Increased serum level of xanthine oxidoreductase in liver transplanted patients.

Xanthine oxidoreductase (XOR) leakage into serum has been observed in various types of liver pathology as well as after liver transplantation (LT). We determined the amount of XOR associated with LT to investigate the changes in serum enzyme level during the LT procedure and the post-operative period. Additionally, we examined whether there was any correlation between XOR levels and the surgical technique. XOR levels were measured by a competitive ELISA. In a first group of patients, the portal vein was flushed before the liver and systemic reperfusions, which occurred simultaneously. In the second group, the graft was flushed with blood from the portal vein before the systemic reperfusion. XOR showed a marked elevation in the caval effluent collected during LT and was higher compared to control serum levels at all time points that were examined after LT. The XOR levels during LT were also higher than samples taken pre-LT or from the portal blood flush before reperfusion. The XOR level was higher in Group 2 than in Group 1. Enhancement of the XOR serum level during LT was not derived from enterocytes, and it should be attributed to enzyme leakage from graft liver cells. We report the elevation of serum XOR during the three weeks following LT for the first time, as well as the influence of the graft reperfusion technique on XOR serum levels.

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.

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 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.

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

Kidney transplantation combined with other organs in Bologna: an update.

BACKGROUND: We retrospectively reviewed our experience in combined liver-kidney (L-KT) and heart-kidney (H-KT) transplantations. PATIENTS AND METHODS: Between January 1997 and April 2007, we performed 25 L-KT and 5 H-KT. Patient mean age was 51+/-8 years in L-KT and 43+/-11 years in H-KT. The main cause of liver failure was chronic viral hepatitis (14 cases). Etiology of heart failure was dilated cardiomyopathy and hypertrophic cardiomyopathy (4 and 1 patients, respectively). The main causes of renal failure in L-KT were chronic glomerulonephritis (n=8) and polycystic disease (n=7). Etiology of renal failure in H-KT was interstitial nephropathy (n=2), vascular nephropathy (n=2), and chronic glomerulonephritis (n=1). RESULTS: Mean follow-up was 32+/-26 months in L-KT and 24+/-17 months in H-KT. Immunosuppression was cyclosporine-based (n=4) or tacrolimus-based (n=21) in L-KT and cyclosporine-based in H-KT. Acute rejection rate was 8% for both liver and kidney in L-KT; 80% (mild) for heart and 40% for kidney in H-KT. In the L-KT group, there was no primary graft nonfunction (PGNF). Two patients experienced liver delayed graft function (DGF); 1 patient required postoperative dialysis. One-year graft and patient survivals were both 84% and overall graft and patient survival was 76%. In the H-KT group, 3 patients needed postoperative dialysis and 1 required a cardiac assistance device for 48 hours; overall graft and patient survival was 100% with good cardiac and renal functions. CONCLUSION: Our experience confirmed that H-KT and L-KT are safe procedures, offering good long-term results.

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.

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.

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.

Coping strategies in intestinal transplantation.

The psychological construct of coping has been studied extensively in other medical populations and has more recently been applied in the field of transplant psychology. Coping can be defined as all abilities used by people to face problematical and stressful situations, as the data in literature describe the experience of transplantation. The purpose of this study was to describe the coping styles used by 25 intestinal transplant recipients. To assess the coping strategies, we used the Italian version of Coping Orientation to Problems Experienced (COPE) by Sica, Novara, Dorz, and Sanavio (1997). The authors divided these strategies into three classes: problem-focused, emotion-focused, and potentially disadaptive strategies. This questionnaire is usually used in a medical setting. Even if the long process of psychological-clinical adaptation required by intestinal transplantation put patients in a passive acceptance of their situation and their incapacity to face it, our patients showed high levels of problem-focused strategies, indicators of positive outcomes for this intervention. Anyway, this is a slow and gradual path that goes with the psychological distress and the need for a peculiar psychological support of problem-focused strategies. The result suggested that assessment of coping strategies should be explored in intestinal transplant to encourage the use of action-oriented methods and discourage those with possible negative effects.

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.

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.

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.

Posttransplant lymphoproliferative disorders in liver transplanted patients: a report of four cases.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) are an uncommon but important cause of morbidity and mortality in solid organ transplant recipients. They are often the result of Epstein-Barr virus (EBV)-induced proliferation of B-lymphocytes in the setting of immunosuppression. PATIENTS AND METHODS: We retrospectively analyzed four cases of PTLD after liver transplantation. In all patients immunosuppression was reduced and anti-CD20 monoclonal antibody (rituximab) was administered. In two of four patients, EBV viral load was positive in the peripheral blood, and gancyclovir was therefore also prescribed. Chemotherapy (CHOP) was used as a rescue in the event of treatment failure. RESULTS: Even if no severe adverse events were observed during the treatment period, our treatment approach to PTLD was not effective, and only one patient out of four is still alive. CONCLUSIONS: Well-designed clinical trials are necessary to evaluate the role of this combined approach in the treatment of PTLD in liver transplant recipients.

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.

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.

Surgical approach to complicated intestinal failure for benign disease in adult patients: transplantation or surgical rehabilitation?

Surgical approaches to complicated benign intestinal failure are gaining acceptance, especially in the pediatric population. Less international experience has been obtained in adult patients, who are usually treated with total parenteral nutrition (TPN). An intestinal rehabilitation program was started in our institution with comprehensive medical rehabilitation, surgical bowel rescue, and transplantation. Among 38 adult patients referred by our gastroenterologists for bowel rehabilitation and surgically treated in our institution, 92.2% received TPN on admission. After careful evaluation, 71% underwent transplantation. Five patients died, but 18 recipients were completely weaned off TPN at follow-up. Eleven patients underwent surgical resection of the affected bowel and a subsequent program of intestinal rehabilitation: they were all alive and weaned off TPN at discharge. At a 2-year mean follow-up, deaths occurred only in the transplant population. Therefore, intestinal surgical rescue, if successful, is optimal in adult patients.

Results of intestinal and multivisceral transplantation in adult patients: Italian experience.

PURPOSE: We report our experience with intestinal and multivisceral transplantation in Italy. METHODS: We performed 23 adult isolated intestinal transplants and seven multivisceral ones, three with liver, between December 2000 and June 2005. Indications for transplantation were loss of venous access (n = 14), recurrent sepsis (n = 10), and electrolyte-fluid imbalance (n = 6), 14 of whom also presented with total parenteral nutrition (TPN)-related liver dysfunction. Immunosuppression was based on induction agents like daclizumab (followed by tacrolimus and steroids) in the first period; alemtuzumab or thymoglobulin (with tacrolimus) in a second period after 2002. RESULTS: The mean follow-up was 742 +/- 550 days. Three-year patient actuarial survival rate was 88% for intestinal transplants and 42% for multivisceral (P = .015). Three-year graft actuarial survival rate was 73% for intestinal patients and 42.8% for multivisceral (P = .1). Graft loss was mainly due to rejection (57%). Complications were mainly represented by bacterial infections (92% of patients), relaparotomies (82%), and rejections (72%). Full bowel function without any parenteral nutrition or intravenous fluid support was achieved in 60% of recipients with functioning bowel including 95% on a regular diet. One patient underwent abdominal wall transplantation as well. DISCUSSION AND CONCLUSION: Intestinal transplantation has achieved high rates of patient and graft survival with even longer follow-up. Early referral of patients, especially in cases of TPN-liver disease, is mandatory to obtain good outcomes and avoid high mortality rates on the transplant waiting list. Immunosuppressive management remains the key factor to increase the success rate.

Comparison between the fifth and sixth editions of the AJCC/UICC TNM staging systems for hepatocellular carcinoma: multicentric study on 393 cirrhotic resected patients.

AIMS: To compare the prognostic efficacy of the 5th and 6th edition of the TNM staging system for HCC. METHODS: We retrospectively applied the old and the new systems to 393 resected patients, comparing the efficacy of both in prognostic evaluation. RESULTS: The 1-, 3- and 5-year overall survival rates were 89.7, 71.1 and 56.3%, respectively. The 1-, 3- and 5-year disease-free survival rates were 79.4, 54.6 and 39.4%, respectively. Among the factors evaluated, Child's grade B and C (p=0.001) and presence of multiple nodules (p=0.01) were found to be related either to a worse long-term survival or to a worse disease-free survival. Stratifying patient survivals according to the old TNM system, we found significant differences only between stages II and IIIA (p=0.001); otherwise stages I and II (p=0.9) as well as stages IIIA and IVA (p=0.9) showed similar survival rates. Analysing the new TNM system, we found a more homogeneous staging stratification, with significant differences both between stage I and II (p=0.02) and between stage II and IIIA (p=0.05). CONCLUSIONS: In the present multicentric study, long term overall and disease-free survival after liver resection for HCC was strongly affected by the number of tumours and the underlying liver disease. Our results suggest that the new classification appears to achieve an accurate stratification of patients, simpler than the previous edition, as well as a more reliable comparative analysis of outcome after hepatic resection for HCC.

Expression of connective tissue growth factor is a prognostic marker for patients with intrahepatic cholangiocarcinoma.

BACKGROUND AND AIMS: Connective tissue growth factor is a member of the 'CCN' protein family. Consistent with its profibrotic properties, it is over-expressed in several human epithelial malignancies. PATIENTS AND METHODS: We have retrospectively evaluated by immunohistochemistry the presence of connective tissue growth factor in archival tissues from 55 resected intrahepatic cholangiocarcinomas and compared its expression to the main pathological parameters, disease free and overall survival. RESULTS: Tumours were scored as high and low/absent expressers (> or =50%, 0-50% cells, respectively). Thirty-three of 55 cholangiocarcinomas (60%) were high and 22 (40%) low expressers. No significant correlation was found between connective tissue growth factor and tumour grade, tumour location, vascular and perineural invasion. Eighteen of 22 (82%) low/absent expressers and 12/33 (36%) high expressers had recurrence of disease (P=0.001). Low/absent expressers showed a poor disease free and overall survival compared with the higher expressers (P<0.001). Vascular invasion was related to tumour recurrence (P=0.025) and to decreased disease free survival (P<0.05). During proportional hazard regression analysis, only connective tissue growth factor was found to influence disease free survival (P=0.01). CONCLUSIONS: Expression of connective tissue growth factor is an independent prognostic indicator of both tumour recurrence and overall survival for intrahepatic cholangiocarcinoma patients regardless of tumour location, tumour grade, vascular and perineural invasion.