Liver transplantation for unresectable hepatocellular carcinoma in normal livers.

BACKGROUND & AIMS: The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC. METHODS: Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC-HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses. RESULTS: Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8 cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation < 12 months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival. CONCLUSIONS: This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients ≥ 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC.

Influence of donor histology on outcome in patients undergoing transplantation for hepatitis C.

BACKGROUND: Risk factors for graft loss and recipient death in liver transplantation for hepatitis C virus (HCV) have been extensively investigated. Donor age was defined as one of the most important predictors of outcome in these patients; however, the mechanism leading to more severe recurrent hepatitis has not yet been investigated. METHOD: In a retrospective analysis, histological findings of 79 donor liver grafts were assessed according to criteria inflammation, fibrosis, fatty degeneration, and necrosis. These findings were correlated with the histological and clinical course of HCV-positive liver graft recipients. RESULTS: The overall 1-, 5- and 10-year graft survival figures were 85%, 77%, and 60%, respectively. We could not identify any correlation between outcome, fat content, and necrosis in the donor liver. However, stage 3 and 4 fibrosis 1 year after liver transplantation was significantly increased in the group of patients receiving a graft from a donor with portal inflammation (P<0.05). Additionally, the occurrence of intrahepatic inflammation was significantly increased in older donors (P<0.05) and donors with prolonged intensive care hospitalization (P<0.05). CONCLUSION: A number of risk factors for detrimental outcome in HCV-positive patients after liver transplantation have been identified. In particular, older donor age significantly impaired outcome in recent analysis, but due to donor shortage it is not possible to provide young grafts for all HCV-positive patients. Our data show that donor histology is helpful in identifying patients with more severe recurrent hepatitis prior to transplantation, and that especially in older donors, prolonged intensive care hospitalization should be avoided.

Fibrosis progression in hepatitis C positive liver recipients after sustained virologic response to antiviral combination therapy (interferon-ribavirin therapy).

The rate of fibrosis progression was analyzed in 28 hepatitis C virus-infected liver graft recipients showing sustained virologic response after treatment with ribavirin plus either standard interferon alpha-2b (n=8), pegylated interferon alpha-2b (n=8), or pegylated interferon alpha-2a (n=12). Protocol biopsies before treatment as well as one, three, and five years after treatment showed no significant increase in mean fibrosis scores within the first three years after treatment (mean score at baseline 1.8 and at one and three years 2.0 and 2.1, respectively). Five years after cessation of treatment, the mean fibrosis score declined to 1.4 (P=0.2). Six of 28 patients (21%) showed an increase in fibrosis, five (18%) a decrease, and 17 (60%) no changes. The yearly fibrosis progression rate was 0.75 before treatment and 0.15 after antiviral treatment. Sustained virologic response is associated with a deceleration of fibrosis progression and might therefore play a major role in prevention of graft cirrhosis in hepatitis C virus-infected liver graft recipients.

Short-term anti-CD4 plus anti-TNF-alpha receptor treatment in allogeneic small bowel transplantation results in long-term survival.

BACKGROUND: Despite improved immunosuppression, intestinal transplantation is still complicated by severe rejection episodes. To further improve immunosuppressive concepts, we evaluated an anti-CD4 antibody and an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody for their immunosuppressive efficacy in the standard rat model of intestinal transplantation. METHODS: Intestinal transplantation was performed in the DA to Lewis combination, and recipients were treated perioperatively with either the anti-CD4 antibody RIB5/2 (day -1, 0, postoperative days 1, 2, 4, 7, 10, 14, 17, and 21), the anti-TNF antibody etanercept (60 min before reperfusion, postoperative days 3, 6, and 9) or a combination of both. Survival, histology and expression of immunologic mediator genes on days 3 and 4 after transplantation were investigated. RESULTS: Treatment with anti-CD4 antibody alone (19.71+/-5.94) and the antibody combination (171.58+/-122.76) prolonged survival. The chemokine MIP-1alpha was significantly decreased in both anti-CD4 antibody treatment groups, possibly indicating an additional effect of the TNF-alpha blockade on the immune modulation by RIB5/2. CONCLUSIONS: Our study demonstrated long-term graft survival in short-term treatment with a combination of an anti-CD4 antibody and a TNF-alpha antibody in more than 50% of the recipients of intestinal grafts. Such a combined approach could also be useful in clinical small bowel transplantation.

Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with colorectal liver metastases: a Phase II-study and historical comparison with the surgical approach.

BACKGROUND: The high complication rates of surgically implanted port catheter systems (SIPCS) represents a major drawback in the treatment of isolated liver neoplasms by hepatic arterial infusion (HAI) of chemotherapy. Interventionally implanted port catheter systems (IIPCS) have evolved into a promising alternative that enable initiation of HAI without laparatomy, but prospective data on this approach are still sparse. Aim of this study was to evaluate the most important technical endpoints associated with the use of IIPCS for the delivery of 5-fluorouracil-based HAI in patients with colorectal liver metastases in a phase 2-study, and to perform a non-randomised comparison with a historical group of patients in which HAI was administered via SIPCS. METHODS: 41 patients with isolated liver metastases of colorectal cancer were enrolled into a phase II-study and provided with IIPCS between 2001 and 2004 (group A). The primary objective of the trial was defined as evaluation of device-related complications and port duration. Results were compared with those observed in a pre-defined historical collective of 40 patients treated with HAI via SIPCS at our institution between 1996 and 2000 (group B). RESULTS: Baseline characteristics were balanced between both groups, except for higher proportions of previous palliative pre-treatment and elevated serum alkaline phosphatase in patients of group A. Implantation of port catheters was successful in all patients of group A, whereas two primary failures were observed in group B. The frequency of device-related complications was similar between both groups, but the secondary failure rate was significantly higher with the use of surgical approach (17% vs. 50%, p < 0.01). Mean port duration was significantly longer in the interventional group (19 vs. 14 months, p = 0.01), with 77 vs. 50% of devices functioning at 12 months (p < 0.01). No unexpected complications were observed in both groups. CONCLUSION: HAI via interventionally implanted port catheters can be safely provided to a collective of patients with colorectal liver metastases, including a relevant proportion of preatreated individuals. It appears to offer technical advantages over the surgical approach.

Peroxisome proliferator-activated receptor gamma is highly expressed in pancreatic cancer and is associated with shorter overall survival times.

PURPOSE: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that has been implicated in carcinogenesis and progression of various solid tumors, including pancreatic carcinoma. We aimed to clarify the expression patterns of PPARgamma in pancreatic ductal carcinomas and to correlate these to clinicopathologic variables, including patient survival. EXPERIMENTAL DESIGN: Array-based expression profiling of 19 microdissected carcinomas and 14 normal ductal epithelia was conducted. Additionally, Western blots of pancreatic cancer cell lines and paraffinized tissue of 129 pancreatic carcinomas were immunostained for PPARgamma. For statistical analysis, Fisher's exact test, chi2 test for trends, correlation analysis, Kaplan-Meier analysis, and Cox's regression were applied. RESULTS: Expression profiles showed a strong overexpression of PPARgamma mRNA (change fold, 6.9; P=0.04). Immunohistochemically, PPARgamma expression was seen in 71.3% of pancreatic cancer cases. PPARgamma expression correlated positively to higher pT stages and higher tumor grade. Survival analysis showed a significant prognostic value for PPARgamma, which was found to be independent in the clinically important subgroup of node-negative tumors. CONCLUSIONS: PPARgamma is commonly up-regulated in pancreatic ductal adenocarcinoma and might be a prognostic marker in this disease. Both findings corroborate the importance of PPARgamma in tumor progression of pancreatic cancer.

Laparoscopic-assisted placement of peritoneal dialysis catheters: implantation technique and results.

BACKGROUND: Peritoneal dialysis is a generally accepted method for the treatment of patients with end-stage renal failure. The laparoscopic placement of peritoneal dialysis catheters is a well-established technique and offers some advantages, such as a safer placement of the catheter, less post-operative complications, and a longer functional survival, compared to the conventional open technique. The aim of this study was to describe our implantation technique and to determine the results of our approach. PATIENTS AND METHODS: Between January 2000 and February 2006, 47 patients with end-stage chronic renal failure underwent a laparoscopic peritoneal dialysis catheter insertion procedure. Perioperative and follow-up data were collected prospectively. RESULTS: The mean operating time was 35 minutes (range, 16-100). There was no perioperative morbidity. Nine (19.1%) patients experienced 10 mechanical complications: fluid leakage in 6 (12.8%) patients, acute hydrothorax in 1 (2.1%), catheter tip migration in 2 (4.3%), and catheter obstruction in 1 (2.1%) patient. Episodes of peritonitis were observed in 5 (10.6%) patients. One (2.1%) patient developed a catheter infection. In 3 (6.4%) patients, a port site hernia occurred that required surgical repair, 5 (10.6%) patients underwent laparoscopic revisions owing to mechanical complications, 9 (19.1%) patients underwent renal transplantation, and 6 (12.8%) patients died during the later follow-up. After a mean follow-up time of 17 months (range, 2-76), 30 (63.8%) catheters are still in use for dialysis. CONCLUSIONS: The functional outcome of the dialysis catheters was satisfactory in the majority of patients in this study. The described technique for catheter implantation is simple and safe, and in our opinion, the laparoscopic technique should be considered as the method of choice in patients with end-stage chronic renal failure.

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer.

BACKGROUND: Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. METHODS: A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. RESULTS: Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. CONCLUSION: There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.

Human hepatocytes are protected from ethanol-induced cytotoxicity by DADS via CYP2E1 inhibition.

We investigated the protective effects of diallyl disulfide (DADS), a potent inhibitor of cytochrome P450 2E1 (CYP2E1), on ethanol-induced toxicity in human hepatocytes. We found a clear dose-dependent response between ethanol and CYP2E1 activity. The ethanol-dependent CYP2E1 enzyme activity and protein expression, lactate dehydrogenase and aspartate transaminase release, malondialdehyde formation and caspase-3 activity decreased dramatically in the presence of DADS. Furthermore, DADS increased the hepatocellular glutathione (GSH) content and prevented the ethanol-dependent cellular GSH depletion. Our data show that DADS reduces ethanol-induced toxicity in human hepatocytes by reducing CYP2E1 activity and/or stabilizing the cellular GSH content, which might be of therapeutic interest.

Transplantation of an eight-organ multivisceral graft in a patient with frozen abdomen after complicated Crohn's disease.

To report an extended multivisceral transplantation (MVTx) including right kidney and ascending colon in a patient with complicated Crohn's disease (CD). A 36-year old female suffering from short bowel syndrome and frozen abdomen due to fistulizing CD after multiple abdominal operations underwent MVTx of eight organs including stomach, pancreatoduodenal complex, liver, intestine, ascending colon, right kidney, right adrenal gland, and greater omentum in November 2003. Immunosuppression consisted of alemtuzumab, tacrolimus and steroids. The patient was off parenteral nutrition by postoperative wk 3. She experienced one episode of pneumonia. The patient recovered completely and discharged 2.5 mo and was doing well 30 mo after MVTx. This is one of the very rare cases in which a complete mulitivisceral graft of eight abdominal organs was transplanted orthotopically.

Extended surgical resection for xanthogranulomatous cholecystitis mimicking advanced gallbladder carcinoma: A case report and review of literature.

Xanthogranulomatous cholecystitis (XGC) is a destructive inflammatory disease of the gallbladder, rarely involving adjacent organs and mimicking an advanced gallbladder carcinoma. The diagnosis is usually possible only after pathological examination. A 46 year-old woman was referred to our center for suspected gallbladder cancer involving the liver hilum, right liver lobe, right colonic flexure, and duodenum. Brushing cytology obtained by endoscopic retrograde cholangiography (ERC) showed high-grade dysplasia. The patient underwent an en-bloc resection of the mass, consisting of right lobectomy, right hemicolectomy, and a partial duodenal resection. Pathological examination unexpectedly revealed an XGC. Only six cases of extended surgical resections for XGC with direct involvement of adjacent organs have been reported so far. In these cases, given the possible coexistence of XGC with carcinoma, malignancy cannot be excluded, even after cytology and intraoperative frozen section investigation. In conclusion, due to the poor prognosis of gallbladder carcinoma on one side and possible complications deriving from highly aggressive inflammatory invasion of surrounding organs on the other side, it seems these cases should be treated as malignant tumors until proven otherwise. Clinicians should include XGC among the possible differential diagnoses of masses in liver hilum.

Indications of mycophenolate mofetil in liver transplantation.

Mycophenolate mofetil (MMF) is approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation as well as for pediatric patients after kidney transplantation. MMF, a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), blocks de novo purine synthesis which leads to an effective inhibition of proliferation selectively in T and B lymphocytes, smooth muscle cells, and fibroblasts. MMF shows additional effects with inhibition of the expression of activating and adhesion molecules on the surface of lymphocytes. The beneficial safety profile with distinct side effects compared to calcineurin inhibitors (CNI) enable efficacious combination with ciclosporin or tacrolimus as de novo therapy after liver transplantation. Furthermore, recent studies show the possibility to reduce CNI induced toxicities by adding MMF to primary immunosuppression. MMF is also used to enable early steroid withdrawal after liver transplantation. MMF can increase efficacy of immunosuppressive therapy and thereby support the treatment of steroid resistant acute rejections, chronic rejections and chronic graft dysfunction.

Extended indications in living-donor liver transplantation: bile duct cancer.

The advantages of living donor liver transplantation are an individually available graft and a tremendously reduced waiting time until transplantation. One consequence is that many centers have extended the pretransplant selection criteria, especially for potential recipients suffering from hepatocellular carcinoma. In contrast, reports on living donor liver transplantation for cholangiocarcinoma are restricted to few case reports. We have analyzed our experience with seven patients suffering from cholangiocarcinoma (Klatskin tumors, n=5; intrahepatic cholangiocarcinoma, n=2). During a median follow-up of 20 months (range 2-46 months), all patients are alive except for one posttransplant death. Four patients suffering from Klatskin tumors are alive without recurrence; both patients suffering from intrahepatic cholangiocarcinoma are alive with bone and peritoneal metastases. Living donor liver transplantation may be beneficial in selected patients suffering from Klatskin tumors, whereas caution should prevail when considering intrahepatic cholangiocarcinoma.

Sirolimus inhibits growth of human hepatoma cells alone or combined with tacrolimus, while tacrolimus promotes cell growth.

AIM: Standard immunosuppression after organ transplantation stimulates tumor growth. Sirolimus has a strong antiproliferative and a tumor inhibiting effect. The purpose is to assess the effect on tumor growth of the immuno-suppressive compounds sirolimus and tacrolimus alone and in combination on cells of human hepatocellular carcinoma. METHODS: We used the human cell lines SK-Hep 1 and Hep 3B derived from hepatocellular carcinoma. Proliferation analyses after treatment with sirolimus, tacrolimus, or the combination of both were performed. FACS analyses were done to reveal cell cycle changes and apoptotic cell death. The expression of apoptosis-related proteins was estimated by Western blots. RESULTS: Sirolimus alone or combined with tacrolimus inhibited the growth of both cell lines after 5 d by up to 35% in SK-Hep 1 cells, and by up to 68% in Hep 3B cells at 25 ng/mL. Tacrolimus alone stimulated the growth by 12% after 5 ng/mL and by 25% after 25 ng/mL in Hep 3B cells. We found an increase of apoptotic Hep 3B cells from 6 to 16%, and a G1-arrest in SK-Hep 1 cells with an increase of cells from 61 to 82%, when sirolimus and tacrolimus were combined. Bcl-2 was down-regulated in Hep 3B, but not in SK-Hep 1 cells after combined treatment. CONCLUSION: Sirolimus appears to inhibit the growth of hepatocellular carcinoma cells alone and in combination with tacrolimus. Sirolimus seems to inhibit the growth stimulation of tacrolimus.

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.

Impact of human leukocyte antigen matching in liver transplantation.

BACKGROUND: Human leukocyte antigen (HLA) compatibilities are beneficial in the setting of kidney transplantation but have demonstrated inconclusive results after liver transplantation. On the basis of recent controversial reports, the authors analyzed the impact of HLA matching in their patients after liver transplantation under modern immunosuppressive drug regimens and new HLA typing techniques with respect to outcome and adverse immunologic events. METHODS: Data from 924 transplants with complete donor-recipient HLA typing were retrospectively analyzed. Immunosuppression was commenced as either cyclosporine A- or tacrolimus-based therapy in different protocols. The follow-up period ranged from 1 to 144.8 months (median, 66 months). RESULTS: The actuarial graft survival was 88% after 1 year and 78.7% after 5 years and was similar in tacrolimus- and cyclosporine A-treated patients. However, cyclosporine A-treated patients underwent significantly more rejection episodes. The number of HLA compatibilities had no influence on graft survival, whereas the number of acute rejections was significantly less in transplants with more HLA compatibilities (P<0.05). Graft survival tended to be improved in patients with chronic hepatitis B and more HLA compatibilities (P=0.05). In contrast, graft survival in transplants for primary sclerosing cholangitis was significantly impaired in the presence of one or two HLA-DR compatibilities (P<0.05). In addition, in autoimmune hepatitis, survival tended to be lower in the presence of more HLA compatibilities (P=0.1). Overall graft survival or frequency of adverse immunologic events was not influenced by any specific donor-recipient HLA allele. CONCLUSION: This study demonstrated fewer acute rejections in transplants with more HLA compatibilities. However, in liver transplantation, a more specific investigation of HLA typing may be necessary, because in some indications HLA antigens play a role in the nature of the disease. Therefore, recurrence of autoimmune disease may be more severe in patients sharing HLA antigens.

Management and outcome of patients with combined bile duct and hepatic arterial injuries after laparoscopic cholecystectomy.

BACKGROUND: Recent collective reviews have described the management and outcome of bile duct injuries during laparoscopic cholecystectomy. However, few have reported on the clinical significance of concomitant right hepatic arterial injuries. This study was conducted to examine the correlation of combined bile duct and vascular injuries and to evaluate the impact of these injuries on patient morbidity. METHODS: From January 1990 to February 2002, a total of 54 patients with bile duct injuries during laparoscopic cholecystectomy were surgically treated in our institution. In 46 patients a Roux-en-Y hepaticojejunostomy was performed. Eleven patients had a concomitant vascular injury. Arterial reconstruction was performed in addition to Roux-en-Y hepaticojejunostomy in 2 patients. Eight patients underwent other surgical procedures and were not included in the statistical analysis. To evaluate the impact of vascular injuries, univariate and multivariate analysis was performed. RESULTS: The rate of postoperative biliary complications was 21.7% for all patients. Univariate and multivariate analysis identified 2 risk factors for the development of biliary complications after reconstructive surgery: (1) combined bile duct and hepatic arterial injuries (6 of 11 patients [54.5%] vs 4 of 35 patients [11.4%]; P=.006) and (2) surgical repair in active peritonitis (8 of 13 patients [61.5%] vs 2 of 33 [6.1%]; P <.001). In the other, late referred patients with concomitant right hepatic arterial injury, the distal part of the artery was not exposable. After a median follow-up time of 44.6 months (range, 2 to 143.5 months) a successful outcome was achieved in 42 of 46 patients (91.3%), which included the patients who required additional endoscopic or surgical treatment after primary reconstruction. CONCLUSIONS: The outcome of bile duct reconstruction is worse in patients with concomitant arterial injuries. We therefore recommend the assessment of patients with major bile duct injuries for additional vascular injuries. Further studies are needed to evaluate the importance of hepatic arterial revascularization in early recognized injuries to the long-term outcome of bile duct reconstructions.

Ischemic preconditioning and methylprednisolone both equally reduce hepatic ischemia/reperfusion injury.

BACKGROUND: Ischemic preconditioning (I/P) and methylprednisolone (MP) have been suggested to protect against ischemia-reperfusion (IR) injury, which results in an increased tolerance against organ hypoxia. METHODS: Before 45 minutes of hepatic ischemia, male Wistar rats were pretreated with either I/P (5/30 minutes) or MP (30 mg/kg BW). The degree of IR injury and the postischemic inflammatory (leukocyte infiltration, myeloperoxidase, intercellular adhesion molecule-1) and apoptotic (TUNEL, caspase 3, cytochrome C) activity was measured in both groups and compared with non-pretreated (ischemic) animals. RESULTS: Histology and enzyme release revealed that I/P and MP treatment provided significant protection as compared with ischemic controls. TUNEL-positive cells, as well as caspase 3 and cytochrome C expression, were clearly reduced in hepatic tissue of MP-treated animals and partially reduced in I/P-treated animals when compared with ischemic animals. The inflammatory response was considerably reduced in MP- and I/P-treated animals, especially in the early period after ischemia. NF-kappaB/Rel-binding activity was increased after I/P and decreased in MP-treated animals, whereas ischemic controls showed a constant binding activity. CONCLUSIONS: MP (probably by downregulation of NF-kappaB-binding activity) and I/P attenuated the postischemic apoptotic and inflammatory response. Both treatments equally reduced IR-related hepatocellular damage, and, thus, may also be applied equally in surgery involving warm organ hypoxia.

A prospective randomized multicenter trial comparing histidine-tryptophane-ketoglutarate versus University of Wisconsin perfusion solution in clinical pancreas transplantation.

We aimed to evaluate early pancreas transplant graft function after histidine-tryptophan-ketoglutarate (HTK) versus University of Wisconsin (UW) perfusion. Prospective randomized multicenter study including 68 pancreas transplantations stratified according to preservation fluid used (27 HTK vs. 41 UW). Primary endpoint was pancreas graft survival at 6 months. Serum alpha-amylase, lipase, C-peptide, HbA1C and exogenous insulin requirement were compared at several time points. Mean pancreas cold ischemia time was 10.8 +/- 3.7 (HTK) vs. 11.8 +/- 3.4 h (UW) (P = 0.247). Simultaneous pancreas-kidney transplantation was performed in 95.6% of the patients, pancreas transplantation alone in 2.9%, and pancreas after kidney transplantation in 1.5%. Six months graft survival was 85.2% (HTK) vs. 90.2% (UW) (P = 0.703). Serum amylase and lipase values did not differ between both the groups during the observation period. C-peptide levels were elevated in both the groups without significant differences at each time point. Higher exogenous insulin requirement early after transplantation in the UW group had resolved at 3 months. Six month patient survival was 96.3% (HTK) vs. 100% (UW) (P = 0.397). With a mean cold ischemia time of 10 h in this study, HTK and UW solutions appear to be equally suitable for perfusion and organ preservation in clinical pancreas transplantation.