Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome.

Background & Aims: The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a life-threatening complication during pregnancy. The associated liver disease may be severe, and maternal hepatic complications may progress to the point that transplantation becomes necessary. CD95 (APO-1, Fas)-mediated apoptosis of liver cells is one of the major pathogenic mechanisms during liver disease. The interaction of CD95 with its ligand, CD95L(FasL), induces apoptosis and thus the source of the death-inducing ligand is critical for understanding the pathomechanism of liver damage involving the CD95-system. Methods: Sera from HELLP patients were analyzed and used in cell culture experiment…

Liver transplanted patients with preoperative autoimmune hepatitis and immunological disorders are at increased risk for Post-Transplant Lymphoproliferative Disease (PTLD).

Long term immunosuppression and therapy of acute rejections result in a 20-120-fold increased risk to develop Non Hodgkin lymphoma (NHL). Since immunosuppressive therapy and immunological disorders are major risk factors for the development of NHL in the non-transplant population we aimed to analyze risk factors for PTLD in our cohort of liver transplanted (LT) patients.We analyzed retrospectively 431 patients liver transplanted between 1998 and 2008.PTLD was diagnosed in eleven of 431 patients (2.6%). PTLD, especially late PTLD, was significantly more frequent in patients who received steroids before LT (Kaplan-Meier: p0.001). Moreover PTLD in immunocompromised patients with preoperative s…

The Intention-to-Treat Effect of Bridging Treatments in the Setting of Milan Criteria–In Patients Waiting for Liver Transplantation

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria (MC), the benefit of locoregional therapies (LRTs) in the context of liver transplantation (LT) is still debated. Initial biases in the selection between treated and untreated patients have yielded conflicting reported results. The study aimed to identify, using a competing risk analysis, risk factors for HCC-dependent LT failure, defined as pretransplant tumor-related delisting or posttransplant recurrence. The study was registered at www.clinicaltrials.gov (identification number NCT03723304). In order to offset the initial limitations of the investigated population, an inverse probability of treatment weighting (IP…

Expression and prognostic significance of insulin‑like growth factor-2 receptor in human hepatocellular carcinoma and the influence of transarterial chemoembolization

Hepatocellular carcinoma (HCC) is one of the most common human malignancies, the incidence of which is growing worldwide. The prognosis of HCC is very poor and it is often accompanied by a high rate of recurrence. Conventional chemotherapeutic approaches are largely inefficient. In order to develop novel effective methods for the early detection and prognosis of HCC, novel markers and therapeutic targets are urgently required. The present study focused on the effects of the expression of the tumor suppressor gene insulin‑like growth factor‑2 receptor (IGF2R) on patient survival and tumor recurrence in patients with HCC; this study paid specific attention to the influence of transarterial ch…

Dosimetric feasibility study for an extracorporeal BNCT application on liver metastases at the TRIGA Mainz

This study investigates the dosimetric feasibility of Boron Neutron Capture Therapy (BNCT) of explanted livers in the thermal column of the research reactor in Mainz. The Monte Carlo code MCNP5 is used to calculate the biologically weighted dose for different ratios of the (10)B-concentration in tumour to normal liver tissue. The simulation results show that dosimetric goals are only partially met. To guarantee effective BNCT treatment the organ has to be better shielded from all gamma radiation.

Strategie des chirurgischen Vorgehens beim hilären Cholangiokarzinom

Surgery is the decisive life-prolonging treatment in patients with hilar cholangiocarcinoma. Surgery is mainly based on empiric data. Since patients without surgery have only about 6 months to survive, to achieve a high resection rate is crucial for these patients. During diagnostic workup, percutaneous transhepatic cholangiography results in the most reliable assessment of longitudinal tumor growth. The extent of the tumor is frequently overestimated leading to the consequence of excluding the patients from surgery. En-bloc resection of the tumor and the adjacent liver should be the preferred surgical approach. So far, surgical radicality (right trisegmentectomy, extended lymphadenectomy a…

Clinical symptomatic de novo systemic transthyretin amyloidosis 9 years after domino liver transplantation

Four years ago, Stangou et al. reported a patient who developed clinical symptoms of amyloidosis 8 years after domino liver transplantation (DLT). In order to alleviate the graft shortage, livers from patients with familial amyloidotic polyneuropathy (FAP) are used as domino grafts for other patients under the assumption that several decades will pass before clinical symptoms due to amyloid accumulation emerge. We now report on another case, the third reported case in the literature, of de novo systemic amyloidosis in a 75-year-old woman 9 years after DLT. The patient underwent DLT at 65 years of age for hepatocellular carcinoma exceeding the Milan criteria in hepatitis C cirrhosis. Transar…

Acute renal failure and liver dysfunction after subcutaneous injection of 3-sn-phosphatidylcholine (Lipostabil®)-case report.

INTRODUCTION Drug-induced tubulointerstitial nephritis and acute tubular necrosis are common, and are often caused by drugs especially antibiotics or non-steroidal anti-inflammatory drugs. Drug-induced liver dysfunction and renal failure after subcutaneous injection of phosphatidylcholine was not reported so far. 3-sn-Phosphatidylcholine has been described as a cell lysis reaction-inducing drug. Its in vitro data indicated a relevant toxicity potential. In particular human cell types such as fibroblast-like preadipocytes, vascular and skeletal muscle cells, or renal epithelial cells react more sensitive than other human cell types. CASE REPORT We present a 28-year-old woman who received 3.5…

CT-Angiographie an einem 16-Schicht-CT zur perioperativen Evaluation der Leberarterien im Vergleich zur MR-Angiographie

Purpose: To evaluate the efficiency of CT angiography (CTA) with 16-row MSCT compared with MR angiography (MRA) in analyzing the arterial anatomy in patients undergoing liver surgery. Materials and Methods: In 30 patients, MRA and CTA studies of the abdominal vessels were reviewed. CT parameters: slice thickness 3 mm; collimation 1.5; reconstruction interval 2 mm (Philips MX 8000 IDT); 120 ml contrast media (400 mg/ml) at a rate of 4 ml/ sec; acquisition of arterial-phase scans. The anatomy of the hepatic artery was evaluated from axial and reconstructed maximum-intensity-projection (MIP) images ("Slab-Viewer", Philips). MR parameters: contrast-enhanced coronal FLASH-3D sequences; slice thi…

Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) is the strongest survival-limiting factor after liver transplantation (LT) in patients with HCC. In the face of donor organ shortage, it is necessary to identify factors associated with HCC recurrence in order to maximize the utility of the available grafts. OBJECTIVE: To study the phenomenon of HCC recurrence after LT at a European transplantation centre over the past 20 years. METHODS: Data from 304 HCC patients who underwent LT were prospectively recorded. Clinical and pathological factors were assessed for their association with recurrence. RESULTS: Fifty-one patients (16.8%) had HCC recurrence after LT. Patients exceeding the…

Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma.

Criteria to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT) are based on tumor size and number of nodules rather than on tumor biology. The present study was undertaken to assess the role of transarterial chemoembolization (TACE) in selecting patients with tumors suitable for LT. Ninety-six consecutive patients with HCC were treated by repeatedly performed TACE, 62 of them exceeding the Milan criteria. Patients meeting the Milan criteria were immediately listed, and patients beyond the listing criteria were listed upon downstaging of the tumor following successful TACE. Fifty patients were finally transplanted. Of these 50 patients, 34 exceeded the Milan c…

Control Of Organ Transplant-Associated Graft-versus-Host Disease By Activated Host Lymphocyte Infusions

Background Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal. Methods Graft-reactive host T cells were generated ex vivo from a patient suffering from a severe and refractory liver-transplant-associated GvHD. To control GvHD, activated alloreactive host T cells were repetitively retransferred into the patient (activated host lymphocyte infusion [aHLI]). Results Adoptive trans…

Hepatocellular carcinoma recurrence after acute liver allograft rejection treatment: A multicenter European experience

During the last decades, several risk factors for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) have been investigated. However, the impact of two important drivers of oncogenesis, namely the immunosuppression and the treatment of acute cellular rejection (ACR) have been marginally addressed. This study aimed at investigating the impact of ACR treatment on the incidence of tumor recurrence in a large European HCC-LT population. Seven hundred and eighty-one adult patients transplanted between February 1, 1985 and June 30, 2016 were retrospectively analyzed. After propensity score match, 116 patients treated for ACR using steroid boluses were compared with …

Methylene blue–aided cholangioscopy unravels the endoscopic features of ischemic-type biliary lesions after liver transplantation

Chemokines: reliable markers for diagnosis of rejection and inflammation following orthotopic liver transplantation.

Ischemic Type Biliary Lesions nach orthotoper Lebertransplantation - ein immunologisches Problem?

Ischemic type biliary lesions (ITBL) are a major complication following orthotopic liver transplantation (OLT). In many cases re-OLT is indicated. Multiple factors have been claimed to be reasonable for ITBL; here we present a new immunological risk factor: CC-Chemokines play a key role in the recruitment of leukocytes during ischemia-reperfusion damage and acute rejection. Therefore the CC-chemokine-receptor 5 (CCR5) and its functionless CCR5-delta-32-polymorphism (CCR5Δ32) might have an influence on the grafts pathology after OLT. In 146 patients after OLT the CCR5 was analyzed with regard to the CCR5Δ32 by PCR. 120 patients (82,1%) showed a normal receptor (wildtype) whereas 26 patients …

Sorafenib perpetuates cellular anti-cancer effector functions by modulating the cross talk between macrophages and natural killer cells.

Alternatively polarized macrophages (Mϕ) shape the microenvironment of hepatocellular carcinoma (HCC) and temper anticancer immune responses. We investigated if sorafenib alters the HCC microenvironment by restoring classical macrophage polarization and triggering tumor-directed natural killer (NK) cell responses. In vivo experiments were conducted with sorafenib (25 mg/kg)-treated C57BL/6 wildtype as well as hepatitis B virus (HBV) and lymphotoxin transgenic mice with and without HCC. Monocyte-derived Mϕ or tumor-associated macrophages (TAM) isolated from HCC tissue were treated with sorafenib (0.07-5.0 μg/mL) and cocultured with autologous NK cells. Mϕ and NK cell activation was analyzed …

Prognostic factors and outcomes of patients with hepatocellular carcinoma in non-cirrhotic liver

To report the outcome of patients with hepatocellular carcinoma (HCC) in non-cirrhotic liver depending on the mode of primary treatment and to define clinicopathological factors influencing patients' prognosis.A retrospective analysis of an unselected cohort of 105 patients was performed. Overall survival (OS) was estimated by the Kaplan-Meier method and potentially prognostic factors were analyzed in Cox regression models.OS of the whole cohort at 1, 3, and 5 years was 66%, 47%, and 29%, respectively. Tobacco consumption, ECOG0, macroscopic vascular invasion, continuous tumor diameter, and treatment other than resection were predictors of decreased OS in the whole cohort. Resection was per…

Graft rinse prior to reperfusion in liver transplantation: literature review and online survey within the Eurotransplant community

Graft rinse prior reperfusion in liver transplantation (LT) is believed to reduce the incidence of postreperfusion syndrome and improve clinical outcome. A MEDLINE search was performed to obtain a comprehensive review of the published literature dealing with graft rinse in LT. Moreover, all thirty-four LT centers in the Eurotransplant (ET) region were invited to participate in an online survey to whether or not graft rinse is performed and whether further research in the field is needed. Seventeen reports have been found to investigate graft rinse protocols in 1894 LT recipients. Eighteen of the thirty centers that participated in the online survey performed graft rinse prior reperfusion in…

Familial Amyloid Polyneuropathy

Familial amyloid polyneuropathy (FAP; also known as familiar amyloidosis and hereditary amyloidosis) is an autosomal dominant inherited disease due to mutations of the transthyretin (TTR) gene coding for the corresponding protein, consisting of 127 amino acids. The gene is located on chromosome 18q. More than 100 different mutations are known. Other mutant precursor proteins produced in the liver, such as apolipoprotein I and II, lysozyme and fibrinogen Aα, may be of etiological importance as well. Amyloidogenic mutations of the TTR gene lead to decreased stability of the corresponding protein and subsequently to extracellular deposition of amyloid in several tissues (peripheral and autonom…

Comparison of resection and transarterial chemoembolisation in the treatment of advanced intrahepatic cholangiocarcinoma--a single-center experience.

Abstract Aims The aim of this study is to evaluate factors associated with the outcome after surgical resection and to compare the efficacy of surgery to transarterial chemoembolisation (TACE) in patients with advanced intrahepatic cholangiocarcinoma (IHC). Materials and methods 273 patients with IHC treated in our department between 1997 and 2012 were included in our study. Patients were divided according to therapy into surgical ( n  = 130), TACE ( n  = 32), and systemic chemotherapy/best supportive care ( n  = 111) groups. Clinicopathological characteristics and survival were reviewed retrospectively. Results The 1-, 3-, and 5-year survival rates in patients after surgical resection were…

Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: A single-center experience

Liver transplantation (LT) is the only curative option for patients with familial amyloid polyneuropathy (FAP) at present. Twenty patients with FAP underwent LT between May 1998 and June 2007. Transthyretin mutations included predominantly the Val30Met mutation but also 10 other mutations. Seven patients received a pacemaker prior to LT, and because of impairment of mechanical cardiac function, 4 combined heart-liver transplants were performed, 1 simultaneously and 3 sequentially. The first patient, who underwent simultaneous transplantation, died. Seven patients died after LT, with 5 dying within the first year after transplantation. The causes of death were cardiac complications (4 patien…

Destruction of Kupffer’s cells increases total liver blood flow and decreases ischemia reperfusion injury in pigs

The relevance of anxiety, depression, and coping in patients after liver transplantation

The aim of this study is to investigate the effects of anxiety, depression, and coping on quality of life in patients after liver transplantation. Patients were asked to fill out a postal survey. Two hundred thirty-six of 375 patients (63%) who entered the study returned the questionnaires, and 186 of these patients could be included in the assessment. Anxiety and depression were surveyed using the Hospital Anxiety and Depression Scale; health-related quality of life, using the 36-Item Short-Form Health Survey; and coping strategies, using the Freiburg Questionnaire on Coping With Illness. In terms of physical and mental dimensions of health-related quality of life, psychosocial factors are…

Krankheitsbewältigung bei Patienten nach Lebertransplantation unter Berücksichtigung der Zugehörigkeit zu einer Selbsthilfegruppe

Background: Within the past 15 years, liver transplantation has proven itself to be the treatment of choice among patients with terminal liver disease. The one-year survival rate is about 80%; after 8 years 61 % of the patients are still alive. The present study investigates the influence of active or depressive coping on the physical and mental quality of life in two different groups of patients after liver transplantation. Methods: Members (n = 65) and non-members (n = 2,0) of a German self-help group were asked to fill out a postal survey. Patients were included if their liver transplantation was conducted 6 to 36 months ago. The health-related quality of life was surveyed using the SF-3…

Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

Abstract Background Recurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenable to surgical approaches is associated with poor outcome. Aims Retrospective evaluation of the safety and efficacy of sorafenib in patients with post-transplant hepatocellular carcinoma recurrence. Methods 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. Results First-line therapy after recurrence was surgery ( n  = 6), radiation therapy ( n  = 1…

Transarterielle Chemoembolisation (TACE) des Hepatozellulären Karzinoms (HCC) bei Patienten mit Pfortaderthrombose - Erfahrungen

PURPOSE: Comparative analysis of the course of disease in patients with initial diagnosis of portal vein thrombosis in HCC treated with sequential TACE. Evaluation of the efficacy and safety of the method in a selected patient cohort. PATIENTS AND METHODS: The study included 22 patients with HCC that were palliatively treated at least 3 times with TACE. All patients presented a portal vein thrombosis in the initial CT investigation. The TACE-procedure was carried out in regular intervals using a suspension consisting of a fixed dosage of Mitomycin C (10 mg) and 10-20 ml Lipiodol. Follow-up investigations were carried out with contrast enhanced Multislice-CT before and after TACE and control…

Preoperative imaging of hilar cholangiocarcinoma: surgical evaluation of standard practises.

UNLABELLED It was the goal of this study to compare the results of the preoperative diagnostic workup (ERC, MRC, and PTC) with the tumor extent of the surgical specimen in patients with hilar cholangiocarcinoma (hilCC). PATIENTS AND METHODS Between 9/97 and 12/2002 82 patients with hilCC were treated at our institution. In 59 patients tumor resection was feasible. Preoperative ERC, MRC and PTC - blinded for the idendity of the patients - were analysed retrospectively and compared with the surgical specimen. RESULTS PTC resulted in significantly superior visualization of the bile ducts including the hilar lesion compared to ERC and MRC (p < 0.01). ERC, MRC and PTC were correct in predicting …

Hepatitis C virus re-infection: new perspectives

Hepatitis C virus (HCV) re-infection of the liver graft has been recognized to be one of the most important factors that determines prognosis and outcome after liver transplantation in HCV-positive patients. Graft loss due to recurrent HCV re-cirrhosis and subsequent hepatic decompensation, which is the predominant cause of death among transplant recipients, reflects the prognostic significance of HCV re-infection. Despite better overall outcome after liver transplantation, the prognosis of HCV-infected patients has not improved during the last two decades. Recent data suggest that increased liver donor age and intensified immunosuppression of transplant patients are the most important cont…

Boron determination in liver tissue by combining quantitative neutron capture radiography (QNCR) and histological analysis for BNCT treatment planning at the TRIGA Mainz.

The typical primary malignancies of the liver are hepatocellular carcinoma and cholangiocarcinoma, whereas colorectal liver metastases are the most frequently occurring secondary tumors. In many cases, only palliative treatment is possible. Boron neutron capture therapy (BNCT) represents a technique that potentially destroys tumor tissue selectively by use of externally induced, locally confined secondary particle irradiation. In 2001 and 2003, BNCT was applied to two patients with colorectal liver metastases in Pavia, Italy. To scrutinize the rationale of BNCT, a clinical pilot study on patients with colorectal liver metastases was carried out at the University of Mainz. The distribution o…

Reply to: Selecting patients with hepatocellular carcinoma for transplantation

Clinicopathologic features and prognosis of young patients with hepatocellular carcinoma in a large German cohort.

GOALS AND BACKGROUND Hepatocellular carcinoma in non-hepatitis B virus endemic areas is rare in patients younger than 40 years of age. The aim of this study was to characterize young patients in a large German cohort in comparison with older patients with regard to underlying liver disease, clinical management, and survival. STUDY We analyzed the clinical data and medical records of 1108 consecutive patients with confirmed hepatocellular carcinoma. Twenty-five patients (2%) were younger than 40 years of age. We compared this subgroup with patients older than 40 years of age. RESULTS Underlying chronic liver disease was less common in young patients and detectable in only 56% of patients. Fi…

Liver Preservation by Aortic Perfusion Alone Compared With Preservation by Aortic Perfusion and Additional Arterial Ex Situ Back-Table Perfusion With Histidine-Tryptophan-Ketoglutarate Solution: A Prospective, Randomized, Controlled, Multicenter Study.

Background. Arterial ex situ back-table perfusion (BP) reportedly reduces ischemic-type biliary lesion after liver transplantation. We aimed to verify these findings in a prospective investigation. Methods. Our prospective, randomized, controlled, multicenter study involved livers retrieved from patients in 2 German regions, and compared the outcomes of standard aortic perfusion to those of aortic perfusion combined with arterial ex situ BP. The primary endpoint was the incidence of ischemic-type biliary lesions over a follow-up of 2 years after liver transplantation, whereas secondary endpoints included 2-year graft survival, initial graft damage as reflected by transaminase levels, and fu…

Sonographic signs of amyloidosis.

INTRODUCTION: Amyloidosis is a rare group of diseases with a variety of symptoms that occurs not only in multimorbid elderly but also in young patients. However, sonographic signs of amyloidosis have not been described so far. PATIENTS AND METHODS: 30 patients with different forms of amyloidosis (19 patients with TTR-amyloidosis (familial amyloid Polyneuropathy [FAP]), 11 patients with other forms of systemic amyloidosis) were sonographically evaluated in a standardised fashion. In all patients amyloidosis was histologically verified. RESULTS: Typical signs of cardiac amyloidosis were myocardial thickness, pericardial effusion, pleural effusion and typical echorich subendocardial deposition…

Pathologic response to preoperative transarterial chemoembolization for resectable hepatocellular carcinoma may not predict recurrence after liver resection.

Early Steroid-Free Immunosuppression With FK506 After Liver Transplantation: Long-Term Results of a Prospectively Randomized Double-Blinded Trial

Background. The aim of this prospective, randomized, double-blinded, placebo-controlled single center study was to evaluate an early steroid-free immunosuppression in liver transplant patients. Methods. From March 2000 to October 2004, 110 patients were included. All patients received tacrolimus and steroids during the first 2 weeks after orthotopic liver transplantation (OLT). Thereafter, patients in the steroid group (n=54) received steroids and the remaining 56 a placebo. After 6 months, the immunosuppression for all was steroid free. Thirty patients were hepatitis C positive. Five years after inclusion, patient survival, organ survival, steroid side effects, and recirrhosis in hepatitis…

Risk Factors in Patients With Rapid Recurrent Hepatitis C Virus–Related Cirrhosis Within 1 Year After Liver Transplantation

Abstract Background Recurrent cirrhosis (RC) due to pretransplant underlying disease leads to organ failure and subsequent death after orthotopic liver transplantation (OLT). RC occurs in up to 30% of patients with recurrent hepatitis C (HCV) within 5 years after OLT. We sought to identify early risk factors for rapid RC within the first year after OLT in HCV-positive patients. Methods Among 404 liver transplanted patients at the University of Mainz between 1998 and 2008, 90 were HCV-RNA positive. To identify predictive factors for rapid RC, we compared HCV-positive patients with advanced fibrosis stages within 1 year after OLT ( n = 13) with these without RC at 5 years after OLT ( n = 23).…

Detection of benign hilar bile duct stenoses – A retrospective analysis in 250 patients with suspicion of Klatskin tumour

Introduction The aim of this study was to identify clinical, laboratory and radiological parameters to distinguish benign from malignant stenoses of the proximal bile duct. Methods Between 1997 and 2011, 250 patients were referred to our clinic with hilar bile duct stenoses suspicious for Klatskin tumour. Medical histories, clinical data, pre-interventional laboratory tests, imaging findings, as well as therapeutic approach and patient outcome were compared to final histological results. All data were retrieved from our prospectively maintained database and analysed retrospectively. Results We found benign bile duct lesions in 34 patients (13.6%). Among the entire study population, uni- and…

Dose calculation in biological samples in a mixed neutron-gamma field at the TRIGA reactor of the University of Mainz

To establish Boron Neutron Capture Therapy (BNCT) for non-resectable liver metastases and for in vitro experiments at the TRIGA Mark II reactor at the University of Mainz, Germany, it is necessary to have a reliable dose monitoring system. The in vitro experiments are used to determine the relative biological effectiveness (RBE) of liver and cancer cells in our mixed neutron and gamma fi eld. We work with alanine detectors in combination with Monte Carlo simulations, where we can measure and characterize the dose. To verify our calculations we perform neutron fl ux measurements using gold foil activation and pin-diodes . Material and methods . When L- α -alanine is irradiated with ionizing …

Familial amyloidosis: great progress for an orphan disease.

Familial amyloidosis: Great progress for an orphan disease Ana Paula Barreiros1,2,*, Gerd Otto3, Bita Kahlen1, Andreas Teufel1,2, Peter R. Galle1 1Department of Internal Medicine I, Universitatsmedizin of the Johannes Gutenberg-University Mainz, Germany; 2Department of Internal Medicine I, Universitatsklinikum of the University Regensburg, Germany; 3Department of Hepatobiliary and Transplantation Surgery, Universitatmedizin of the Johannes Gutenberg-University Mainz, Germany. *Corresponding author. Address: Universitatsklinikum Regensburg, Department of Internal Medicine I, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany. Tel.: +49 941-944-7021. E-mail address: Ana.Barreiros@ukr.de …

Sunitinib in patients with advanced hepatocellular carcinoma after progression under sorafenib treatment.

&lt;i&gt;Objective:&lt;/i&gt; To evaluate the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) after progression under sorafenib treatment. &lt;i&gt;Methods:&lt;/i&gt; Sunitinib was administered at 37.5 mg daily (4-weeks-on/2-weeks-off schedule) after progression under sorafenib treatment. Adverse events (AEs) were assessed using NCI-CTCAE v3.0, and tumor response was evaluated according to RECIST. Data were analyzed retrospectively. &lt;i&gt;Results:&lt;/i&gt; Eleven patients with metastatic disease were treated. Seven patients (64%) presented with no liver cirrhosis, including 3 patients with a history of liver transplantation. The first radiologic…

MRI versus 64-row MDCT for diagnosis of hepatocellularcarcinoma

To compare the diagnostic capability of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) for the detection of hepatocellular carcinoma (HCC) tumour nodules and their effect on patient management.A total of 28 patients (25 male, 3 female, mean age 67 +/- 10.8 years) with biopsy-proven HCC were investigated with 64-row MDCT (slice 3 mm native, arterial and portal-venous phase, 120 mL Iomeprol, 4 mL/s, delay by bolus trigger) and MRI (T1fs fl2d TE/TR 2.72/129 ms, T2tse TE/TR 102/4000 ms, 5-phase dynamic contrast-enhanced T1fs fl3d TE/TR 1.56/4.6, Gadolinium-DTPA, slice 4 mm). Consensus reading of both modalities was used as reference. Tumour nodules were analyzed w…

Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma

Cholangiocellular carcinoma (CCA) is a primary hepatic malignancy derived from cholangiocytes. The prognosis for CCA patients is very poor and conventional chemotherapy has been proven ineffective in improving long‑term patient survival rates. Organic cation transporters (OCTs) mediate the transport of a broad spectrum of endogenous substrates and the detoxification of xenobiotics. Moreover, OCTs are considered responsible for the responsiveness towards platinum‑based chemotherapies. Currently, there are no data available regarding the role of OCTs in CCA. Therefore, the aim of this study was to investigate the expression of OCT1 and OCT3 in CCA and the corresponding non-neoplastic tumor‑su…

Evaluation of domino liver transplantations in Germany.

Summary A retrospective multicenter study has been conducted to evaluate domino liver transplantations (DLTs) in Germany. The study provides insight into survival and features having an impact on the assessment of neuropathy after DLT. In addition, a neurologic follow-up program with a scheme to estimate the likelihood of de novo amyloidosis is presented. A series of 61 DLTs at seven transplant centers in Germany was enrolled. The mean age of domino recipients at the time of transplantation was 58 years, 46 of them being men, and 15 being women. The median follow-up was 46 months. The overall 1-, 3-, and 5-year survival of domino recipients was 81.6%, 70.8% and 68.8%, respectively. Causes o…

Cloning and characterization of the promoter of Hugl-2, the human homologue of Drosophila lethal giant larvae (lgl) polarity gene.

The human lgl gene, Hugl-2 (llgl2, Lgl2), codes for a cytoskeletal protein involved in regulating cell polarity. Here, we report the identification and functional characterization of the promoter region ( approximately 1.2kb) of the Hugl-2 gene. Luciferase expression assays show a high basal Hugl-2 promoter activity in different cell lines and primary human hepatocytes. Truncations of the promoter identified a GC-rich region important for this activity. Alignment of human and mouse genomic sequences demonstrate that this is an evolutionary conserved region fcontaining putative binding sites for several transcription factors including Elk-1 and Sp-1. Mithramycin A reduces Hugl-2 expression i…

The recipient CYP2D6 allele 4-associated poor metabolizer status correlates with an early fibrosis development after liver transplantation

Summary CYP2D6 is part of the cytochrome P450 system, which catalyzes biotransformation of endogenous substrates and xenobiotics. Approximately 10% of the Caucasian population has two null alleles, resulting in a poor metabolizer (PM) status. Mostly, allele four (CYP2D6*4) is responsible for the PM status, which is suspected to be associated with an accelerated fibrosis progression (FP). The aim of the present study was to analyze the role of the CYP2D6*4 genotype for FP after liver transplantation (LT). Genotypes were determined in liver biopsies (donor) and peripheral blood (recipient) by fluorescence resonance energy transfer. Data were correlated with clinical variables and risk factors…

Dose determination using alanine detectors in a mixed neutron and gamma field for boron neutron capture therapy of liver malignancies

IntroductionBoron Neutron Capture Therapy for liver malignancies is being investigated at the University of Mainz. One important aim is the set-up of a reliable dosimetry system. Alanine dosimeters have previously been applied for dosimetry of mixed radiation fields in antiproton therapy, and may be suitable for measurements in mixed neutron and gamma fields.Materials and MethodsTwo experiments have been carried out in the thermal column of the TRIGA Mark II reactor at the University of Mainz. Alanine dosimeters have been irradiated in a phantom and in liver tissue.ResultsFor the interpretation and prediction of the dose for each pellet, beside the results of the measurements, calculations …

Defizite bei der Erfassung transplantationsrelevanter Daten in Deutschland

Collection of data in transplantation medicine is required to define ethical standards, to assess indications and contra-indications and to determine rules for organ allocation. Similarly, assessment of quality of the transplantation process and practice of transplantation centres requires relevant data in transplantation medicine. Apart from data in quality reports, Eurotransplant and organ procurement, any form of data collection is lacking in Germany. In this article the problems caused by this shortcoming are described.

Report on the 16th Congress of the German Transplantation Society October 1113, 2007 in Mainz

Transarterial Chemoembolization in Patients Not Eligible for Liver Transplantation: Single-Center Results

OBJECTIVE. The purpose of this study was to evaluate the effectiveness of transarterial chemoembolization in the care of patients not eligible for liver transplantation.CONCLUSIONS. Prognosis depends on local response, Okuda score, α-fetoprotein level, and tumor size and is independent of the presence of portal venous thrombosis.

Focal nodular hyperplasia proceeds hepatocellular carcinoma in an adult with congenital absence of the portal vein

12-month follow-up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus.

The LIS2T study was an open-label, multicenter study in which recipients of a primary liver transplant were randomized to cyclosporine microemulsion (CsA-ME) (Neoral) (n = 250) (monitoring of blood concentration at 2 hours postdose) C2 or tacrolimus (n = 245) (monitoring of trough drug blood level [predose]) C0 to compare efficacy and safety at 3 and 6 months and to evaluate patient status at 12 months. All patients received steroids with or without azathioprine. At 12 months, 85% of CsA-ME patients and 86% of tacrolimus patients survived with a functioning graft (P not significant). Efficacy was similar in deceased- and living-donor recipients. Significantly fewer hepatitis C–positive pati…

Tacrolimus effects and side effects after liver transplantation: is there a difference between immediate and extended release?

Abstract Background Immunosuppressive therapy after orthotopic liver transplantation (OLT) requires a high degree of patient compliance to guarantee safety and avoid side effects. In 2007, prolonged-release tacrolimus was launched in Europe to improve compliance. In this prospective observational crossover single-center trial, we analyzed effects and side effects of prolonged-release tacrolimus in OLT patients. Methods LT patients at our center were included if they were older than l8 years of age, had had the procedure at least 6 months prior, and were outpatients currently on twice-daily tacrolimus. Patients were observed for 6 months before switching to once-daily tacrolimus. Patient his…

Charting the Path Forward for Risk Prediction in Liver Transplant for Hepatocellular Carcinoma: International Validation of HALTHCC Among 4,089 Patients.

Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out [25.2%]) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre-…

Five cases of de novo inflammatory bowel disease after orthotopic liver transplantation.

Immunosuppression is currently the treatment of choice for severe inflammatory bowel disease (IBD). Thus, it was anticipated that the course of preexisting IBD should improve after orthotopic liver transplantation (OLT). Despite sufficient allograft immunosuppressive therapy, however, exacerbation of IBD or the development of de novo IBD after OLT were described in some cases, primarily in patients transplanted for end-stage primary sclerosing cholangitis (PSC). In addition, the development of de novo IBD in patients undergoing OLT for indications other than PSC was described. Evaluating our collective of 314 liver transplanted patients we found five patients transplanted for various indica…

285 DOWNREGULATION OF ORGANIC CATION TRANSPORTERS OCT1 (SLC22A1) AND OCT3 (SLC22A3) IN HUMAN HEPATOCELLULAR CARCINOMA AND THEIR PROGNOSTIC SIGNIFICANCE

Background Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).

Survival and recurrence after liver transplantation versus liver resection for hepatocellular carcinoma: a retrospective analysis.

Objective This study compares the results of liver transplantation (LTx) and liver resection (LR) for hepatocellular carcinoma (HCC) to test the widespread hypothesis that LTx is the preferable approach for small HCCs. Summary Background Data With respect to scarcity of donor organs and poor results, LTxs for large HCCs are obsolete. Small HCC transplantations have been reported to result in an excellent survival rate. However, the data of comparative studies are controversial. Methods Patients who were treated curatively by LTx (n = 50) or LR (n = 52) for HCC were included in this retrospective study. Survival and freedom from recurrence were analyzed. Patients were stratified according to…

Budd-Chiari Syndrom – eine seltene Manifestation der hereditären Thrombophilie

Das Budd-Chiari Syndrom ist eine seltene Manifestationsform der hereditaren oder erworbenen Thrombophilie. Bei einer 30 jahrigen Patientin konnte, nach anfanglichen diagnostischen Schwierigkeiten, ein BCS diagnostiziert und erfolgreich, durch portocavalen Seit-zu-Seit Shunt, behandelt werden. Bei der Chiari-Trias aus abdominellen Schmerzen, Hepatomegalie und Ascites mus das BCS in die differentialdiagnostischen Uberlegungen mit einbezogen und gegebenenfalls durch invasive Diagnostik ausgeschlossen werden. Therapiemoglichkeiten sind die Anticoagulation und die Anlage eines portosystemischen Shunts (TIPS oder chirurgischer Shunt). Eine Lebertransplantation kommt als ultima ratio bei Leberinsu…

Determination of boron concentration in blood and tissue samples from patients with liver metastases of colorectal carcinoma using Prompt Gamma Ray Activation Analysis (PGAA).

As part of the studies on Boron Neutron Capture Therapy at the University of Mainz, Germany, a clinical trial has been started, in which our patients suffering from liver metastases of colorectal carcinoma, have been enrolled. Specimens of blood and healthy tissue samples taken from the patients were measured at the PGAA facilities at the HFR in Petten, The Netherlands, and at the FRM II in Munich, Germany. From the measured boron concentrations, pharmacokinetic curves and blood-to-tissue concentration ratios were produced.

Metabolic syndrome and its association with fatty liver disease after orthotopic liver transplantation

The metabolic syndrome (MetS) might contribute to morbidity after orthotopic liver transplantation (OLT). For this reason, we searched for MetS-associated risk factors and analyzed the link with nonalcoholic fatty liver disease (NAFLD) in OLT recipients. De novo MetS affected 32.9% of our cohort (n = 170) within 2 years after OLT. Multivariate analysis identified glycosylated hemoglobin (HbA1c) levels ≥5% [odds ratio (OR) = 3.5; 95% confidence interval (CI) = 1.56-8.13, P = 0.003], diabetes mellitus (OR = 4.31, CI = 1.69-10.99, P = 0.002), and arterial hypertension (OR = 4.59, CI = 1.46-14.49, P = 0.009) as independent risk factors for de novo MetS. MetS incidence correlated with steroid do…

An Intention-to-Treat Competing-Risk Model for Candidates with Hepatocellular Cancer Awaiting Liver Transplantation

Background: Since the introduction of the Milan Criteria (MC), all systems, which describe post-transplant prognosis of patients with hepatocellular cancer (HCC), are exclusively based on characteristics available at surgery, and neglect the intention-to-treat principles. This study, based on a large international HCC patient cohort, aimed to develop comprehensive intention-to-treat models through a competing-risk analysis. We used data available at first referral to predict the risk of delisting and HCC-related death after liver transplantation (LT).   Methods: Twelve centres in the United States, Europe and Asia created a Derivation Set (n=2,318) and an external Validation Set (n=773) of …

Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases.

Hepatitis A virus (HAV) or hepatitis B virus (HBV) superinfection is associated with an increased mortality in patients with chronic liver diseases (CLD). Despite official recommendations, it was reported that the vaccination rate against HAV is low in patients with chronic hepatitis C infection. To evaluate the situation in patients with autoimmune liver diseases, we conducted a retrospective cohort study.Susceptibility to HAV and HBV infections, course of HAV and HBV infections, vaccination rates against HAV and HBV, and efficacy of hepatitis A/B vaccines were evaluated by antibody testing in 225 patients with autoimmune liver diseases during 1,677 person-years.Susceptibility to HAV/HBV i…

High pretreatment static and dynamic alpha‐fetoprotein values predict reduced overall survival in hepatocellular carcinoma

Abstract Background Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha‐fetoprotein (AFP) is a well‐established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static AFP values is limited and the clinical potential is a matter of ongoing scientific discussion. Objective We here evaluated the prognostic impact of pretreatment static and dynamic AFP variables on overall survival of hepatocellular carcinoma patients in a Western cohort. Methods Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenber…

Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells

The cylindromatosis gene (CYLD) was identified as a tumor suppressor gene, which is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an autosomal-dominant predisposition to multiple tumors of the skin appendages. CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear factor κB (NF-κB) signaling pathway by removing lysine-63-linked polyubiquitin chains from NF-κB activating proteins. In order to investigate the role of CYLD in apoptotic signaling in human hepatocellular carcinoma (HCC) cells, we first studied the expression levels of CYLD in HCC tissues. CYLD expression was lower in HCC both at protein and mRNA levels compared to the surrounding non-ma…

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

International audience; BACKGROUND:We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).METHODS:In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overal…

Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance

Abstract Background Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC). Methods OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by…

Der solid pseudopapilläre Pankreastumor (SPT) – eine seltene Raumforderung der Bauchspeicheldrüse

BACKGROUND: In general, the rare SPT is a tumour of low malignancy predominantly affecting young women. The outcome after radical resection is favourable. In exceptional cases the tumour presents as solid pseudopapillary carcinoma (SPC) with typical malignant features and even metastases. Unresectable liver metastases can be treated with RFA, TACE or chemotherapy. METHODS: We retrospectively reviewed the surgical approach, immunohistochemistry and clinical outcome in five female patients (1998 - 2007). RESULTS: The mean age was 16 years (range: 13 - 47 years). For radical tumour removal a pancreato - duodenectomy (n = 3), a distal pancreatectomy (n = 1) and an enucleation (n = 1) were perfo…

Multicentric evaluation of model for end-stage liver disease-based allocation and survival after liver transplantation in Germany - Limitations of the 'sickest first'-concept

Summary Since the introduction of model for end-stage liver disease (MELD) in 2006, post-orthotopic liver transplantation (OLT) survival in Germany has declined. The aim of this study was to evaluate risk factors and prognostic scores for outcome. All adult OLT recipients in seven German transplant centers after MELD implementation (December 2006–December 2007) were included. Recipient data were analyzed for their influence on 1-year outcome. A total of 462 patients (mean calculated MELD = 20.5, follow-up: 1 year) were transplanted for alcoholic cirrhosis (33.1%), hepatocellular carcinoma (26.6%), Hepatitis-C (17.1%), Hepatitis-B (9.5%), primary sclerosing cholangitis (5.6%) and late graft-…

Der Einfluss des RANTES −403 Genpolymorphismus auf den Langzeitverlauf nach orthotoper Lebertransplantation

Introduction: By the recruitment of leukocytes chemokines are able to mediate a protective as well as a harming influence on rejections after human orthotopic liver transplantation. There is a base exchange (G/A) known at position-403 in the RANTES promoter region which leads to an increased RANTES expression. Due to the crucial influence of a raised hepatic RANTES synthesis on the course after liver transplantation we investigated the effect of the RANTES −403 polymorphism on organ survival and rejection frequency. Materials and methods: Genomic DNA has been extracted from EDTA-blood of liver transplanted patients. The RANTES −403 polymorphism has been analysed by hybridisation with FRET (…

Organ recipients suffering from undifferentiated neuroendocrine small-cell carcinoma of donor origin: a case report.

Abstract Background Transmission of donor-derived cancer by organ transplantation is rare, but the risk has been increasing due to the aging donor pool. Undifferentiated neuroendocrine small-cell carcinoma is an agressive tumor with the tendency to spread. Herein we have demonstrated different approaches to treat organ recipients with transmitted tumors. Methods and Results Grafts were retrieved from a decreased donor without any history of previous diseases. Autopsy was not performed after donation. The recipient of the liver graft presented with suspected nodules on routine abdominal ultrasound. After computed tomography (CT) scan, biopsy confirmed the diagnosis of a small-cell carcinoma.…

Sequentielle transarterielle Chemoembolisation (TACE) des hepatozellulären Karzinoms (HCC) - Erfahrungsbericht eines einzelnen Zentrums über 5 Jahre

PURPOSE: To analyze the course of disease of patients treated with sequential TACE and to evaluate the dependent and independent prognostic factors for patient survival using the Cox Proportional Hazard Model. MATERIALS AND METHODS: 94 patients palliatively treated with TACE. Patients were selected if they had been treated at least 3 times. The TACE procedure was carried out at 8-week intervals using a suspension consisting of a fixed dosage of Mitomycin C (10 mg) and 10 ml Lipiodol. Follow-up investigations included contrast-enhanced multislice CT before and after TACE and assessment of the laboratory test results (i. e., blood count, liver enzymes, and coagulation). RESULTS: In 66.7 % of …

Alpha-fetoprotein and modified response evaluation criteria in Solid Tumors progression after locoregional therapy as predictors of hepatocellular cancer recurrence and death after transplantation

Locoregional therapy (LRT) is being increasingly used for the management of hepatocellular cancer (HCC) in patients listed for liver transplantation (LT). Although several selection criteria have been developed, stratifications of survival according to the pathology of explanted livers and pre-LT LRT are lacking. Radiological progression according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and alpha-fetoprotein (AFP) behavior was reviewed for 306 patients within the Milan criteria (MC-IN) and 116 patients outside the Milan criteria (MC-OUT) who underwent LRT and LT between January 1999 and March 2010. A prospectively collected database originating from 6 collabor…

Safety and Efficacy of Sorafenib in Patients With Advanced Hepatocellular Carcinoma in Consideration of Concomitant Stage of Liver Cirrhosis

GOALS AND BACKGROUND: The multikinase inhibitor sorafenib provides survival benefit for patients with advanced hepatocellular carcinoma (HCC) and liver cirrhosis (LCI) Child-Pugh A. We report our experiences with sorafenib in advanced HCC, particularly in patients with LCI Child-Pugh B/C, where only limited data are available in regard to safety and efficacy of sorafenib. METHODS: Thirty-four patients with advanced HCC were treated with sorafenib regardless of liver function and prior anticancer therapy. Adverse events (AEs) were graded using Common Toxicity Criteria version 3.0, tumor response was assessed according to Response Evaluation Criteria in Solid Tumors. RESULTS: Fifteen patients…

Effektiver Schutz vor Ischemic Type Biliary Lesions nach orthotoper Lebertransplantation durch arterielle ex situ-Nachperfusion unter Druck

Einleitung: Ischemic Type Biliary Lesions (ITBL) sind eine gefurchtete Komplikation nach Lebertransplantation, welche zum einem die Lebensqualitat des Patienten stark einschrankt und zum anderen mit erheblicher Mortalitat verbunden ist. In der Literatur werden verschiedene Faktoren, wie z. B. lange kalte Ischamiezeit, Alter des Organspenders und der Einsatz von University of Wisconsin (UW)-Losung als ursachlich angeschuldigt. Die hochviskose UW-Losung erreicht moglicherweise nicht die kleinen Arteriolen der Gallenwege und fuhrt dadurch zu einer mangelhaften Konservierung der Gallenwege. Im folgenden berichten wir uber die Moglichkeit der arteriellen Nachperfusion unter Druck nach der Explan…

Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met…

Managing hepatitis C in liver transplant patients with recurrent infection

Tim Zimmermann1, Gerd Otto2, Marcus Schuchmann11Department of Internal Medicine, 2Transplantation Surgery, University of Mainz, GermanyAbstract: Hepatitis C virus (HCV) reinfection after liver transplantation (LT) and recurrent hepatitis C often lead to recurrent cirrhosis (RC). RC is one of the most frequent complications resulting in organ failure and early death after LT in HCV-positive patients with reported 5-year rates from 20% to 40%. As HCV-cirrhosis is one of the leading indications for LT, the therapeutic management is a central issue. To date, the best available therapy is a combination of pegylated interferon + ribavirin in patients with established recurrent hepatitis C proven …

Reply: Selection criteria for liver transplantation in patients with hepatocellular carcinoma: Beyond tumor size and number?

Hepatocellular carcinoma in Child's A cirrhosis: a retrospective analysis of matched pairs following liver transplantation vs. liver resection according to the intention-to-treat principle.

This is the first matched pair analysis on the puzzling clinical problem of whether to perform liver transplantation (LT) or liver resection (LR) for Child's A hepatocellular carcinoma (HCC) patients. A total of 201 patients diagnosed with HCC and Child's A liver cirrhosis were treated with LT transarterial chemoembolization (TACE) or LR between 1998 and 2012. To achieve the most accurate study design, two groups of 57 patients were matched retrospectively according to their tumor characteristics detected by the initial computerized tomography (CT) scan. Sixteen of 57 LT candidates were not transplanted due to tumor progress during pre-treatment (TACE). Nevertheless, the retrospective analy…

Reperfusion of liver graft during transplantation: techniques used in transplant centres within Eurotransplant and meta-analysis of the literature

Abstract: It remains unclear which liver graft reperfusion technique leads to the best outcome following transplantation. An online survey was sent to all transplant centres (n=37) within Eurotransplant (ET) to collect information on their technique used for reperfusion of liver grafts. Furthermore, a systematic review of all literature was performed and a meta-analysis was conducted based on patients' mortality, number of retransplantations and incidence of biliary complications, depending on the technique used. Of the 28 evaluated centres, 11 (39%) reported performing simultaneous reperfusion (SIMR), 13 (46%) perform initial portal vein reperfusion (IPR), 1 (4%) performs an initial hepati…

Die Diagnostik des hilären Cholangiokarzinoms: Wertigkeit von präoperativer ERC, MRC und PTC im Vergleich zur Histopathologie

PURPOSE To compare the results of the preoperative workup consisting of endoscopic retrograde cholangiography (ERC), magnetic resonance cholangiography (MRC), and percutaneous resonance cholangiography (PTC) with the tumor extent of the surgical specimen in patients with hilar cholangiocarcinoma (hilCC). MATERIALS AND METHODS Between 9/1997 and 12/2002, 59 patients with hilCC tumor underwent surgical resection. Preoperative ERC, MRC, and PTC were analyzed, blinded for the identity of the patient, and compared with the surgical specimen. For this retrospective analysis, 55 of the initial 59 ERCs, 39 of the initial 40 MRCs and 32 of the initial 38 PTCs were available. Most of the ERCs and MRC…

CC chemokine receptor 5Δ32 polymorphism-a risk factor for ischemic-type biliary lesions following orthotopic liver transplantation

Ischemic-type biliary lesions are a major complication following orthotopic liver transplantation. They occur in up to 26% of liver transplant recipients. Among other factors, unknown immunologic factors have always been assumed to be partly responsible for these lesions. CC-chemokines and their receptors play a key role in postoperative immunomodulation after liver transplantation. The non-function CC-chemokine receptor 5Δ32 polymorphism (CCR5Δ32) has been shown to lead to a lower rate of acute rejection after kidney transplantation; in liver transplantation the role of CCR5Δ32 is unclear. We investigated the influence of the CCR5Δ32 after liver transplantation with special regard to ische…

Survival analysis of proposed BCLC-B subgroups in hepatocellular carcinoma patients

Background & Aims The BCLC-staging system is used to facilitate treatment decisions in patients with hepatocellular carcinoma (HCC). Owing to the observed clinical heterogeneity of the intermediate stage BCLC-B, a subclassification was proposed taking Child–Pugh score and extended criteria for transplantation into account. Analysis of the prognostic significance of a proposed subclassification of the BCLC-B score in a European cohort of HCC patients. Methods Eight hundred and eighty four consecutive HCC patients were retrospectively analysed. Patients with stage BCLC-B were grouped according to the proposed subclassification. Baseline patient and tumour characteristics, therapy and overall …

The Programmed Death (PD)‐1/PD‐Ligand 1 Pathway Regulates Graft‐Versus‐Host‐Reactive CD8 T Cells After Liver Transplantation

Acute graft-versus-host disease (aGVHD) is a life-threatening complication after solid-organ transplantation, which is mediated by host-reactive donor T cells emigrating from the allograft. We report on two liver transplant recipients who developed an almost complete donor chimerism in peripheral blood and bone marrow-infiltrating T cells during aGVHD. By analyzing these T cells directly ex vivo, we found that they died by apoptosis over time without evidence of rejection by host T cells. The host-versus-donor reactivity was selectively impaired, as anti-third-party and antiviral T cells were still detectable in the host repertoire. These findings support the acquired donor-specific allotol…

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

Abstract Background The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibito…

Supplemental material for Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

Supplemental Material for Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre by Friedrich Foerster, Maria Hoppe-Lotichius, Johanna Vollmar, Jens U Marquardt, Arndt Weinmann, Marcus-Alexander Wörns, Gerd Otto, Tim Zimmermann and Peter R Galle in United European Gastroenterology Journal

Surgical therapy of liver cancer: resection and transplantation

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is estimated to cause approximately half a million deaths per year. Most tumours (80%) develop in cirrhotic livers caused by viral hepatitis C or B and alcoholic liver disease. In the natural course survival depends on the stage of the disease. At an early stage 3-year survival is 65% without treatment, in the intermediate stage between 10% and 50% of patients are reported to be alive after 2 years, and in the final stage median survival only rarely exceeds 6 months. Surgical treatment is capable of doubling survival. The results of local ablative treatment in early carcinoma are very similar to surgical treatment1…

Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure

Abstract Background/Aims Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published. Methods A retrospective analysis was performed of patients treated for liver disease between 1992 and 2002 at our department to evaluate the incidence, clinical findings and histopathology of coumarin-induced hepatotoxicity. Results The retrospective analysis revealed eight cases of phenprocoumon-induced hepatotoxicity, including three cases of (sub-) acute liver failure which resulted in two orthotopic liver transpl…

Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis in primary human hepatocytes

Background/aims The accumulation of endogenous bile acids contributes to hepatocellular damage during cholestatic liver disease. To evaluate the potential role of apoptotic cell death due to increased concentrations of bile acids, primary human hepatocytes were treated with hydrophobic and hydrophilic bile acids. Because the Fas receptor–ligand system may mediate apoptosis in human liver cells, the effect of toxic bile acids on hepatocellular Fas receptor expression was evaluated. Materials and methods Primary human hepatocytes were incubated with 50 and 100 μM glycochenodeoxycholic acid (GCDCA) and co-incubated with equimolar concentrations of tauroursodeoxycholic acid (TUDCA). To evaluate…

Radiofrequency ablation as first-line treatment in patients with early colorectal liver metastases amenable to surgery.

Aiming at avoidance of futile surgery, we have tested whether radiofrequency ablation (RFA) may be used as first-line treatment in patients with colorectal metastases (CRLM) occurring within the first year after colorectal surgery.Surgical resection is the standard treatment in patients with CRLM. Major retrospective analyses have identified the interval between colorectal surgery and the occurrence of CRLM to be of prognostic importance. So far, it is unknown whether survival of the respective patients is hampered if RFA is used as first-line treatment.According to a clinical pathway, we have treated patients with CRLM detected within the first year after colorectal surgery preferentially …

Die Leberfunktion vor Lebertransplantation bestimmt das Überleben nach Lebertransplantation beim hepatozellulären Karzinom

Klatskin Tumour: Meticulous Preoperative Work-Up and Resection Rate

BACKGROUND: Surgery represents the only potentially curative treatment of hilar cholangiocarcinoma (hilCC). It may be suggested that meticulous preoperative work-up in Asian countries leads to higher resection rates. METHOD: One hundred and eighty-two patients treated in our department between 1998 and 2008 were included in an analysis based on our prospectively recorded database. Among them, 75 % had a percutaneous transhepatic cholangiography as part of their diagnostic work-up. A total of 160 patients underwent explorative surgery and 123 patients were resected (77 % of patients undergoing exploration, 68 % of all patients). RESULTS: Ninety-one percent of the patients were diagnosed to h…

Psychological Conflicts Between Relatives During the Long-Term Course After Successful Living Organ Donation

The German transplantation law prefers living organ donation between close relatives and spouses, which is assumed to guarantee unequivocal altruistic motivation. Since 2001, 68 recipient-donor-pairs, who aspired to have a renal or liver transplantation, underwent a systematic psychosomatic evaluation. Meanwhile, 43 transplantations were performed including 34 renal and 9 liver cases. Seventeen recipient-donor-pairs were readministered evaluations by the department of psychosomatic medicine after 1 to 6 years after transplantation for long-term follow-up. In 10 cases of medically successful transplantation, we identified severe conflicts between donor, recipient, and next-of-kin. Major conf…

Differenzielle Expression von CC-Chemokinen nach orthotoper Lebertransplantation während Rejektion und Infektion

Einleitung: Chemokine sind niedermolekulare Zytokine, die fur die Geweberekrutierung inflammatorischer Leukozyten verantwortlich sind. Eine Leukozyteninfiltration ist charakteristisch fur die akute Transplantatabstosung nach Lebertransplantation. Wir vermuten, dass die hepatische Chemokinsekretion als Vermittler von Abstosungsreaktionen nach Lebertransplantation eine Rolle spielen konnte. Daten zum Chemokinverlauf nach Lebertransplantation im peripheren Blut liegen bislang nicht vor. Material und Methoden: In dieser Untersuchung wurden die Serumchemokinkonzentrationen fur die CC-Chemokine CCL2 (Monocyte chemoattractant protein 1, MCP-1), CCL3 (Macrophage inflammatory protein I alpha, MIP-1γ…

Efficacy of an escalating dose regimen of pegylated interferon ?-2a plus ribavirin in the early phase of HCV reinfection after liver transplantation

We evaluated the safety and efficacy of an escalating dose regimen of pegylated interferon alpha-2a (PEG-IFN(alpha-2a)) and ribavirin in the early phase of recurrent hepatitis C after orthotopic liver transplantation (OLT). In this prospective study, 26 patients transplanted for hepatitis C virus cirrhosis with recurrent hepatitis C were treated 3.4 +/- 3.6 months after OLT and compared with an untreated historical control. PEG-IFN(alpha-2a) was initiated as monotherapy, following stepwise dose escalation up to 180 mug/week and the addition of ribavirin up to 1200 mg/day or maximally tolerated doses for 48 weeks. In the intent-to-treat analysis, 38% showed an early virological response (EVR…

Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses.

Fibrinogen A α-chain (AFib) and apolipoprotein AI (AApoAI) amyloidosis due to variants in the AFib and ApoAI genes are the most common types of hereditary amyloidosis in Europe and the United States. Liver is the exclusive source of the aberrant amyloidogenic protein in AFib and responsible for supplying approximately half of the circulating variant ApoAI. Nephrotic syndrome and renal impairment due to renal amyloidosis are common disease manifestations; however, recent research provides evidence to support a more diverse and systemic disease phenotype, which in turn has implications in the management of the hereditary amyloidoses with solid organ transplantation and, in particular, liver t…

Segmentanatomie der Leber in der Computertomographie: Lokalisieren wir die Läsionen richtig?*

Purpose: To evaluate if Couinaud's model using the planes of the major veins is an adequate tool for the presurgical localization of focal liver lesions. Methods: Biphasic helical CT scans were performed on patients evaluated for liver resection using an increased IV bolus of contrast medium (180 ml lopamidol) and 2 mm image reconstruction increments. During the first evaluation, all liver lesions were localized in the conventional way using the planes of the 3 major hepatic veins and the portal trunks as segmental boundaries. In a second review, all lesions were attributed to the nearest peripheral portal branches. The path and the segmental attribution of the portal branches were analysed…

Comparative analysis of in situ versus ex situ perfusion on micro circulation in liver procurement--an experimental trial in a porcine model.

The Achilles heel of liver transplantation remains the biliary system. The crucial step for liver preservation is effective rinsing and perfusion of the peribiliary plexus (PBP). Due to the physiology of the vascular tree, it seems almost impossible to achieve the necessary physiologic ranges of pressure and flow by the in situ perfusion technique. We investigated the role of additional ex situ perfusion via the hepatic artery in this animal model.Fifteen German Landrace pigs underwent standardized multiorgan procurement. In situ perfusion and additional ex situ perfusion were performed consecutively. Meanwhile the external pressure applied to the perfusion system was increased stepwise. To…

Erratum to "Determination of the irradiation field at the research reactor TRIGA Mainz for BNCT" [J. Appl. Radiat. Isot. 67 (2009) S242-S246].

The role of monocyte chemoattractant protein-1 in orthotopic liver transplantation.

Hepatic ischemia reperfusion injury as well as acute graft rejection (RE) after orthotopic liver transplantation (OLT) are associated with leukocyte invasion of the graft. Local synthesis of chemokines is a key reaction in the recruitment and activation of inflammatory leukocytes and consequent liver damage. In this paper we describe the role of monocyte chemoattractant protein (MCP)-1 (CCL2) in human OLT. We investigated the serum CC-chemokine levels for MCP-1 by specific ELISAs after OLT in 105 human liver allografts between September 1997 and January 2001. One hour after reperfusion we saw a significant (t test) increase of MCP-1 in peripheral blood (92.5 +/- 85.8 pg/mL to 774.2 +/- 319.…

Irradiation facility at the TRIGA Mainz for treatment of liver metastases

Abstract The TRIGA Mark II reactor at the University of Mainz provides ideal conditions for duplicating BNCT treatment as performed in Pavia, Italy, in 2001 and 2003 [Pinelli, T., Zonta, A., Altieri, S., Barni, S., Braghieri, A., Pedroni, P., Bruschi, P., Chiari, P., Ferrari, C., Fossati, F., Nano, R., Ngnitejeu Tata, S., Prati, U., Ricevuti, G., Roveda, L., Zonta, C., 2002. TAOrMINA: from the first idea to the application to the human liver. In: Sauerwein et al. (Eds.), Research and Development in Neutron Capture Therapy. Proceedings of the 10th International Congress on Neutron Capture Therapy, Monduzzi editore, Bologna, pp. 1065–1072]. In order to determine the optimal parameters for the…

Prevention of ischemic-type biliary lesions by arterial back-table pressure perfusion

Abstract Ischemic-type biliary lesions (ITBLs) lead to considerable morbidity after orthotopic liver transplantation (OLT). The exact pathogenesis is unknown. We tested the hypothesis that insufficient perfusion of biliary arterial vessels might be responsible for ITBLs. This could be prevented by improved perfusion techniques. Since February 2000, we performed a controlled study using arterial back-table pressure perfusion (AP) to achieve reliable perfusion of the biliary-tract capillary system, which may be impaired by the high viscosity of University of Wisconsin solution. We retrospectively analyzed 190 OLTs performed between September 1997 and July 2002 with regard to ITBLs. One hundre…

GM-CSF restores innate, but not adaptive, immune responses in glucocorticoid-immunosuppressed human blood in vitro.

Abstract Infection remains the major complication of immunosuppressive therapy in organ transplantation. Therefore, reconstitution of the innate immunity against infections, without activation of the adaptive immune responses, to prevent graft rejection is a clinically desirable status in transplant recipients. We found that GM-CSF restored TNF mRNA and protein expression without inducing IL-2 production and T cell proliferation in glucocorticoid-immunosuppressed blood from either healthy donors or liver transplant patients. Gene array experiments indicated that GM-CSF selectively restored a variety of dexamethasone-suppressed, LPS-inducible genes relevant for innate immunity. A possible ex…

Midterm follow-up after DC-BEAD™-TACE of Hepatocellular Carcinoma (HCC)

Abstract Aim To determine local response, its predictors and survival and complication rates after DC-Bead™-TACE in patients with hepatocellular carcinoma (HCC). Materials and methods DC-Beads™ are non-resorbable, polyvinyl-alcoholic hydrophilic microspheres. They release high amounts of chemotherapeutics directly into the tumour. Delivery is sustained over time, tumour feeders are embolised. We used beads from 100–300 to 500–700 μm loaded with Doxorubicin (max. 150 mg/4 ml). Fifty patients (mean age: 68.5 ± 8.8 years) with HCC were analysed. DC-Bead™-TACE was performed once or repeated in two-month intervals. Imaging scans (CT or MRI) were done one-month following each procedure. To evalua…

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

The hepatitis B virus (HBV) is a major causative agent of chronic liver disease and subsequent liver cirrhosis worldwide. The reduced sensitivity of virus-infected liver cells to apoptosis may play a role in the failure to remove virus-infected cells and eventually promote viral chronicity. The purpose of our study was to investigate whether survival factors induced during compensatory liver regeneration may protect hepatocytes against apoptosis. We evaluated the serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in HBV-infected patients and found significant increases in HGF and EGF in patients with active virus infection. In primary human hepatocytes we show …

Alloimmune hemolytic anemia after liver transplantation from an ABO-identical and Rh-nonidentical donor in a patient with postpartum Budd-Chiari syndrome

The efficacy of N-acetylcysteine as a hepatoprotective agent in liver transplantation

One of the most common complications after liver transplantation is primary graft dysfunction which results from severe deterioration of the microcirculation. The data obtained from our experimental studies indicate that N-acetylcysteine (NAC) is able to reduce the severity of ischemia/reperfusion injury and improves postoperative graft function after liver transplantation in rats. The aim of this pilot study was to evaluate the efficacy of NAC as a hepatoprotective agent under clinical conditions. A group of 30 liver transplanted patients were treated with NAC, and 30 patients (control group) were treated with a 5 % solution of glucose only. In the NAC group we observed a distinct reductio…

Tacrolimus Monotherapy Without Steroids After Liver Transplantation – A Prospective Randomized Double-Blinded Placebo-Controlled Trial

Early steroid withdrawal after liver transplantation (LT) is desirable in order to reduce steroid side effects. Between February 2000 and August 2004, 110 patients after LT were included in this prospective, randomized, double-blind, placebo-controlled trial. Randomization was performed before LT. In all patients, tacrolimus was used without induction therapy. All patients received methylprednisolon for 14 days, thereafter a double-blinded medication containing either placebo (n = 56) or methylprednisolon (n = 54) for 6 months, which was completely stopped thereafter. End points were patient and graft survival, acute and chronic rejection, and incidence of steroid side effects during the fi…

Differential diagnosis of cytomegalovirus infection and acute rejection by serum CC-Chemokine measurement after orthotopic liver transplantation

Ten Years of Simultaneous Pancreas-Kidney Transplantation: A Retrospective Single-Center Analysis of Prospectively Obtained Data

Simultaneous pancreas-kidney transplantation (SPK) is a standardized and life-saving procedure for a patient suffering from both insulin-dependent diabetes mellitus type 1 (IDDM 1) and end-stage diabetic nephropathy. To expand the donor pool and to determine the influence of the preprocurement pancreas suitability scoring system (P-PASS) on pancreas graft survival we retrospectively analyzed our data on SPK.From 1999 to 2010 we performed 55 SPKs, using systemic-enteric drainage as surgical approach. The immunosuppressive therapy was induced with basiliximab; maintenance therapy was based on tacrolimus, mycophenolate mofetil, and steroids. Data were prospectively obtained, analyzed, and corr…

Trends in Epidemiology, Treatment, and Survival of Hepatocellular Carcinoma Patients Between 1998 and 2009

The aim of this study was to analyze clinical presentation, course of disease, and management of patients with hepatocellular carcinoma (HCC) in a German referral center between 1998 and 2009.HCC is a rare tumor in Germany, but its incidence has increased over the last 30 years. New therapies such as chemoembolization with drug-eluting beads, selective internal radiotherapy, and sorafenib were introduced recently; however, the impact on clinical management and overall survival (OS) is unclear.In this retrospective analysis, 1066 patients with HCC, separated into two 6-year periods (n=385; 1998 to 2003 and n=681; 2004 to 2009) were evaluated.The number of patients presenting each year (64 vs…