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Susanne Beckebaum

Publications and source records attributed to Susanne Beckebaum.

At least 19 recordsLinked to original sources
PubMed2006

Increased frequencies of CD8+ T lymphocytes recognizing wild-type p53-derived epitopes in peripheral blood correlate with presence of epitope loss tumor variants in patients with hepatocellular carcinoma.

Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8+ T cells specific for WT p53(149-157) and WT p53(264-272) HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8+ T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8+ T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines.

Aged↗
PubMed2006

[Recurrent disease after liver transplantation. A therapeutic dilemma or treatable?].

BACKGROUND: Side effects of immunosuppressive drugs, the development of de novo malignancies and disease relapse determine the prognosis of liver transplant patients in the long-term course. RECURRENT DISEASE AFTER LIVER TRANSPLANTATION: Treatment of carefully selected and monitored hepatitis C liver transplant patients with interferon-alpha and ribavirin is safe but less efficacious as compared to the non-transplant setting. Postoperative hepatitis B hyperimmune globulin and nucleoside analog combination therapy has resulted in a decrease of reinfection rates to < 10%. New molecular techniques as well as genotyping of hepatocellular carcinoma gain increasing importance for estimation of recurrence-free survival. Diagnosis of disease relapse in cholestatic and autoimmune liver disease is more challenging than in the non-transplant setting and therapeutic options are limited. Psychiatric evaluation and careful validation of compliance are important issues for estimation of the risk of disease recurrence in patients with alcohol-related liver disease. During long-term course, up to one half of patients die of transplant-related causes; 30-70% of these cases are attributed to relapse of primary disease. CONCLUSION: Further improvement of strategies for prevention and treatment of recurrent disease after liver transplantation is warranted in order to increase long-term survival.

Age Factors↗
PubMed2006

Surgery for hepatocellular carcinoma arising in hereditary hemochromatosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a well-known complication of hereditary hemochromatosis. The benefit of surgical therapy in this clinical entity is not well documented. The purpose of this study was to evaluate the outcome of such patients both in our own experience as well as in the published literature. METHODS: 320 patients with a diagnosis of HCC were evaluated at our institution to undergo either surgical resection (n = 262) or liver transplantation (n = 58) during the 4- year period from January 2001 to December 2004. We identified 5 patients with HCC arising in the setting of hemochromatosis. A literature search was performed to estimate resectability rates as well as outcomes after liver transplantation for HCC arising in hemochromatosis. RESULTS: HCC was multifocal in 4 instances and solitary in 1 case. The liver was cirrhotic in all but 1 case. Three patients underwent an exploratory laparotomy, 1 an exploratory laparoscopy, and 1 underwent transplantation. HCC was unresectable in all cases. The patient with a solitary tumor and cirrhosis underwent 5 sessions of transarterial chemoembolization and is alive 37 months after surgical exploration. The 3 patients with multifocal tumors who underwent exploratory laparotomies died within 6 months after the intervention. The fifth patient who underwent a deceased donor split liver transplantation for multifocal tumor is alive without recurrence 3 years after transplantation. These results are similar to those in the literature that concur with the low resectability rate and the favorable outcome after liver transplantation. CONCLUSION: Resectability rates of HCCs arising in hemochromatosis are extremely low, given that tumors are usually multifocal and the livers cirrhotic in the majority of the instances. Early detection of hemochromatosis as well as intensive tumor screening of cirrhotic patients with hemochromatosis could possibly optimize the role of surgery or accelerate the decision to proceed with liver transplantation.

Aged↗
PubMed2006

Cyclosporine versus tacrolimus in patients with HCV infection after liver transplantation: effects on virus replication and recurrent hepatitis.

AIM: To determine the effects of the calcineurin inhibitors, cyclosporine and tacrolimus, on hepatitis C virus (HCV) replication and activity of recurrent hepatitis C in patients post liver transplantation. METHODS: The data of a cohort of 107 patients who received liver transplantation for HCV-associated liver cirrhosis between 1999 and 2003 in our center were retrospectively analyzed. The level of serum HCV-RNA and the activity of recurrent hepatitis were compared between 47 patients who received either cyclosporine or tacrolimus as the primary immunosuppressive agent and an otherwise similar immunosuppressive regimen which did not lead to biliary complications within the first 12 mo after transplantation. RESULTS: HCV-RNA increased within 3 mo after transplantation but the differences between the cyclosporine group and the tacrolimus group were insignificant (P=0.49 at 12 mo). In addition, recurrent hepatitis as determined by serum transaminases and histological grading of portal inflammation and fibrosis showed no significant difference after 12 mo (P=0.34). CONCLUSION: Cyclosporine or tacrolimus as a primary immunosuppressive agent does not influence the induction or severity of recurrent hepatitis in HCV-infected patients after liver transplantation.

Adult↗
PubMed2006

Living donor liver transplantation for hepatocellular carcinoma: a single-center preliminary report.

Liver transplantation (LT) is the treatment of choice for early hepatocellular carcinoma (HCC) in patients with end-stage liver disease but is limited by the availability of donor organs. Living donor liver transplantation (LDLT) represents an alternative therapeutic option for patients with disease confined to the liver. Between April 1998 and December 2003, 537 patients underwent liver transplantation in our center. Thirty patients with HCC and associated terminal cirrhosis and 4 patients with tumor recurrence after liver resection who underwent LDLT were reviewed. Nineteen patients (55.8%) met the Milan criteria for LT, whereas 15 patients (44.2%) "exceeded" them. The overall survival rates at 1 and 2 years were 68% and 62%, respectively, with a median follow-up of 41 months (range, 17-64 months). Five patients (14.7%) died in the first 30 days after LDLT. Hospital mortality was significantly correlated with age > 60 years. Four patients developed recurrence between 6 and 35 months after LDLT. Recurrence was significantly related to the presence of more than 3 tumor lesions in our series. In conclusion, LDLT is a promising treatment option for patients with HCC. Even longer follow-up and bigger patients' series are needed to fully assess the benefits of LDLT for HCC patients exceeding the Milan criteria.

Adolescent↗
PubMed2006

Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients.

In contrast to other secondary liver malignancy, orthotopic liver transplantation (OLT) is considered as a treatment modality for nonresectable endocrine liver metastases in selected patients. However, only few series have assessed patient selection criteria and long-term results, and no reports have focused on the impact of new technologies in this regard. Between 1992 and 2004, 28 patients with malignant endocrine tumors underwent evaluation for OLT according to our protocol. Data were entered into a prospective database. During pretransplant evaluation, somatostatin receptor scintigraphy detected extrahepatic metastases not diagnosed in standard imaging in 10 patients. Of them, 3 showed aberrant Ki67 labeling results. One patient was excluded from further evaluation due to severe carcinoid heart. Thus far, 15 patients, 10 men and 5 women, aged 37 to 67 years, were subjected to the transplant procedure (11 deceased donor OLT, 3 living donor liver transplantations, and 1 cluster transplantation). Four patients died during the hospital treatment. The median follow-up of the discharged patients was 60.8 months. The actuarial patient survival was 78.3% at 1 year and 67.2% at 5 years. The actuarial 1-, 2-, and 5-year tumor-free survival amounted to 69.4%, 48.3%, and 48.3%, respectively. Two patients underwent surgery for isolated tumor recurrence. In 2 patients, peptide receptor radiotherapy was carried out because of multilocular recurrent disease. In conclusion, liver transplantation is a realistic therapeutic option for highly selected patients with hepatic metastases of endocrine tumors. Our strategy, which implements strict pretransplant selection and aggressive surgical approach, in case of disease recurrence, in addition to systemic radiopeptide treatment, led to an excellent long-term survival cure, however, is unlikely to be achieved.

Adult↗
PubMed2006

[Manualised group therapy concept for patients with alcoholic cirrhosis awaiting liver transplantation].

OBJECTIVES: Patient compliance after transplantation is of key importance since even moderate deviations from the prescribed therapy regime may cause organ rejection. Patients with alcoholic liver cirrhosis require special therapeutic preparation before the liver transplantation. METHODS: A manualised group therapy with the aim of maintaining alcohol abstinence, increasing coping skills and therapy adherence is presented and illustrated with a case history. The manual is based on the elements of psychoeducation and problem-solving training. In a second article the results of the clinical evaluation are described.

Behavior Therapy↗
PubMed2006

[Stabilisation of abstinence by means of psychoeducation for patients with alcoholic liver disease awaiting liver transplantation].

BACKGROUND: A manualised six-month psychoeducational intervention was conducted in patients with alcoholic liver disease and abstinence problems who were waiting for a transplantation. OBJECTIVES: In a naturalistic design it was investigated whether the intervention could improve patients' alcohol abstinence. METHODS: Between January 2002 and November 2003, 72 patients were enrolled in the therapeutic intervention, 48 of whom participated in group therapy. Health-related quality of life (SF-12), anxiety and depression (HADS-D), symptom strain (BSI) and social support (F-SOZU) were measured. Alcohol abstinence was examined in each group session by measuring the alcohol concentration in breath. RESULTS: At the beginning and end of the group therapy patients showed subsyndromal measures of anxiety and depression and minor symptoms of psychopathology. Physical quality of life was reduced (t = -8.694; df = 44; p < .001). Mental quality of life was in the range of the normative sample and was correlated with depression (r = -0.400; p = .009). Patients perceived high social support (t = 8.213; df = 45; p < .001). During the course of therapy four patients had relapses but the remaining patients stayed abstinent. Physical quality of life improved (t = -2.275; df = 27; p = .031), mental quality of life and symptom strain remained stable. CONCLUSIONS: The therapy presented here facilitated a stabilisation of mental well-being in patients with alcoholic liver disease who were waiting for organ transplantation. The relapse rate measured by alcohol concentration in breath remained low.

Adult↗
PubMed2005

Impact of p53-based immunization on primary chemically-induced tumors.

In mice as well as humans, cytotoxic T lymphocytes (CTL) specific for wild-type-sequence (wt) p53 peptides have been shown to react against a wide range of tumors, but not normal cells. As such, they are attractive candidates for developing broadly applicable cancer vaccines. Of particular interest is the potential of using p53-based vaccines in high-risk individuals to prevent cancer. Methylcholanthrene, an immunosuppressive polycyclic hydrocarbon carcinogen implicated as a causative agent in human cancers, has long been used to induce murine tumors with a high incidence of genetic alterations and sensitivity to wt p53-specific CTL. To analyze the potential of p53-based vaccines on primary tumors, we evaluated the efficacy of DNA and dendritic cell vaccines targeting wt p53 peptides given to methylcholanthrene-treated mice in the protection or therapy settings. The results indicate that the efficacy of these vaccines relative to reducing tumor incidence were severely compromised by vaccine-induced tumor escape. As compared to tumors induced in non-immunized mice, a higher incidence of epitope-loss tumors was detected in tumors from the immunized mice. The increase in tumor escape arose as a consequence of either increased frequencies of mutations within/flanking p53 epitope-coding regions or downregulation of expression of the major histocompatibility complex Class I molecules that present these epitopes for T cell recognition These findings are consistent with current views of immunoselection occurring in patients receiving tumor peptide-based immunotherapy, and impact on the design and implementation of p53-based vaccines, in particular, those aimed at treating individuals at high risk for developing cancer.

Adenoviridae↗
PubMed2005

Effectiveness of a new carrier-bound fibrin sealant versus argon beamer as haemostatic agent during liver resection: a randomised prospective trial.

BACKGROUND AND AIMS: A new carrier-bound fibrin sealant, TachoSil, is expected to be efficacious and safe as a haemostatic treatment in hepatic resection. DESIGN: A prospective, randomised, open and controlled multicentre trial with intraoperative as well as postoperative assessment of efficacy and a 1 month follow-up period. SETTING: Tertiary care centres. PATIENTS/METHODS: One hundred and twenty-one patients requiring secondary haemostasis during planned liver resection. Patients with coagulation disorders and patients with persistent major bleeding after primary haemostatic measures were excluded. INTERVENTION: Application of either carrier-bound fibrin sealant (n=59) or argon beamer (argon beam coagulator) (n=62) as secondary haemostatic treatment. MAIN OUTCOME MEASURE: Time to intraoperative haemostasis. RESULTS: There was a significant superiority of TachoSil over argon beamer with regard to time to haemostasis (3.9 min, median 3.0, range 3-20 min vs 6.3 min, median 4.0, range 3-39 min) (P=0.0007). Haemoglobin concentration of drainage fluid was significantly lower on day 2 after surgery in TachoSil patients (1.1 mmol/l) than in argon beamer patients (2.3 mmol/l) (P=0.012). Overall, the frequency and causality of adverse events did not differ between the two treatment groups. CONCLUSION: TachoSil is superior to argon beamer in obtaining effective and fast intraoperative haemostasis. The safety data show TachoSil to be tolerable and safe for haemostatic treatment in liver resection.

Drug Carriers↗
PubMed2005

Unpulsed dendritic cells induce broadly applicable anti-tumor immunity in mice.

The discovery of dendritic cells (DC) as professional antigen presenting cells has opened up new possibilities for their use in the development of cancer vaccines. Here we show that unpulsed BM-derived CD11c+CD8alpha-DC administered s.c. to mice enhanced their resistance to subsequent lethal tumor challenges. The tumor resistance-inducing activity of unpulsed DC was dependent on their maturation status, involved CD4+ and CD8+ T cell activities, and was abrogated by pulsing with an irrelevant class I MHC-restricted peptide. Although the BALB/c Meth A tumor system was employed extensively to demonstrate the tumor resistance inducing activity of unpulsed DC, the immunogenicity of this vaccine was evident in other inbred strains of mice against a variety of syngeneic tumors. The broad anti-tumor responses induced by unpulsed DC appears to be due to their capacity to present "self" tumor-associated antigens, such as the H2-Kd-restricted, wild type sequence p53(232-240) peptide. These findings highlight the potential broad applicability of unpulsed DC as a tumor vaccine.

Animals↗
PubMed2004

Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets.

Increased levels of interleukin (IL)-10 have been described as a negative prognostic indicator for survival in patients with various types of cancer. IL-10 exerts tolerogenic and immunosuppressive effects on dendritic cells, which are crucial for the induction of an antitumor immune response. Blood dendritic cell antigen (BDCA)-2 and BDCA-4 are specifically expressed by CD123(bright) CD11c- plasmacytoid dendritic cells; whereas BDCA-1 and BDCA-3 define 2 distinct subsets of CD11c+ myeloid dendritic cells. In this study, the T-helper cell (Th)1/Th2 cytokine serum profile of 65 hepatocellular carcinoma patients was assessed. We found that serum levels of IL-10 were substantially increased in hepatocellular carcinoma patients as compared with controls. Peripheral blood mononuclear cells from healthy volunteers were exposed to recombinant human (rh)IL-10 in vitro to additionally characterize its impact on distinct blood dendritic cell subsets. A dramatic decrease of all myeloid dendritic cell (MDC) and plasmacytoid dendritic cell (PDC) subsets was detectable after 24 hours of continuous rhIL-10 exposure. Moreover, the expression of HLA-DR, CD80 and CD86, was significantly reduced on rhIL-10-treated dendritic cell subsets. Direct ex vivo flow cytometric analysis of various dendritic cell subpopulations in peripheral blood from hepatocellular carcinoma patients revealed an immature phenotype and a substantial reduction of circulating dendritic cells that was associated with increased IL-10 concentrations in serum and with tumor progression. These findings confirm a predominantly immunosuppressive role of IL-10 for circulating dendritic cells in patients with hepatocellular carcinoma and, thus, may indicate novel aspects of tumor immune evasion.

Adult↗
PubMed2004

Molecular profiling of human hepatocellular carcinoma defines mutually exclusive interferon regulation and insulin-like growth factor II overexpression.

Molecular subtyping of human hepatocellular carcinoma (HCC) with potential mechanistic and therapeutic impact has not been achieved thus far. We have analyzed the mRNA expression patterns of 43 different human HCC samples and 3 HCC cell lines in comparison with normal adult liver using high-density cDNA microarrays. Two main groups of HCC, designated group A (65%) and group B (35%), were distinguished based on clustering of the most highly varying genes. Group A HCCs were characterized by induction of a number of interferon (IFN)-regulated genes, whereas group B was characterized mainly by down-regulation of several apoptosis-relevant and IFN-regulated genes. The number of apoptotic tumor cells and tumor-infiltrating lymphocytes was significantly higher in tumors of group A as compared with those of group B. Based on the expression pattern, group B was further subdivided into two subgroups, designated subgroup B1 (6 of 43 tumors, 14%) and subgroup B2 (9 of 43 tumors, 21%). A prominent characteristic of subgroup B1 was high overexpression of insulin-like growth factor (IGF)-II. All tested HCC cell lines expressed equally high concentrations of IGF-II transcripts and co-segregated with group B1 in clustering. IGF-II overexpression and induction of IFN-related genes were mutually exclusive, even when analysis was extended to other cancer expression profile studies. Moreover, IFN-gamma treatment substantially reduced IGF-II expression in HCC cells. In conclusion, cDNA microarray analyses provided subtyping of HCCs that is related to intratumor inflammation and tumor cell apoptosis. This profiling may be of mechanistic and therapeutic impact because IGF-II overexpression has been linked to reduced apoptosis and increased proliferation and may be accessible to therapeutic intervention.

Carcinoma, Hepatocellular↗
PubMed2004

Latest development in split liver transplantation.

Currently, orthotopic liver transplantation (LT) represents the treatment of choice for most end-stage liver diseases. Advances in surgical techniques and immunosuppressive therapy have markedly increased its success. However, the main obstacle in LT remains the lack of donor organs with a current mortality rate for patients on the waiting list of up to 20%. This chapter focuses on developments in SLT techniques and living-donor LT to alleviate this problem. SLT yields a net gain of organs, in that it uses one organ to save either an adult and a child, or two adults. The initially used technique of ex-situ splitting is being replaced progressively by the in-situ splitting technique, which yields better preserved grafts. The latest step has been the introduction of living-donor segmental LT. The systematic combination of both techniques may lead to a further reduction of mortality for patients on the waiting list for LT.

Female↗
PubMed2003

Efficacy of combined lamivudine and adefovir dipivoxil treatment for severe HBV graft reinfection after living donor liver transplantation.

Resistance to lamivudine and hyperimmune globulin (HBIG) may cause severe graft reinfection with progression to fulminant hepatic failure in liver transplant recipients. In this report, we describe the clinical course of a patient with perinatally acquired chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma who developed severe fibrosing cholestatic hepatitis after living donor liver transplantation because of the emergence of lamivudine and HBIG-resistant chronic hepatitis B. Immunohistochemistry demonstrated that more than 30% of hepatocytes stained positively for hepatitis B core antigen. Hepatitis B virus sequence analysis revealed several mutations in the polymerase gene (L528M, M552I, M552V) as well as in the surface gene region encoding the immunogenic major hydrophilic loop of the small surface protein (G130N, M133T, D144G). The amino acid exchange at codon 144 has already been described to escape neutralization by HBIG. Combined treatment with lamivudine and adefovir dipivoxil (ADV) was associated with a dramatic biochemical, virological and clinical response with resolution of jaundice, ascites, peripheral edema and pleural effusions. Serum bilirubin normalized, HBV DNA levels significantly decreased and liver biopsy was remarkable for the absence of viral protein. These results indicate that ADV may provide a sustained rescue treatment for aggressive courses of HBV graft reinfection in liver transplant recipients.

Adenine↗
PubMed2003

Hepatitis B virus-induced defect of monocyte-derived dendritic cells leads to impaired T helper type 1 response in vitro: mechanisms for viral immune escape.

Dendritic cells (DC) are the most potent antigen-presenting cells and play a central role in the induction of antiviral immune responses. Recently, we have shown that monocyte-derived DC (MoDC) from patients with chronic hepatitis B virus (HBV) infection are functionally impaired. In our present study MoDC from healthy subjects were propagated in vitro and inoculated with HBV particles to investigate the precise mechanisms that underly MoDC dysfunction. T-cell proliferation assays revealed an impaired allostimulatory capacity of HBV-inoculated MoDC (HBV-MoDC) as well as a lower potential of stimulating autologous T cells against a recall antigen in comparison to control-MoDC. Interleukin-2, tumour necrosis factor-alpha and interferon-gamma production by T cells in proliferation assays with HBV-MoDC was significantly lower than with control-MoDC and correlated with lower IL-12 production in HBV-MoDC cultures. The presence of the nucleoside analogue lamivudine (3TC), an inhibitor of HBV replication, restored impaired allostimulatory function of HBV-MoDC and up-regulated major histocompatibility complex class II expression. These results show that HBV infection compromises the antigen-presenting function of MoDC with concomitant impairment of T helper cell type 1 responses. This may play an important role for viral immune escape leading to chronic HBV infection. However, 3TC treatment can overcome HBV-MoDC-related T-cell hyporeactivity and this underscores its important role in enhanced immune responses to HBV.

Adult↗