Chantal De Reyck

Tacrolimus monotherapy in liver transplantation: one-year results of a prospective, randomized, double-blind, placebo-controlled study.

Background:Minimal immunosuppression (IS) is desirable in organ transplantation to reduce side effects and to promote the process of tolerance induction. Material and Methods:Between February 2000 and September 2004, 156 adults (>15 years old) receiving a primary liver graft were enrolled in a prospective, randomized, double-blind, placebo-controlled, investigator-driven single-center study comparing tacrolimus (TAC)-placebo (PL) and TAC-low-dose, short-term (64 days) steroid (ST) IS. There were no exclusion criteria at moment of randomization. All patients had a 12-month follow-up (range, 12–84). Results:Three- and 12-month patient survival rates were 93.6% and 87.2% in the TAC-PL group and 98.7% and 94.7% in TAC-ST group (P = 0.096 and P = 0.093, respectively). Three- and 12-month graft survival rates were 92.3% and 85.9% versus 97.4% and 92.3% (P = 0.14 and 0.13, respectively). By 3 and 12 months, rejection treatment had been given in 20.5% (16 pts) and 23% (18 pts) of TAC-PL patients and in 12.7% (10 pts) and 20.5% (16 pts) of TAC-ST patients (P = 0.20 and 0.54). Corticosteroid-resistant rejection (CRR) at 3 and 12 months was recorded in 12.8% (10 pts) of TAC-PL patients and 3.8% (3 pts) of TAC-ST patients (P = 0.04). When considering the 145 patients transplanted without artificial organ support (n = 145), CRR at 3 and 12 months was recorded in 8.8% (6/68 pts) of TAC-PL patients and in 3.9% (3/77 pts) of TAC-ST patients (P = 0.22). Vanishing bile duct syndrome was diagnosed in 1 (1.2%) TAC-PL patient and 4 (5.1%) TAC-ST patients (P = 0.17). By 1 year, 78.2% (61/78) of TAC-PL patients and 82% (64/78) of TAC-ST patients were on TAC monotherapy (P = 0.54). When considering 67 TAC-PL and 74 TAC-ST survivors, rates of monotherapy were 91% (61 pts) and 86.5% (64 pts) (P = 0.39). At 1 year, 62.5% (42 pts) of TAC-PL survivors and 64.9% (48 pts) of TAC-ST survivors were on low-dosage (<6 ng/mL) TAC monotherapy (P 0.79). Conclusion:TAC monotherapy can be achieved safely without compromising graft nor patient survival in a primary, even unselected, adult liver transplant population. The higher incidence of early CRR in the TAC-PL group related to the significantly higher number of patients transplanted while being on artificial organ support. In such condition, this monodrug immunosuppressive strategy needs to be adapted. TAC monotherapy strategy should lay the basis for further large scale minimization studies in liver transplantation.

Validation of a liquid chromatography-mass spectrometric assay for tacrolimus in liver biopsies after hepatic transplantation: correlation with histopathologic staging of rejection.

The aims of this work were both to validate a sensitive and specific method to quantify tacrolimus (TAC) in liver biopsies after hepatic transplantation and to evaluate the predictive value of either tissue or blood TAC concentrations for rejection in 146 adult patients under a TAC-based immunosuppression. Trough blood levels were monitored daily during the hospital stay by immunoassay. Liver biopsies were routinely performed at day 7 posttransplantation. The tissue assay was developed by liquid chromatography-mass spectrometry. The limit of quantification was 5 pg/mg, with intra- and interassay precision ranging from 3.9% to 14.3% and 4.7% to 15.9%, respectively. The extraction efficiency was approximately 80%. TAC found in liver biopsies ranged from less than 5 up to 387 pg/mg. Blood TAC levels ranged from 2.7 to 19.3 ng/mL. Tissue levels displayed excellent correlation with liver histopathologic BANFF rejection score, whereas blood levels did not. Clinically significant rejections (BANFF scores ≥6) were characterized by mean TAC tissue and blood concentration of 13.1 pg/mg and 7.6 ng/mL, respectively, whereas these mean values became, respectively, 74.9 pg/mg (P < 0.05) and 7.1 ng/mL (not significant) for nonclinically significant rejection episodes (BANFF <6). In this study, hepatic tissue TAC concentrations were distributed in a wider range and displayed a significantly better correlation with the severity of the organ rejection than predose blood levels. A tissue TAC concentration less than 30 pg/mg is 89% sensitive and 98% specific to discriminate clinically significant cellular rejection. Further studies are required to better understand the factors affecting TAC distribution within liver tissue (such as carrier proteins and cytochrome genetic polymorphism, liver function, age, hepatic blood flow, type of organ transplanted, time posttransplantation) and to define its value in the treatment of liver allograft rejection.

Liver transplantation for hepatocellular cancer : UCL experience in 137 adult cirrhotic patients. Alpha-foetoprotein level and locoregional treatment as refined selection criteria.

Liver transplantation (LT) is a validated treatment for selected cirrhotics with hepatocellular cancer (HCC). A retrospective single center study including 137 recipients having proven HCC was done to refine inclusion criteria for LT as well as to look at impact of locoregional treatment (LRT) on outcome. At pre‐LT imaging, 42 (30.6%) patients were Milan criteria (MC)‐OUT; 28 (20.4%) were University of California San Francisco criteria (UCSFC)‐OUT. Pre‐LT LRT was performed in 109 (79.6%) patients. Multivariate analysis identified four factors to be independently predictive of recurrence: tumour number >3, AFP level ≥400 ng/ml, microvascular invasion and rejection needing anti‐lymphocytic antibodies. When considering pre‐transplant variables only, AFP level ≥400 ng/ml (HR = 5.13; P < 0.0001) was the unique risk factor for recurrence; conversely, application of LRT was protective (HR = 0.42; P = 0.04). MC‐IN patients having LRT (n = 79) had the best 5‐year tumour‐free survival (TFS) (91.6%). MC‐IN patients without LRT (n = 16) and MC‐OUT patients with LRT (n = 30) had similar good TFS (72.7% vs.77.5%); finally MC‐OUT patients without LRT (n = 12) had the worst results (45.0%; vs. 1st group: P < 0.0001). Immediate pre‐LT AFP and aggressive pre‐transplant LRT strategy, especially in MC‐OUT patients, are both important elements to further expand inclusion criteria without compromising long‐term results of HCC liver recipients.

Use of anti-HBc positive allografts in adult liver transplantation: toward a safer way to expand the donor pool

The use of livers from anti‐hepatitis B core (HBc) positive donors can alleviate donor shortage. Nineteen of 367 (6%) adults receiving anti‐HBc positive allografts [three were hepatitis B antigen (HBsAg) negative, hepatitis B antibody (HBsAb) positive; four were HBsAg positive and 12 were not exposed to hepatitis B viral (HBV) infection] were retrospectively reviewed. In HBsAg negative recipients, immunoprophylaxis (IP) was guided by viral serology and immunohistochemistry (IH) of day 0 and day 7 liver biopsies. If IH was negative, IP was stopped. None of three HBsAg negative, HBsAb positive recipients infected; one (replicating) of four HBsAg positive recipients reinfected and seven of eight (87.5%) HBsAg, HBsAb negative recipients, who did not receive long‐term IP, infected after a median time of 2 years (range 1–5); one patient died of liver failure. Four HBsAg, HBsAb negative recipients, receiving life‐long IP, remained infection free. Anti‐HBc positive donor livers must be directed selectively first to HBsAg positive recipients, next to recipients having HBV antibodies and finally to HBV‐naive recipients. Identification of both donor and recipient risk factors for HBV infection before transplantation allows indiscriminate use of antiviral prophylaxis. The necessity for IP therapy should be guided by HBV‐DNA testing of donor liver tissue and serum. IH of early liver biopsies is an unreliable marker for predicting antiviral treatment requirements.

Is minimal, [almost] steroid-free immunosuppression a safe approach in adult liver transplantation? Long-term outcome of a prospective, double blind, placebo-controlled, randomized, investigator-driven study

Objective:To investigate the safety of minimal immunosuppression (IS) in liver transplantation (LT). Background:The lack of long-term follow-up studies, including pathologic data, has led to a protean handling of IS in LT. Methods:Between February 2000 and September 2004, 156 adults were enrolled in a prospective, randomized, double-blind, placebo-controlled minimization trial comparing tacrolimus placebo (TAC-PLAC) and TAC short-term steroid (TAC-STER) IS. All patients had a minimum clinical, biochemical, and histological follow-up of 5 years. Results:Five-year actual patient and graft survival rates in TAC-PLAC and TAC-STER groups were 78.1% and 82.1% (P = 0.89) and 74.2% and 76.9% (P = 0.90), respectively. Five-year biopsies were available in 112 (89.6%) of 125 survivors. Twelve patients refused a biopsy because of their excellent evolution; tissue material was insufficient in 1 patient; 11 had normal liver tests; and 2 patients had developed alcoholic and secondary biliary cirrhosis. Histology was normal in 44 (39.3%) patients; 35 (31.3%) had disease recurrence. The remaining biopsies showed nonspecific chronic hepatitis (14.3%), mild inflammatory infiltrates (10.7%), and steatosis (3.5%). All findings were equally distributed between both groups. In each group, 3 patients (4.8%) presented with acute cellular rejection after the first year and only 1 (0.9%) TAC-PLAC patient developed chronic rejection after IS withdrawal because of pneumonitis. Arterial hypertension, diabetes mellitus, renal insufficiency, hypercholesterolemia, gout, and obesity were equally low in both groups. Conclusions:Excellent long-term results can be obtained under minimal IS and absence of steroids. TAC-based monotherapy is feasible in most adult liver recipients until 5 years of follow-up.

Professional interpersonal dynamics and burnout in European transplant surgeons.

Burnout within the health professions has become an increasingly important topic. Evidence suggests there are differences in burnout across different countries. Research has yet to examine burnout in transplant surgeons throughout Europe.

Tacrolimus (TAC) and Single Intra-Operative High-Dose of r-ATG Induction vs. Tacrolimus Monotherapy as Immunosuppression (IS) in Adult Liver Transplantation (LT): One-Year Results of an Investigator-Driven, Prospective, Randomized, Controlled Trial (RCT)

Introduction The role of induction therapy using anti-lymphocytic serum is poorly understood in LT as it is its utility in tolerance induction. We aimed to assess efficacy of a high-dose of rabbit anti-lymphocytic serum (r-ATG, Grafalon®, Neovii) administered intra-operatively in combination with TAC (Prograft®, Astellas) in primary adult LT. Materials and Methods Investigator-driven, single-centre, open-label, prospective RCT stratifying pts into an intra-operative dose of 9 mg/kg r-ATG followed by TAC monotherapy maintenance IS (TAC-ATG group; n=97) and TAC monotherapy IS (TAC group, n=109).The primary endpoint was minimization of IS to monotherapy within 12 months. Safety endpoints were patient (PS) and graft survival (GS). The secondary endpoint was one-year biopsy-proven acute cellular rejection (ACR). 200 patients were required to provide a power of 80% to detect a difference of 9% in attaining TAC monotherapy within 12 mo, accepting 5% level of &agr; error. Means were compared with t-test and proportions with Pearson’s &khgr;2 test. Time to clinical rejection, PS and GS were analysed with the Kaplan–Meier method and compared with the log-rank test. All patients had similar clinical, biochemical and histological follow-up (FU) including protocol biopsies. ACR treatment was based on concordance of Banff score > 5 and biochemical score (including bilirubin, platelet and eosinophilia) >2. Steroid-resistant rejection (SRR) was defined as absence of response to 3-5 pulses of 200 mg methylprednisolone. Mean FU for TAC-ATG and TAC groups were 87 and 95 months. Results 78/80 (97.5%) TAC-ATG and 100/101 (99.0%) TAC pts were steroid free (p=0.429). A second immunosuppressant (steroids, mycophenolate, azathioprine or mTOR inhibitor) was administered in 29/80 (36.3%) TAC-ATG and 35/101 (34.7%) TAC pts (p=0.823). One-year mean TAC trough level was 5.19 (±3.06) mg, in TAC-ATG and 5.04 (±2.80) mg in TAC pts (p=0.738). No statistically significant differences in one-year PS (83% TAC-ATG vs. 92% TAC pts, p=0.260) and GS (76% TAC-ATG vs. 90% TAC pts, p=0.054) were observed. A 6-9 Banff score was seen in 27/107 (25.2%) TAC and 14/83 (16.9%) TAC-ATG pts (p=0.164). No difference was observed in relation to the number of treated rejection (15% TAC-ATG vs. 18% TAC pts developed steroid-sensitive rejection (SSR), p=0.449); 2% TAC-ATG and 3% TAC pts (p=0.628) developed SRR. Chronic rejection was diagnosed in 1% in TAC-ATG vs. 4% in TAC pts (p=0.307). Discussion This first ever-done RCT comparing TAC and single intra-operative high-dose of r-ATG induction vs. TAC monotherapy as IS in adult LT did not show any benefit in relation to IS minimization nor survival. Rejection treatment based on concordance between histology and biochemistry was similar in both groups. Conclusions The studied induction protocol did not offer short-term clinical benefit. Long-term results have to be awaited in order to analyse its’ influence on tolerance induction. (EudraCT 2006-004830-34). Unrestricted grant from Neovii - Fresenius for immunological research not presented in this study.