Ulf P. Neumann

Long-term outcome of liver transplants for chronic hepatitis C: a 10-year follow-up.

Background. Recurrence of hepatitis C (HCV) infection after orthotopic liver transplantation (OLT) in HCV-positive patients is almost universal. Severity of graft hepatitis increases during the long-term follow-up, and up to 30% of patients develop severe graft hepatitis and cirrhosis. However, there are still no clear predictors for severe recurrence. The aim of this study was to examine the 10-year outcome and risk factors for graft failure caused by HCV recurrence. Methods. In a prospective analysis, 234 OLTs in 209 HCV-positive patients with a median age of 53 years were analyzed. Immunosuppression was based on cyclosporine A or tacrolimus in different protocols. Predictors for outcome were genotype, viremia, donor variables, recipient demographics, postoperative immunosuppression, and human leukocyte antigen (HLA) compatibilities. Results. Actuarial 5-, and 10-year patient survival was 75.8% and 68.8%. Eighteen of 209 (8.7%) patients died because of HCV recurrence, which was responsible for 35.9% of the total 53 deaths. Significant risk factors for HCV-related graft failure in an univariate analysis were multiple steroid pulses, use of OKT3, and donor age greater than 40. However, in a multivariate analysis, multiple rejection treatments with steroids and OKT3 treatment proved to be significantly associated with HCV-related graft loss. Conclusions. The analysis of causes leading to graft failure in patients with HCV showed that HCV recurrence is responsible for one of three deaths in HCV-positive patients. Rejection treatment contributed significantly to an enhanced risk for HCV-related graft loss. New antiviral treatments, as well as adapted immunosuppressive protocols, will be necessary to further improve the outcome of HCV-positive patients after liver transplantation.

Treatment of Patients with Recurrent Hepatitis C after Liver Transplantation with Peginterferon Alfa-2b Plus Ribavirin

Background. Recurrent hepatitis C virus (HCV) after liver transplantation (OLT) is a major cause of graft loss in HCV-positive patients. In this study, we evaluated the efficacy and safety of pegylated interferon alfa-2b (peginterferon) and ribavirin treatment for recurrent HCV after OLT and analyzed the influence of antiviral treatment on the histological course of recurrent hepatitis. Methods. Twenty-five patients with recurrent HCV (genotype 1 n=20 and 2–4 n=5) received peginterferon (1 mg/kg/weekly) and ribavirin (600 mg) for 48 weeks. Viral load prior to treatment was below 1,000,000 (IU/ml) in 11 of 25 patients. Sustained antiviral response was defined as undetectable HCV-RNA in serum 6 months after stopping of therapy. All patients underwent liver biopsy prior to treatment and after 72 weeks. Results. Seventeen of 25 patients became HCV-RNA-negative after treatment (68%). Sustained virologic response (SVR) was achieved in 9/25 (36%) patients. Liver specimen showed increase of fibrosis from 1.7 to 2.0 within 72 weeks. Side effects like neutropenia (60%) and anemia (36%) were treated with G-CSF, erythropoietin, and dose reduction of peginterferon and ribavirin. Conclusions. The use of peginterferon is safe and effective in patients with recurrent HCV. Treatment of side effects, especially neutropenia or anemia, helped to maintain antiviral therapy. Despite a viral response of 68% during treatment, the patients showed further progress of recurrent hepatitis in liver specimen.

Extended liver resection for intrahepatic cholangiocarcinoma: A comparison of the prognostic accuracy of the fifth and sixth editions of the TNM classification.

Objective:The present study was conducted to analyze the outcome after liver resection for intrahepatic cholangiocarcinoma (IHC) and to compare the prognostic accuracy of the fifth and sixth editions of the TNM classification of malignant tumors. Summary Background Data:A comparison of the prognostic accuracy of the fifth and sixth editions of the TNM classification of malignant tumors is missing for IHC as yet. The present report is, to our knowledge, the largest series on surgical resection of IHC in the world literature and the first comparison of long-term outcome according to the fifth and sixth edition of the TNM classification of malignant tumors. Methods:From 1988 to 2007, 195 liver resections for IHC were performed in our institution. Staging was performed according to the liver chapters of the fifth and sixth edition of the TNM classification of malignant tumors. Results:In a multivariate analysis of prognostic variables, R0-resection, UICC-stage I/II according to the sixth edition, highly or moderately differentiated IHC, and lymph node negative IHC were identified as favorable prognostic variables. UICC-stage IIIc of the sixth edition, which was almost identical to the group of lymph node positive IHC was identified as unfavorable predictor of postoperative prognosis. Formally, curative resections (R0-resections) were achieved in 138 patients (71%). One- and 5-year survival rates after R0-resections were 72.4% and 30.4%, respectively. Conclusions:Extended resections for IHC resulted in a favorable rate of R0-resection, which is the most important prognostic variable. Staging of IHC according to sixth edition of the TNM classification is superior in comparison with the fifth edition as indicated by the results of the multivariate analysis.

Description of B lymphocytes and plasma cells, complement, and chemokines/receptors in acute liver allograft rejection.

Background. Although antibody mechanisms play a pathogenetic role in liver allograft rejection, no data exist on B lymphocytes, plasma cells, complement, and chemokines in rejected liver tissue. Methods. Liver biopsy specimens from 25 patients with acute allograft rejection (AR) (rejection activity index, RAI score: 1–9) were analyzed by immunohistochemistry (IH) and reverse transcriptase-polymerase chain reaction (RT-PCR) and compared with biopsy specimens taken prior to implantation (PI). The number of CD20+ and CD138+ cells was evaluated, and the presence and abundance of the chemokines macrophage inflammatory protein (MIP)-3&agr;, CXCL9, CXCL10, CXCL11, CXCL12, and their receptors CCR-6, CXCR3, and CXCR4 were examined. Complement depositions were visualized by C4d IH. Results. The numbers of B lymphocytes (P=0.002) and plasma cells (P=0.022) were significantly higher in AR biopsy specimens compared with PI biopsy specimens. MIP-3&agr;+ and CCR-6+ cells were detected in the portal fields of all AR biopsy specimens. IH double staining revealed a colocalization of MIP-3&agr;+/CD20+ cells; C4d deposits could be demonstrated along the portal capillaries. All examined chemokines and receptors could be detected in normal liver tissue and in AR biopsy specimens by RT-PCR and semiquantitative RT-PCR, demonstrating an overexpression of CXCL10 and -11. Conclusions. The significant increase of B lymphocytes and plasma cells during acute rejection, together with the lack of a significant increase of proliferating cells, indicates that the migration of B lymphocytes and plasma cells—promoted by the expression of B-cell activating chemokines/receptors—plays a key role in acute liver rejection. The C4d deposits along the portal capillaries indicate a humorally mediated alloresponse caused by the accumulated B and plasma cells.

Promoter methylation of the Wnt/beta-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer.

Abnormal activation of the Wnt/β‐catenin signaling pathway is common and critical in the pathogenesis of digestive cancers. In this study, the authors investigated the promoter methylation of the dickkopf homolog 3 gene Dkk‐3 in these cancers and its prognostic significance in gastric cancer.

Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients

Abstract: Orthotopic liver transplantation (OLT) is the only effective curative therapy for end‐stage primary biliary cirrhosis (PBC). Survival after OLT is excellent, although recent data have shown a recurrence rate of PBC of up to 32% after transplantation. The aim of this study is to investigate the course after disease recurrence, particularly with regard to liver function and survival in a long‐term follow‐up. Between April 1989 and April 2003, 1553 liver transplantations were performed in 1415 patients at the Charité, Virchow Clinic. Protocol liver biopsies were taken after one, three, five, seven, 10 and 13 yr. One hundred (7%) patients suffered from histologically proven PBC. Primary immunosuppression consisted of cyclosporine (n=54) or tacrolimus (Tac) (n=46). Immediately after OLT, all patients received ursodeoxycholic acid. Corticosteroids were withdrawn three to six months after OLT. The median age of the 85 women and 15 men was 55 yr (range 25–66 yr). The median follow‐up after liver transplantation was 118 months (range 16–187 months) and after recurrence 30 months (range 4–79 months). Actuarial patient survival after five, 10 and 15 yr was 87, 84 and 82% respectively. Ten patients (10%) died after a median survival time of 32 months. Two of these patients developed organ dysfunction owing to recurrence of PBC. Histological recurrence was found in 14 patients (14%) after a median time of 61 months (range 36–122 months). Patients with Tac immunosuppression developed PBC recurrence more often (p<0.05) and also earlier (p<0.05). Fifty‐seven patients developed an acute rejection and two patients a chronic rejection episode. Liver function did not alter within the first five yr after histologically proven PBC recurrence. Multivariate analysis of the investigated patients showed that the recipients age and Tac immunosuppression were significant risk factors for PBC recurrence. Long‐term follow‐up of up to 15 yr after liver transplantation, owing to PBC, in addition to maintenance of liver function, shows excellent organ and patient survival rates. Although protocol liver biopsies revealed histological recurrence in 14 (14%) patients, only two patients developed graft dysfunction. Tac‐treated patients showed more frequently and also earlier histologically proven PBC recurrence; however, in our population we could not observe an impact on graft dysfunction and patients survival.

Biliary reconstruction using a side-to-side choledochocholedochostomy with or without T-tube in deceased donor liver transplantation: a prospective randomized trial.

Objective:The biliary anastomosis is still one of the major causes for morbidity after orthotopic liver transplantation. The optimal method of reconstruction remains controversial. The aim of the study was to assess biliary complications after liver transplantation using a choledochocholedochostomy with or without a temporary T-tube. Background Data:Several reports have suggested that biliary reconstruction without T-tube is a safer method with a lower rate of biliary complications compared with T-tube insertion. Methods:A total of 194 recipients of deceased donor liver grafts were randomized. In group 1 the biliary reconstruction was performed by side-to-side choledochocholedochostomy with (n = 99) and in group 2 (n = 95) without a T-tube. The T-tube was removed after 6 weeks. Results:The overall biliary complication rate was significantly increased in group 2 (P < 0.0005). Biliary leaks occurred in 5 patients in group 1 and in 9 patients in group 2 (5.05% vs. 9.47%; P = 0.2756 ns). Anastomotic strictures of the bile duct were seen in 7 patients in group 1 and in 8 patients in group 2 (7.07% vs. 8.42%; P = 0.7923 ns). Two of the patients in group 1 and 5 patients in group 2 developed an ischemic type biliary lesion (2.02% vs. 5.26%; P = 0.2716 ns). The rate of reoperations was comparable in both groups. The rate of invasive interventions was higher in the group without T-tubes (9% vs. 18%, P = ns), as was the rate of cholangitis (5% vs. 11%. P = ns) and pancreatitis (4% vs. 14%, P = 0.0218). No complications after removal of the T-tube were observed. Conclusion:This study is a large prospective randomized trial to assess biliary complications that occur following liver transplantation, after anatomizing the bile duct with or without T-tubes. A significant increased rate of complications in the group without T-tube insertion was observed. In summary, our results indicate that the usage of T-tubes is safe and an excellent tool for the quality control of biliary anastomoses.

Postoperative tracheal extubation after orthotopic liver transplantation

Background: The duration of postoperative mechanical ventilation and its influence on pulmonary function in liver transplant recipients is still debated controversially.

A prospective randomized trial comparing interleukin-2 receptor antibody versus antithymocyte globulin as part of a quadruple immunosuppressive induction therapy following orthotopic liver transplantation.

BACKGROUND Quadruple immunosuppressive induction therapy has been shown to markedly reduce the incidence of acute rejection episodes without increasing the incidence of infectious complications after liver transplantation. However, the use of polyclonal antibody preparations (e.g. antithymocyte globulin [ATG]) is associated with side effects such as fever and tachycardia. To evaluate the efficacy and the safety of a monoclonal antibody directed against the interleukin-2 receptor (BT563) in comparison with ATG as part of a quadruple induction regimen, a prospective, randomized study was conducted. METHODS Eighty consecutive adult recipients of primary orthotopic liver transplants were randomized to receive either BT563 (10 mg/day; days 0-12; n=39) or ATG (5 mg/kg/day; days 0-6; n=41) in addition to the standard immunosuppressive protocol consisting of cyclosporine, and prednisolone, and azathioprine. RESULTS Patients treated with BT563 had a significantly lower incidence of steroid-sensitive rejection episodes (3 vs. 11; P<0.025) and also significantly fewer drug-related side effects (4 vs. 18, P<0.038) when compared with patients treated with ATG. The incidence of infectious complications was not different between the two groups. Patient survival did not differ significantly between the two groups (84.6% at 1, 2, and 3 years in the BT563 group and 90.2% at 1 year and 87.8% at 2 and 3 years for the ATG group). Analysis of graft function showed an advantage for the BT563 group in terms of postoperative bilirubin levels. However, no differences were observed in long-term follow-up between the two groups. CONCLUSIONS Our results indicate that treatment with anti-interleukin-2 receptor antibody as part of quadruple induction therapy after orthotopic liver transplantation is safe and effective and shows fewer steroid-sensitive rejection episodes as well as fewer side effects when compared with quadruple induction therapy including ATG.

Clinical Implications of Hepatic Preservation Injury After Adult Liver Transplantation

Several advances in organ preservation have allowed for improved results after liver transplantation; however, little information is available regarding the clinical impact of preservation injury on the postoperative course. The medical records of 889 liver transplants were retrospectively reviewed. Preservation injury was classified according to postoperative aspartate aminotransferase values as minor (<1000 U/L), moderate (1000–5000 U/L), or severe (>5000 U/L). The following criteria were analyzed and compared according to the extent of preservation injury: patient and graft survival, retransplantation rate, duration of hospitalization and postoperative ventilation, as well as incidence of rejection, infection, and hemodialysis. The majority of patients received a liver with minor preservation injury (75.9%), whereas 22.7% and 1.3% of grafts showed moderate or severe injury. Graft survival was significantly lower in patients with severe preservation injury, when compared to minor or moderate injury. The relative risk for initial nonfunction was 39.36‐fold increased (95% confidence interval (ci): 10.3–150.2), as it was increased for duration of postoperative ventilation (6.92‐fold; 95%ci: 2.1–22.3) and hemodialysis (6.13‐fold; 95%ci: 1.9–19.3). Since the incidence of retransplantation was significantly increased (50%), patient survival remained comparable between all groups. Severe preservation injury had a tremendous impact on the postoperative clinical course, requiring the maximum medical effort to achieve adequate patient survival.