After the introduction of cyclosporine into liver transplantation in 1983, 1-year patient surviva... more After the introduction of cyclosporine into liver transplantation in 1983, 1-year patient survival more than doubled. Later, with the improved microemulsified formulation of cyclosporine (Neoral) more stable pharmacokinetics were achieved. Today, C 2 monitoring of cyclosporine blood levels allows a more accurate estimation of the area under the concentration-versus-time curve as the single best indicator of cyclosporine exposure. As a consequence, with better control of side effects as well as desired effects the results of cyclosporine in liver transplantation have been further improved. The introduction of mycophenolate mofetil and basiliximab/daclizumab combination therapy has provided new options for the prevention of allograft rejection. The safety profile of individual immunosuppressive regimens comes more into focus since acute allograft rejection may be controlled successfully with competing strategies. As the focus in liver transplantation is shifting toward greatly improved long-term results, late posttransplant mortality with a functioning graft is a major concern. Prevention of long-term complications associated with highly effective immunosuppressants-posttransplant lymphoproliferative disease, cytomegalovirus infection, diabetes, hypertension, and hyperlipidemia-gains importance. Technical advances in living-related and cadaveric split-liver transplantation have lead to increasing use of segmental liver transplantation with the need to consider the effects of immunosuppression on liver regeneration and metabolism. The individualized orchestration of immunosuppression taking into account the underlying liver disease as well as other individual predispositions remains a future challenge. I N THIS PAPER we review the published literature on the use of cyclosporine (CsA) in liver transplantation. Published data were identified by a systematic search of the English-language literature from January 1999 through September 2003 using the databases Dok, Novabase, Ovid, Biological Abstracts, Current Contents, EMBASE, and MEDLINE with the search terms "cyclosporine" and "liver transplantation." Relevant conference abstracts, publications of historic relevance, as well as recent review articles were also included.
Infectious tolerance" or inducing immunologic tolerance of infection in allografts is still poorl... more Infectious tolerance" or inducing immunologic tolerance of infection in allografts is still poorly understood. We investigated whether transfusing blood from LEW.1A rats tolerant of LEW.1W hearts could transmit tolerance to naïve LEW.1A rats. In 4 of 6 cases, transfusing blood from tolerant animals was followed by immunologic tolerance of heart transplants from LEW.1W donor rats in LEW.1A recipient animals, whereas transplanting heart grafts that were tolerated in previous transplantations across MHC barriers did not transfer tolerance in major histocompatibility complex (MHC)-incompatible animals. We conclude that in rat heart transplantation, the transfer of immunologic tolerance can be enhanced by transfusing blood from tolerant animals to naïve animals before transplantation across MHC barriers. J Heart Lung Transplant 2005;24:614 -7.
Abstract: Background and aims: In fulminant hepatic failure, the clinical use of bioartifical l... more Abstract: Background and aims: In fulminant hepatic failure, the clinical use of bioartifical liver support with porcine hepatocytes is the subject of a controversial debate. Cytochrome P450 (CYP) metabolic functions have relevant implications for drug metabolism and detoxification. In this study, we investigate interspecies differences in CYP gene expression between human and porcine primary hepatocytes and the impact of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) exposition mimicking cytokine release in fulminant hepatic failure.Methods: Primary hepatocyte cultures were isolated from human resection specimens and from German landrace pigs. Cell cultures (single and co-cultures) were exposed to porcine vs. human IL-6 and TNF-α, respectively. Changes in quantitative CYP gene expression were investigated by semi-quantitative RT-PCR.Results: Significant differences in species-specific CYP gene expression by human and porcine hepatocytes were found after exposure to species-identical IL-6 (10 ng/ml) for CYP 1A1, CYP 2C, CYP 3A (P = 0.002, 0.022, 0.017, respectively) or species-identical TNF-α (30ng/ml) for CYP 1A2 and CYP 2A (P = 0.037, 0.023, respectively). In single vs. co-culture, human hepatocytes demonstrated stronger repression of CYP 1A1, 2C8 and 3A4 expression after dosage with human IL-6 (10ng/ml) (P = 0.022, 0.031, 0.014, respectively).Conclusion: Our findings demonstrate significant species-specific differences in CYP gene expression and regulation when high doses of IL-6 and TNF-α are used (10 and 30 ng/ml, respectively). These findings may point to species-specific physiological incompatibilities of porcine hepatocytes and thus limit their clinical versatility.
Bei ausgewählten Indikationen wurden exzellente Ergebnisse nach Lebertransplantation berichtet. D... more Bei ausgewählten Indikationen wurden exzellente Ergebnisse nach Lebertransplantation berichtet. Die Ergebnisse in unserem Zentrum wurden über 23 Jahre mit 2114 konsekutiven Lebertransplantationen in 1773 Patienten untersucht (Epochen I–III jeweils 5,5 Jahre, Epoche IV 6,5 Jahre). Nach 20 Jahren erreichte das Gesamtüberleben 29,8%. Die häufigsten führenden Todesursachen waren Infektionen unterschiedlicher Genese (30%), Tumorrezidive (14,2%) und Pneumonie (8,4%). Die häufigsten führenden Ursachen für den Transplantatverlust waren Infektionen unterschiedlicher Genese (19,6%), initiale Nichtfunktion des Transplantates (14,6%) und Tumorrezidive (9,6%). Das Patientenüberleben und das Transplantatüberleben waren beide signifikant besser nach primärer Transplantation als nach erster Retransplantation (p Liver transplantation has been reported to reach excellent results for selected indications. We analysed the results of liver transplantation in our centre over a period of 23 years, with a total of 2,114 consecutive liver transplants in 1,773 patients (eras I–III 5.5 years each, era IV 6.5 years). Overall 20-year survival after liver transplantation was 29.8%. The most frequent leading causes of death were infections of various origins (30%), tumour recurrence (14.2%), and pneumonia (8.4%). The most frequent leading causes for graft loss were infection of various origins (19.6%), initial nonfunction of the graft (14.6%), and tumour recurrence (9.6%). Both long-term patient and graft survival were significantly better after primary liver transplantation than after first retransplantation (P
Historically, surgical shunts have played an important role in the treatment of patients with por... more Historically, surgical shunts have played an important role in the treatment of patients with portal hypertension associated with ascites and/or variceal esophageal bleeding. Today, in the era of liver transplantation most patients with end-stage liver disease and concomitant portal hypertension and associated problems are best treated by liver grafting. The successful introduction of transjugular intrahepatic portosystemic shunting (TIPS), performed by radiologists and gastroenterologists, provides a very effective alternative to surgical shunt procedures. One advantage of TIPS is that this procedure does not interfere with subsequent liver grafting. Today, surgical shunts have clearly lost ground to the less invasive TIPS procedure. Surgical shunts still maintain a role: as a salvage procedure in selected cases and in emergency situations. Surgical shunts are associated with a high rate of encephalopathy. In most cases selective surgical shunts should be preferred to nonselective surgical shunts. The role of partial surgical shunts versus selective surgical shunts remains to be determined. Hepatic encephalopathy is a common complication of all shunt procedures and is dependent on the shunt volume. Liver grafting is able to reverse encephalopathy because of a shunting procedure. In our institution, we prefer TIPS over surgical shunts as a bridging procedure before liver transplantation.
Bei der Diskussion der Möglichkeit, den Mangel an Leichennierenspenden durch Lebendnierenspenden ... more Bei der Diskussion der Möglichkeit, den Mangel an Leichennierenspenden durch Lebendnierenspenden zu kompensieren, wird häufig auf Unterschiede zwischen den skandinavischen Ländern und Deutschland hingewiesen. Hierbei erscheint in der Regel Skandinavien als leuchtendes Beispiel, dessen Strukturen nur übernommen werden müssten, damit in Deutschland eine ähnlich hohe Quote von Lebendspendetransplantationen vorgenommen werden kann. Bevor aber Schlussfolgerungen gezogen werden können, muss dargestellt werden, welche tatsächlichen Unterschiede zwischen den skandinavischen Ländern und Deutschland bestehen. Bei der genauen Betrachtung fällt auf, dass eine deutlich höhere Rate an Lebendspenden in Skandinavien nur in Schweden und Norwegen erreicht werden. In Norwegen kann die häufig postulierte Beeinträchtigung der Leichennierenspende durch eine besonders hohe Rate an Lebendnierenspenden nicht nachvollzogen werden. Aus geographischen Gründen wird im Gegensatz zu Deutschland in Norwegen bereits seit mehr als 35 Jahren die Nierentransplantation als primäre Therapie der terminalen Niereninsuffizienz angesehen. Die Lebendspende wurde dementsprechend frühzeitig aktiv verfolgt und stellt traditionell die Transplantation der ersten Wahl dar. Im Gegensatz hierzu wird in Deutschland die Lebendspende im Transplantationsgesetz nachrangig zur Leichenspende behandelt. Eine deutliche Verbesserung der Lebendspendefrequenz wäre in Deutschland mit einer wie in Norwegen praktizierten aktiven Lebendspendersuche möglich. The discussion of compensating for shortages of cadaveric donation with increased living donation often reveals differences between the Scandinavian countries and Germany. Possible adoption of Scandinavian structures to improve the rate of living donations in Germany warrants analysis of the actual differences between these two regions. Close examination reveals that significantly higher rates of living donation are achieved only in Sweden and Norway. In Norway, a frequently postulated negative effect on cadaveric donation due to very high rates of living donation could not be confirmed. In contrast to Germany and as a consequence of Norwegian geography, kidney transplantation has been regarded in Norway as the first-line therapy for endstage renal disease for more than 35 years. Living donation has since been actively pursued and is traditionally the transplantation of first choice. In Germany, living donation is still regarded as the second choice after cadaveric donation, due to legal regulations. Significant improvements in living donation frequencies could be achieved there by adopting the active Norwegian approach to living donor identification.
The aim of this study was to evaluate the role of p53 mutations in European hepatocarcinogenesis.... more The aim of this study was to evaluate the role of p53 mutations in European hepatocarcinogenesis. DNA extracts from 20 microdissected tumor samples were investigated. Nucleotide sequence analysis of subcloned polymerase chain reaction-fragments of the conserved domain exons 5-8 was performed in order to detect heterogeneous distribution of p53 mutated cells within the tumors. In a screening procedure four clones of each exon 5-8 were analyzed. To confirm the observed mutations polymerase chain reaction and subcloning was repeated. Sequence analysis confirmed a mutation in only two cases (10%). One at codon 220 (exon 6) was a homogeneous transition in nearly all clones from TAT to TGT. The other mutation was a transition from cGG to CAG at the known hot spot codon 248 (exon 7). It was found in 30% of the clones. We conclude that the other mutations from the first step were artefacts due to the infidelity of the taq-polymerase. All tumors had wild type sequence at the reported hot spot codon 249. The minor importance of p53 gene alterations in European hepatocarcinogenesis was further confirmed at the protein level by immunohistochemistry. Only the tumors with the heterogeneous p53 mutation at codon 248 showed a p53 overexpression in nearly 30% of the nuclei. None of the other tumors showed higher levels of p53 expression. We therefore conclude that the incidence of p53 mutations in European hepatocellular carcinomas is very low. Generally there may be no heterogeneous distribution of p53 mutated cells within a tumor. The contribution of this genetic alteration to hepatocarcinogenesis in Europe seems of little importance.
Mutational changes in the pre-S region of hepatitis B virus (HBV) were analyzed in 20 patients wh... more Mutational changes in the pre-S region of hepatitis B virus (HBV) were analyzed in 20 patients who experienced HBV reinfection after orthotopic liver transplantation (OLT). HBV DNA was extracted from patient sera before and after OLT. The pre-S sequence was amplified via polymerase chain reaction, subcloned, sequenced, and analyzed. In 18 of 20 patients, mutational changes were found in the pre-S region pre- or post-OLT; 11 showed point mutations (1-10) and 7 cases major changes (insertions/deletions). For the point mutations, there was no trend in the selection of wild-type (wt) HBV before or after OLT in the pre-S region. Additional HBV reinfection during hepatitis B surface antigen antibody (anti-HBS) administration had no influence on selection pressure in the pre-S region. In contrast, insertions/deletions were more frequently found before OLT. In the 7 patients with deletions/insertions, changes in the hepatocyte attachment site were not seen after OLT. Interestingly, the only patient with changes in a major virus population after OLT had changes in the CCAAT-box of the S-promoter. As shown by gel shift analysis, this mutation was associated with loss of specific binding to this element and thus probably led to dysregulation of S-gene transcription. Major changes in the pre-S genome are mainly seen before OLT, and HBV reinfection does occur with the intact hepatocyte attachment sites after OLT. Anti-HBs (hepatitis B immune globulin [HBIg]) creates no selection pressure on the pre-S region. The mutation in the CCAAT-box of the S-promoter potentially leads to its dysregulation and may be associated with the occurrence of fibrosing cholestatic hepatitis after OLT.
The discussion of compensating for shortages of cadaveric donation with increased living donation... more The discussion of compensating for shortages of cadaveric donation with increased living donation often reveals differences between the Scandinavian countries and Germany. Possible adoption of Scandinavian structures to improve the rate of living donations in Germany warrants analysis of the actual differences between these two regions. Close examination reveals that significantly higher rates of living donation are achieved only in Sweden and Norway. In Norway, a frequently postulated negative effect on cadaveric donation due to very high rates of living donation could not be confirmed. In contrast to Germany and as a consequence of Norwegian geography, kidney transplantation has been regarded in Norway as the first-line therapy for endstage renal disease for more than 35 years. Living donation has since been actively pursued and is traditionally the transplantation of first choice. In Germany, living donation is still regarded as the second choice after cadaveric donation, due to legal regulations. Significant improvements in living donation frequencies could be achieved there by adopting the active Norwegian approach to living donor identification.
Reconstructive procedures of the gastrointestinal tract after resection or for bypass surgery are... more Reconstructive procedures of the gastrointestinal tract after resection or for bypass surgery are well established and almost completely standardized but still may cause significant morbidity. Deviations from standard reconstructive procedures have pitfalls, especially when complex reconstructions are required, and may lead to substantial morbidity. Scientific evidence for the indication to reoperate as well as the best methods to be applied is lacking and surgical experience indispensable. We report on 10 reoperative cases between 1999 and 2003 after uncommon reconstructive procedures in the gastrointestinal tract associated with substantial morbidity. In five cases (five of seven), operative correction of uncommon reconstructions in the upper gastrointestinal tract after gastrectomy, completion gastrectomy, or distal gastric resection could completely alleviate the complaints including refiux esophagitis, whereas incomplete relief of symptoms was achieved in the remaining two cases (two of seven). Corrective procedures used end-to-side esophagojejunostomy or end-to-side gastrojejunostomy with a retrocolic isoperistaltic jejunal Roux-en-Y loop and end-to-side jejunojejunostomy approximately 40 cm distal to the proximal anastomosis for biliary and exocrine pancreatic drainage. After biliodigestive anastomosis, problematic cholangitis could be completely alleviated in three cases (three of three) using end-to-side hepaticojejunostomy with a retrocolic isoperistaltic jejunal Roux-en-Y loop and end-to-side jejunojejunostomy 40 cm distal to the hepaticojejunostomy for reconstruction of the continuity of the gastrointestinal tract. Compliance with well-established standard reconstructive procedures is of elementary importance in the gastrointestinal tract. Operative correction of uncommon reconstructions associated with morbidity is usually indicated.
P RIMARY graft non-function (PNF) after liver transplantation occurs in 4% to 5% of transplanted ... more P RIMARY graft non-function (PNF) after liver transplantation occurs in 4% to 5% of transplanted patients. Retransplantation is the only therapeutic choice. 2 A number of factors are known to influence liver function after transplantation, eg, donor age, steatosis, or donor nutritional status. Other important factors are storage and reperfusion injury. 4 Long lasting cold storage (Ͼ24 hours) is associated with possible graft failure. 5 Reperfusion causes loss of viability of sinusoidal endothelial cells as well as activation of Kupffer cells and finally reveals the summation of damage to the transplanted liver. It is generally accepted, that sinusoidal endothelial cell damage is a reperfusion event and precedes hepatocellular injury. To understand the basic mechanisms and improve the quality of liver preservation it is important to analyse the influence cold ischemia and warm ischemia have on hepatocyte and endothelial function.
In clinical pancreas transplantation the choice of preservation solution may have an impact on gr... more In clinical pancreas transplantation the choice of preservation solution may have an impact on graft pancreatitis. Experience with histidine-tryptophan-ketoglutarate (HTK) is still limited whereas University of Wisconsin (UW) solution is currently the preferred perfusate worldwide.
After the introduction of cyclosporine into liver transplantation in 1983, 1-year patient surviva... more After the introduction of cyclosporine into liver transplantation in 1983, 1-year patient survival more than doubled. Later, with the improved microemulsified formulation of cyclosporine (Neoral) more stable pharmacokinetics were achieved. Today, C 2 monitoring of cyclosporine blood levels allows a more accurate estimation of the area under the concentration-versus-time curve as the single best indicator of cyclosporine exposure. As a consequence, with better control of side effects as well as desired effects the results of cyclosporine in liver transplantation have been further improved. The introduction of mycophenolate mofetil and basiliximab/daclizumab combination therapy has provided new options for the prevention of allograft rejection. The safety profile of individual immunosuppressive regimens comes more into focus since acute allograft rejection may be controlled successfully with competing strategies. As the focus in liver transplantation is shifting toward greatly improved long-term results, late posttransplant mortality with a functioning graft is a major concern. Prevention of long-term complications associated with highly effective immunosuppressants-posttransplant lymphoproliferative disease, cytomegalovirus infection, diabetes, hypertension, and hyperlipidemia-gains importance. Technical advances in living-related and cadaveric split-liver transplantation have lead to increasing use of segmental liver transplantation with the need to consider the effects of immunosuppression on liver regeneration and metabolism. The individualized orchestration of immunosuppression taking into account the underlying liver disease as well as other individual predispositions remains a future challenge. I N THIS PAPER we review the published literature on the use of cyclosporine (CsA) in liver transplantation. Published data were identified by a systematic search of the English-language literature from January 1999 through September 2003 using the databases Dok, Novabase, Ovid, Biological Abstracts, Current Contents, EMBASE, and MEDLINE with the search terms "cyclosporine" and "liver transplantation." Relevant conference abstracts, publications of historic relevance, as well as recent review articles were also included.
Infectious tolerance" or inducing immunologic tolerance of infection in allografts is still poorl... more Infectious tolerance" or inducing immunologic tolerance of infection in allografts is still poorly understood. We investigated whether transfusing blood from LEW.1A rats tolerant of LEW.1W hearts could transmit tolerance to naïve LEW.1A rats. In 4 of 6 cases, transfusing blood from tolerant animals was followed by immunologic tolerance of heart transplants from LEW.1W donor rats in LEW.1A recipient animals, whereas transplanting heart grafts that were tolerated in previous transplantations across MHC barriers did not transfer tolerance in major histocompatibility complex (MHC)-incompatible animals. We conclude that in rat heart transplantation, the transfer of immunologic tolerance can be enhanced by transfusing blood from tolerant animals to naïve animals before transplantation across MHC barriers. J Heart Lung Transplant 2005;24:614 -7.
Abstract: Background and aims: In fulminant hepatic failure, the clinical use of bioartifical l... more Abstract: Background and aims: In fulminant hepatic failure, the clinical use of bioartifical liver support with porcine hepatocytes is the subject of a controversial debate. Cytochrome P450 (CYP) metabolic functions have relevant implications for drug metabolism and detoxification. In this study, we investigate interspecies differences in CYP gene expression between human and porcine primary hepatocytes and the impact of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) exposition mimicking cytokine release in fulminant hepatic failure.Methods: Primary hepatocyte cultures were isolated from human resection specimens and from German landrace pigs. Cell cultures (single and co-cultures) were exposed to porcine vs. human IL-6 and TNF-α, respectively. Changes in quantitative CYP gene expression were investigated by semi-quantitative RT-PCR.Results: Significant differences in species-specific CYP gene expression by human and porcine hepatocytes were found after exposure to species-identical IL-6 (10 ng/ml) for CYP 1A1, CYP 2C, CYP 3A (P = 0.002, 0.022, 0.017, respectively) or species-identical TNF-α (30ng/ml) for CYP 1A2 and CYP 2A (P = 0.037, 0.023, respectively). In single vs. co-culture, human hepatocytes demonstrated stronger repression of CYP 1A1, 2C8 and 3A4 expression after dosage with human IL-6 (10ng/ml) (P = 0.022, 0.031, 0.014, respectively).Conclusion: Our findings demonstrate significant species-specific differences in CYP gene expression and regulation when high doses of IL-6 and TNF-α are used (10 and 30 ng/ml, respectively). These findings may point to species-specific physiological incompatibilities of porcine hepatocytes and thus limit their clinical versatility.
Bei ausgewählten Indikationen wurden exzellente Ergebnisse nach Lebertransplantation berichtet. D... more Bei ausgewählten Indikationen wurden exzellente Ergebnisse nach Lebertransplantation berichtet. Die Ergebnisse in unserem Zentrum wurden über 23 Jahre mit 2114 konsekutiven Lebertransplantationen in 1773 Patienten untersucht (Epochen I–III jeweils 5,5 Jahre, Epoche IV 6,5 Jahre). Nach 20 Jahren erreichte das Gesamtüberleben 29,8%. Die häufigsten führenden Todesursachen waren Infektionen unterschiedlicher Genese (30%), Tumorrezidive (14,2%) und Pneumonie (8,4%). Die häufigsten führenden Ursachen für den Transplantatverlust waren Infektionen unterschiedlicher Genese (19,6%), initiale Nichtfunktion des Transplantates (14,6%) und Tumorrezidive (9,6%). Das Patientenüberleben und das Transplantatüberleben waren beide signifikant besser nach primärer Transplantation als nach erster Retransplantation (p Liver transplantation has been reported to reach excellent results for selected indications. We analysed the results of liver transplantation in our centre over a period of 23 years, with a total of 2,114 consecutive liver transplants in 1,773 patients (eras I–III 5.5 years each, era IV 6.5 years). Overall 20-year survival after liver transplantation was 29.8%. The most frequent leading causes of death were infections of various origins (30%), tumour recurrence (14.2%), and pneumonia (8.4%). The most frequent leading causes for graft loss were infection of various origins (19.6%), initial nonfunction of the graft (14.6%), and tumour recurrence (9.6%). Both long-term patient and graft survival were significantly better after primary liver transplantation than after first retransplantation (P
Historically, surgical shunts have played an important role in the treatment of patients with por... more Historically, surgical shunts have played an important role in the treatment of patients with portal hypertension associated with ascites and/or variceal esophageal bleeding. Today, in the era of liver transplantation most patients with end-stage liver disease and concomitant portal hypertension and associated problems are best treated by liver grafting. The successful introduction of transjugular intrahepatic portosystemic shunting (TIPS), performed by radiologists and gastroenterologists, provides a very effective alternative to surgical shunt procedures. One advantage of TIPS is that this procedure does not interfere with subsequent liver grafting. Today, surgical shunts have clearly lost ground to the less invasive TIPS procedure. Surgical shunts still maintain a role: as a salvage procedure in selected cases and in emergency situations. Surgical shunts are associated with a high rate of encephalopathy. In most cases selective surgical shunts should be preferred to nonselective surgical shunts. The role of partial surgical shunts versus selective surgical shunts remains to be determined. Hepatic encephalopathy is a common complication of all shunt procedures and is dependent on the shunt volume. Liver grafting is able to reverse encephalopathy because of a shunting procedure. In our institution, we prefer TIPS over surgical shunts as a bridging procedure before liver transplantation.
Bei der Diskussion der Möglichkeit, den Mangel an Leichennierenspenden durch Lebendnierenspenden ... more Bei der Diskussion der Möglichkeit, den Mangel an Leichennierenspenden durch Lebendnierenspenden zu kompensieren, wird häufig auf Unterschiede zwischen den skandinavischen Ländern und Deutschland hingewiesen. Hierbei erscheint in der Regel Skandinavien als leuchtendes Beispiel, dessen Strukturen nur übernommen werden müssten, damit in Deutschland eine ähnlich hohe Quote von Lebendspendetransplantationen vorgenommen werden kann. Bevor aber Schlussfolgerungen gezogen werden können, muss dargestellt werden, welche tatsächlichen Unterschiede zwischen den skandinavischen Ländern und Deutschland bestehen. Bei der genauen Betrachtung fällt auf, dass eine deutlich höhere Rate an Lebendspenden in Skandinavien nur in Schweden und Norwegen erreicht werden. In Norwegen kann die häufig postulierte Beeinträchtigung der Leichennierenspende durch eine besonders hohe Rate an Lebendnierenspenden nicht nachvollzogen werden. Aus geographischen Gründen wird im Gegensatz zu Deutschland in Norwegen bereits seit mehr als 35 Jahren die Nierentransplantation als primäre Therapie der terminalen Niereninsuffizienz angesehen. Die Lebendspende wurde dementsprechend frühzeitig aktiv verfolgt und stellt traditionell die Transplantation der ersten Wahl dar. Im Gegensatz hierzu wird in Deutschland die Lebendspende im Transplantationsgesetz nachrangig zur Leichenspende behandelt. Eine deutliche Verbesserung der Lebendspendefrequenz wäre in Deutschland mit einer wie in Norwegen praktizierten aktiven Lebendspendersuche möglich. The discussion of compensating for shortages of cadaveric donation with increased living donation often reveals differences between the Scandinavian countries and Germany. Possible adoption of Scandinavian structures to improve the rate of living donations in Germany warrants analysis of the actual differences between these two regions. Close examination reveals that significantly higher rates of living donation are achieved only in Sweden and Norway. In Norway, a frequently postulated negative effect on cadaveric donation due to very high rates of living donation could not be confirmed. In contrast to Germany and as a consequence of Norwegian geography, kidney transplantation has been regarded in Norway as the first-line therapy for endstage renal disease for more than 35 years. Living donation has since been actively pursued and is traditionally the transplantation of first choice. In Germany, living donation is still regarded as the second choice after cadaveric donation, due to legal regulations. Significant improvements in living donation frequencies could be achieved there by adopting the active Norwegian approach to living donor identification.
The aim of this study was to evaluate the role of p53 mutations in European hepatocarcinogenesis.... more The aim of this study was to evaluate the role of p53 mutations in European hepatocarcinogenesis. DNA extracts from 20 microdissected tumor samples were investigated. Nucleotide sequence analysis of subcloned polymerase chain reaction-fragments of the conserved domain exons 5-8 was performed in order to detect heterogeneous distribution of p53 mutated cells within the tumors. In a screening procedure four clones of each exon 5-8 were analyzed. To confirm the observed mutations polymerase chain reaction and subcloning was repeated. Sequence analysis confirmed a mutation in only two cases (10%). One at codon 220 (exon 6) was a homogeneous transition in nearly all clones from TAT to TGT. The other mutation was a transition from cGG to CAG at the known hot spot codon 248 (exon 7). It was found in 30% of the clones. We conclude that the other mutations from the first step were artefacts due to the infidelity of the taq-polymerase. All tumors had wild type sequence at the reported hot spot codon 249. The minor importance of p53 gene alterations in European hepatocarcinogenesis was further confirmed at the protein level by immunohistochemistry. Only the tumors with the heterogeneous p53 mutation at codon 248 showed a p53 overexpression in nearly 30% of the nuclei. None of the other tumors showed higher levels of p53 expression. We therefore conclude that the incidence of p53 mutations in European hepatocellular carcinomas is very low. Generally there may be no heterogeneous distribution of p53 mutated cells within a tumor. The contribution of this genetic alteration to hepatocarcinogenesis in Europe seems of little importance.
Mutational changes in the pre-S region of hepatitis B virus (HBV) were analyzed in 20 patients wh... more Mutational changes in the pre-S region of hepatitis B virus (HBV) were analyzed in 20 patients who experienced HBV reinfection after orthotopic liver transplantation (OLT). HBV DNA was extracted from patient sera before and after OLT. The pre-S sequence was amplified via polymerase chain reaction, subcloned, sequenced, and analyzed. In 18 of 20 patients, mutational changes were found in the pre-S region pre- or post-OLT; 11 showed point mutations (1-10) and 7 cases major changes (insertions/deletions). For the point mutations, there was no trend in the selection of wild-type (wt) HBV before or after OLT in the pre-S region. Additional HBV reinfection during hepatitis B surface antigen antibody (anti-HBS) administration had no influence on selection pressure in the pre-S region. In contrast, insertions/deletions were more frequently found before OLT. In the 7 patients with deletions/insertions, changes in the hepatocyte attachment site were not seen after OLT. Interestingly, the only patient with changes in a major virus population after OLT had changes in the CCAAT-box of the S-promoter. As shown by gel shift analysis, this mutation was associated with loss of specific binding to this element and thus probably led to dysregulation of S-gene transcription. Major changes in the pre-S genome are mainly seen before OLT, and HBV reinfection does occur with the intact hepatocyte attachment sites after OLT. Anti-HBs (hepatitis B immune globulin [HBIg]) creates no selection pressure on the pre-S region. The mutation in the CCAAT-box of the S-promoter potentially leads to its dysregulation and may be associated with the occurrence of fibrosing cholestatic hepatitis after OLT.
The discussion of compensating for shortages of cadaveric donation with increased living donation... more The discussion of compensating for shortages of cadaveric donation with increased living donation often reveals differences between the Scandinavian countries and Germany. Possible adoption of Scandinavian structures to improve the rate of living donations in Germany warrants analysis of the actual differences between these two regions. Close examination reveals that significantly higher rates of living donation are achieved only in Sweden and Norway. In Norway, a frequently postulated negative effect on cadaveric donation due to very high rates of living donation could not be confirmed. In contrast to Germany and as a consequence of Norwegian geography, kidney transplantation has been regarded in Norway as the first-line therapy for endstage renal disease for more than 35 years. Living donation has since been actively pursued and is traditionally the transplantation of first choice. In Germany, living donation is still regarded as the second choice after cadaveric donation, due to legal regulations. Significant improvements in living donation frequencies could be achieved there by adopting the active Norwegian approach to living donor identification.
Reconstructive procedures of the gastrointestinal tract after resection or for bypass surgery are... more Reconstructive procedures of the gastrointestinal tract after resection or for bypass surgery are well established and almost completely standardized but still may cause significant morbidity. Deviations from standard reconstructive procedures have pitfalls, especially when complex reconstructions are required, and may lead to substantial morbidity. Scientific evidence for the indication to reoperate as well as the best methods to be applied is lacking and surgical experience indispensable. We report on 10 reoperative cases between 1999 and 2003 after uncommon reconstructive procedures in the gastrointestinal tract associated with substantial morbidity. In five cases (five of seven), operative correction of uncommon reconstructions in the upper gastrointestinal tract after gastrectomy, completion gastrectomy, or distal gastric resection could completely alleviate the complaints including refiux esophagitis, whereas incomplete relief of symptoms was achieved in the remaining two cases (two of seven). Corrective procedures used end-to-side esophagojejunostomy or end-to-side gastrojejunostomy with a retrocolic isoperistaltic jejunal Roux-en-Y loop and end-to-side jejunojejunostomy approximately 40 cm distal to the proximal anastomosis for biliary and exocrine pancreatic drainage. After biliodigestive anastomosis, problematic cholangitis could be completely alleviated in three cases (three of three) using end-to-side hepaticojejunostomy with a retrocolic isoperistaltic jejunal Roux-en-Y loop and end-to-side jejunojejunostomy 40 cm distal to the hepaticojejunostomy for reconstruction of the continuity of the gastrointestinal tract. Compliance with well-established standard reconstructive procedures is of elementary importance in the gastrointestinal tract. Operative correction of uncommon reconstructions associated with morbidity is usually indicated.
P RIMARY graft non-function (PNF) after liver transplantation occurs in 4% to 5% of transplanted ... more P RIMARY graft non-function (PNF) after liver transplantation occurs in 4% to 5% of transplanted patients. Retransplantation is the only therapeutic choice. 2 A number of factors are known to influence liver function after transplantation, eg, donor age, steatosis, or donor nutritional status. Other important factors are storage and reperfusion injury. 4 Long lasting cold storage (Ͼ24 hours) is associated with possible graft failure. 5 Reperfusion causes loss of viability of sinusoidal endothelial cells as well as activation of Kupffer cells and finally reveals the summation of damage to the transplanted liver. It is generally accepted, that sinusoidal endothelial cell damage is a reperfusion event and precedes hepatocellular injury. To understand the basic mechanisms and improve the quality of liver preservation it is important to analyse the influence cold ischemia and warm ischemia have on hepatocyte and endothelial function.
In clinical pancreas transplantation the choice of preservation solution may have an impact on gr... more In clinical pancreas transplantation the choice of preservation solution may have an impact on graft pancreatitis. Experience with histidine-tryptophan-ketoglutarate (HTK) is still limited whereas University of Wisconsin (UW) solution is currently the preferred perfusate worldwide.
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Papers by Harald Schrem