The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0-2.5 µM) of OCA were added to culture media and, after 3-10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 µM. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients.

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.

Harm and benefits of primary liver resection and salvage transplantation for hepatocellular carcinoma.

Primary transplantation offers longer life-expectancy in comparison to hepatic resection (HR) for hepatocellular carcinoma (HCC) followed by salvage transplantation; however, livers not used for primary transplantation can be reallocated to the remaining waiting-list patients, thus, the harm caused to resected patients could be balanced, or outweighed, by the benefit obtained from reallocation of livers originating from HCC patients first being resected. A Markov model was developed to investigate this issue based on literature data or estimated from the United Network for Organ Sharing database. Markov model shows that primary transplantation offers longer life-expectancy in comparison to HR and salvage transplantation if 5-year posttransplant survival remains higher than 60%. The balance between the harm for resected patients and the benefit for the remaining waiting list depends on (a) the proportion of HCC candidates, (b) the percentage shifted to HR and (c) the median expected time-to-transplant. Faced with a low proportion of HCC candidates, the harm caused to resected patients was higher than the benefit that could be obtained for the waiting-list population from re-allocation of extra livers. An increased proportion of HCC candidates and/or an increased median time-to-transplant could lead to a benefit for waiting-list patients that outweighs this harm.

Daclizumab and alemtuzumab as induction agents in adult intestinal and multivisceral transplantation: rejection and infection rates in 40 recipients during the early postoperative period.

BACKGROUND: Allograft rejection in intestinal transplantation occurs frequently, and bacterial, fungal, and viral infections related to strong immunosuppression regimens remain an important complication posttransplantation. Induction therapy has enabled improvement in graft and patient survival rates. OBJECTIVES: In analyze the effects of daclizumab and alemtuzumab as induction therapies on inflections complications and incidence of acute cellular rejection (ACR) during the early posttransplantation period. PATIENTS AND METHODS: Between December 2000 and August 2009, we performed 43 intestinal transplantation procedures in 42 adult recipients (median [SD] age, 34.8 [9.5] years; male-female ratio, 22:20; isolated or multivisceral graft, 32/11), and compared findings during the first 30 days posttransplantation in 40 recipients. Patients were divided into 2 groups: 12 treated with daclizumab (Zenapax; Hoffman-La Roche Ltd, Basel, Switzerland): 8 isolated intestinal grafts and 4 multivisceral grafts) and 28 treated with alemtuzumab (Campath-1H: 22 isolated intestinal grafts and 6 multivisceral grafts). Maintenance immunosuppression was based on tacrolimus and steroids in the first group and low-dose tacrolimus in the second group. RESULTS: During the first month posttransplantation, 8 daclizumab recipients (66.6%) experienced 9 episodes of mild ACR, which were successfully treated with steroid therapy, and 8 patients (66.6%) developed a bacterial infection requiring treatment. Fourteen episodes of ACR occurred in 12 alemtuzumab recipients (42.8%): 11 mild, 1 mild to moderate, and 2 moderate; 16 patients (57.1%) required treatment for infections. Five-year patient cumulative survival was 66% in daclizumab recipients and 43% in alemtuzumab recipients. Five-year graft survivals was 66% in daclizumab recipients and 41% in alemtuzumab recipients. In both groups, P was not statistically significative. CONCLUSIONS: The infection rate is considerably high with both protocols. Alemtuzumab seems to offer better immunosuppression against ACRs during the first month posttransplantation.

Comprehensive surgical intestinal rescue and transplantation program in adult patients: Bologna experience.

INTRODUCTION: Surgical approaches to complicated benign intestinal failure are accepted worldwide, especially in the pediatric population. Intestinal transplant surgery is thought to rescue patients in whom complications of total parenteral nutrition (TPN) develop. OBJECTIVE: To report our experience with surgical intestinal rescue in an adult population with intestinal failure. PATIENTS AND METHODS: An intestinal rehabilitation program initiated at our institution included comprehensive medical rehabilitation, surgical bowel rescue, and transplantation. From 2000 to 2009, of 81 adult patients referred by our gastroenterologists for bowel rehabilitation, 42 (51,8%) underwent 43 transplantations (32 isolated intestinal grafts and 11 multivisceral grafts). Underlying diseases were primarily short-bowel syndrome, Gardner syndrome, and intestinal pseudo-obstruction. Thirty-nine patients (48,2%) underwent surgical rescue (40 cases) consisting of bowel resection, adhesiolysis, stricturoplasty, liver transplantation with portocaval hemitransposition (6 cases in 5 patients). Underlying diseases were primarily intestinal fistulas, stenosis, or perforations, short-bowel syndrome, cocoon syndrome, and complete portal thrombosis. RESULTS: After a mean (SD) follow-up of 1043 (1016) days, in the transplantation population, 21 patients (50%) are alive, with a 1-, 3-, 5-year patient survival of 76%, 59%, and 52%, respectively, and graft survival of 66%, 54%, and 48%, respectively. After 901 (404) days in the rescue population, 32 patients (82%) are alive (2 died, and 5 were lost to follow-up); in 75%, TPN 25% was discontinued, and are receiving oral feeding with TPN support. The 1- and 3-year survival rate was 100% and 83%, respectively. CONCLUSIONS: Deaths occurred primarily in the transplantation population. Intestinal surgical rescue, when possible, is optimal.

Psychological adaptation and quality of life of adult intestinal transplant recipients: University of Bologna experience.

INTRODUCTION: Intestinal transplantation has become an accepted therapy for individuals permanently dependent on total parenteral nutrition (TPN) with life-threatening complications. Quality of life and psychological well-being can be seen as important outcome measures of transplantation surgery. METHODS: We evaluated 24 adult intestinal transplant recipients and 24 healthy subjects (a control group). All subjects were administered the Italian Version of the Psychological Well-Being Scales (PWB) by C. Ryff, the World Health Organization Quality of Life-Brief (WHOQOL), and the Symptom Questionnaire (SQ) by R. Kellner and G.A. Fava, a symptomatology scale. Quality of life and psychological well-being were assessed in transplant recipients in relationship to the number of rejections, the number of admissions, and the immunosuppressive protocol. RESULTS: Intestinal transplant recipients reported significantly higher scores in the "personal growth" category (P = .036) and lower scores in the "positive relation with others" (P = .013) and "autonomy" (P = .007) dimensions of PWB, compared with the controls. In the WHOQOL, the scores of transplant recipients were lower only in the psychological domain (P = .011). Transplant recipients reported significantly higher scores in the "somatic symptom" (P = .027) and "hostility" (P = .018) dimensions of the SQ, compared with the controls. Transplant recipients with number of admissions >8 reported higher scores in "anxiety" (P = .019) and "depression" (P = .021) scales of the SQ, and the patients with a Daclizumab protocol reported higher scores in "depression" (P = .000) and "somatic symptom" (P = .008) of the SQ. There were no significant differences regarding number of rejections and socio-demographic variables. CONCLUSION: Improvement of psychological well-being in the transplant population may be related to the achievement of the goal of transplantation: recovery of bowel function. But the data confirmed that the transplant experience required a long and difficult adaptation trial to the new condition of "transplant recipient."

The role of liver surgery in the treatment of non-colorectal non-neuroendocrine metastases (NCRNNE). Analysis of 134 resected patients.

AIM: The aim of this study was to evaluate the role of surgery in the treatment of non-colorectal, non-neuroendocrine (NCRNNE) liver metastases. METHODS: One hundred and thirty-four patients undergoing curative liver resection for NCRNNE liver metastases were retrospectively analyzed. Perioperative results (blood transfusion, hospital stay, morbidity and mortality), 3 and 5-year overall and disease-free survival were evaluated. The following prognostic factors were analyzed: age (cut-off 50 year old), single vs. multiple nodules, diameter (cut-off 5 cm), disease-free interval less vs. more than one year, type of primary tumor, blood transfusion, major hepatectomy vs. minor hepatectomy. Survival of patients undergoing liver resection for metastatic colorectal cancer was also analyzed to compare the results with the study population. RESULTS: Mortality and morbidity rate were 3% and 23.1%, respectively. The 3 and 5-year survival were 56.5% and 40%, respectively. The 3 and 5-year disease-free survival were 44% and 30%, respectively. Diameter, disease-free interval and metastases from gastrointestinal cancers were independently related to the survival at the multivariate analysis. Thirty-nine patients (27%) survived over five years. Patients with liver metastases from gastrointestinal primary tumors were those with a worse survival (25% and 19% at 3 and 5 years, respectively). CONCLUSIONS: Surgery is an effective treatment for patients with NCRNNE liver metastases, providing satisfactory long-term outcomes with acceptable morbidity and mortality, in particular when excluding patients with gastro-intestinal metastases.

Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria.

Conventional criteria for liver transplantation for patients with hepatocellular carcinoma are single HCC

Model for End-Stage Liver Disease (MELD) system to allocate and to share livers: experience of two Italian centers.

BACKGROUND: The use of the Model for End-stage Liver Disease (MELD) score to prioritize patients on liver waiting lists and to share organs among centers was effective according to US data, but few reports are available in Europe. MATERIALS AND METHODS: We evaluated the outcome of 887 patients listed between April 2004 and July 2006 in a common list by two transplant centers (University of Bologna [BO] and University of Modena [MO] ordered according to the MELD system. Patients with hepatocellular carcinoma had a score calculated according to their real MELD, tumor stage, and waiting time. RESULTS: Five hundred eighty-six (67%) patients were listed from BO and 291 (33%) from MO. The clinical features of recipients (sex, age, blood group, and real MELD) were comparable between centers. The number of liver transplantations performed was 307, and 273 (89%) recipients had a calculated MELD >or=20. Liver transplantations were equally distributed according to the number of patients listed: 215 out of 586 (36.7%) for BO and 92 out of 291 (31.6%) for MO. The median real MELD of patients transplanted was 20, and 246 out of 307 (80.1%) grafts transplanted were functioning. The dropouts from the list were 124 (14%), and 87 (70%) of these patients had a calculated MELD >or=20. CONCLUSION: The MELD system was effective to share livers among the two Italian centers. According to this policy, livers were allocated to the recipients with the highest probability of dropout and who had a satisfactory survival after liver transplantation.

MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma.

The identification of target mRNAs is a key step for assessing the role of aberrantly expressed microRNAs in human cancer. MiR-221 is upregulated in human hepatocellular carcinoma (HCC) as well as in other malignancies. One proven target of miR-221 is CDKN1B/p27, whose downregulation affects HCC prognosis. Here, we proved that the cyclin-dependent kinase inhibitor (CDKI) CDKN1C/p57 is also a direct target of miR-221. Indeed, downregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to miR-221 transfection into HCC-derived cells and a significant upregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to antimiR-221 transfection. A direct interaction of miR-221 with a target site on the 3' UTR of CDKN1C/p57 mRNA was also demonstrated. By controlling these two CDKIs, upregulation of miR-221 can promote growth of HCC cells by increasing the number of cells in S-phase. To assess the relevance of these studies in primary tumors, matched HCC and cirrhosis samples were assayed for miR-221, for CDKN1B/p27 and CDKN1C/p57 expression. MiR-221 was upregulated in 71% of HCCs, whereas CDKN1B/p27 and CDKN1C/p57 proteins were downregulated in 77% of cases. A significant inverse correlation between miR-221 and both CDKN1B/p27 and CDKN1C/p57 was found in HCCs. In conclusion, we suggest that miR-221 has an oncogenic function in hepatocarcinogenesis by targeting CDKN1B/p27 and CDKN1C/p57, hence promoting proliferation by controlling cell-cycle inhibitors. These findings establish a basis toward the development of therapeutic strategies aimed at blocking miR-221 in HCC.

Liver transplantation for recurrent hepatocellular carcinoma on cirrhosis after liver resection: University of Bologna experience.

Liver resection (LR) for patients with small hepatocellular carcinoma (HCC) with preserved liver function, employing liver transplantation (LT) as a salvage procedure (SLT) in the event of HCC recurrence, is a debated strategy. From 1996 to 2005, we treated 227 cirrhotic patients with HCC transplantable: 80 LRs and 147 LTs of 293 listed for transplantation. Among 80 patients eligible for transplantation who underwent LR, 39 (49%) developed HCC recurrence and 12/39 (31%) of these patients presented HCC recurrence outside Milan criteria. Only 10 of the 39 patients underwent LT, a transplantation rate of 26% of patients with HCC recurrence. According to intention-to-treat analysis of transplantable HCC patients who underwent LR (n = 80), compared to all those listed for transplantation (n = 293), 5-year overall survival was 66% in the LR group versus 58% in patients listed for LT, respectively (p = NS); 5-year disease-free survival was 41% in the LR group versus 54% in patients listed for LT (p = NS). Comparable 5-year overall (62% vs. 73%, p = NS) and disease-free (48% vs. 71%, p = NS) survival rates were obtained for SLT and primary LT for HCC, respectively. LR is a valid treatment for small HCC and in the event of recurrence, SLT is a safe and effective procedure.

Italian experience in adult clinical intestinal and multivisceral transplantation: 6 years later.

PATIENTS AND METHODS: Between December 2000 and November 2006, 28 isolated intestinal transplants and nine multivisceral transplants (five with liver) from cadaveric donors have been performed for short gut syndrome (n = 15), chronic intestinal pseudo-obstruction (n = 10), Gardner's syndrome (n = 9), radiation enteritis (n = 1), intestinal atresia (n = 1), and massive intestinal angiomatosis (n = 1). Indications for transplantations were: loss of venous access, recurrent sepsis due to central line infection, and/or major electrolyte and fluid imbalance. Liver dysfunction was present in 19 cases. All patients were adults of median age at transplant of 34.7 years and mean weight 59.6 kg. All recipients were on total parenteral nutrition for a mean time of 38.8 months. Mean donor/recipient body weight ratio was 1.1. RESULTS: The mean follow-up was 892 +/- 699 days. Twenty-five patients were alive (67.5%) with 3-year patient survivals of 70% for isolated intestinal transplantations and 41% for the multivisceral transplantations (P = .01). The mortality rate was 32.5% with losses due to sepsis (63%) or rejection. Our 3-year graft survival rates were 70% for isolated intestinal transplantations and 41% for multivisceral transplantations (P = .02); graftectomy rate was 16%. These were 88% of grafts working properly with patients on regular diet with no need for parenteral nutrition. DISCUSSION AND CONCLUSIONS: Induction therapy has reduced the doses of postoperative immunosuppressive agents, especially in the first period, lowering the risk of renal failure and sepsis, mucosal surveillance protocol for early detection of rejection dramatically reduced the number of severe acute chronic rejections.

Rejection episodes and 3-year graft survival under sirolimus and tacrolimus treatment after adult intestinal transplantation.

PURPOSE: Mammalian target of rapamycin (mTOR) inhibitors have been recently introduced in clinical practice after intestinal transplantation. We focused on Sirolimus (Rapamycin) to examine effects on rejection and graft survival following intestinal transplantation. PATIENTS AND METHODS: Twenty isolated intestinal recipients and 5 multivisceral patients (2 with liver) in our series were divided into 3 groups: patients started on Sirolimus (because of nephrotoxicity or biopsy-proven rejection), who continued therapy longer than 3 months (n = 11); patients started on Sirolimus (because of nephrotoxicity or biopsy-proven rejection), who received therapy less than 3 months because of side effects (n = 4); and a control group, who never received rapamycin (n = 10). RESULTS: During prolonged treatment combined with Tacrolimus (Prograf), both Sirolimus groups showed a decreased number of acute cellular rejections (P < .01). Cumulative 3-year graft and patient survival rates were 81% in the Sirolimus greater than 3 months group, 100% in the Sirolimus less than 3 months group, and 80% and 90% in the control group, respectively (P = .63 and P = .62). CONCLUSION: In our experience, the use of mTOR-inhibitors in combination with calcineurin-inhibitors seemed to be more effective than monotherapy to reduce the number of rejections. Side effects can limit its use as maintenance therapy.

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

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; thymoglobulin 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. RESULTS: The mean hospital stay was 37 days. The mean follow-up 27 months. Twenty patients are alive (80%) with two- and five-yr patient survival rate of 80% and 66%; mortality rate was 20% due to sepsis in all cases. Our two- and five-yr graft survival rate is 76% and 64%, graftectomy rate was 16%. Sixteen grafts are working properly, with no need of parenteral nutrition. We diagnosed 35 mild acute cellular rejection (ACRs), seven moderate ACRs and three severe ACRs (two needed graftectomy). We experienced two episodes of chronic rejection biopsy-proven. Rapamicine was added in case of renal failure or biopsy-proven intestinal rejection. Graft-vs.-host disease was not seen in our series while post-transplant lymphoproliferative disease in two cases. After discharge, the most common indication for medical support was dehydration. The abdominal wall transplant did not experience any rejection. DISCUSSION AND CONCLUSIONS: Induction therapy has reduced the amount of postoperative immunosuppressive agents, especially in the first period, lowering the risk of renal failure and sepsis and the mucosal surveillance protocol for early detection of rejection dramatically reduced the number of severe ACR.

Daclizumab and alemtuzumab as induction agents in adult intestinal and multivisceral transplantation: A comparison of two different regimens on 29 recipients during the early post-operative period.

INTRODUCTION: Induction therapy has been recently adopted for intestinal transplant. PATIENTS AND METHODS: We compared during first 30 days post-transplantation 29 recipients, allocated in two groups, treated with Daclizumab (Zenapax) or Alemtuzumab (Campath-1H). RESULTS: During first month, 45% of Daclizumab recipients experienced six acute cellular rejections (ACRs) of mild degree, while 63% of them developed an infection requiring treatment. We found three acute cellular rejections in 17.6% of Alemtuzumab recipients, two with moderate degree; 64.7% of them required treatment for infection. DISCUSSION AND CONCLUSIONS: Graft and patient 3-years cumulative survival rate were not significantly different between groups. Alemtuzumab seems to offer a better immunosuppression during first month.

Recovery from liver dysfunction after adult isolated intestinal transplantation without liver grafting.

PURPOSE: We sought to evaluate liver function recovery after isolated intestinal transplantation in adults with irreversible intestinal failure. PATIENTS AND METHODS: Over a 5-year period, we transplanted 34 adult patients, 25 of whom received an isolated intestinal graft, 4 a multivisceral graft without a liver, and 5, a multivisceral graft with a liver. Among the group of patients transplanted with the isolated graft we selected 14 recipients with pretransplant liver dysfunction, namely, a serum bilirubin >2 mg/dL (normal value: 1.2) and/or transaminases >100 IU/mL (NV, 37/40). Other inclusion criteria were total parenteral nutrition, period > 3 months, no diagnosis of portal hypertension or cirrhosis. Two patients had biopsy-proven liver fibrosis. RESULTS: At discharge, all patients recovered liver function to normal values: mean bilirubin blood level was 0.9 +/- 0.96 mg/dL (range: 0.3-1.6) and mean transaminases were 26 +/- 9 and 31 +/- 18 IU/mL (range: 10-44/27-65). After a mean follow-up of 2 years, only one patient has an elevated alanine aminotransferase level without clinical signs of liver disease. Type of pretransplant liver disease did not impact on survival rates. CONCLUSION: In selected cases, an isolated intestinal or a multivisceral graft without a liver can represent a "liver salvage therapy" for an early failing liver in patients with irreversible intestinal failure. Pretransplant liver disease is not a negative prognostic factor.

Long-term outcomes in liver transplant patients with hepatic C infection receiving tacrolimus or cyclosporine.

Choice of calcineurin inhibitor may be a contributing factor to deteriorating patient and graft survival following liver transplantation for hepatitis C virus (HCV). In our multicenter, open-label LIS2T study, de novo liver transplant patients stratified by HCV status were randomized to cyclosporine or tacrolimus. Follow-up data were obtained in an observational study of 95 patients. Mean follow-up was 34 and 37 months, respectively, for cyclosporine-treated (n = 47) and tacrolimus-treated (n = 48) patients. In patients not receiving antiviral therapy, 22 of 31 given cyclosporine (72%) and 24 of 29 given tacrolimus (83%) had biochemical recurrence of HCV. In 68 patients with at least one biopsy, histological evidence of HCV-related hepatitis was present in 27 of 31 (87%) cyclosporine-treated patients and 37 of 37 (100%) tacrolimus-treated patients (P = .02, chi-square test). Three-year actuarial risk of fibrosis stage 2 was 66% with cyclosporine and 90% with tacrolimus; for fibrosis stage 3 or 4 it was 46% and 80%, respectively. Three graft losses were attributed to HCV recurrence in cyclosporine-treated patients and six in tacrolimus-treated patients. Tacrolimus may be associated with increased risk of histological HCV disease recurrence compared to cyclosporine.

Incidence, clinical significance, and outcome of vascular alterations in intestinal biopsies after isolated small bowel transplantation: a single-center experience.

BACKGROUND: Mild and moderate vascular alterations in intestinal biopsies after isolated small bowel transplantation (SBT) have uncertain clinical significance. METHODS: We retrospectively investigated the incidence, association with acute cellular rejection (ACR), treatment, and outcome of mild and moderate vascular changes in 15 adult SBTs performed between December 2000 and October 2003. The semiquantitative Ruiz score for vascular changes in intestinal mucosa was used. RESULTS: A total of 332 biopsies were analyzed. All patients had at least one sample showing mild or moderate vascular injury, which was globally found in 117 biopsies (35% of the total; 29% mild and 6% moderate). No cases of severe vascular injury were observed. First appearance of vascular alterations occurred 2 to 36 days after SBT (median: 6). Patients with vascular injury had a higher incidence of associated ACR than patients without this feature (16% vs 5%, P = .001). Patients with moderate vascular injury were also more likely to have moderate-to-severe ACR than patients showing no or mild vascular changes (14% vs 2%; P = .015). Treatment of rejection was more frequently administered with simultaneous diagnosis of ACR than in cases of isolated vascular alterations (84% vs 26%; P < .0001). Only one graft (7%) was lost due to severe ACR. DISCUSSION: Mild and moderate vascular changes are common findings in early post-SBT biopsies. They are frequently associated with ACR and parallel its severity. The clinical impact of mild or moderate vascular injury appears to be of little relevance.

Liver transplantation with the Meld system: a prospective study from a single European center.

The efficacy of the Meld system to allocate livers has never been investigated in European centers. The outcome of 339 patients with chronic liver disease listed according to their Meld score between 2003 and 2005 (Meld era) was compared to 224 patients listed during the previous 2 years according to their Child score (Child era). During the Meld era, hepatocellular carcinomas (HCCs) had a 'modified' Meld based on their real Meld, waiting time and tumor stage. The dropouts were deaths, tumor progressions and too sick patients. The rate of removals from the list due to deaths and tumor progressions was significantly lower in the Meld than in the Child era: 10% and 1.2% versus 16.1% and 4.9%, p < 0.05. The 1-year patient survival on the list was significantly higher in the Meld era (84% vs. 72%, p < 0.05). The prevalence of transplantation for HCC increased from 20.5% in the Child to 48.9% in the Meld era (p < 0.001), but between HCCs and non-HCCs of this latter era the dropouts were comparable (9.4% vs. 14.9%, p = n.s.) as was the 1-year patient survival on the list (83% vs. 84%, p = n.s.). The Meld allocation system improved the outcome of patients with or without HCC on the list.

Successful treatment of rhinomaxillary form of mucormycosis infection after liver transplantation: a case report.

Mucormycosis is a rare opportunistic infection, usually associated with immunocompromised states. Several conditions such as hematologic malignancy (leukemia, lymphoma, myeloma), solid organ transplantation, diabetes mellitus, corticosteroid therapy, or chemotherapy predispose patients to infection. The aim of this study was to present a single case of mucor infection after 900 consecutive liver transplantations. Rhinomaxillary mucormycosis must be suspected in a transplant recipient showing fever, maxillary swelling, and edema. This condition can be successfully treated with early diagnosis and a combination of aggressive surgery and antifungal therapy.