A. Dazzi

Effect of different immunosuppressive schedules on recurrence-free survival after liver transplantation for hepatocellular carcinoma

Background. Tumor recurrence represents the main limitation of liver transplantation in patients with hepatocellular carcinoma (HCC) and can be favored by exposure to calcineurin inhibitors. Methods. We investigated the effect of an immunosuppressant schedule that minimizes the exposure to calcineurin inhibitors on patients transplanted for HCC to ascertain whether this can reduce the tumor recurrence rate. For this purpose, we conducted a matched-cohort study: 31 patients with HCC transplanted between 2004 and 2007 who received sirolimus as part of their immunosuppression (group A) were compared with a control group of 31 patients (group B) transplanted in the same period who had the same prognostic factors but were given standard immunosuppression based on tacrolimus. Results. Three-year recurrence-free survival was 86% in group A and 56% in group B (P=0.04). Although the prevalence of microvascular invasion G3-G4 grading and alpha-fetoprotein more than 200 ng/mL was identical in the two groups, exposure to tacrolimus was significantly higher in patients of group B (median, 8.54; range, 5.5–13.5) in comparison with those of group A (median, 4.6; range, 1.8–9.1) (P=0.0001). Conclusions. By using sirolimus, exposure to calcineurin inhibitors can be minimized, reducing the risk of HCC recurrence.

Liver transplantations with donors aged 60 years and above: the low liver damage strategy

According to transplant registries, grafts from elderly donors have lower survival rates. During 1999–2005, we evaluated the outcomes of 89 patients who received a liver from a donor aged ≥ 60 years and managed with the low liver‐damage strategy (LLDS), based on the preoperative donor liver biopsy and the shortest possible ischemia time (group D ≥ 60‐LLDS). Group D ≥ 60‐LLDS was compared with 198 matched recipients, whose grafts were not managed with this strategy (89 donors < 60 years, group D < 60‐no‐LLDS and 89 donors aged ≥60 years, group D ≥ 60‐no‐LLDS). In the donors proposed from the age group of ≥60 years, the number of donors rejected decreased during the study period and the LLDS was found to be responsible for this in a significant manner (47% vs. 60%, respectively P < 0.01). Among the recipients transplanted, the clinical features (age, gender, viral infection, child and model for end‐stage liver disease score) were comparable among groups, but group D ≥ 60‐LLDS had a lower mean ischemia time: 415 ± 106 min vs. 465 ± 111 (D < 60‐no‐LLDS), P < 0.05 and vs. 476 ± 94 (D ≥ 60‐no‐LLDS), P < 0.05. After a median follow‐up of 3 years, the 1‐ and 3‐year graft survival rates of group D ≥ 60‐LLDS (84% and 76%) were comparable with group D < 60‐no‐LLDS (89% and 76%) and were significantly higher than group D ≥ 60‐no‐LLDS (71% and 54%), P < 0.005. In conclusion, the LLDS optimized the use of livers from elderly donors.

Sirolimus in Liver Transplant Recipients: A Large Single-Center Experience

Sirolimus (SRL) is a newer immunosuppressant whose possible benefits and side effects in comparison to calcineurin inhibitors (CNIs) still have to be addressed in the liver transplantation setting. We report the results of the use of SRL in 86 liver transplant recipients, 38 of whom received SRL as the main immunosuppressant in a CNI-sparing regimen. Indications for the use of SRL were: impaired renal function (n = 32), CNI neurotoxicity (n = 16), hepatocellular carcinoma (HCC) at high risk of recurrence (n = 21), recurrence of HCC (n = 6), de novo malignancies (n = 4), cholangiocarcinoma (n = 1), and the need to reinforce immunosuppression (n = 6). Among patients on SRL-based treatment, four episodes of acute rejection were observed, three of which occurred during the first postoperative month. Renal function significantly improved when sirolimus was introduced within the third postoperative month, while no change was observed when it was introduced later. Neurological symptoms resolved completely in 14/16 patients. The 3-year recurrence-free survival of patients with HCC on SRL was 84%. Sixty-two patients developed side effects that required drug withdrawal in seven cases. There was a reduced prevalence of hypertension and new-onset diabetes among patients under SRL. In conclusion, SRL was an effective immunosuppressant even when used in a CNI-sparing regimen. It was beneficial for patients with recently developed renal dysfunction or neurological disorders.

Prognostic factors for tumor recurrence after a 12-year, single-center experience of liver transplantations in patients with hepatocellular carcinoma.

Background. Factors affecting outcomes after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) have been extensively studied, but some of them have only recently been discovered or reassessed. Methods. We analyzed classical and more recently emerging variables with a hypothetical impact on recurrence-free survival (RFS) in a single-center series of 283 patients transplanted for HCC between 1997 and 2009. Results. Five-year patient survival and RFS were 75% and 86%, respectively. Thirty-four (12%) patients had HCC recurrence. Elevated preoperative alpha-fetoprotein (AFP) levels, preoperative treatments of HCC, unfulfilled Milan and up-to-seven criteria at final histology, poor tumor differentiation, and tumor microvascular invasion negatively affected RFS by univariate analysis. Milan and up-to-seven criteria applied preoperatively, and the use of m-TOR inhibitors did not reach statistical significance. Coxs proportional hazard model showed that only elevated AFP levels (Odds Ratio = 2.88; 95% C.I. = 1.43–5.80; P = .003), preoperative tumor treatments (Odds Ratio = 4.84; 95% C.I. = 1.42–16.42; P = .01), and microvascular invasion (Odds Ratio = 4.82; 95% C.I. = 1.87–12.41; P = .001) were predictors of lower RFS. Conclusions. Biological aggressiveness and preoperative tumor treatment, rather than traditional and expanded dimensional criteria, conditioned the outcomes in patients transplanted for HCC.

Survival benefit after liver transplantation: a single European center experience.

Background. The evaluation of the survival achieved with liver transplantation (LT) compared with remaining on the waiting list, the transplant benefit, should be the underlying principle of organ allocation. Methods. During 2004 to 2007 with an allocation system based on Model for End-Stage Liver Disease (MELD) score with exceptions, we prospectively evaluated the transplant benefit and its relation to the match between recipient and donor characteristics. Results. Among 575 patients listed for chronic liver disease, 218 (37.9%) underwent LT and 115 (20%) were removed from the list (76 deaths, 25 tumor progressions, and 14 sick conditions). The 1- and 3-year survival rates on the list were significantly related to MELD score more than or equal to 20 (57% and 33% vs. 88% and 66%, P<0.001) and to its progression during the waiting time, such as s-Na levels less than or equal to 135 mEq/L (73% and 48% vs. 86% and 69%, P<0.001). These two variables had no impact on survival after LT, except in hepatitis C virus positive recipients. The multivariate Cox model confirmed a positive transplant benefit for all cases with MELD score more than or equal to 20 and without hepatocellular carcinoma (HR 2.9; CI 1.3–6.2) independently of the type of donors. Only hepatocellular carcinoma patients with low MELD scores showed a positive transplant benefit (MELD <15; HR 2; CI 1.1–5.1). Conclusions. LT should be reserved for cirrhotic patients with MELD score more than or equal to 20 independently of other recipient and donor matches or for cases with lower MELD score but with hepatocellular carcinoma.

Incidence and management of abdominal closure-related complications in adult intestinal transplantation.

Background. We sought to determine the best strategy to overcome difficult abdominal wall closures in intestinal transplantation (ITx). Methods. Among 38 adult recipients of 39 ITxs from deceased donors, the median number of previous laparotomies was 2.0 per patient, with a median donor-to-recipient body weight ratio of 1.1. Eight patients (21%) had full residual intestinal length before transplant. Abdominal wall closure after transplant was considered difficult in 15 (39.5%) patients (group A). To overcome size mismatching, we performed two graft reductions, five skin-only closures, one two-step abdominal wall closure, four prosthetic mesh closures, and three abdominal wall transplants. In the remaining 23 (60.5%) patients, a regular abdominal closure was performed (group B). Results. Twelve patients (32%) experienced complications related to abdominal wall closure, 10 (67%) in group A and 2 (8.7%) in group B (P<0.0001). Abdominal closure-related mortality was 6.7% (1/15) and 4.3% (1/23), respectively (P=1.0). In group A, there were six incisional hernias (one of them after abdominal wall transplant), although all four patients with mesh experienced mesh infection. Two of them developed intestinal fistulae, leading to patient death in one case. In group B, one patient with unfavorable donor/recipient size matching had fatal vascular thrombosis of a multivisceral graft caused by compression after abdominal closure. Conclusions. A careful evaluation of abdominal cavity is necessary in candidates for ITx. In our experience, closure with mesh should be avoided because of the high rate of complications. Abdominal wall transplantation is a feasible option when a difficult abdominal wall closure is expected.

Twenty-five consecutive isolated intestinal transplants in adult patients: a five-yr clinical experience

Abstract: Patients and Methods:  Between December 2000 and December 2005, 25 isolated intestinal transplants from cadaveric donors have been performed for short gut syndrome (short bowel syndrome, 52%), chronic intestinal pseudo‐obstruction (24%), Gardner syndrome (16%), radiation enteritis (4%) and massive intestinal angiomatosis (4%). Indications for transplantation were: loss of venous access, recurrent sepsis due to central line infection, major electrolyte and fluid imbalance. Liver dysfunction was present in 13 cases. All patients were adult; median age was 36.3 yr and mean weight at transplantation 61.6 kg. All recipients were on life‐threatening parenteral nutrition for a mean time of 23.7 months. Mean donor/recipient body weight ratio was 1.08. Rejection monitoring was accomplished by graft ileoendoscopies and intestinal biopsies through the temporary ileostomy. Our immunosuppressive regimen was based on induction therapy with three different protocols: daclizumab for induction, tacrolimus and steroids as maintenance therapy; alemtuzumab for induction and low‐dose tacrolimus as maintenance; thymoglobulinTM for induction and maintenance based on low‐dose tacrolimus. Closure of the abdomen at the end of transplantation represented a technical problem with several options performed: graft reduction, only skin closure, prothesic meshes, abdominal closure in two steps, cutaneous flaps and abdominal wall transplant in one case.

Identification of miR-31-5p, miR-141-3p, miR-200c-3p, and GLT1 as human liver aging markers sensitive to donor–recipient age-mismatch in transplants

To understand why livers from aged donors are successfully used for transplants, we looked for markers of liver aging in 71 biopsies from donors aged 12–92 years before transplants and in 11 biopsies after transplants with high donor–recipient age‐mismatch. We also assessed liver function in 36 age‐mismatched recipients. The major findings were the following: (i) miR‐31‐5p, miR‐141‐3p, and miR‐200c‐3p increased with age, as assessed by microRNAs (miRs) and mRNA transcript profiling in 12 biopsies and results were validated by RT–qPCR in a total of 58 biopsies; (ii) telomere length measured by qPCR in 45 samples showed a significant age‐dependent shortage; (iii) a bioinformatic approach combining transcriptome and miRs data identified putative miRs targets, the most informative being GLT1, a glutamate transporter expressed in hepatocytes. GLT1 was demonstrated by luciferase assay to be a target of miR‐31‐5p and miR‐200c‐3p, and both its mRNA (RT–qPCR) and protein (immunohistochemistry) significantly decreased with age in liver biopsies and in hepatic centrilobular zone, respectively; (iv) miR‐31‐5p, miR‐141‐3p and miR‐200c‐3p expression was significantly affected by recipient age (older environment) as assessed in eleven cases of donor–recipient extreme age‐mismatch; (v) the analysis of recipients plasma by N‐glycans profiling, capable of assessing liver functions and biological age, showed that liver function recovered after transplants, independently of age‐mismatch, and recipients apparently ‘rejuvenated’ according to their glycomic age. In conclusion, we identified new markers of aging in human liver, their relevance in donor–recipient age‐mismatches in transplantation, and offered positive evidence for the use of organs from old donors.

Bacterial Translocation in Adult Small Bowel Transplantation

The application of intestinal transplantation is limited by the high rate of infectious complications that can occur; the migration of enteric microorganisms to extraintestinal sites (bacterial translocation) has been suggested to be responsible for this event. We reviewed 95 intestinal biopsies performed on 28 transplanted patients to identify histologic features predictive of isolation of enteric microorganisms in extraintestinal sites within the first month after transplantation. At least 1 isolation of enteric microorganisms in the peritoneal cavity and/or in blood samples was obtained in 13 patients (46.4%); this event led to higher 1-year mortality (38.5% vs. 6.7%; P = .041). Of the 95 biopsies, 38 were followed by positive cultures (40.0%), showing higher degrees of mucosal vascular alterations (Ruiz grade) and ischemia/reperfusion injuries (Park/Chiu grade) compared with the negative cases (P < .05). We also observed an higher prevalence of positive cultures in relation to acute cellular rejection episodes (P = .091). Neither clinical or surgical factors nor immunosuppressive therapy were observed to be significantly related to positive cultures. Histologic alterations of the small bowel allograft are related to isolation of enteric microorganisms in extraintestinal sites. The degree of these histologic features can identify patients at high risk of potentially life-threatening infectious complications and death.

Disease-related intestinal transplant in adults: results from a single center.

Intestinal transplantation is gaining worldwide acceptance as the main option for patients with irreversible intestinal failure and complicated total parenteral nutrition course. In adults, the main cause is still represented by short bowel syndrome, but tumors (Gardner syndrome) and dismotility disorders (chronic intestinal pseudo-obstruction [CIPO]) have been treated increasingly by this kind of transplantation procedure. We reviewed our series from the disease point of view: although SBS confirmed results achieved in previous years, CIPO is nowadays demonstrating an excellent outcome similar to other transplantation series. Our results showed indeed that recipients affected by Gardner syndrome must be carefully selected before the disease is to advanced to take advantage of the transplantation procedure.