occurred in eight patients with one developing chronic cellular rejection. Overall patient and graft survivals at 80 months were 50% and 45% respectively.. LT in HIV-positive patients is a feasible procedure, even if in our experience was burdened by a greater incidence of complications including HCV recurrence and infection compared with HIV-negative patients.

Topics: Adult; Antiretroviral Therapy, Highly Active; Carcinoma, Hepatocellular; CD4 Lymphocyte Count; Cyclosporine; Drug Substitution; End Stage Liver Disease; Female; Graft Rejection; Graft Survival; Hepatitis C, Chronic; HIV; HIV Infections; Hospitals, University; Humans; Immunosuppressive Agents; Italy; Kaplan-Meier Estimate; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Recurrence; RNA, Viral; Severity of Illness Index; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome; Viral Load

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12-hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus-related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3-month patient survival (88.8% versus 95.4%) and 5-year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64-patient group with CNS complications and the asymptomatic group of 331 patients.

Topics: Adult; Carcinoid Tumor; Carcinoma, Hepatocellular; Central Nervous System Diseases; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus

Patients who undergo organ transplantation are now known to be at increased risk of the development of de novo malignant tumors. This is primarily a consequence of immunosuppression, which may promote tumor development and progression by a variety of mechanisms. It was also reported recently that the relative ratio of lung tumors developing in orthotopic liver transplantation patients was 3.7 times greater than in the general population. We report a case of de novo lung cancer diagnosed in a 65-year-old man 32 months after he underwent liver transplantation for hepatocellular carcinoma secondary to hepatitis C virus cirrhosis. He had received tacrolimus as immunosuppressive therapy after the liver transplantation. The tumor was resected, and he remains well almost 3 years later. Previous reports provide evidence that immunosuppressive therapy is a risk factor for de novo lung cancer; thus, it is important to reduce immunosuppression for orthotropic liver transplantation patients, and to screen them carefully to detect the tumor at an early stage.

Topics: Adenocarcinoma; Aged; Carcinoma, Hepatocellular; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Lung Neoplasms; Male; Neoplasms, Second Primary; Tacrolimus

To identify the levels of functional immunity measured by the ImmuKnow assay in Chinese liver transplantation recipients and its application in monitoring the risk of posttransplant infection.. Forty-five apparent healthy Chinese and 106 adult liver transplant (LT) recipients were under investigation. LTs were grouped in stable status or infection according to their clinical diagnosis. Whole blood samples were collected freshly and cultured within 6 hr, the CD4(+) T cells were selected, and their adenosine triphosphate (ATP) value was assayed the next day. Before stimulation, we also examined the percentage of T-helper (Th; CD3(+) CD4(+)) and T-suppress (Ts; CD3(+) CD8(+)) lymphocyte subpopulations and the ratio of Th/Ts.. The average ImmuKnow assay in infectious LT recipients was 128 + or - 84 ng/mL, significantly lower (P<0.05) than that in stable LTs (305 + or - 149 ng/mL) or in normal adults (301+ or - 101 ng/mL). The ImmuKnow values in LTs had a good negative correlation to infection clinically (r = -0.6217, P<0.001). Infectious risk was high when the ImmuKnow value was less than 130 ng/mL (odds ratio=13, 95% confidence interval 6.0-29.4, P<0.01). The sensitivity of low ImmuKnow values in posttransplant infection was 85.2%, significantly higher than those of Th/Ts ratio and immunosuppressant trough levels (P<0.01); specificity was 76.3%, comparable with that of Th/Ts ratio (75.5%), but greatly higher than immunosuppressant trough levels (P<0.01). ImmuKnow ATP values had no correlation with Th/Ts ratio or immunosuppressant trough levels.. ImmuKnow ATP levels are lower in LT recipients with infection, which provides a new tool in monitoring posttransplant infection, and an index of tailoring immunosuppression clinically.

Topics: Adult; Aged; Carcinoma, Hepatocellular; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Environmental Monitoring; Epidemiological Monitoring; Female; Humans; Immunosuppressive Agents; Infections; Liver Neoplasms; Liver Transplantation; Lymphocytes; Male; Middle Aged; Postoperative Complications; Retrospective Studies; T-Lymphocytes, Helper-Inducer; Tacrolimus; Young Adult

Tumor recurrence represents the main limitation of liver transplantation in patients with hepatocellular carcinoma (HCC) and can be favored by exposure to calcineurin inhibitors.. We investigated the effect of an immunosuppressant schedule that minimizes the exposure to calcineurin inhibitors on patients transplanted for HCC to ascertain whether this can reduce the tumor recurrence rate. For this purpose, we conducted a matched-cohort study: 31 patients with HCC transplanted between 2004 and 2007 who received sirolimus as part of their immunosuppression (group A) were compared with a control group of 31 patients (group B) transplanted in the same period who had the same prognostic factors but were given standard immunosuppression based on tacrolimus.. Three-year recurrence-free survival was 86% in group A and 56% in group B (P=0.04). Although the prevalence of microvascular invasion G3-G4 grading and alpha-fetoprotein more than 200 ng/mL was identical in the two groups, exposure to tacrolimus was significantly higher in patients of group B (median, 8.54; range, 5.5-13.5) in comparison with those of group A (median, 4.6; range, 1.8-9.1) (P=0.0001).. By using sirolimus, exposure to calcineurin inhibitors can be minimized, reducing the risk of HCC recurrence.

Topics: Adrenal Cortex Hormones; Adult; Aged; Carcinoma, Hepatocellular; Cohort Studies; Disease-Free Survival; Drug Administration Schedule; Female; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Risk Factors; Sirolimus; Survivors; Tacrolimus; Young Adult

To study the effects of sirolimus (SRL) on the growth of transplanted human hepatocellular carcinoma (HCC) in nude mice.. HepG2 cells were Implanted into the liver of nude mice. The implanted mice were then treated with SRL and tacrolimus (FK506). The expression of vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) was detected by immunohistology, microvessel density (MVD) was counted by immunostaining with anti-CD34 antibody for endothelial cells. Tumor apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay.. The tumor weight was (352+/-38) mg, (683+/-53) mg and (675+/-45) mg in SRL, FK506 and control group respectively. The tumor weight was significantly decreased in SRL group (P < 0.01), and there was no difference between FK506 group and control group. The expression of VEGF and PCNA protein was remarkably down-regulated in SRL group compared to control group (P < 0.05), and it was not significantly different between FK506 group and control group (P > 0.05). Compared to the control group, MVD was significanly decreased in SRL group, and the apoptosis index of tumor cell was significantly higher in SRL group (P < 0.01).. SRL inhibits transplanted HCC tumor growth by reducing tumor angiogenesis, inhibiting tumor proliferation and inducing tumor apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Hep G2 Cells; Humans; Immunohistochemistry; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Proliferating Cell Nuclear Antigen; Sirolimus; Tacrolimus; Treatment Outcome; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Tumor recurrence after liver transplantation for hepatocellular carcinoma is associated with a poor prognosis. Because immunosuppression is a well-known risk factor for tumor growth, it is surprising that its possible role in the outcome of liver transplantation has been poorly evaluated. We performed a case-control review of prospectively collected data and compared 2 groups of patients according to the type of immunosuppression after liver transplantation for hepatocellular carcinoma at a single center. One hundred six patients received tacrolimus and mycophenolate mofetil, and 121 received sirolimus. Patients in the sirolimus group had significantly higher recurrence-free survival rates than patients in the tacrolimus group (P = 0.0003). The sirolimus group also had significantly higher patient survival rates than the tacrolimus group at 1 year (94% versus 79%), 3 years (85% versus 66%), and 5 years (80% versus 59%; P = 0.001). Sirolimus was well tolerated, and the patients in this study did not have the increase in surgical complications noted by other investigators. Leukopenia was the most common side effect, but it typically resolved with dose reduction. Dyslipidemia and mouth ulcers were common but were easily controlled. In summary, the data suggest a beneficial effect of sirolimus immunosuppression on recurrence-free survival, which translates into patient survival benefits.

Topics: Carcinoma, Hepatocellular; Case-Control Studies; Chemotherapy, Adjuvant; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Recurrence; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

We assessed the effect of tacrolimus on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) and compared it with that of the other calcineurin inhibitor, cyclosporine.. HCC recurrence after LT can be favored by overexposure to cyclosporine. Tacrolimus is now the most widely used main immunosuppressant after LT; its possible effect on HCC recurrence has never been investigated.. One hundred and thirty nine HCC patients who had LT were reviewed; 60 of them were administered tacrolimus, and 79, cyclosporine. The exposure to the drugs was calculated with the trapezoidal rule in each patient, using blood levels measured after transplantation and compared with HCC recurrence together with several clinical and pathologic risk factors.. HCC recurred in 12 of the 60 (20%) patients under tacrolimus in comparison with that in 9 of the 79 (11.4%) patients under cyclosporine; however, the proportion of poorly differentiated and more advanced tumors was significantly higher in the tacrolimus group than in the cyclosporine group. Exposure to tacrolimus was 11.6 +/- 1.5 ng/mL in patients with recurrence and 8.6 +/- 1.7 ng/mL in those without recurrence (P < 0.001). The optimal cut-off values of exposure identified with receiver operating characteristics analysis to categorize the risk of recurrence were 10 ng/mL for tacrolimus (area under the curve (AUC) = 0.913) and 220 ng/mL for cyclosporine (AUC = 0.752). In the tacrolimus group, high drug exposure independently predicted recurrence (P = 0.005). Multivariate analysis, including all patients (tacrolimus + cyclosporine) characterized higher exposure to immunosuppression (P = 0.01), alpha-fetoprotein levels (P = 0.001), tumor grading (P = 0.009), and microvascular invasion (P = 0.04) as independent predictors of HCC recurrence.. Just as it is with cyclosporine, overexposure to tacrolimus increases the risk of HCC recurrence after LT. Careful management of calcineurin inhibitors is recommended in HCC patients.

Topics: Adult; alpha-Fetoproteins; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Female; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Risk Factors; ROC Curve; Sensitivity and Specificity; Tacrolimus

Sirolimus (SRL) acts as a primary immunosuppressant or antitumor agent. The aim of the present study was to evaluate the influence of SRL on the recurrence rate and survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) exceeding the Milan criteria.. We retrospectively examined 73 consecutive patients who underwent OLT for HCC exceeding the Milan criteria from March 2004 through December 2005. Among them, 27 patients were treated with SRL-based immunosuppressive protocols after OLT, and 46 patients by an FK506-based protocol. Statistical analysis was based on the intent-to-treat method.. The 2 groups were comparable in all clinicopathologic parameters. The mean overall survival was 594 +/- 35 days in the SRL group and 480 +/- 42 days in the FK506 group (P = .011); the mean disease-free survival period was 519 +/- 43 days in the SRL group and 477 +/- 48 days in the FK506 group (P = .234). Multivariate analysis revealed Child's status (P = .004) and immunosuppressive protocol (P = .015) were the significant factors affecting overall survival. Only microvascular invasion (P = .004) was significantly associated with disease-free survival. Among 24 surviving patient in the SRL group, 2 patients had SRL discontinued for toxicity; 10 had SRL monotherapy immunosuppression.. The SRL-based immunosuppressive protocol improved the overall survival of patients after OLT for HCC exceeding the Milan criteria, probably by postponing recurrence and with better tolerability.

Topics: Adolescent; Adult; Carcinoma, Hepatocellular; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Patient Selection; Retrospective Studies; Sirolimus; Survival Analysis; Survivors; Tacrolimus

An enzyme multiplied immunoassay technique (EMIT) provides convenient and accurate measurements of mycophenolic acid (MPA) concentrations for determination of immunosuppression during treatment with mycophenolate mofetil (MMF). No abbreviated model for estimating the full 12-hour MPA AUC using an EMIT assay in liver transplant recipients has been described previously.. This study was conducted to determine the best model for predicting the MPA AUC using the EMIT method and a limited-sampling strategy in Chinese patients undergoing liver transplantation.. The study enrolled consecutive liver transplant patients who were receiving MMF 1 g BID along with tacrolimus. A complete MPA pharmacokinetic profile was obtained for each patient on a single day, 7 to 14 days after transplantation. The EMIT method was used to determine MPA concentrations before dosing and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing on the sampling day. Multiple linear regression analysis was used to evaluate potential models for estimating the full 12-hour MPA AUC. The accuracy and robustness of the models were evaluated using bootstrap analysis. Prediction error and prediction bias were calculated. Agreement between the estimated MPA AUC(0-12) and the full 12-hour MPA AUC was investigated using Bland-Altman analysis.. The study enrolled 48 Chinese liver transplant recipients (45 male, 3 female) with a mean (SD) age of 50 (12) years, mean weight of 64 (12) kg, and mean height of 169 (6) cm. Twenty-four models that included blood sampling at 1 through 4 time points were developed (r(2) = 0.015-0.950). Four models with the highest r(2) values were selected; the lack of significant differences from the original dataset on bootstrap analysis indicated acceptable accuracy and robustness. The best model for predicting the MPA AUC(0-12) employed concentrations at 1, 2, 4, and 8 hours; 40 of 48 (83.3%) MPA AUC(0-12) values estimated using this model were within 15% of the full 12-hour MPA AUC. This model had a minimal mean prediction error (mean [SD], 0.27% [1.79%]) and mean absolute prediction error (8.83% [1.24%]). On Bland-Altman analysis, this model also had the best agreement between the estimated MAP AUC(0-12) and the full 12-hour MPA AUC, with a mean error of 9.02 mg . h/L.. In this small group of Chinese liver transplant patients receiving MMF and concomitant tacrolimus, models for estimating the MPA AUC(0-12) were developed using the EMIT method and a limited-sampling strategy. The best model for prediction of the full 12-hour MPA AUC was 4.46 + 0.81 . C1 + 1.78 . C(2)+2.51.C(4)+4.94.C8.

Topics: Adult; Antibiotics, Antineoplastic; Area Under Curve; Asian People; Bile Duct Neoplasms; Carcinoma, Hepatocellular; China; Enzyme Multiplied Immunoassay Technique; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Injections, Intravenous; Liver Neoplasms; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Models, Biological; Mycophenolic Acid; Prednisone; Tacrolimus; Time Factors

Experience with sirolimus (SRL)-based immunosuppression following orthotopic liver transplantation (OLT) is rapidly accumulating. In combination with calcineurin inhibitors (CNIs), SRL may reduce the incidence of acute rejection and lower overall required drug levels. This study sought to quantify long-term outcome following OLT in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC) who were treated with an SRL-based regimen as a primary therapy. From January 2000 to June 2007, 97 patients underwent OLT for end-stage liver disease and HCC at the University of Colorado Health Sciences Center. Of those, 45 patients received SRL, in addition to CNIs, as a component of their primary immunosuppression regimen post-OLT. Conversely, 52 patients received the standard immunosuppression regimen including CNIs, mycophenolate mofetil, and corticosteroids. The 2 treatment groups were compared with respect to the following variables: age, gender, tumor stage by explant, grade, size, presence of vascular invasion, focality, Child's class, baseline creatinine, and warm and cold ischemic times. The 2 groups were comparable by all factors save for cold ischemic time, which was significantly longer in the CNI-treated group. Overall survival at 1 and 5 years post-OLT for patients treated with SRL was 95.5% and 78.8%, respectively. Conversely, survival in patients treated with CNIs exclusively at the same time intervals was 83% and 62%. Although there was no difference in the incidence of major complications, the SRL group experienced a modest improvement in renal function. Cumulatively, these data suggest a potential survival benefit with SRL-based therapy in patients undergoing OLT for end-stage liver disease and concomitant malignancy.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Liver Failure; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Tumor recurrence after liver transplantation still remains a significant problem in patients with hepatocellular carcinoma. The small GTPase Rho/Rho-associated kinase (ROCK) pathway is involved in the motility and invasiveness of cancer cells. We investigated whether tacrolimus activated the Rho/ROCK signal pathway to promote the invasiveness of rat hepatocellular carcinoma cells. We also investigated whether the ROCK inhibitor Y-27632 suppressed tumor recurrence after experimental liver transplantation in a rat hepatocellular carcinoma model. Orthotopic liver transplantation was performed in hepatocellular carcinoma cell line McA-RH7777-bearing rats. Tacrolimus was administered to liver transplant rats and these rats were divided into two groups: the Y-27632-treated (10 mg/kg, for 28 days) group and the Y-27632-untreated group. Tacrolimus enhanced the cancer cell migration and stimulated phosphorylation of the myosin light chain (MLC), a downstream effector of Rho/ROCK signaling. Y-27632 suppressed the cancer cell migration and tacrolimus-induced MLC phosphorylation. Suppression of tumor recurrence after liver transplantation and significant prolongation of survival were observed in the Y-27632-treated rats in comparison with theY-27632-untreated rats. Tacrolimus stimulates the Rho/ROCK signal pathway to enhance the invasiveness of hepatocellular carcinoma, and the ROCK inhibitor Y-27632 can be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.

Topics: Amides; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Enzyme Inhibitors; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Liver Neoplasms, Experimental; Liver Transplantation; Male; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Protein Serine-Threonine Kinases; Pyridines; Rats; Rats, Inbred BUF; rho-Associated Kinases; Signal Transduction; Tacrolimus

To evaluate the impact of early steroid withdrawal on the incidence of rejection, tumor recurrence and complications after liver transplantation for advanced-stage hepatocellular carcinoma.. Fifty-four patients underwent liver transplantation for advanced-stage hepatocellular carcinoma from April 2003 to June 2005. These cases were divided into a steroid-withdrawal group (group A, n = 28) and a steroid-maintenance group (group B, n = 26). In group A, steroid was withdrawn 3 mo after transplantation. In group B, steroid was continuously used postoperatively. The incidence of rejection, 6-mo and 1-year recurrence rate of carcinoma, 1-year survival rate, mean serum tacrolimus trough level, and liver and kidney function were compared between the two groups.. In the two groups, no statistical difference was observed in the incidence of rejection (14.3 vs 11.5%, P > 0.05), mean serum tacrolimus trough levels (6.9 +/- 1.4 vs 7.1 +/- 1.1 microg/L, P > 0.05), liver and kidney function after 6 mo [alanine aminotransferase (ALT): 533 +/- 183 vs 617 +/- 217 nka/L, P > 0.05; creatinine: 66 +/- 18 vs 71 +/- 19 micromol/L, P > 0.05], 6-mo recurrence rate of carcinoma (25.0 vs 42.3%, P > 0.05), and 1-year survival rate (64.2 vs 46.1%, P > 0.05). The 1-year tumor recurrence rate (39.2 vs 69.2%, P < 0.05), serum cholesterol level (3.9 +/- 1.8 vs 5.9 +/- 2.6 mmol/L, P < 0.01) and fasting blood sugar (5.1 +/- 2.1 vs 8.9 +/- 3.6 mmol/L, P < 0.01) were significantly different. These were lower in the steroid-withdrawal group than in the steroid-maintenance group.. Early steroid withdrawal was safe after liver transplantation in patients with advanced-stage hepatocellular carcinoma. When steroids were withdrawn 3 mo post-operation, the incidence of rejection did not increase, and there was no demand to maintain tacrolimus at a high level. In contrast, the tumor recurrence rate and the potential of adverse effects decreased significantly. This may have led to an increase in long-term survival rate.

Topics: Adult; Carcinoma, Hepatocellular; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Steroids; Survival Rate; Tacrolimus

To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapamune, rapamycin) in a consecutive cohort of 248 liver allograft recipients.. Thirty-six liver transplant patients with hepatocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n = 18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT.. The patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT. Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo posttransplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable.. The conversion to SRL-based immunosuppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.

Topics: Adaptor Proteins, Signal Transducing; Adult; Calcineurin; Carcinoma, Hepatocellular; Female; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phosphoproteins; Renal Insufficiency; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation; Transplantation, Homologous

To investigate the effects of inflammation cytokines, (FK506) and cyclosporine (CSA) on albumin secretion, and the effects of FK506 and CSA on the IL-6 induced suppression of albumin synthesis in cultured human hepatocytes.. Human hepatoma cell lines (HepG2 cells) were separately cultured with IL-6, IL-2 and IL-10 (0 approximately 10 microg/L) and FK506, CSA (0 approximately 100 microg/L) for 48 h. In another experiment, HepG2 cells were stimulated with different doses of FK506 and CSA (0 approximately 10 microg/L) in the presence of IL-6 (5 microg/L) for 48 h. Albumin levels in the supernatant of all groups were measured by radioimmunoassay (RIA). The concentration of LDH secreted by cells stimulated with FK506 and CSA were detected with spectrophotometry.. For cultured HepG2 cells, IL-6 significantly decreased albumin levels in a dose-dependent manner (P <0.01), and the maximal inhibition occurred at 5 microg/L. CSA mildly decreased albumin levels and a significant reduction in albumin production was first visible at 10 microg/ L (P <0.05). In contrast, IL-2, IL-10 and FK506 did not significantly influence albumin pro- duction (P > 0.05). FK506 obviously decreased LDH levels in the supernatant (P < 0.05) and attenuated IL-6 induced suppression of albumin synthesis (P < 0.01). But CSA slightly increased LDH concentration and could not block the IL-6 induced decrease of albumin synthesis (P > 0.05).. IL-6 but not IL-2 and IL-10 suppressed the production of hepatic albumin in vitro. FK506 protected against the suppression of hepatic albumin synthesis caused by IL-6, suggesting its potential role in improving hypoalbuminaemia in immune glomerulonephritis.

Topics: Albumins; Carcinoma, Hepatocellular; Cyclosporine; Hepatocytes; Humans; Interleukin-10; Interleukin-2; Interleukin-6; Liver Neoplasms; Tacrolimus; Tumor Cells, Cultured

Relative adrenal insufficiency is now a well-known clinical condition that occurs in critically ill patients particularly with septic complication. However, this pathology has long been unrecognized until recently in liver transplantation patients, for whom postoperative immunosuppressive therapies almost always comprise corticosteroids. We report an obvious case of relative adrenal insufficiency manifested by severe multiple organ dysfunction in a recipient after living donor liver transplantation (LDLT). A 38-year-old woman with multiple hepatocellular carcinoma developed refractory liver failure 2 months after the completion of the dual treatment; namely a cytoreductive right hepatectomy for bulky main tumors followed by 2 courses of percutaneous isolated hepatic perfusion for residual tumors in the remnant liver. She underwent a right-lobe LDLT, and postoperative immunosuppression was initiated with a low-dose tacrolimus monotherapy without corticosteroid because of a severe septic condition before transplantation. Postoperatively, she developed progressive hyperbilirubinemia, renal dysfunction, and coagulopathy. As the corticotropin stimulation test suggested the relative adrenal insufficiency, corticosteroid was commenced 40 days after LDLT. Thereafter, multiple organ dysfunction resolved dramatically and promptly. The patient is presently alive and well with completely normalized liver function 45 months after LDLT.

Topics: Adrenal Insufficiency; Adult; Carcinoma, Hepatocellular; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Methylprednisolone; Multiple Organ Failure; Postoperative Complications; Radiography, Abdominal; Tacrolimus; Tomography, Spiral Computed

Standard immunosuppression after organ transplantation stimulates tumor growth. Sirolimus has a strong antiproliferative and a tumor inhibiting effect. The purpose is to assess the effect on tumor growth of the immuno-suppressive compounds sirolimus and tacrolimus alone and in combination on cells of human hepatocellular carcinoma.. We used the human cell lines SK-Hep 1 and Hep 3B derived from hepatocellular carcinoma. Proliferation analyses after treatment with sirolimus, tacrolimus, or the combination of both were performed. FACS analyses were done to reveal cell cycle changes and apoptotic cell death. The expression of apoptosis-related proteins was estimated by Western blots.. Sirolimus alone or combined with tacrolimus inhibited the growth of both cell lines after 5 d by up to 35% in SK-Hep 1 cells, and by up to 68% in Hep 3B cells at 25 ng/mL. Tacrolimus alone stimulated the growth by 12% after 5 ng/mL and by 25% after 25 ng/mL in Hep 3B cells. We found an increase of apoptotic Hep 3B cells from 6 to 16%, and a G1-arrest in SK-Hep 1 cells with an increase of cells from 61 to 82%, when sirolimus and tacrolimus were combined. Bcl-2 was down-regulated in Hep 3B, but not in SK-Hep 1 cells after combined treatment.. Sirolimus appears to inhibit the growth of hepatocellular carcinoma cells alone and in combination with tacrolimus. Sirolimus seems to inhibit the growth stimulation of tacrolimus.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Division; Cell Line, Tumor; Drug Combinations; G1 Phase; Humans; Immunosuppressive Agents; Liver Neoplasms; Sirolimus; Tacrolimus

The effect of tacrolimus (FK506) and 5-fluorouracil (5-FU) on hepatocellular carcinoma remains elusive. The aim of this study was to assess the effect of tacrolimus on the proliferation, and apoptosis in liver cancer cell line of SMMC-7721 and its sensitivity to fluorouracil (5-FU).. The liver cancer cell line of SMMC-7721 was cultured in vitro, and the MTT assay was used to examine the antiproliferative effect of FK506. Flow cytometry (FCM) was used to examine the effect of 5-FU alone or in combination with FK506 on the apoptosis and cell cycle of SMMC-7721 cells.. FK506 produced concentration-dependent antiproliferative effect on SMMC-7721 cells at all experimental concentrations (P<0.05), but no effect on induction of apoptosis. 5-FU induced apoptosis in a concentration-dependent manner, whereas the percentage of G0/G1-phase cells and proliferation index (PI) were increased with the increased concentration of 5-FU. Pretreatment with FK506 for 2 hours enhanced the effect of 5-FU on the induction of apoptosis.. FK506 inhibits the growth of SMMC-7721 cells and enhances their sensitivity to 5-FU. This may be associated with the synergic effect of FK506 and 5-FU in inducing apoptosis and G0/G1-phase stasis.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Female; Fluorouracil; Hepatocytes; Humans; Liver Neoplasms; Male; Probability; Sampling Studies; Sensitivity and Specificity; Tacrolimus

Liver transplantation is the only curative treatment option for patients with cirrhosis and unresectable hepatocellular carcinoma (HCC) without extrahepatic dissemination. Criteria for transplantation in HCC are controversial. In this study, we evaluate the early results of liver transplantation for unresectable HCC. Between 2003 and 2004, 10 patients (three woman, seven men; aged 1.1 to 64 years) with occult or incidental HCC underwent liver transplantation. The inclusion criteria (independent of tumor size and number of tumor nodules) were: no invasion of major vascular structures and no evidence of extrahepatic disease, including that based on hilar lymph node biopsy and cytopathological examination of intraperitoneal fluid. Eight patients (80%) received tacrolimus and two patients (20%) received rapamycin monotherapy with early withdrawal of the corticosteroid. Four patients had neoadjuvant chemoembolization before transplantation. None of the patients received adjuvant chemotherapy. Two patients with hepatitis B virus cirrhosis underwent antiviral prophylaxis with anti-HBs antibody and lamivudine. During follow-up (range, 8 to 19 months), all patients did well with excellent graft function. There was no evidence of tumor recurrence on imaging studies, and there were no elevations in alpha fetoprotein or carcinoembryonic antigen levels. Low-dose immunosuppression and expanded criteria for liver transplantation for HCC appear to have beneficial effects on disease recurrence and patient outcomes, especially in regard to living donation.

Topics: Adolescent; Adult; Carcinoma, Hepatocellular; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Patient Selection; Recurrence; Tacrolimus; Time Factors; Treatment Outcome

The prognosis of liver transplantation for liver cancer is determined by recurrence in the liver graft. In this study, the effects of immunosuppressors, FK506 and cyclosporine A (CsA) on the migration of liver cancer cells were investigated.. The effects of FK506 at concentrations of 1-100 ng/mL and CsA at 1-1000 ng/mL on the growth of poorly and well differentiated human hepatocellular carcinoma cell lines, HLE and HuH-7, respectively, were examined. After treatment of these cells with FK506 and CsA, the growth of these cells, their cytotoxicities and invasion assay on the Matrigel basement membrane invasion chamber were evaluated. In addition, the effects of FK506 and CsA on the changes in the production of a soluble intercellular adhesion molecule-1 (sICAM-1) of these cells were measured.. FK506 and CsA at concentrations of 1-10 ng/mL inhibited the growth of both HLE and HuH-7 and those immunosuppressors at concentrations over 100 ng/mL exhibited cytotoxicity on these cells. FK506 at concentration of 1 ng/mL significantly inhibited the invasion of poorly differentiated HLE, but not well differentiated HuH-7, after treatment for 2-5 days in culture (p<0.05), but FK 506 at 10 ng/mL showed less inhibitory efficient. CsA at concentrations of 1-10 ng/mL, however, did not inhibit or transiently inhibited the invasion of both cell lines. The production of ICAM-1 in HLE and HuH-7 was suppressed by FK506 at concentrations of 1-10 ng/mL after treatment for 3-5 days but the effect was not significant in the initial phase at days 1-2 and the last phase at days 5-6.. FK506, but not CsA, at a clinical dose of 1 ng/mL significantly inhibited the invasion of the poorly-differentiated HLE, but not HuH-7 and also inhibited the production of sICAM-1 in HLE.

Topics: Carcinoma, Hepatocellular; Cell Division; Cell Line, Tumor; Cyclosporine; Humans; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Liver Neoplasms; Neoplasm Invasiveness; Tacrolimus

Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2(k)), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 x 10(6) MH134 cells (H-2(k)) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-gamma, and IFN-gamma-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2(d)) and tumors, B7-p815 (H-2(d)) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Immunologic; Electroporation; Female; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Graft Rejection; Growth Inhibitors; Immunosuppressive Agents; Interleukin-12; Killer Cells, Natural; Liver Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Neoplasm Metastasis; Neoplasm Transplantation; Skin Transplantation; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Tacrolimus

FKBP51 and FKBP52 are large molecular weight FK506-binding immunophilins that have diverse biochemical functions. Best studied is the role that they play as components of steroid hormone receptors. Differential display and gene array screens have identified FKBP51 as a progestin-inducible gene. Here we demonstrate progestin enhancement of FKBP51 mRNA and protein in T-47D cells. FKBP51 mRNA and protein levels were increased 3-fold by 20 nM R5020. Induction of FKBP51 mRNA was unaffected by 1 micro g/ml cycloheximide but was blocked by the progestin receptor (PR) antagonist RU486 (1 micro M). Reporter plasmids containing 3.4 kb and 427 bp of 5'-flanking sequences of the human FKBP51 protein gene (FKBP5) exhibited regulation by progestin in T-47D cells. A construct containing 19 bp of upstream sequence demonstrated diminished basal activity and no stimulation by R5020. To test whether elevated FKBP51 affects progestin responsiveness, HepG2 cells were transfected with human FKBP51, PR, and mouse mammary tumor virus-luciferase plasmids, and treated with R5020 (0.03-10 nM). Expression of FKBP51 increased the EC(50) for PR transactivation by 3.2-fold. Expression of FKBP51 from squirrel monkey, a New World primate with naturally occurring progestin resistance, increased the EC(50) more dramatically (11.7-fold vs. control). Expression of FKBP51 bearing a double-point mutation in the tetratricopeptide repeat domain had no effect on PR transactivation. These results suggest that increased expression of FKBP51 by progestin may attenuate progestin responsiveness in hormone-conditioned cells. Furthermore, overexpression of FKBP51 in the squirrel monkey may be a contributing cause of progesterone resistance in this species.

Topics: Animals; Base Sequence; Breast Neoplasms; Carcinoma, Hepatocellular; Gene Expression; Humans; Liver Neoplasms; Molecular Sequence Data; Progesterone Congeners; Promegestone; Promoter Regions, Genetic; Saimiri; Sequence Homology, Nucleic Acid; Tacrolimus; Tacrolimus Binding Proteins; Transcription, Genetic; Tumor Cells, Cultured

To investigate the effect of combined CsA and FK506 with 5-FU on hepatocellular carcinoma rats.. A syngeneic rat model of hepatocellular carcinoma was used. Control group (A) underwent 4 ml 5% GS. Treatment group was divided into 3 groups namely, group B: only 5-FU and 5% GS; group C: 5-FU, CsA and 5% GS; group D: 5-FU, FK506 and 5%GS. Cell cycle, apoptosis, necrosis and mitochondrial transmembrane potential were measured by flow cytometry, laser scanning confocal microscopy, and electron transmission microscopy. Statistical analysis was performed by SPSS 10.0 for Windows software. Statistical comparisons were made with ANOVA followed by Dunnett's T3 or LSD test.. Compared to the control group, the percentage of apoptotic cells including trifle necrotic cells was significantly higher, and among the treatment group, group D was the highest, and group C was higher than group B. In the treatment group, cell cycle of hepatoma cells was mainly arrested at S phase, but in group D, G0/G1 phase cells were significantly decreased and S phase cells significantly increased. Compared to the control group, mitochondrial transmembrane potential was significantly decreased in the treatment group, among with, group B was the lowest, group C was higher than group D. Morphological changes demonstrated by electron microscopy included dispersed nuclear chromatin, loss of nucleoli, membrane bleeding, cell shrinkage, typical apoptotic bodies and marked swelling of mitochondria in the treatment group. In the control group, however, they were characterized by normal cell ultrastructure.. The present study reveals that 5-FU combined with CsA or FK506 demonstrated a synergistic effect on hepatocellular carcinoma rats. For FK506, the powerful mutual effect is related to the increase of tumor cell's quantity in S phase. Both CsA and FK506 can provide protection on mitochondrial transmembrane potential reduction against hepatoma cells damage from 5-FU.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cyclosporine; Fluorouracil; Liver Neoplasms; Male; Membrane Potentials; Mitochondria; Necrosis; Rats; Rats, Wistar; Tacrolimus

Topics: Carcinoma, Hepatocellular; Cell Division; Humans; Immunosuppressive Agents; Liver Neoplasms; Sirolimus; Tacrolimus; Tumor Cells, Cultured

Five cases that were referred to the Division of Transplantation at NYU School of Medicine for consideration for liver transplantation were discussed among a panel of hepatitis B and liver transplant experts. Opinions were obtained on the management at every stage of treatment of patients with the following initial information: Case one: young Asian woman in stage IV hepatic coma; intubated; prothrombin time (PT): 30 s; serum glutamic oxaloacetic transaminase (SGOT): 8,000 IU; total bilirubin: 25 mg/dL; hepatitis B surface antigen (HBsAg) positive. Case two: 70-yr-old woman, native of Greece; decompensated cirrhosis with encephalopathy; Child-Pugh Class C; HBsAg positive; hepatitis B surface antibody (HBsAb) negative; hepatitis B e antigen (HBeAg) positive; hepatitis B e antibody (HBeAb) negative; hepatitis B virus (HBV) DNA titer: 10,000. Case three: Muscular detective working full-time; cirrhosis; Child Pugh Class B; ascites controlled with spironolactone and furosemide; PT: 19s; HBsAg positive; HBsAb negative; HBV DNA titer: 50,000; low platelet count. Case four: 45-yr-old baker; cirrhosis and resectable 4-cm hepatoma; Child-Pugh Class B; PT: 16 s; Blood type O; United Network for Organ Sharing (UNOS) 2B; HBV DNA titer: 3,000. Case five: 40-yr-old Indian man; 300 pounds with massive ascites; Child Pugh Class C; PT: 17 s; HBsAg positive; HBV DNA titer: 22,000; transplanted with intra-operative hypotension; tacrolimus; graft functioning; HBIg 10,000 IU intra-operative and around the clock during the first post-operative week; required huge doses of hepatitis B immune globulin (HBIg) to maintain adequate HBsAb level; daily loss of 5 6 L of ascites fluid; post-operative day 8: anuric, blood urea nitrogen (BUN) 127, creatinine 3, mental status changes.

Topics: Adult; Aged; Antiviral Agents; Ascites; Carcinoma, Hepatocellular; Female; Hepatic Encephalopathy; Hepatitis B; Humans; Immunization, Passive; Immunoglobulins; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Middle Aged; Tacrolimus

Liver transplantation (LTx) for alcohol-related liver disease (ALD) is an accepted modality of treatment and is one of the most common indications for LTx in the United States. The present report examines the long-term patient survival, graft survival, rates of recidivism, and development of de novo cancers in this group, and compares these results with a contemporaneous group of patients who were transplanted for non-ALD indications.. Between August 1989 and December 1992, 185 adults received LTx for ALD (group I). During the same time interval, 649 adults received LTx for non-ALD (group II). The mean follow-up time was 94+/-10.7 months for group I vs. 92+/-11 months for group II. Kaplan-Meier survival estimates and the incidence of cancers using Surveillance Epidemiologic End Result data were compared in both groups.. At 5 years after orthotopic LTx, the overall patient survival and graft survival for group I were 72.0% and 66.5% vs. 66.5% and 60.3% for group II, respectively. After 5 years, the patient survival and graft survival for the alcoholic group were significantly lower (P=0.001) compared to the non-alcoholic group. The rate of de novo oropharyngeal cancer and lung cancer was 25.5 times and 3.7 times higher, respectively, in ALD group compared with the general population matched for age, sex, and length of follow-up (P=0.001), whereas this was not higher in the non-ALD group. Prior pretransplant length of sobriety and alcohol rehabilitation was not associated with the rate of post-LTx rate of recidivism, which was 20%. Out of 79 deaths in group I, only 1 was attributed to recidivism and 3 to noncompliance with recidivism. The other deaths occurred from de novo cancer (n=13), posttransplant lymphoproliferative disorder (n=5), age-related complications (n=23), and other infection or miscellaneous causes (n=34).. Patient and graft survival past 5 years after orthotopic LTx is significantly lower for ALD for a variety of reasons (P=0.001). The rate of upper airway malignances was significantly higher in ALD patients than for non-ALD post-LTx patients and the general public. Graft loss/death related to recidivism or chronic rejection was extremely low. More attention is needed for early diagnosis of de novo cancer and prevention of cardiorespiratory and cerebrovascular complications.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Survival Rate; Tacrolimus; Time Factors

The present study was designed to elucidate the effectiveness of portal decompression and FK506 (FK) pretreatment in extended hepatectomy in dogs. In the first set of experiment the effect of portal decompression was evaluated in two groups of dogs which underwent extended hepatectomies (80%) with or without (control) a side-to-side portacaval shunt. The presence of the shunt significantly (p < 0.05) improved the 7-day survival of the animals (57.1%) when compared with those of the control group (28.6%) and eventually the portal pressure was significantly lower and mean arterial pressure was significantly higher in the shunt group (p < 0. 05). Moreover, the animals with lower portal pressure (

Topics: Animals; Carcinoma, Hepatocellular; Dogs; Female; Hepatectomy; Humans; Hypertension, Portal; Liver Neoplasms; Liver Regeneration; Male; Portacaval Shunt, Surgical; Tacrolimus

A new case of anti-factor V inhibitor is described in a 46-year-old man, who received a liver transplantation for hepatocellular carcinoma, without exposure to bovine thrombin or fibrin glue during the operative course. The inhibition occurred on the 14th postoperative day, while the patient was being treated with oxacillin, azathioprine, and a new immunosuppressive drug, FK506. The inhibition was of short duration (3 days), and no bleeding complication occurred despite a very low plasmatic level of factor V activity and antigen (<5%). Plasma samples drawn after cessation of FK506 disclosed a dose-dependent inhibitory activity when alcoholic solutions of FK506 were exogeneously added; this suggests a possible role of the FK506 drug in the occurrence of this anti-factor V inhibitor.

Topics: Carcinoma, Hepatocellular; Dose-Response Relationship, Drug; Factor V; Humans; Immunoglobulins; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Tacrolimus

Topics: Acute-Phase Proteins; Carcinoma, Hepatocellular; Cell Survival; Cyclosporine; Humans; Immunosuppressive Agents; L-Lactate Dehydrogenase; Liver; Liver Neoplasms; Serum Albumin; Tacrolimus; Transferrin; Tumor Cells, Cultured

Topics: Carcinoma, Hepatocellular; Cyclosporine; Graft Rejection; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Postoperative Complications; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus

Topics: Carcinoma, Hepatocellular; Cyclosporine; Follow-Up Studies; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma; Neoplasms; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Carcinoma, Hepatocellular; Cyclosporine; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms; Liver Transplantation; Muromonab-CD3; Mycophenolic Acid; Tacrolimus

As resolved by electrophoresis in non-reducing SDS gels, transferrin newly made in Hep G2 cells migrates as a very diffuse set of species. During a subsequent 1-h chase all transferrin polypeptides are converted to a single, rapidly migrating species. These changes in gel mobility are due to alterations in the pattern of disulfide bonding, are not caused by carbohydrate processing, and occur while the protein is in the rough endoplasmic reticulum. Cyclosporin A causes an approximately 10-min lag in transferrin folding, after which folding resumes at the normal rate. Cyclosporin A also retards transferrin maturation from the endoplasmic reticulum and its secretion, at concentrations that do not affect secretion of other hepatoma proteins. Neither FK506 nor rapamycin affect transferrin folding. We conclude that an initial stage in transferrin folding is accelerated by an endoplasmic reticulum peptidyl-proline isomerase that is inhibited by cyclosporin A.

Topics: Animals; Anti-Bacterial Agents; Carcinoma, Hepatocellular; Cyclosporins; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Humans; Kinetics; Liver Neoplasms; Mice; Polyenes; Precipitin Tests; Protein Conformation; Sirolimus; Tacrolimus; Transferrin; Tumor Cells, Cultured

Topics: Amino Acid Isomerases; Animals; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line; Cyclosporins; DNA Replication; Gene Expression; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Liver Neoplasms; Liver Neoplasms, Experimental; Organ Specificity; Peptidylprolyl Isomerase; Polyenes; Rats; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins; Transcription, Genetic