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Background/aims: To externally validate the predictive mathematical model of survival designed by Linhares et al. (2006)., Methodology: This retrospective study was conducted on 217 individuals submitted to liver retransplantation from January 2000 to December 2008 in four European centers. The following variables were obtained on the recipient: age, creatinine, urgency of retransplantation and time between transplantation and retransplantation. The Kaplan-Meier survival curve and ROC curve were used to validate the mathematical model., Results: The present results showed a similar pattern of survival compared to the study of Linhares et al. (2006) concerning the biological variations, when survival curves were compared for each of the four variables analyzed between both samples. When compared, the areas below the ROC curve (aROC) of derivation (0.733) and validation samples (0.593) presented significant difference (p = 0.005), revealing low relationship of sensitivity and specificity between the two curves. Similarity was observed in Kaplan-Meier survival curves., Conclusion: This study allowed external validation by the Kaplan-Meier survival curves of the predictive mathematical model of survival in liver retransplantation proposed by Linhares et al. (2006). However, validation through the ROC curve, the aROC, evidenced weak discrimination ability.

Objective: To critically evaluate the outcome of the peer review process of the European Surgical Association (ESA) and its contribution to Annals of Surgery., Background: The ESA was created in 1993 as an equivalent of the well-established American Surgical Association. Submitted abstracts and manuscripts were subjected to a stringent multistep peer review process to offer only the best studies for publication in the special issue of Annals of Surgery. A critical evaluation was felt necessary to identify factors that favored the acceptance of abstracts and manuscripts, respectively. The citations of the manuscripts published in Annals of Surgery and the outcome of the rejected studies were also researched., Methods: All submissions to the ESA between 2002 and 2007 were analyzed and followed over a period of 2 years. A database was established to identify factors favoring acceptance. A comprehensive search was undertaken to identify plagiarisms and the 2-year citations of all accepted manuscripts and later publications of the rejected studies in Annals of Surgery or elsewhere., Results: Altogether, 545 abstracts were submitted to the ESA during the study period. About one-third was accepted for presentation at the annual meeting, and, of those, 40% were published in Annals of Surgery. The majority of these studies originated from 4 European Countries. The only independent factors favoring presentation were randomized controlled trials and a sample size of more than 100 patients. All plagiarisms were identified before acceptance. Only 4% and 2% of the rejected abstracts and manuscripts, respectively, were published in higher impact factor journals than in Annals of Surgery. Twelve percent of the rejected manuscripts were eventually published in a later issue of Annals of Surgery, whereas more than two-thirds of the rejected studies appeared in a journal with a lower impact factor. The 2-year citations of the ESA manuscripts were in the range of all the other types of manuscripts published in Annals of Surgery. Only manuscripts originating from the American Surgical Association had slightly higher citations., Conclusions: The ESA successfully spent its early years, providing high-quality manuscripts to Annals of Surgery. Only few rejected manuscripts reached higher-ranked journals. The focus should now turn toward stimulating other European countries to submit their best studies and attract more well-designed randomized controlled trials.

Background: The number of registries is increasing, but few of them perform reliability audits by comparing the data contained in the database with data contained in hospital charts., Methods: The European Liver Transplant Registry (ELTR) cocoordinating committee appointed an independent team to check the reliability of data contained in ELTR. Centers were selected at random. Ten percent of each center's files were selected at random, and 25 items per file were checked during the site visits. The rates of completeness and inconsistencies and the agreement between ELTR and charts were established. We also assessed the correlation between the quality of data and the visited centers' activity., Results: Seven hundred thirty-four files from 21 centers have been audited between June 1998 and June 2001. The rate of ELTR completeness was 95%, and the rate of consistency between charts and ELTR was 98%. The agreement between the ELTR and charts review was very good for all conditions (kappa value < or =0.81). However, comparisons of rates between items indicated that specific items, mostly cause of death or graft failure and patient outcome, should be targeted for improvement. No significant correlation was found between the quality of data and the experience of visited centers. The mean (min-max) and median cost per audited file were EUR 60 (8-150) and EUR 44, respectively., Conclusion: The results of audit visits indicate that ELTR data are reliable, and the scientific results of ELTR can be considered credible and representative of liver transplantation in Europe. The method could serve as a model for auditing a registry.

Background: No model exists for liver transplantation to estimate the mortality risk in a given patient, and no standard by which to assess performance in different centres. We investigated the intrinsic mortality risk in the absence of known mortality risk factors., Methods: We identified mortality risk factors and risk ratios quantified in data from the European Liver Transplant Registry (22,089 patients at 102 centres in 18 countries) registered from 1988 to 1997. To develop a model of the intrinsic risk and the risk ratios for specific factors, univariate and multivariate analyses were done separately for the overall population, for adults, and for children younger than 15 years, and the number of deaths were estimated. We validated the model by comparing mortality in patients without risk factors with the model-adjusted mortality in patients with risk factors., Findings: Overall 5-year and 8-year actuarial survival was 66% (95% CI 65-66) and 61% (60-62). 65% of deaths occurred within 6 months. Retransplantation, transplantation for cancer, acute liver failure, fewer than 20 split-liver grafts per year, and a centre workload of fewer than 25 transplants per year were the main risk factors of 12 identified factors. 1-year and 5-year death rates among adults with no risk factors were similar to model estimates (15 [13-16] vs 14% [13-15], and 22 (20-24) vs 23% [21-24]). Corresponding data for paediatric transplants were 9% (7-12) compared with 11% (9-12) and 13% (10-17) compared with 14% (11-16). The reduction of mortality risk in high-volume centres was even greater in patients without risk factors (48 vs 23%, p<0.001)., Interpretation: The normalised intrinsic mortality risk can be combined with the relative risk ratios of known risk factors to better estimate the mortality risk of a given procedure in a given patient. Centres can assess performance by removing potential bias of donor and recipient selection.

p53 alterations are considered to be predictive of poor prognosis in hepatocellular carcinoma (HCC) and may induce a humoral response. Anti-p53 serum antibodies were assessed by enzyme-linked immunosorbent assay (ELISA) using purified recombinant human p53 on 130 European HCC patients before treatment and during the clinical course of the disease. p53 immunohistochemistry was performed on tumours from the 52 patients who underwent surgery, and DNA sequencing analysis was initiated when circulating anti-p53 antibodies were detected. Nine (7%) HCC patients had anti-p53 serum antibodies before treatment. During a mean period of 30 months of follow-up, all the negative patients remained negative, even when recurrence was observed. Of the nine positive patients, eight were still positive 12-30 months after surgery. The presence of anti-p53 serum antibodies was correlated neither with mutation of the p53 gene nor the serum alpha-fetoprotein levels and clinicopathological characteristics of the tumours. However, a greater incidence of vascular invasion and accumulation of p53 protein were observed in the tumours of these patients (P<0.03 and P<0.01 respectively) as well as a better survival rate without recurrence (P = 0.05). In conclusion, as was recently shown in pancreatic cancer, anti-p53 serum antibodies may constitute a marker of relative 'good prognosis' in a subgroup of patients exhibiting one or several markers traditionally thought to be of bad prognosis.

Genetic instability has been detected in many types of cancers but poorly investigated in hepatocellular carcinoma (HCC). We have studied the incidence of microsatellite instability (MI) at eight highly polymorphic microsatellite markers and the poly A tract BAT26 and tested for mutations at two sites of repetitive sequence (poly-A nucleotides 709-718 and GT repeat-nucleotides 1931-1936) in the Transforming Growth Factor beta (TGFbeta) type II receptor (RII) gene, in a group of 46 European HCCs and the surrounding nontumour tissue. This analysis showed that 63% of HCCs exhibit MI in at least one chromosome locus and 41% in two or more loci. No mutations of the TGFbetaRII gene were found in the MI positive tumours. No correlation was found with clinicopathological characteristics of the tumours such as cirrhosis, etiology, number of nodules, Edmondson's grade and vascular invasion. However, in patients who had a rearranged D16S402 microsatellite in their tumour, the recurrent disease and the number of nodules were significantly higher than in the others (P<0.005 and P<0.02, respectively). We propose to consider D16S402 rearrangement in HCC as a prognostic factor to identify patients presenting a higher risk of recurrence.

Fulminant hepatic failure is associated with high mortality. Liver transplantation is an effective therapy that improves survival, and because of donor organ shortage and urgency, a bioartificial liver could act as an effective bridge to liver transplantation in patients with fulminant hepatic failure. We discuss the place of the bioartificial liver in the treatment of other causes of liver failure.

Approximately 11% of all liver transplants performed in Europe are for acute liver failure, with one-year patient survival rates ranging between 50% and 75%. This review summarizes the selection, perioperative management, and outcome of patients transplanted for acute liver failure, with particular reference to the experience at the Hôpital Paul Brousse in Paris and at King's College Hospital, London. In both centers, the decision to proceed to liver transplantation is based on criteria that predict a survival of less than 20% with medical management alone. Infectious complications and cerebral edema remain the most common causes of death, and highlight the importance of intensive monitoring and early treatment of perioperative complications. In selected patients, auxiliary partial orthotopic liver transplantation may be a therapeutic option, with the potential for native liver generation and eventual immunosuppression withdrawal in approximately two-thirds of patients.

From September 1990 to January 1992, 545 liver transplant patients were randomised to treatment with either FK506 and prednisolone or a conventional cyclosporin-based immunosuppressive regimen (CBIR). Eight European centres participated in the study. Adverse events were reported as defined by each centre. Hyperglycaemia was reported as an adverse event in 30.7% of patients receiving FK 506 compared with 20.5% in the CBIR group (P < 0.01). Diabetes mellitus was reported in 17.2% of patients treated with FK 506 and 9.5% of CBIR-treated patients (P < 0.05). Treatment with insulin was required in 12.0% of patients in the DK 506 treatment group and in 5% in the CBIR group at 6 months. Initially, higher doses of FK 506 were used. During the study, the protocol was changed to allow a lower dose of FK 506. When the early and late cohorts of patients were compared, the incidence of diabetes mellitus fell from 23.9% to 10.5% in FK 506-treated patients but remained relatively constant in the CBIR group (10.4% to 8.7%). The median cumulative doses of i.v. and p.o. corticosteroids were significantly greater in the CBIR group. Thus, in the overall series, the incidence of diabetes mellitus was significantly greater in the FK 506 group as compared with the CBIR group. However, when a lower FK 506 dose was used during the second half of the study, the difference in the incidence of diabetes mellitus disappeared.

We examined the occurrence of renal complications and hypertension in 540 primary liver recipients entered into the European liver trial comparing primary FK 506 to a cyclosporin A based immunosuppression regimen (CBIR). No difference in serious renal impairment or mean creatinine levels was observed with similar rates of "kidney failure" (FK 506 9.4% vs. CBIR 7.3%) and dialysis requirements (FK 506 12% vs. CBIR 11%). "Abnormal kidney function", a less serious parameter of renal impairment, was reported in 89 recipients (33%) in the FK 506 group versus 58 (21%) in the CBIR group (P < 0.01). Development of this complication was associated with elevated intravenous FK 506 dosing schedules, with the mean cumulative dose 43% higher than treated patients with unaffected kidney function. In a later cohort of patients where intravenous dosing was lower, no significant difference in renal complications was detectable. The 6-month prevalence rate of systemic arterial hypertension was noted to be lower in the FK 506-treated patients compared to the CBIR group [33 (17.2%) vs. 47 (25.7%)].

Neurological complications were examined in a multicentre, randomized, parallel-group study of 545 patients undergoing primary liver transplantation to compare the efficacy and safety of FK 506- and cyclosporin A-based immunosuppressive regimens (CBIR). In an additional analysis, patients were divided into early and late randomized cohorts to detect the influence of protocol amendements that allowed for FK 506 dose reductions. Initial follow-up was for 6 months. Tremor, headache and insomnia were the most frequently reported adverse events involving the neurological system. Whereas these neurological symptoms were observed significantly more often in FK 506-treated patients (P < 0.05 vs. CsA for the overall population), this was no longer the case for the late FK 506 and CBIR cohorts. The risk of FK 506-treated patients developing tremor was related to the initial i.v. dose, the rate of administration of the i.v. dose and the daily dose (P < 0.01). Headache was significantly correlated with the FK 506 dose (P < 0.05), and insomnia was not related to any dosing variable. Major neurological symptoms, including psychosis, convulsion, coma, aphasia and intracranial haemorrhage, were reported with a low frequency (0.4-5.2%), and differences between both treatment groups were neither significant for the overall population nor for the early and late cohorts of FK 506 and CBIR. Data from the late cohorts showed no differences in the overall incidence of neurological adverse events between FK 506- and CBIR-treated patients.

The incidence of intractable rejection was evaluated during the course of a multicentre, randomised, parallel-group study comparing the efficacy and safety of FK 506 and conventional cyclosporin A-based immunosuppressive regimens in patients undergoing primary liver transplantation. A diagnosis of intractable rejection was made if there was histological evidence of unchanged or worsening acute rejection, or chronic rejection after two discrete courses of antirejection therapy. Antirejection regimens were specific to each centre. Patients who experienced intractable rejection could be withdrawn from the study. Patients who were withdrawn from the cyclosporin A treatment group could subsequently receive FK 506 therapy and vice-versa. Intractable rejection was diagnosed in 32/540 patients (5.9%): 7/267 patients (2.6%) in the FK 506 treatment group and 25/273 patients (9.2%) receiving cyclosporin A therapy (P < 0.01). Of these 32 patients, 25 were withdrawn from the study: 3 and 22, from the FK 506 and cyclosporin A treatment groups, respectively. All three patients withdrawn from the FK 506 treatment group are alive: two having undergone retransplantation. Of the 22 patients withdrawn from the cyclosporin A group and converted to FK 506 therapy, 6 were retransplanted, 4 of whom subsequently died. A further two patients died without retransplantation. Thus, in 14 of the 16 patients who were still alive at 6 months, the liver graft was saved after conversion to FK 506 treatment. The reduced incidence of intractable rejection in patients receiving treatment with FK 506, together with the successful rescue of patients developing intractable rejection while receiving cyclosporin A, suggests that FK 506 is an effective immunosuppressive agent following orthotopic liver transplantation.

In a retrospective study, we analysed the FK 506 dosage used in primary liver graft recipients enrolled in the European FK 506 multicenter trial conducted from September 1990 to January 1992. In addition, a second cohort of patients treated more recently in a single centre was investigated. The impact of different dosing strategies on the clinical course of the patients was analysed with special emphasis on the incidence of rejection episodes and FK 506 side-effects. Among the patients enrolled in the European FK 506 multicenter trial, those patients enrolled during the "early" phase of the study received a higher oral FK 506 dose [mean oral dosage on day 7 = 0.19 mg/kg body weight (bw) per day, n = 134] compared to patients enrolled during the "late" period of the study (mean oral dosage on day 7 = 0.14 mg/kg bw per day, n = 133). This lower dosage was the result of several protocol amendments performed to reduce the incidence of FK 506 side-effects. Lowering of the FK 506 dosage was accompanied by a reduction in the long-term prevalence of side-effects such as diabetes (n. s.) or hypertension (P < 0.05), while patient survival and rejection frequency remained constant. Patients treated in centres with online FK 506 blood level monitoring experienced significantly less hypertension, less episodes of diabetes and less rejection episodes compared to patients treated in centres without. The clinical course of those patients enrolled in the multicentre trial was compared with the course of a cohort of liver-grafted patients treated with FK 506 more recently in a single centre. These patients had a further reduction in the FK 506 dosage (0.10 mg/kg bw per day p.o. or less according to whole blood levels, with no intravenous FK 506 administration). When compared to patients enrolled in the multicentre trial, these patients experienced less side-effects (nephrotoxicity, hypertension, serious early neurotoxicity) while adaequate immunosuppression was maintained.

The steroid-sparing effect and the use of concomitant medication during the treatment of liver transplant patients with the novel immunosuppressant FK 506 were evaluated within the European multicentre, randomized, parallel-group study in liver transplantation. Patients undergoing primary liver transplantation were randomized to treatment with FK 506 (n = 267) or with a cyclosporin-based immunosuppressive regimen (n = 273). The total cumulative steroid usage was significantly reduced in the FK 506 treatment group, which is likely to have resulted from the lower incidence of acute rejection in these patients. The number of patients receiving antidiabetic, diuretic and antihypertensive therapy did not differ between the two treatment groups, even though the incidence of diabetes mellitus and oliguria was significantly higher in the FK 506 group. It can, therefore, be assumed that in a number of such cases the severity of these events was very mild necessitating no specific therapy.

At the 32 European centres where livers are transplanted the actuarial survival rate for 1218 patients was 44% at 1 year and 41% at 2 years. Perioperative mortality (30 days) was 30%. Recipients aged under 15 years had a higher survival rate than those aged over 15; the differences were 22% at 1 year and 32% at 2 years. For the 97 patients who received two or more liver grafts, actuarial survival was 27.7% at 1 and 2 years. Two-thirds of the transplantations were done since 1984. Since then the best results have been obtained for biliary atresia (88 cases; survival rates at 30 days, 1 year, and 2 years were 87%, 74%, and 68%). Primary biliary cirrhosis was the commonest benign indication for transplantation, with survival of 64% at 1 and 2 years. The proportion of transplantations that were done for patients with hepatocellular carcinoma was smaller after than before 1984; among transplantations done in adults after 1984, those done because of hepatocellular carcinoma gave the best perioperative survival rate (76%) but the worst 2 year survival (30.8%).