M. Bahra

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

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 Corticosteroids were withdrawn three to six months after OLT.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

MMF and Calcineurin Taper in Recurrent Hepatitis C After Liver Transplantation: Impact on Histological Course

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is almost universal. The optimal immunosuppression for these patients is still under discussion. We designed a retrospective case‐control study to evaluate the effect of mycophenolate mofetil (MMF) treatment in patients with recurrent hepatitis C.

Prospective Randomized Comparison between a New Mattress Technique and Cattell (duct-to-mucosa) Pancreaticojejunostomy for Pancreatic Resection

The majority of lethal complications after pancreatic head resection are due to septic complications after leakage from the pancreatojejunostomy. Especially the smooth pancreatic remnant is prone to develop parenchymal leaks from shear forces applied during tying of the sutures. We developed a new mattress technique that avoids such shear forces, and we compared this method to the standard Cattell (duct-to-mucosa) technique. A total of 113 patients undergoing standard pancreatic head resection were prospectively randomized to receive either the standard Cattell anastomosis (n = 56) or the new mattress technique (n = 57). All patients were evaluated for surgical and medical complications until discharge. Primary diagnosis and further demographic data compared well between the groups. The time to perform the mattress anastomosis was significantly shorter (15 vs. 22 minutes; p < 0.0001). The incidence of complications at the pancreatojejunostomy, and the length of hospital stay and survival were not significantly different between the two groups; however, a trend toward more reoperations was noted in the Cattell group (10 vs. 5; p < 0.097). The new mattress technique is simple, and our data show that the two techniques yield similar incidences of complications. Therefore the mattress technique for pancreatojejunostomy seems to be safe and is, in our opinion, well suitable for training schedules in pancreatic surgery.

Combination therapy of poly (ADP-ribose) polymerase inhibitor 3-aminobenzamide and gemcitabine shows strong antitumor activity in pancreatic cancer cells

Background and Aim:  Poly (ADP‐ribose) polymerase (PARP) inhibitors such as 3‐aminobenzamide (3‐ABA) enhance the in vitro cytotoxicity of DNA mono‐functional alkylating agents such as radiation or chemotherapeutic agents. The aim of this study was to test an approach combining the PARP inhibitor 3‐ABA with standard gemcitabine therapy in human pancreatic cancer cells.

Nonresponse to pre-operative chemotherapy does not preclude long-term survival after liver resection in patients with colorectal liver metastases

BACKGROUND Liver resection is the only curative treatment offering a chance of long-term survival in patients with colorectal liver metastases (CRM). Recent data indicated that liver resection in patients with tumor progression while receiving chemotherapy was associated with poor outcome. The aim of the study was to identify risk factors for poor outcome in patients with pre-operative chemotherapy of CRM. METHODS We analyzed 160 patients after liver resection for CRM with preoperative systemic. chemotherapy. Three groups of patients were identified: 44 patients (27.5%) had a tumor response, 20 (12.5%) showed stable disease, and 96 (60%) patients had tumor progression while on chemotherapy. Median follow-up was 2.4 years (range, 6 days-11.1 years). All available clinicopathologic variables possibly associated with outcome were evaluated. RESULTS Survival was 88%, 53%, and 37% at 1, 3, and 5 years. Noncurative resection, carcinoembryonic antigen levels >200 ng/ml, tumor grading, size of the largest tumor >5 cm, and number of metastases were associated with poor patient outcome. In the multivariate analysis, tumor free margin and tumor grading correlated with the outcome. Tumor progression while on chemotherapy had no influence on the long-term survival. CONCLUSION Liver resection offers a long-term survival benefit for patients with CRM, even when tumor growth proceeds during pre-operative chemotherapy.

Influence of donor/recipient HLA‐matching on outcome and recurrence of hepatitis C after liver transplantation

The aim of this study was to analyze the effect of human leukocyte antigen (HLA) matching on outcome, severity of recurrent hepatitis C and risk of rejection in hepatitis C positive patients after liver transplantation (LT). In a retrospective analysis, 165 liver transplants in patients positive for hepatitis C virus (HCV) with complete donor/recipient HLA typing were reviewed for recurrence of HCV and outcome. Follow‐up ranged from 1 to 158 months (median, 74.5 months). Immunosuppression consisted of either cyclosporine‐A‐ or tacrolimus‐based quadruple induction therapy including or an interleukin 2‐receptor antagonist. Protocol liver biopsies were performed after 1, 3, 5, 7, and 10 years and staged according to the Scheuer scoring system. The overall 1‐, 5‐, and 10‐year graft survival figures were 81.8%, 69.11 and 62%, respectively. There was no correlation in the study population between number of HLA mismatches and graft survival. The number of rejection episodes increased significantly in patients with more HLA mismatches (P < 0.05). In contrast to this, the fibrosis progression was significantly faster in patients with 0–5 HLA mismatches compared to patients with a complete HLA mismatch. In conclusion, HLA matching did not influence graft survival in patients after LT for end‐stage HCV infection, however, despite less rejection episodes, the fibrosis progression increased in patients with less HLA mismatches within the first year after LT. Liver Transpl 12:644–651, 2006.

Carcinoma of the distal and middle bile duct: surgical results, prognostic factors, and long-term follow-up

BACKGROUND/PURPOSE Carcinoma of the distal bile duct is associated with poor prognosis. Surgical resection remains the only potentially curative treatment. We conducted a retrospective study to identify prognostic factors determining longterm survival. METHODS From 1990 to 2006, 95 patients with distal and/or middle bile duct carcinoma had resections. Fifty-four patients underwent pylorus-preserving pancreaticoduodenectomy (57%) and 41 patients underwent standard Kausch-Whipple pancreaticoduodenectomy (43%). Nine patients underwent pancreaticoduodenectomy including portal vein resection (9%). RESULTS Overall 1-, 3-, and 5-year survival rates were 60%, 36%, and 29%, respectively. Five-year survival after R0 resection was 34%, and after R1 resection it was 0%. Four patients died during their hospital stay (4%). Multivariate analysis showed negative resection margins (P = 0.040), lymphatic vessel invasion (P = 0.036), and portal vein infiltration (P = 0.027) as strong predictors for survival, whereas the location of the tumor (distal bile duct vs middle bile duct) and lymph node status were not identified as independent prognostic factors. CONCLUSIONS Five-year survival depends strongly on negative resection margins, independent of nodal status. Portal vein resections in patients with portal vein involvement fail to ameliorate long-term survival. Primary tumor site--middle bile duct or distal bile duct--did not determine prognosis.

Outcome after liver re-transplantation in patients with recurrent chronic hepatitis C

Long‐term outcome after liver retransplantation for recurrent hepatitis C has been reported to be inferior to other indications. The identification of factors associated which improved long‐term results may help identify hepatitis C positive patients who benefit from liver retransplantation. Outcome after liver retransplantation for recurrent hepatitis C was analyzed in 18 patients (group 1) and compared with hepatitis C positive patients undergoing liver retransplantation for initial nonfunction (group 2, n = 11) and patients with liver retransplantation for other indications (group 3, n = 169). Five‐year patient survival following retransplantation for groups 1, 2 and 3 was 59% 84% and 60%. Increased alanine aminotransferase (ALT) and serum bilirubin, as well as white cell count and MELD score at day of retransplantation were associated with impaired patient outcome. Five‐year survival after retransplantation in patients with recurrent hepatitis C is similar to that in patients undergoing liver retransplantation for other indications. Our analysis showed MELD score, bilirubin, ALT levels and white cell counts preorthotopic liver transplantation are important predictive factors for outcome. This observational study may help select patients and identify the optimal time‐point of liver retransplantation in ‘‘Hepatitis C’’ virus positive patients in the future.

Donor Age Does Not Influence 12-Month Outcome After Orthotopic Liver Transplantation

OBJECTIVE Orthotopic liver transplantation (OLT) is the most effective treatment for patients with end-stage liver disease to date. The discrepancy between the numbers of donor livers and recipients has become a significant problem, resulting in a high patient mortality on the waiting list. Due to this, an expansion of the donor pool is necessary, for example, by accepting donor grafts from elderly donors. The aim of this study was to investigate the outcome after OLT depending on donor age. METHODS We retrospectively evaluated the outcome of 272 full-size cadaveric initial single OLTs within 12 months after OLT. The outcome was analyzed by dividing the collective into four donor age categories: donor age under 50, between 50 and 59, between 60 and 69, and 70 years or above. The outcome after OLT in these patients was retrospectively reviewed by using a prospective database. Patients positive for hepatitis C were excluded from the analysis. RESULTS No increase of initial nonfunction was observed. Furthermore, no significant differences with regard to surgical complications and serum liver parameter were observed between the groups. Neither patient mortality rates nor rejection rates were different between the groups. However, ischemic-type biliary lesion rates increased significantly with donor age over 70 years (P<.05). CONCLUSIONS The acceptance of liver grafts from older donors is a possible alternative to narrow the gap between donated and required organs. Safe use under optimal protocols is necessary to avoid a deterioration of post-OLT results.

Langzeitverlauf von Patienten mit einer Hepatitis C-bedingten Leberzirrhose nach Lebertransplantation

Einleitung: Die Hepatitis C (HCV) im Endstadium ist inzwischen eine der haufigsten Indikationen fur eine Lebertransplantation. Komplizierend kommt es bei fast allen Patienten mit einer HCV nach der Lebertransplantation (OLT) zu einem Rezidiv der Hepatitis. Dies fuhrt in bis zu 15% der Falle erneut zu einer Leberzirrhose. Ziel dieser retrospektiven Analyse war es den Langzeitverlauf nach OLT bei HCV unter spezieller Berucksichtigung von Leberbiopsien zu betrachten. Methodik: Insgesamt wurden zwischen 1989 und Mai 2001 213 HCV positive Empfanger transplantiert. Das Frauen/Manner Verhaltnis war 85/128. Das mediane Alter der Patienten war 53 Jahre (15–72 Jahre). Die Immunsuppression erfolgte mit Cyclosporin A oder Tacrolimus als Basisimmunsuppressivum. Routinebiopsien erfolgten 6 Monate, 1, 3, 5, 7 und 10 Jahre nach Transplantation. Insgesamt wurden 826 Biopsien bei allen Transplantationen ausgewertet. Bei 11 Transplantationen lagen keine Biopsien vor. Hierbei handelte es sich um Transplantationen, die bei einer initialen Nichtfunktionen nach OLT keine Biopsie hatten. Ergebnisse: Das 1-, 5- und 10-Jahres uberleben der Patienten betrug 87%, 75% und 69%. Bei insgesamt 23/239 (9,6%) der Transplantationen kam es zu einem Organversagen aufgrund einer Reinfektion mit dem Hepatitis C Virus. Nach OLT kam es bei 79/239 (33%) in einem medianen Interval von 651 (37 - 3653) Tagen zu einer Septenbildenden Fibrose. 24/239 Patienten entwickelten durchschnittlich 709 (41 - 2446) Tage nach der OLT eine Leberzirrhose. Mindestens 5 Jahre nach OLT lag noch bei 70 Transplantationen eine Histologie vor. Hiervon zeigte sich bei 23 Pat (32,8%) eine Fibrose und bei 12 Pat (17,1%) eine Zirrhose oder ein beginnender zirrhotischer Umbau. Die Inzidenz der Leberfibrose und Leberzirrhose sowie das Transplantatversagen war unabhangig vom primaren Immunsuppressionsprotokoll. Bei Patienten mit mehrfachen Steroidbolustherapien oder OKT3 Gabe kam es signifikant haufiger zu einem HCV Reinfekt-bedingten Transplantatversagen sowie der Entwicklung einer Leberzirrhose. Diskussion: Die Reinfektion der Hepatitis C nach OLT stellt ein klinisch relevantes Problem dar. Mit moderner Immunsuppression sind bisher nur Langzeitverlaufe bei einzelnen Patienten und bis maximal 8 Jahre nach OLT beschrieben. Unsere Daten zeigen das 30% der lange uberlebenden Patienten (> 5 Jahre nach OLT) eine Fibrose und zusatzlich 17% eine Zirrhose entwickeln. Negativ prognostische Faktoren sind hier die Abstossungstherapie mit Steroiden und OKT3. Dies betrifft 50% der Patienten, wobei davon auszugehen ist das im Verlauf noch ein weiterer Teil der Patienten ein Organversagen entwickeln wird. Neue Therapien zur Behandlung der Hepatitis C, sowie Verbesserung und Adaptation der Immunsuppression sind notwendig um dieses Problem in der Zukunft zu reduzieren.