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

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

Claudin-7 expression in hepatocellular carcinoma.

BACKGROUND: The importance of adhesion molecules for local invasion by neoplastic cells and development of metastasis has been confirmed by numerous studies over the past decade. Claudins are integral parts of tight junctions. The aim of the present study was to examine the significance of the expression of claudin-7 messenger RNA (mRNA) as a prognostic factor for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We examined liver tumor and nontumor tissues from 20 HCC patients who underwent resection or liver transplantation. RESULTS: A significant increase in the expression of claudin-7 was observed in tumor versus nontumor tissues. There was no significant correlation between the expression profile of claudin-7 mRNA and patient demographic data, the presence of cirrhosis, or the histological stage of tumor differentiation or vascular invasion. Survival analysis showed a trend toward a better prognosis among patients with overexpression of claudin-7 in tumor tissues.

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

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

A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT.

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection.

Long-term outcomes of liver transplant patients with human immunodeficiency virus infection and end-stage-liver-disease: single center experience.

OBJECTIVE: Orthotopic-liver-transplantation (OLT) in patients with Human-Immunodeficiency-Virus infection (HIV) and end-stage-liver-disease (ESDL) is rarely reported. The purpose of this study is to describe our institutional experience on OLT for HIV positive patients. MATERIAL AND METHODS: This is a retrospective study of all HIV-infected patients who underwent OLT at the University Hospital of Essen, from January 1996 to December 2009. Age, sex, HIV transmission-way, CDC-stage, etiology of ESDL, concomitant liver disease, last CD4cell count and HIV-viral load prior to OLT were collected and analysed. Standard calcineurin-inhibitors-based immunosuppression was applied. All patients received anti-fungal and anti-pneumocystis carinii pneumonia prophylaxis post-OLT. RESULTS: Eight transplanted HIV-infected patients with a median age of 46 years (range 35-61years) were included. OLT indications were HCV (n = 5), HBV (n = 2), HCV/HBV/HDV-related cirrhosis (n = 1) and acute liver-failure (n = 1). At OLT, CD4 cell-counts ranged from 113-621 cells/µl, and HIV viral-loads from <50-175,000 copies/ml. Seven of eight patients were exposed to HAART before OLT. Patients were followed-up between 1-145 months. Five died 1, 3, 10, 31 and 34 months after OLT due to sepsis and graft-failure respectively. Graft-failure causes were recurrent hepatic-artery thrombosis, HCV-associated hepatitis and chemotherapy-induced liver damage due to Hodgkin-disease. One survivor is relisted for OLT due to recurrent chronic HCV-disease but non-progredient HIV-infection 145 months post-OLT. Two other survivors show stable liver function and non-progredient HIV-disease under HAART 21 and 58 months post-OLT. CONCLUSIONS: OLT in HIV-infected patients and ESLD is an acceptable therapeutic option in selected patients. Long-term survival can be achieved without HIV disease-progression under antiretroviral therapy and management of the viral hepatitis co-infection.

Donor/recipient algorithm for management of the middle hepatic vein in right graft live donor liver transplantation.

BACKGROUND: The aim of this study was to delineate an algorithm for donor and recipient criteria and middle hepatic vein (MHV) management in right-graft live-donor liver transplantation (LDLT) on the basis of computerized 3-dimensional computed tomographic image analysis. METHODS: Data on 94 consecutive right-graft LDLTs were prospectively collected. Graft and remnant data for the first 23 cases were retrospectively evaluated by means of 3-dimensional computed tomographic reconstructions, and on the basis of that preliminary series, a graft selection algorithm using 3 parameters-hepatic vein dominance classification, graft and remnant graft volume/body weight ratios, and congestion volumes-was created. It was subsequently applied to the next 71 right-graft LDLTs. RESULTS: Fifty-nine right grafts contained the MHV. Four of the 12 grafts with no MHVs required MHV reconstructions. In 18 cases, small liver grafts were used. The postoperative function of liver grafts and remnants with versus without MHVs was not statistically different. CONCLUSIONS: The proposed algorithm favored the inclusion of the MHV with the right grafts. It also allowed for the procurement of grafts that were potentially small for size without compromising donor or recipient safety.

Established and emerging therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a worldwide increasing incidence. The incidence of HCC is closely related to the epidemiology of the risk factors which are mainly represented by chronic viral hepatitis B and C. Obesity and type II diabetes, often associated with chronic nonalcoholic fatty liver disease, are emerging independent risk factors for HCC development. Although the risk factors for HCC are well characterized, the molecular mechanisms responsible for malignant transformation of hepatocytes are not well understood. HCC diagnosis and therapy follow defined algorithms according to the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases guidelines. Liver transplantation has been shown the best outcome for selected patients with early tumor stage but its application is limited by the shortage of liver grafts. After hepatic resection prognosis remains unsatisfactory due to a high incidence of tumor recurrence. Selective internal radiation therapy is emerging as promising loco-regional treatment for patients with advanced HCC having good performance status and liver reserve but not amenable to surgery. The recently introduced orally active multikinase inhibitor sorafenib has been established as palliative systemic therapy. Further improved understanding of molecular mechanisms underlying HCC development will facilitate the development of new targeted therapeutic strategies.

Current immunosuppressive approaches in liver transplantation.

A significant increase of potent immunosuppressive agents over the last two decades has contributed to improved patient and graft survival after liver transplantation (LT). Numerous ongoing studies aim to determine the most effective immunosuppressive protocols while minimizing drug-related side effects. These protocols often combine several drugs with different mechanisms of action and toxicities allowing dosage adjustment. There is also a trend towards tailored immunosuppressive regimens according to the etiology of liver disease and comorbidities such as renal dysfunction and cardiovascular disease. The introduction of antibody induction therapies and antimetabolites resulted in an increasing number of studies with steroid minimization and calcineurin inhibitor (CNI) reduction protocols. Combined mycophenolate mofetil and minimal dose CNI therapy has shown to be safe and to improve kidney function and cardiovascular risk profile in the majority of studies. Sirolimus (SRL) and everolimus constitute a new class of compounds designated as the mammalian target of rapamycin (mTOR) inhibitors, which exhibit immunosuppressive and antiproliferative effects. There are conflicting results with respect to renal improvement upon switch to mTOR inhibitor therapy with concomitant reduction/elimination of CNI. Further trials will determine whether earlier conversion to mTOR inhibitors enable prevention of CNI-related renal dysfunction. Future results from randomized controlled studies will also show whether SRL can improve recurrence-free survival in patients transplanted for hepatocellular carcinoma.

Liver transplantation for hepatocellular carcinoma after yttrium therapy: a case report.

Yttrium-90 microspheres constitute one of the most recent treatment options for hepatocellular carcinoma (HCC) in the setting of cirrhosis. As such, their spectrum of indication is not yet fully established. Herein, we have reported the case of a patient with HCC beyond the listing criteria for liver transplantation (OLT) who was treated preoperatively with selective transarterial chemoembolization and yttrium-90 microspheres. He was subsequently transplanted with a liver from an 81-year-old donor allocated through Eurotransplant as a "rescue offer." The posttransplant course was uneventful. Pathologic examination revealed a multifocal, well-differentiated pT2 tumor with no vascular invasion. The patient is currently alive and in good condition at 14 months posttransplant, with no evidence of tumor recurrence by a current computed tomography scan. This report provided encouraging information on the potential of yttrium-90 microspheres as a bridging option before OLT for multifocal HCC.

"Preemptive" live donor liver transplantation for fibrolamellar hepatocellular carcinoma: a case report.

Fibrolamellar (FL) hepatocellular carcinoma (HCC) is a distinctive form of primary HCC that occurs principally in children and young adults. Although liver transplantation is not contraindicated for FL-HCC, noncirrhotic patients with large HCC tumors (including FL-HCCs) are not prioritized. Although hepatic resection is considered to be the primary treatment for FL-HCC, living donor liver transplantation is evolving into a potentially better alternative. Herein we have reported successful "preemptive" living donor liver transplantation for presumed recurrence of FL-HCC after an extended right hepatectomy with resection and synthetic graft replacement of the inferior vena cava.

Role of osteopontin and CD44s expression for patients with hepatocellular carcinoma undergoing liver transplantation or resection.

BACKGROUND: Detection of new biomarkers for hepatocellular carcinoma (HCC) is needed to estimate prognosis after liver transplantation (OLT) or hepatic resection. Osteopontin (OPN) is a secreted, calcium-binding, phosphorylated, acidic glycoprotein that is overexpressed in various cancers. Cluster differentiation 44 standard isoform (CD44s) is one of the primary receptors of OPN; it may contribute to metastatic tumor spread. MATERIALS AND METHODS: Tumor tissue and surrounding hepatic parenchyma were obtained from 53 HCC patients who underwent liver resection. Their RNA was extracted from nitrogen-frozen tissues, and OPN mRNA levels were estimated by quantitative reverse transcription-polymerase chain reactions. Formalin-fixed, paraffin-embedded tissues were obtained from the same patients, and additionally from 60 OLT HCC patients to perform expression analysis for OPN and CD44s by standard avidin-biotin immunostaining methods. RESULTS: Expression of OPN and CD44s was significantly higher among HCC compared with adjacent nontumor tissue. The OPN mRNA expression and protein abundance correlated positively; OPN overexpression was associated with high tumor grade. A positive correlation existed between OPN and CD44s expression; both proteins were significantly overexpressed in HCC lesions with positive lymph nodes. No significant correlation existed between patient survival and OPN and CD44s expression. CONCLUSION: Expression of both OPN and CD44s in HCC is associated with advanced tumor stage, thus possibly contributing prognostic information when evaluated together with classical clinicopathological parameters.

Living donor liver transplantation for hepatocellular carcinoma in patients exceeding the UCSF criteria.

BACKGROUND: Living donor liver transplantation (LDLT) represents an alternative to expand the organ pool for adult patients with hepatocellular carcinoma (HCC) and end-stage liver disease. The purpose of this study was to demonstrate our institutional experience using criteria exceeding those of the University of California San Francisco (UCSF). PATIENTS AND METHODS: Between September 1998 and December 2006, 22 LDLTs were performed for HCC among patients exceeding the UCSF criteria. RESULTS: There were 17 men and 5 women of median age 55 years. Multifocal tumors were present in 19 of 22 patients. Tumor grading was: grade I (n = 8), grade II (n = 10), and grade III (n = 4). Microvascular invasion was observed in 7 liver explants. Five patients died from complications unrelated to HCC recurrence at 2, 6, 9, 10, and 14 months' posttransplant. Seven patients developed tumor recurrences at 3, 3, 5, 7, 9, 10, and 35 months after LDLT, and 4 died at 6, 10, 17, and 75 months' posttransplantation. Currently, 13 patients are alive (3 with tumor recurrence) at a median of 24 months' posttransplant. Rates for 1- and 3-year overall versus recurrence-free survivals were 73% and 62% versus 54% and 34%, respectively. CONCLUSIONS: LDLT for HCC patients exceeding the UCSF criteria is characterized by an acceptable overall but poor recurrence-free survival. Its application requires an honest approach to donor and recipient information.

Liver transplantation as a primary indication for intrahepatic cholangiocarcinoma: a single-center experience.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is not a widely accepted indication for orthotopic liver transplantation (OLT). The present study describes our institutional experience with patients who underwent transplantation for ICC as well as those with ICC who underwent transplantation with the incorrect diagnosis of hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Data corresponding to ICC patients were reviewed for the purposes of this study. Patients with hilar cholangiocarcinoma and incidentally found ICC after OLT for benign diseases were excluded from further consideration. RESULTS: Among the 10 patients, 6 underwent transplantation before 1996 and 4 after 2001. Those who underwent transplantation in the early period had a preoperative diagnosis of inoperable ICC (n = 4) and ICC in the setting of primary sclerosing cholangitis (n = 2). In the latter period the subjects had a diagnosis of HCC in cirrhosis (n = 3) or recurrent ICC after an extended right hepatectomy (n = 1). Median survival was 25.3 months for the whole series and 32.2 months (range, 18-130 months) when hospital mortality was excluded (n = 3). Four patients are currently alive after 30, 35, 42, and 130 months post-OLT, respectively. Two patients died of tumor recurrence at 18 and 21 months post-OLT, respectively. One-, 3-, and 5-year survival rates were 70%, 50%, and 33%, respectively. CONCLUSIONS: The role of OLT in the setting of ICC may be re-evaluated in the future under strict selection criteria and with prospective multicenter randomized studies. Potential candidates to be included are those with liver cirrhosis and no hilar involvement who meet the Milan criteria for HCC.

Long-term results after liver transplantation with "livers that nobody wants" within Eurotransplant: a center's experience.

BACKGROUND: Orthotopic liver transplantation (OLT) represents the only curative treatment for end-stage liver disease, but its application is limited because of organ shortages. The purpose of this study was to review the long-term outcomes after OLT during a 2-year period of 45 rescue offers organs within Eurotransplant. PATIENTS AND METHODS: Forty-five deceased donor liver allografts had been officially offered to and rejected by other transplantation centers 162 times prior to our acceptance. Data analysis addressed recurrence of primary disease, ischemic-type biliary lesions (ITBL), re-evaluation or relisting for OLT, re-OLT, as well as overall patient and graft survivals. RESULTS: Six patients underwent retransplantation because of primary nonfunction (n = 4), hepatitis C recurrence (n = 1), and secondary biliary cirrhosis following ITBL (n = 1). Five additional patients developed ITBL and received endoscopic treatment. Currently, 34 patients are alive after a median follow-up of 44.5 months. Median graft survival is 43.2 months. Patient versus patient/first graft survival at 1, 3, and 5 years is 82%, 78%, and 74%, versus 76%, 69%, and 65%, respectively. CONCLUSIONS: OLT with rescue organs is a reasonable policy, with acceptable long-term patient/graft survivals, providing a real expansion of the donor pool.

Incidence of liver retransplantation and its effect on patient survival.

PURPOSE: The purpose of this study was to review our institutional experience with re-liver transplantation (OLT) after split and full-size OLT. PATIENTS AND METHODS: We evaluated data corresponding to retransplanted patients over an 8-year period who underwent deceased donor OLT at our institution. Variables analyzed included indications for primary OLT, and re-OLT, the type of graft used during the initial versus re-OLT, the time from initial to re-OLT, and patient survival after re-OLT. RESULTS: Sixty-four of 697 first OLT (9.2%) required re-OLT. Forty-nine cases were among 637 (7.6%) full-size OLT, while 15 were among 60 (25%) split OLT (P < .001). Median time to re-OLT was 8 days (range = 1-1885 days). Main indications for re-OLT were primary nonfunction/initial poor function (44%), hepatic artery thrombosis (26%), biliary complications (11%), and hepatitis C recurrence (6%). Forty-eight percent of the re-OLTs were performed within the first posttransplant week. The overall survival for these 64 patients was 55% and 48% at 1 and 3 years after the primary OLT, and 44% at both 1 and 3 years after the re-OLT, respectively. CONCLUSIONS: The overall incidence of re-OLT remains 9%. Approximately half of all re-OLT occured within the first posttransplant week. Early retransplantation was associated with the best patient survival. Overall survival after re-OLT was about 10% to 20% lower than that after primary OLT.

Single-center experience on liver transplantation for hepatocellular carcinoma arising in alcoholic cirrhosis: results and ethical issues.

BACKGROUND: Liver transplantation is currently recognized as the optimal treatment for both early hepatocellular carcinoma in the setting of cirrhosis (HCC) as well as for alcoholic liver disease (ALD). The purpose of this study was to evaluate the outcome of patients with HCC and ALD in the absence of viral hepatitic infections. METHODS: Twelve recipients were transplanted with a diagnosis of HCC and ALD in the absence of viral hepatitis during a 6-year period. Nine received deceased donor livers, and 3 live donor grafts. Our results were compared to those obtained by a search of the world literature. RESULTS: The postoperative course was uneventful in all but one patient. All recipients experienced a good quality of life postoperatively. Three-year overall and recurrence-free survival rates were 82 and 73%, respectively. Nine patients are currently alive, after a median follow-up of 29 months. CONCLUSION: This is the first study to evaluate liver transplantation for HCC in ALD. Although outcomes are excellent, the evaluation of patients with ALD and HCC constitutes a challenging topic in transplantation surgery, especially when live liver donation is considered. An interdisciplinary structured approach is recommended, with special emphasis on ethical considerations.

Meta-analysis of tumor recurrence after liver transplantation for hepatocellular carcinoma based on 1,198 cases.

BACKGROUND: The purpose of this study was to systematically review tumor characteristics leading to recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT). MATERIAL AND METHODS: A computer search of the Medline database was carried out. Tumor characteristics examined were: 1) no vascular versus vascular invasion, 2) solitary versus multifocal tumors, 3) well differentiated versus not well differentiated HCCs, 4) HCC meeting versus HCC exceeding the Milan criteria, 5) HCC < or =5 cm versus HCC>5 cm. RESULTS: Of 45 clinical studies screened, 9 fulfilled the study criteria. These studies included from 21 to 316 patients, for a total of 1198 patients. A fixed effects model was applied. A significant correlation between vascular invasion, not well differentiated HCC, tumor size >5 cm, HCC exceeding the Milan criteria, and HCC recurrence post transplant was shown (common odds ratio of 8.727, 2.89, 13.32 and 4.205, respectively). Heterogeneity for the parameter solitary versus multifocal tumor was shown. CONCLUSION: High risk pathology for HCC recurrence is characterized by not well differentiated tumors and by HCCs that exceed the Milan criteria. A clinical application of these data may be a scoring system which includes the tumor grading in the evaluation and listing of HCC patients to LT.

[New techniques in liver transplantation]. / Neue Techniken in der Lebertransplantation.

Due to innovative surgical techniques, improved immunosuppressive regimens and better postoperative management, orthotopic liver transplantation achieved patient and allograft survival rates of 80 to 90% that have expanded both the indications for transplantation as well as the number of potential recipients awaiting liver transplantation. One of the major challenges facing organ transplantation is the current shortage of donors. Despite supportive legislation, media network systems and the attempt to raise public awareness, the actual donor numbers have remained relatively constant and do not meet the growing need for more organs. In 2002 the mortality among patients waiting for a liver organ reached 20%. Among the several measures that can be undertaken to expand the donor pool is the use of previously unused donors, such as marginal livers, domino-, split- or living related liver transplantation.

[Surgical and interventional treatment of liver metastases]. / Lebermetastasen möglichst resezieren.

The liver is the most common target organ for metastatic disease. The majority of patients undergoing surgical treatment for liver metastases have colorectal primaries. Endocrine liver metastases, or metastases from other tumors such as mammary carcinoma, sarcomas, renal tumors or gastrointestinal stromal tumors (GIST) are appreciably less common for surgical treatment. The gold standard of treatment is resection of the metastatic lesions. In the meantime, advances in surgical techniques and improved perioperative patient management make it possible to perform extensive resections with acceptable morbidity and mortality rates. In the event of metastases that are not primarily resectable, various downstaging procedures are available, with the aid of which secondary resectability can be achieved. Among the interventional treatment options that should be applied only in palliative intent, radiofrequency ablation is in widespread use.