Anti-tumour necrosis factor treatment of inflammatory bowel disease in liver transplant recipients.

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease can sometimes relapse and be refractory to standard treatment following orthotopic liver transplantation (OLT) despite post-transplantation immunosuppressive therapy. AIM: To evaluate the efficacy and safety of anti-tumour necrosis factor (anti-TNF) agents for the management of IBD following OLT. METHODS: We reviewed the records of patients with a diagnosis of IBD who underwent OLT at Mayo Clinic Rochester between 1985 and 2009. Patients were included if they had received anti-TNF therapy post-OLT. Clinical response was defined as a physician's assessment of improvement after 12 weeks of anti-TNF usage, and mucosal healing was defined as the absence of ulcerations on follow-up endoscopy. RESULTS: The median age of the eight study patients was 42.0 years and 37.5% were female patients. All had been diagnosed with IBD prior to OLT (UC in three and Crohn's disease in five). Indication for OLT was cirrhotic stage primary sclerosing cholangitis (PSC), and three concomitantly had cholangiocarcinoma. Clinical response was demonstrated in seven of eight patients (87.5%) and mucosal healing was demonstrated in three of seven (42.9%). Four infections (oral candidiasis, Clostridium difficile colitis, bacterial pneumonia and cryptosporidiosis) in three patients were reported. One patient developed an Epstein-Barr virus-positive post-transplant lympho-proliferative disorder. One death occurred due to complications from recurrent PSC. CONCLUSIONS: Starting Anti-TNF therapy following orthotopic liver transplantation appears to be a potential option for inflammatory bowel disease management. Additional studies are needed, however, to confirm these findings and to further assess risks associated with this treatment strategy.

Recurrent primary biliary cirrhosis after liver transplantation.

Recurrent primary biliary cirrhosis (PBC) is an important clinical outcome after liver transplantation (LT) in selected patients. Prevalence rates for recurrent PBC (rPBC) reported by individual LT programs range between 9% and 35%. The diagnostic hallmark of rPBC is histologic identification of granulomatous changes. Clinical and biochemical features are frequently absent with rPBC and cannot be used alone for diagnostic purposes. Some of the risk factors of rPBC may include recipient factors such as age, gender, HLA status and immunosuppression, as well as donor factors such as age, gender and ischemic time, although controversy exists. Most patients have early stage disease at the time of diagnosis, and there may be a role for therapy with ursodeoxycholic acid. While short- and medium-term outcomes remain favorable, especially if compared to patients transplanted for other indications, continued follow-up may identify reduced long-term graft and patient survival.

Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection.

Recurrent hepatitis C virus (HCV) infection is a major cause of morbidity and mortality after liver transplantation for HCV-related end stage liver disease. Although previous studies have shown a short-term effect of interferon-based treatment on fibrosis progression, it is unclear whether this translates to improved graft survival. We evaluated whether treatment of recurrent HCV leads to an improved graft survival. Cohort study included consecutive HCV patients who underwent liver transplantation between 1 January 1995 and 1 January 2005 in the Mayo Clinic, Rochester, MN. Two hundred and fifteen patients were included in the study. During a median follow-up of 4.4 years (interquartile range 2.2-6.6), 165 patients (77%) had biopsy-proven recurrent HCV infection confirmed by serum HCV RNA testing. Seventy-eight patients were treated. There were no differences in MELD-score, fibrosis stage or time towards HCV recurrence between treated and untreated patients at time of recurrence. There was a trend for greater frequency of acute cellular rejection among untreated patients. The incidence of graft failure was lower for patients treated within 6 months of recurrence compared to patients not treated within this time-period (log rank p = 0.002). Time-dependent multivariate Cox regression analysis showed that treatment of recurrent HCV infection was statistically significantly associated with a decreased risk of overall graft failure (hazard ratio 0.34; CI 0.15-0.77, p = 0.009) and a decreased risk of graft failure due to recurrent HCV (hazard ratio 0.24; CI 0.08-0.69, p = 0.008). In conclusion, although a cause and effect relationship cannot be established, treatment of recurrent HCV infection after liver transplantation is associated with a reduced risk of graft failure.

Reduced priority MELD score for hepatocellular carcinoma does not adversely impact candidate survival awaiting liver transplantation.

The liver organ allocation policy of the United Network for Organ Sharing (UNOS) is based on the model for end-stage liver disease (MELD). The policy provides additional priority for candidates with hepatocellular carcinoma (HCC) who are awaiting deceased donor liver transplantation (DDLT). However, this priority was reduced on February 27, 2003 to a MELD of 20 for stage T1 and of 24 for stage T2 HCC. The aim of this study was to determine the impact of reduced priority on HCC candidate survival while on the waiting list. The UNOS database was reviewed for all HCC candidates listed after February 27, 2002, The HCC candidates were grouped into two time periods: MELD 1 (listed between February 27, 2002, and February 26, 2003) and MELD 2 (listed between February 27, 2003 and February 26, 2004). For the two time periods, the national DDLT incidence rates for HCC patients were 1.44 versus 1.53 DDLT per person-year (p = NS) and the waiting times were similar for the two periods (138.0 +/- 196.8 vs. 129.0 +/- 133.8 days; p = NS). Furthermore, the 3-, 6- and 12-month candidate, patient survival and dropout rates were also similar nationally. Regional differences in rates of DDLT for HCC were observed during both MELD periods. Consequently, the reduced MELD score for stage T1 and T2 HCC candidates awaiting DDLT has not had an impact nationally either on their survival on the waiting list or on their ability to obtain a liver transplant within a reasonable time frame. However, regional variations point to the need for reform in how organs are allocated for HCC at the regional level.

Post-transplant lymphoproliferative disorders following liver transplantation: incidence, risk factors and survival.

This study investigates retrospectively the incidence, risk factors and mortality of post-transplant lymphoproliferative disorders (PTLD) in adult orthotopic liver transplant (OLT) recipients. Among 1206 OLT recipients at a single institution, 37 developed a PTLD. The incidence of PTLD was highest during the first 18 months and relatively constant thereafter with cumulative incidence of 1.1% at 18 months and 4.7% at 15 years. The risk of PTLD was approximately 10% to 15% of the risk of death without PTLD. During the first 4 years following OLT, PTLD were predominantly related to EBV, while afterward most PTLD were EBV negative. Significant risk factors for PTLD in OLT recipients were transplantation for acute fulminant hepatitis during the first 18 months following OLT (HR=2.6, p=0.007), and rejection therapy with high-dose steroids (HR=4.5, p=0.049) and OKT3 (HR=3.9, p=0.016) during the previous year. Therapy with high-dose steroids or OKT3 (HR=3.6, p=0.0071) were also significant risk factors for PTLD-associated mortality. OLT recipients remain at risk for PTLD years after transplantation. The strong association of PTLD with rejection therapy and the worse post-PTLD prognosis among recipients of rejection therapy indicate the need to balance the risk of immunosuppression against the risk of PTLD following rejection treatment.

Addition of MMF to dual immunosuppression does not increase the risk of malignant short-term death after liver transplantation.

Immunosuppression is often incriminated for the increased risk of post-transplant malignancies. To examine whether triple- (MMF+Tacro+CS) versus dual-drug therapy (Tacro+CS) is associated with an increased incidence of malignancy, or death due to malignancy, data from a large registry of liver transplant recipients were analyzed. Data from adult primary liver recipients reported to the Scientific Registry of Transplant Recipients between June 1, 1995, and April 30, 2004, and recorded at transplant on triple-drug (n = 9180) or dual-drug (n = 10 099) therapy were included. Kaplan-Meier survival analysis showed no significant differences in death due to malignancy 4 years post-transplantation between the treatment groups. Multivariable analysis using Cox proportional hazard models confirmed no differences in risk of death due to malignancy between the groups (HR: 0.83, p = 0.107). Incidence of any post-transplant malignancy was also not significantly different. Older recipient age and cause of liver disease were significantly associated with an increased risk of malignancy-related death. These data utilizing relatively short follow-up suggest the addition of MMF to Tacro+CS at transplant is not associated with death due to malignancy, at least in the short term. Individual recipient factors appear to be important risk factors for malignancy-related death; elucidating these risk factors can assist in identifying who should be monitored most aggressively for post-transplant malignancies.

Late hepatic allograft dysfunction.

1. Lifelong monitoring of graft function, immunosuppressive levels, and screening for drug toxicity is required in all liver recipients. 2. Late hepatic allograft dysfunction is common and is caused by a variety of etiologies including rejection, infection, biliary/vascular abnormalities, recurrence of disease, and drug hepatotoxicity. 3. In all patients with late hepatic allograft dysfunction, liver biopsy should be performed to assess for the presence of rejection, and to thus avoid excessive use of bolus corticosteroid therapy and guide appropriate immunosuppressive management. 4. Recurrence of disease is the most common cause of late hepatic allograft dysfunction. 5. Hepatitis C universally reinfects the hepatic allograft, and is associated with decreased patient and graft survival and leads to the recurrence of cirrhosis in 28% of patients within 5 years of transplantation. 6. Major advances have been made in preventing recurrence of hepatitis B by the use of hepatitis B immune globulin in combination with lamivudine therapy. 7. Autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis have a recurrence rate of approximately 20% to 30%. 8. In patients developing recurrence of autoimmune hepatitis, steroid withdrawal is the most common cause. 9. Recurrent hepatocellular cancer can be markedly reduced if strict guidelines are adhered to in selecting patients. 10. Drug hepatotoxicity must always be considered in the differential diagnosis of late hepatic allograft dysfunction.

Liver transplantation for primary sclerosing cholangitis: timing, outcome, impact of inflammatory bowel disease and recurrence of disease.

Over the past decade, the outcome of liver transplantation in primary sclerosing cholangitis (PSC) patients with end-stage liver disease has improved significantly with many centres reporting 1-year patient and graft survival of 90-97% and 85-88%, respectively. Based on these results, liver transplantation has emerged as the treatment of choice for PSC patients. Specific complications related to PSC remain problematical. Inflammatory bowel disease (IBD) occurs in 70% of patients, and there is a distinctly increased risk of colorectal neoplasia both pre- and post-transplantation. Furthermore, symptoms related to IBD post-transplantation can become severe and lead to the need for proctocolectomy. Cholangiocarcinoma remains a major risk facing the PSC patient and develops in 15-30% of patients. Markers to detect the early neoplastic changes of cholangiocarcinoma are not available. To date, outcome following liver transplantation in PSC patients who have associated cholangiocarcinoma has been dismal. However, those patients who are found to have an incidental cholangiocarcinoma have an acceptable low incidence of recurrence of disease. To assess optimal timing of liver transplantation, natural history risk scores have been developed and utilized. Utilizing such risk scores, estimated survival for the individual PSC patient can be obtained. Finally, there is an increased incidence of both acute and chronic rejection, hepatic artery thrombosis and biliary stricturing in PSC patients undergoing liver transplantation. A late rise in serum alkaline phosphatase level is almost always indicative of biliary stricturing and recurrence of disease. Approximately 20% of patients followed for 5 years or more will have recurrence of PSC documented both on cholangiography and histology.

Recurrent autoimmune hepatitis after orthotopic liver transplantation.

To determine the frequency, risk factors, and consequences of recurrent autoimmune hepatitis after liver transplantation, 41 patients with type 1 disease were monitored after surgery in accordance with a surveillance protocol. Tacrolimus or cyclosporine plus prednisone were administered to each patient, and liver biopsy examinations were performed at least annually according to protocol. Corticosteroid therapy was ultimately discontinued in only 2 patients. Recurrent disease was defined as the presence of lymphoplasmacytic infiltrates in liver tissue in the absence of other causes of allograft dysfunction. Autoimmune hepatitis recurred in 7 patients (17%), and the mean time to recurrence was 4.6 +/- 1 years. Recurrence was asymptomatic in 4 of 7 patients and detected only by surveillance liver biopsy assessment in 2 patients. Histological changes were mild, and there was no progression to cirrhosis during 4.9 +/- 0.9 years of observation. Five-year patient (86% v. 82%; P =.9) and graft (86% v. 67%; P =.5) survival rates were not statistically different between patients with and without recurrent disease. HLA-DR3 or HLA-DR4 occurred more commonly in patients with than without recurrence (100% v. 40%; P =.008) and healthy subjects (100% v. 49%; P =.01). Recurrent disease was unrelated to donor HLA status. In conclusion, recurrence after transplantation for type 1 autoimmune hepatitis is common. Its mild manifestations and favorable prognosis may reflect early detection by a surveillance protocol and/or continuous corticosteroid treatment. HLA-DR3- or HLA-DR4-positive recipients are at risk for recurrence regardless of donor HLA status.

Current therapies and clinical controversies in the management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology characterized by fibrosing inflammation of the intrahepatic and extrahepatic bile ducts, leading ultimately to cirrhosis and death caused by complications from liver failure if liver transplantation is not peformed. Despite a better understanding of the natural history of the disease, no significant breakthroughs have been made into its pathogenesis. Over the past decade and a half, many clinical trials of medical therapy have been conducted; however, none have demonstrated real efficacy. This reflects our lack of understanding into the basic mechanisms of disease pathogenesis in PSC. Progress has been made in the area of orthotopic liver transplantation for PSC, and to some extent in the diagnosis and management of complications, the most grave of which is the development of cholangiocarcinoma. This review highlights the progress that has been made, describes our current deficiencies, and discusses likely developments in the future. The authors also discuss management controversies and provide current practice guidelines where applicable.

Comparative allograft histology after liver transplantation for cryptogenic cirrhosis, alcohol, hepatitis C, and cholestatic liver diseases.

BACKGROUND: End-stage liver disease for which no cause can be identified, cryptogenic cirrhosis, is a common indication for liver transplantation. Allograft inflammation and fibrosis have been reported to recur with similar frequencies after liver transplantation for cryptogenic cirrhosis and hepatitis C (HCV). METHODS: We determined sequential posttransplant allograft histology in four groups of recipients: 31 transplanted for cryptogenic cirrhosis, 70 for cholestatic etiologies, 40 for alcoholic liver disease, and 56 for HCV. Modified hepatitis activity index (HAI) and fibrosis stage were determined at 4 months, 1 year, and at most recent biopsy posttransplantation. RESULTS: The prevalence of HAI > or = 2 among cryptogenic recipients was similar to that of cholestatic and alcoholic recipients at 4 months, 1 year, and at most recent evaluation (mean 45+/-17 months posttransplantation). For HCV-infected recipients, the frequency of HAI > or = 2 was more than for cryptogenic recipients at 1 year (52 vs. 29%, P=0.04) and at most recent evaluation (64 vs. 15%, P=0.003). Fibrosis scores for cryptogenic, cholestatic, and alcoholic recipients were similar at all timepoints. The proportion of HCV-infected recipients with fibrosis stage >2 was more than that of cryptogenic recipients at 4 months (29 vs. 12%, P=0.05), 1 years (46 vs. 7%, P=0.0002), and at most recent evaluation (42 vs. 15%, P=0.06). None of the cryptogenic recipients developed cirrhosis. RESULTS: The frequency of elevated HAI and fibrosis stage in recipients who undergo transplantation for cryptogenic cirrhosis is similar to that of recipients who undergo transplantation for cholestatic etiologies and significantly less than that of HCV-infected recipients. Fibrosis stage and HAI are generally stable after transplantation for cryptogenic cirrhosis. These data do not suggest a viral etiology of liver disease in the majority of patients with cryptogenic cirrhosis.

A revised natural history model for primary sclerosing cholangitis.

OBJECTIVE: To describe a natural history model for primary sclerosing cholangitis (PSC) that is based on routine clinical findings and test results and eliminates the need for liver biopsy. PATIENTS AND METHODS: Using the Cox proportional hazards analysis, we created a survival model based on 405 patients with PSC from 5 clinical centers. Independent validation of the model was undertaken by applying it to 124 patients who were not included in the model creation. RESULTS: Based on the multivariate analysis of 405 patients, a risk score was defined by the following formula: R = 0.03 (age [y]) + 0.54 loge (bilirubin [mg/dL]) + 0.54 loge (aspartate aminotransferase [U/L]) + 1.24 (variceal bleeding [0/1]) - 0.84 (albumin [g/dL]). The risk score was used to obtain survival estimates up to 4 years of follow-up. Application of this model to an independent group of 124 patients showed good correlation between estimated and actual survival. CONCLUSIONS: A new model to estimate patient survival in PSC includes more reproducible variables (age, bilirubin, albumin, aspartate aminotransferase, and history of variceal bleeding), has accuracy comparable to previous models, and obviates the need for a liver biopsy.

Intragraft localization of activated nuclear factor kappaB in recurrent hepatitis C virus disease following liver transplantation.

Nuclear factor kappaB (NF-kappaB) is activated during viral infection and is central to the regulation of host immune responses. The NF-kappaB activation status and its morphological sources were assessed by immunohistochemistry in allograft biopsy specimens of orthotopic liver transplantation patients with recurrent hepatitis C virus (HCV). Hepatocellular NF-kappaB immunostaining was detected in HCV cases compared with controls (nontransplant: P <.001; transplant: P =.006), which correlated with the number of NF-kappaB positive hepatocytes (P =.007) and contrasted to the absent to weak staining of controls (nontransplant: P =.001; transplant: P =.009). Enhanced NF-kappaB staining of cytokeratin 19-positive bile ducts and proliferating ductules in the HCV group was in contrast to controls. Intense NF-kappaB immunoreactivity was detected in CD68-positive Kupffer cells and macrophages of all HCV specimens compared with a few controls (nontransplant: P <.001; transplant: P =.001) and contrasted to the weak staining of controls (nontransplant: P <.001; transplant: P =.001). NF-kappaB-positive immunoreactivity correlated with the number of T cell receptor (TCR) alpha/beta-positive lymphocytes (P <.001), which was not observed in controls. In those HCV cases showing evidence of necroinflammatory activity (grade) and individual features of portal inflammation, periportal inflammation/piecemeal necrosis, lobular inflammation, and fibrosis (stage), higher NF-kappaB staining intensity scores within bile ducts, proliferating ductules, hepatocytes (piecemeal necrosis: P =.016; stage: P =.030), and lymphocytes (stage: P =.044) and increased number of NF-kappaB-positive cells within bile ducts, proliferating ductules (grade, lobular inflammation, piecemeal necrosis, stage: P =.022), hepatocytes, and lymphocytes were observed. Increased staining intensity and frequency of NF-kappaB-positive cells were similarly observed in HCV-positive allografts obtained from patients under tacrolimus- compared with cyclosporine-based immunosuppression. These data implicate an immunoregulatory role of intragraft NF-kappaB activation in the pathogenesis and progression of posttransplantation HCV disease recurrence.

Early detection of hepatitis C allograft reinfection after orthotopic liver transplantation: a molecular and histologic study.

After orthotopic liver transplantation (OLT), patients with chronic hepatitis C virus (HCV) infection show nearly universal persistence of viremia and reinfection of the liver, but identifying the point at which the liver is reinfected morphologically can be difficult. One tool that may potentially be useful to detect reinfection is reverse transcriptase-polymerase chain reaction (RT-PCR), which has proven to be highly sensitive for detecting HCV RNA in formalin-fixed paraffin-embedded liver tissue. Our purpose was to gain insight into the time frame of HCV reinfection by assaying for HCV RNA in serial posttransplant liver biopsy specimens. Our study population consisted of 14 patients who underwent liver transplantation for hepatitis C and had confirmed HCV RNA in pretransplant serum, absence of HCV RNA in donor livers, and available consecutive posttransplant liver allograft specimens. We performed RT-PCR for HCV RNA in serial posttransplant liver biopsy specimens, beginning at 1 week until at least one biopsy from each tested positive. HCV RNA was detected in liver tissue by RT-PCR in 1-week post-OLT liver samples in 6 of 14 (42.8%) patients, the earliest being 5 days post-OLT. Eventually, each of the remaining eight samples became RT-PCR positive as well; the first detections occurred in these at 3 weeks (three cases), 4 weeks (three cases), 48 weeks (one case), and 144 weeks (one case). Histologic identification of hepatitis C recurrence was relatively insensitive in relation to these molecular data. These data suggest that (1) HCV RNA reinfection is nearly universal after liver transplantation in patients with chronic hepatitis C infection, (2) molecular reinfection by HCV occurs at a variable interval post-OLT, with the majority of allograft livers reinfected as early as 1 week, and (3) morphologic features of hepatitis C are usually appreciable at the time of "molecular" recurrence.

Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.

Liver transplantation is the only effective therapeutic option for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC). In this study, we analyzed a single center's experience with 150 consecutive PSC patients who received 174 liver allografts. Mean follow-up was 55 months. Actuarial patient survival at 1, 2, 5, and 10 years was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, whereas graft survival was 83.4%, 83.4%, 79.0%, and 60. 5%, respectively. The main indication for retransplantation was hepatic artery thrombosis, and the major cause of death was severe infection. Patients with PSC had a higher incidence of acute cellular and chronic ductopenic rejection compared to a non-PSC control group. Chronic ductopenic rejection adversely affected patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, were frequent and occurred in 16.2% and 27.2% of patients, respectively. The incidence of recurrent PSC was 20%. A negative impact on patient survival was not seen in patients with either postoperative biliary strictures or recurrence of PSC. Six patients (4%) had cholangiocarcinoma and 1 patient died related to recurrence of malignant disease. Seventy-eight percent of PSC patients had associated inflammatory bowel disease, most commonly chronic ulcerative colitis, which did not adversely impact patient outcome posttransplantation. Nine patients required proctocolectomy after liver transplantation; 5 because of intractable symptoms related to inflammatory bowel disease and 4 due to the development of colorectal carcinoma/high-grade dysplasia. Our data show that liver transplantation provides excellent long-term patient and graft survival for patients with end-stage PSC.

Evolving concepts in the diagnosis, pathogenesis, and treatment of chronic hepatic allograft rejection.

Chronic hepatic allograft rejection is characterized by the histological findings of ductopenia and a decreased number of hepatic arteries in portal tracts in the presence of foam cell (obliterative) arteriopathy. Recent studies have extended the histological spectrum of chronic rejection to include the presence of biliary epithelial atrophy or pyknosis involving the majority of small ducts present in the liver biopsy specimen. Overall, the incidence of chronic rejection in adults appears to be decreasing and is currently approximately 4%. However, the incidence of chronic rejection in pediatric liver transplant recipients has been more stable and ranges from 8% to 12% in most studies. Clinical risk factors associated with chronic rejection include: underlying liver disease, HLA donor-recipient matching, positive lymphocytotoxic cross-match, cytomegalovirus infection, recipient age, donor-recipient ethnic origin, male donor into female recipient, number of acute rejection episodes, histological severity of acute rejection episodes, low cyclosporine trough levels, and retransplantation for chronic rejection. Chronic rejection, once diagnosed, frequently leads to graft failure; however, a number of reports indicated 20% to 30% of the patients with this diagnosis may respond to additional immunosuppressive therapy or even resolve spontaneously receiving baseline immunosuppression. Newer immunosuppressive agents, such as tacrolimus and mycophenolate, may successfully reverse chronic rejection, particularly when it is diagnosed in its early histological stages.

Late recurrence and rapid evolution of severe hepatopulmonary syndrome after liver transplantation.

Recurrence of hepatopulmonary syndrome (HPS) after orthotopic liver transplantation (OLT) in an adult has never been reported. We describe a 23-year-old woman who initially underwent OLT because of debilitating and severe HPS associated with nonalcoholic steatohepatitis (NASH). Although the clinical resolution of HPS was well documented day 117 post-OLT, the reappearance of NASH was documented by liver biopsy. Severe hypoxemia because of recurrent HPS rapidly evolved beginning approximately day 700 post-OLT. Retransplantation was attempted, but the patient died post-OLT of sepsis and/or multiorgan failure.

Hepatic retransplantation in cholestatic liver disease: impact of the interval to retransplantation on survival and resource utilization.

The aim of our study was to quantitatively assess the impact of hepatic retransplantation on patient and graft survival and resource utilization. We studied patients undergoing hepatic retransplantation among 447 transplant recipients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) at 3 transplantation centers. Cox proportional hazards regression analysis was used for survival analysis. Measures of resource utilization included the duration of hospitalization, length of stay in the intensive care unit, and the duration of transplantation surgery. Forty-six (10.3%) patients received 2 or more grafts during the follow-up period (median, 2.8 years). Patients who underwent retransplantation had a 3.8-fold increase in the risk of death compared with those without retransplantation (P <.01). Retransplantation after an interval of greater than 30 days from the primary graft was associated with a 6.7-fold increase in the risk of death (P <.01). The survival following retransplantations performed 30 days or earlier was similar to primary transplantations. Resource utilization was higher in patients who underwent multiple consecutive transplantations, even after adjustment for the number of grafts during the hospitalization. Among cholestatic liver disease patients, poor survival following hepatic retransplantation is attributed to late retransplantations, namely those performed more than 30 days after the initial transplantation. While efforts must be made to improve the outcome following retransplantation, a more critical evaluation may be warranted for late retransplantation candidates.

Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma.

In our experience, the primary obstacle precluding the widespread use of orthotopic liver transplantation (OLT) for definitive therapy of hepatocellular carcinoma (HCC), even for early-stage disease, is preventing tumor recurrence. Chemoembolization is an attractive strategy to minimize tumor progression before OLT because of its shown antitumor effect, ability to be repeated, and minimal systemic toxicity. Thus, this pilot study was undertaken to determine the tolerability and treatment outcomes of pretransplantation chemoembolization of HCC followed by OLT. Between 1992 and 1997, 27 patients with HCC who had cirrhosis, no extrahepatic metastasis, less than three tumor nodules of less than 5 cm each, and no evidence of vascular invasion on preoperative imaging studies were enrolled onto the protocol. Chemoembolization was performed using Ivalon particles with mitomycin, doxorubicin, and cisplatin. Twenty-four patients completed the protocol with chemoembolization and a liver transplant. The mean United Network of Organ Sharing waiting time was 167 days. Chemoembolization was well tolerated. On examination of the explanted liver, the majority of patients had a single lesion, mean tumor size was 3.66 cm (range, 1.5 to 6 cm), and the majority of patients had stage II disease. None of the transplant recipients has developed recurrent HCC (mean follow-up, 29.2 months; range, 9 to 55 months). The 1- and 2-year disease-free survival rates are 91% and 84%, respectively. In conclusion, chemoembolization followed by OLT is well tolerated and associated with excellent outcomes in selected patients with HCC.