Umberto Baccarani

Once-Daily Prolonged-Release Tacrolimus (ADVAGRAF) Versus Twice-Daily Tacrolimus (PROGRAF) in Liver Transplantation

The efficacy and safety of dual‐therapy regimens of twice‐daily tacrolimus (BID; Prograf) and once‐daily tacrolimus (QD; Advagraf) administered with steroids, without antibody induction, were compared in a multicenter, 1:1‐randomized, two‐arm, parallel‐group study in 475 primary liver transplant recipients. A double‐blind, double‐dummy 24‐week period was followed by an open extension to 12 months posttransplant. The primary endpoint, event rate of biopsy‐proven acute rejection (BPAR) at 24 weeks, was 33.7% for tacrolimus BID versus 36.3% for tacrolimus QD (Per‐protocol set; p = 0.512; treatment difference 2.6%, 95% confidence interval −7.3%, 12.4%), falling within the predefined 15% noninferiority margin. At 12 months, BPAR episodes requiring treatment were similar for tacrolimus BID and QD (28.1% and 24.7%). Twelve‐month patient and graft survival was 90.8% and 85.6% for tacrolimus BID and 89.2% and 85.3% for tacrolimus QD. Adverse event (AE) profiles were similar for both tacrolimus BID and QD with comparable incidences of AEs and serious AEs. Tacrolimus QD was well tolerated with similar efficacy and safety profiles to tacrolimus BID.

Mobilization of Bone Marrow-Derived Hematopoietic and Endothelial Stem Cells After Orthotopic Liver Transplantation and Liver Resection

In animals, the bone marrow (BM) is a source of liver‐repopulating cells with therapeutic potential in case of tissue damage. However, the early response of human BM‐derived stem cells (SC) to liver injury is still unknown. Here, we studied 24 patients undergoing orthotopic liver transplantation (OLT) for end‐stage liver disease or hepatocellularcarcinoma, and 13 patients submitted to liver resection. The concentration of circulating BM‐derived SC was determined by phenotypic analysis and clonogenic assays. Moreover, we assessed the serum level of inflammatory and tissue‐specific cytokines. Reverse transcriptase‐polymerase chain reaction and fluorescence‐in situ hybridization were also used to characterize mobilized SC. At baseline, patients showed a significant lower concentration of circulating CD133+, CD34+ SC and clonogenic progenitors (colony‐forming unit cells) than healthy controls. However, the time‐course evaluation of peripheral blood cells after OLT demonstrated the significant early mobilization of multiple subsets of hematopoietic and endothelial stem/progenitor cells. Cytogenetic and molecular analyses of CD34+ cells showed the host origin of mobilized SC and the expression of transcripts for GATA‐4, cytokeratin 19, and α‐fetoprotein hepatocyte markers. In contrast with OLT, only total circulating CD34+ cells significantly increased after liver resection. Mobilization of BM cells after OLT or liver surgery was associated with increased serum levels of granulocyte‐colony stimulating factor, interleukin‐6, stem cell factor, hepatocyte growth factor, and vascular endothelial growth factor. In summary, we demonstrate that tissue damage after OLT and liver resection induces increased serum levels of multiple cytokines but only ischemia/reperfusion injury associated with OLT results in the remarkable mobilization of BM stem/progenitor cells.

Overoxidation of peroxiredoxins as an immediate and sensitive marker of oxidative stress in HepG2 cells and its application to the redox effects induced by ischemia/reperfusion in human liver

Oxidative stress is a major pathogenetic event occurring in several liver disorders and is a major cause of liver damage due to Ischemia/Reperfusion (I/R) during liver transplantation. While several markers of chronic oxidative stress are well known, early protein targets of oxidative injury are not well defined. In order to identify these proteins, we used a differential proteomics approach to HepG2 human liver cells treated for 10 min with 500 μM H2O2. This dose was sufficient to induce a slight decrease of total GSH and total protein thiol content without affecting cell viability. By performing Differential Proteomic analysis, by means of two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, we identified four proteins which resulted sensitive to H2O2 treatment. The main changes were due to post-translational modifications of native polypeptides. Three of these proteins belong to the Peroxiredoxin family of hydroperoxide scavengers, namely PrxI, PrxII and PrxVI, that showed changes in their pI as result of overoxidation. Mass mapping experiments demonstrated the specific modification of peroxiredoxins active site thiol into sulphinic and/or sulphonic acid, thus explaining the increase in negative charge measured for these proteins. The oxidation kinetic of all peroxiredoxins was extremely rapid and sensitive, occurring at H2O2 doses unable to affect the common markers of cellular oxidative stress. Recovery experiments demonstrated a quite different behaviour between 1-Cys and 2-Cys containing Prxs as their retroreduction features is concerned, thus suggesting a functional difference between different class of Prxs. The in vivo relevance of our study is demonstrated by the finding that overoxidation of PrxI occurs during I/R upon liver transplantation and is dependent on the time of warm ischemia. Our present data could be of relevance in setting up more standardized procedures to preserve organs for transplantations.

Percutaneous mechanical fragmentation and stent placement for the treatment of early posttransplantation portal vein thrombosis

BACKGROUND Early portal vein thrombosis is a rare but severe complication of liver transplantation requiring retransplantation or at least surgical thrombectomy, both hampered by high morbidity and mortality. METHODS We describe of a case of successful long-term recanalization of early posttransplantation portal vein thrombosis by a minimally invasive percutaneous transhepatic angiographic approach using both mechanical fragmentation and pharmacological lysis of the thrombus followed by stent placement. RESULTS Mechanical fragmentation and contemporaneous local urokinase administration resulted in complete removal of the clot; the use of a vascular stent after balloon dilatation allowed restoration of normal blood flow to the liver after 9 months of follow-up. CONCLUSIONS This case report confirms the possibility of successful recanalization of the portal vein after early posttransplantation thrombosis by a minimally invasive angiographic approach. Balloon dilatation and placement of a vascular stent could help to decrease the risk of recurrent thrombosis.

Percutaneous Transhepatic Portography for the Treatment of Early Portal Vein Thrombosis After Surgery

We treated three cases of early portal vein thrombosis (PVT) by minimally invasive percutaneous transhepatic portography. All patients developed PVT within 30 days of major hepatic surgery (one case each of orthotopic liver transplantation, splenectomy in a previous liver transplant recipient, and right extended hepatectomy with resection and reconstruction of the left branch of the portal vein for tumor infiltration). In all cases minimally invasive percutaneous transhepatic portography was adopted to treat this complication by mechanical fragmentation and pharmacological lysis of the thrombus. A vascular stent was also positioned in the two cases in which the thrombosis was related to a surgical technical problem. Mechanical fragmentation of the thrombus with contemporaneous local urokinase administration resulted in complete removal of the clot and allowed restoration of normal blood flow to the liver after a median follow-up of 37 months. PVT is an uncommon but severe complication after major surgery or liver transplantation. Surgical thrombectomy, with or without reconstruction of the portal vein, and retransplantation are characterized by important surgical morbidity and mortality. Based on our experience, minimally invasive percutaneous transhepatic portography should be considered an option toward successful recanalization of early PVT after major liver surgery including transplantation. Balloon dilatation and placement of a vascular stent could help to decrease the risk of recurrent thrombosis when a defective surgical technique is the reason for the thrombosis.

Multicenter Italian Experience in Liver Transplantation for Hepatocellular Carcinoma in HIV-Infected Patients

BACKGROUND The aim of our work is to assess the clinical outcomes of liver transplantation (LT) for hepatocellular carcinoma (HCC) in HIV-coinfected patients. This is a multicenter study involving three Italian transplant centers in northern Italy: University of Modena, University of Bologna, and University of Udine. PATIENTS AND METHODS We compared 30 HIV-positive patients affected by HCC who underwent LT with 125 HIV-uninfected patients who received the same treatment from September 2004 to June 2009. At listing, there were no differences between HIV-infected and -uninfected patients regarding HCC features. Patients outside the University of California, San Francisco criteria (UCSF) were considered eligible for LT if a down-staging program permitted a reduction of tumor burden. RESULTS HIV-infected patients were younger, they were more frequently anti-HCV positive, and a higher number of HIV-infected patients presented a coinfection HBV-HCV. Pre-LT treatments (liver resection and or locoregional treatments) were similar between the two groups. Histological characteristics of the tumor were similar in patients with and without HIV infection. No differences were observed in terms of overall survival and HCC recurrence rates. CONCLUSION LT for HCC is a feasible procedure and the presence of HIV does not particularly affect the post-LT outcome.

Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression

Abstract:  Liver transplantation (OLT) recipients who receive a graft from donors positive for hepatitis B virus (HBV) anti‐core antibodies may develop overt “de novo” HBV infection. The study was undertaken to explore how often HBV infection may remain occult after OLT for hepatitis C, and whether it may represent a factor of graft fibrosis progression. We studied 30 consecutive patients transplanted for hepatitis C liver disease. Specimens from the native liver and from the graft were searched for occult HBV infection (O‐HBV). In the native liver, 8/30 patients had detectable O‐HBV; during the follow‐up, O‐HBV infection was demonstrated in 14 graft specimens. Graft O‐HBV was associated with older donor age (≥50 yr; 8/9 vs. 6/21, p < 0.005). Recipients with graft O‐HBV and no O‐HBV in the native liver who received their grafts from donors aged >40 yr had faster fibrosis progression than recipients with no post‐transplant O‐HBV, whose grafts came from donors aged >40 yr and recipients whose grafts came from donors aged ≤40 yr (4/7 vs. 1/7 vs. 2/16, p < 0.05). In OLT recipients, O‐HBV is more likely to occur when grafts are obtained from aged donors and may affect the rate of fibrosis progression because of recurrent hepatitis C.

Kidney Transplanted Population and Risk for De Novo Tumors. Is itPossible to Improve the Outcome? Definition of a Personal Risk Score

Also solid tumors have increased incidence in transplant population than in general population; many studies have shown that the transplanted organ is related to different rate of risk for different kind of solid tumors [1,4]. In a previous study about de novo solid tumors (excluding skin non melanoma cancer) of our group we found that urogenital cancer and gastrointestinal cancer were the most occurring solid cancer in the kidney transplant population at the center of Udine [5].

Magnetic resonance cholangiopancreatography in assessing living liver donors biliary anatomy: opportunities and challenges

Although it is questionable whether Magnetic Resonance Cholangiopancreatography (MRCP) should be considered the new standard of reference in biliary imaging (1), state-of-the-art MRCP provides panoramic images with high spatial and temporal resolution, leading to successful applications in different clinical settings (2). As a consequence, MRCP has gained acceptance as the most reliable alternative to direct cholangiography in depicting the biliary system (2).

Necrosis Percentage of Radiologically Treated Hepatocellular Carcinoma at Hepatectomy for Liver Transplantation

Among a cohort of 414 liver transplantations (OLT) performed form 1996 to 2009, we analyzed 86 patients (20.7%) who were affected by hepatocellular carcinoma (HCC) superimposed on cirrhosis, including 82 with a preoperative diagnosis of tumor; 4 cases had the diagnosis established upon histologic examination after hepatectomy. The gender of 75 patients was male (91.5%), and female in 7 cases (8.5%). The median Model for End-Stage Liver Disease score was 10 (range, 6-23). The underlying liver disease was hepatitis C virus (HCV)-related cirrhosis (41.46%), hepatitis B virus (HBV)-related cirrhosis (15.6%), or alcohol-related cirrhosis (29.3%); cryptogenic; HCV+HIV; HBV+HIV; or HCV+HBV+HIV cirrhosis were present in an other few patients. The diagnosis of HCC and the preoperative staging were defined through radiologic evaluations, without biopsy confirmation in any case. All patients underwent pretransplant radiologic treatments to reduce the drop-out risk while a waiting OLT; OLT was performed for HCC patients within the Milan criteria. Upon histologic examination, the median HCC necrosis was 57 ± 36%; in 22 cases (26.8%), there were no necrotizing effects. Forty patients (48.8%) display a satisfying degree of disease control with 26 patients (31.7%) downstaged effect; 15 patients (18.3%) showed neoplastic progression with advanced neoplastic disease exceeding the Milan criteria at hepatectomy. One patient had nonevaluable necrosis (1.2%). Our experience showed preoperative radiologic treatments to be not curative but serving as a bridge to OLT.