Liver Transplantation for Hepatocellular Carcinoma: Impact of Wait Time at a Single Center.

INTRODUCTION AND AIM: Liver transplantation (LT) provides durable survival for hepatocellular carcinoma (HCC). However, there is continuing debate concerning the impact of wait time and acceptable tumor burden on outcomes after LT. We sought to review outcomes of LT for HCC at a single, large U.S. center, examining the influence of wait time on post-LT outcomes. MATERIAL AND METHODS: We reviewed LT for HCC at Mayo Clinic in Florida from 1/1/2003 until 6/30/2014. Follow up was updated through 8/1/ 2015. RESULTS: From 2003-2014, 978 patients were referred for management of HCC. 376 patients were transplanted for presumed HCC within Milan criteria, and the results of these 376 cases were analyzed. The median diagnosis to LT time was 183 days (8 - 4,337), and median transplant list wait time was 62 days (0 - 1815). There was no statistical difference in recurrence-free or overall survival for those with wait time of less than or greater than 180 days from diagnosis of HCC to LT. The most important predictor of long term survival after LT was HCC recurrence (HR: 18.61, p < 0.001). Recurrences of HCC as well as survival were predicted by factors related to tumor biology, including histopathological grade, vascular invasion, and pre-LT serum alpha-fetoprotein levels. Disease recurrence occurred in 13%. The overall 5-year patient survival was 65.8%, while the probability of 5-year recurrence-free survival was 62.2%. CONCLUSIONS: In this large, single-center experience with long-term data, factors of tumor biology, but not a longer wait time, were associated with recurrence-free and overall survival.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

BACKGROUND: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. OBJECTIVE: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. DESIGN: Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440). SETTING: 31 liver disease and transplant centers in the United States. PATIENTS: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). MEASUREMENTS: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). RESULTS: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. LIMITATIONS: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. CONCLUSION: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Multicenter experience using telaprevir or boceprevir with peginterferon and ribavirin to treat hepatitis C genotype 1 after liver transplantation.

The safety, efficacy, and effect on immunosuppression levels of telaprevir (TVR) or boceprevir (BOC) in combination with peginterferon (PEG-IFN) and ribavirin (RBV) in recipients of liver transplantation (LT) with hepatitis C virus (HCV) genotype 1 have not been defined. We report our 3 centers' preliminary experiences with administering triple antiviral treatment protocols containing PEG-IFN, RBV, and TVR or BOC. Patients with biopsy-proven HCV recurrence (METAVIR grade ≥ 3 and/or stage ≥ 2) received TVR with PEG-IFN/RBV for 12 weeks and then PEG-IFN/RBV for 36 weeks or BOC with PEG-IFN/RBV for 44 weeks after 4 weeks of lead-in PEG-IFN/RBV. Maintenance immunosuppression was changed to cyclosporine whenever possible, and the levels were followed closely. PEG-IFN/RBV dose adjustments were based on patients' tolerance. Sixty patients started triple antiviral treatment, and they were followed for up to 66 weeks (mean = 35 weeks); all were followed at least 12 weeks. Thirty of the 35 patients treated with TVR (86%) achieved undetectable HCV RNA levels after an average of 6 weeks, whereas 12 patients (48%) in the BOC-treated group achieved undetectable HCV RNA levels after a mean of 11 weeks. According to an intention-to-treat analysis, 14 of 21 TVR-treated patients (67%) and 10 of 22 patients who received BOC (45%) achieved undetectable HCV RNA levels at week 24 without viral breakthrough at the last follow-up. Cytopenias complicated both regimens; all patients required dose reductions of PEG-IFN and/or RBV or the administration of hematological growth factors. One death occurred in each group on triple antiviral treatment. In conclusion, TVR or BOC combined with PEG-IFN/RBV achieved on-treatment virological response rates of approximately 50% to 60% in patients with recurrent HCV after LT, but significant side effects were common.

Retransplantation for donor-derived neuroendocrine tumor.

Although tumor transmission through liver transplantation (LT) is a rare occurrence, the consequences can be devastating, even when a very aggressive management approach is adopted. We report the case of a donor-derived small cell neuroendocrine tumor (NET) in a patient who underwent LT for cholangiocarcinoma. Despite locoregional therapy, chemotherapy and ultimately retransplantation, the patient died from metastases. The high grade nature of the NET was the most important determinant of prognosis in this case. Our experience suggests that retransplantation for donor-derived NET should only be considered when tumor biology is favorable.

Improving graft survival for patients undergoing liver transplantation.

Liver transplant (LT) outcomes are reported to be improving in non-HCV recipients but not for those infected with HCV. Our aim was to evaluate graft survival and predictors of outcome in HCV and non-HCV patients before and after 2003. Patients with primary LT between February 1, 1998, and December 31, 2005, were included. Patients were divided into Era 1 (1998-2002) and Era 2 (2003-2005) with follow-up through May 31, 2009. Graft survival was compared for HCV, non-HCV, and all patients. There was significant improvement in graft survival in Era 2 for HCV patients. Graft survival in Era 2 of HCV patients was equivalent to non-HCV patients. The most significant improvement between eras was in outcomes of grafts from donors ≥60 yr with three-yr graft survival 58.6 (51.3-65.9) vs. 75.4 (68.9-81.9), p = 0.002. The use of donors ≥60 did not change between eras: 31% vs. 34%; however, utilization in HCV recipients decreased from 36% to 3% (p < 0.001). In conclusion, graft survival of HCV patients has improved significantly since 2003 and was comparable to non-HCV patients up to three yr. The change in management of donor organs into HCV and non-HCV patients likely contributed to this outcome.

HCV recurrence in HIV-infected patients after liver transplant.

Patients coinfected with hepatitis C virus (HCV) and HIV undergoing liver transplantation (LT) are at risk of early, aggressive HCV recurrence. This study investigates the use of frequent protocol-driven biopsies to identify HCV recurrence post LT in coinfected patients. Five consecutive HIV/HCV-coinfected patients underwent LT. Liver biopsies were obtained post LT at 1 hour; days 7, 120, and 365; then annually; and as clinically indicated. Stage 2 (Ishak) or higher fibrosis occurred in 4 of the 5 patients by 60, 120, 270, and 365 days. Two patients died of HCV recurrence and liver failure at 6 and 35 months post LT. Three patients survived more than 4 years after LT, 2 having sustained virologic responses to anti-HCV treatment. Another has histologic recurrence not responding to treatment. Hepatitis C virus recurrence can be rapid and aggressive after LT in HIV-coinfected patients. Serial biopsies identify recurrence early, allowing for prompt initiation of treatment.

Liver transplantation using controlled donation after cardiac death donors: an analysis of a large single-center experience.

The use of donation after cardiac death (DCD) donors may provide a valuable source of organs for liver transplantation. Concerns regarding primary nonfunction (PNF) and intrahepatic biliary stricture (IHBSs) have limited the enthusiasm for their use. A retrospective analysis of 1436 consecutive deceased donor liver transplants performed between December 1998 and October 2006 was conducted. These included 108 DCD liver transplants, which were compared to 1328 transplants performed with organs from donors meeting the criteria for donation after brain death (DBD). The median follow-up was 48 months. The 1-, 3-, and 5-year patient survival and graft survival for DCD donors were 91.5%, 88.1%, and 88.1% and 79.3%, 74.5%, and 71.0%, respectively. The 1-, 3-, and 5-year patient survival and graft survival for DBD donors were 87.3%, 81.1%, and 77.2% and 81.6%, 74.7%, and 69.1%, respectively. Patient survival and graft survival were not significantly different between DCD donors less than 60 years old, DCD donors greater than 60 years old, and DBD donors. Causes of graft loss included IHBSs (n = 9), PNF (n = 4), recurrent hepatitis C virus (n = 4), hepatic artery thrombosis (n = 1), rejection (n = 2), and patient death (n = 13). Contrary to previously published data, excellent long-term patient survival and graft survival can be obtained with DCD allografts, and in our experience, they are equivalent to those obtained from DBD allografts.

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non-heart-beating or donation after cardiac death (DCD) are encouraging. However, long-term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow-up >4.5 years. During 1998-2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart-beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non-function and biliary complications as compared with SCD and ECD. The overall one-, two-, and five-yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long-term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.

Disseminated Mycobacterium interjectum Infection with Bacteremia, Hepatic and Pulmonary Involvement Associated with a Long-Term Catheter Infection.

We present a 49-year-old female with one year of intermittent fevers, chills, night sweats, and significant weight loss. Liver and lung biopsy showed evidence of a granulomatous process. Blood and liver biopsy cultures yielded growth of presumed Mycobacterium interjectum, thought to be related to a disseminated long-term central venous catheter infection. She successfully received one year of combined antimicrobial therapy after catheter removal without recurrence of disease. M. interjectum has been previously described as a cause of lymphadenitis in healthy children and associated with pulmonary disease in adults, although other localized infections have been reported. This is the first case described of a disseminated M. interjectum infection with bacteremia, hepatic and pulmonary involvement associated with a long-term catheter infection.

Donor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C.

BACKGROUND: The use of liver allografts from an older donor (OD) (age>50 years) is a widespread strategy to manage the disparity between supply and demand of organs for liver transplantation. This study determines the effect of OD allografts on fibrosis progression and graft survival after liver transplantation in patients with and without infection caused by hepatitis C virus (HCV). METHODS: All patients undergoing liver transplantation at our center from March 1998 to December 2001 were analyzed. Protocol liver biopsies were performed at 1, 16, and 52 weeks after transplantation and yearly thereafter. One liver pathologist scored all biopsy specimens for modified hepatic activity index (0-18) and fibrosis (0-6). RESULTS: A total of 402 patients (167 with HCV and 235 without HCV) underwent liver transplantation during the study period. Among patients with HCV, baseline characteristics of OD recipients were similar to younger donor (YD) (age<50 years) recipients. In patients with HCV, graft survival was shorter in OD graft recipients than in YD recipients (P<0.001). In patients without HCV, graft survival was independent of donor age. In patients with HCV, a fibrosis score of 3 or greater was present in 17% of OD recipients at 4 months and in 26% at 12 months after transplantation, compared with 8% of YD recipients at 4 months and 13% at 12 months (P<0.001). CONCLUSIONS: Liver transplantation with OD grafts is associated with rapid progression of fibrosis and decreased graft survival in patients with HCV, but not in patients without HCV. OD grafts should be considered preferentially for patients without HCV.

Cardiac troponin elevation predicts mortality in patients undergoing orthotopic liver transplantation.

Introduction. While patients undergoing orthotopic liver transplantation (OLT) have high cardiovascular event rates, preoperative risk stratification may not necessarily predict those susceptible patients. Troponin T (TnT) may help predict patients at risk for cardiovascular complications. Methods. Consecutive patients undergoing OLT at Mayo Clinic in Florida between 1998 and 2010 who had TnT obtained within 10 days following surgery were included. Three groups were compared based on TnT level: (1) normal (TnT ≤0.01 ng/mL), (2) intermediate (TnT 0.02-0.11 ng/mL), and (3) elevated (TnT >0.11 ng/mL). Overall and cardiovascular mortality was assessed. Results. Of the 78 patients included, there was no difference in age, gender, severity of liver disease, and echocardiographic findings. Patients in the normal and intermediate TnT groups had a lower overall mortality rate (14.3% and 0%, resp.) when compared with those with elevated TnT (50%; P = 0.001). Patients in the elevated TnT group had a cardiovascular mortality rate of 37.5% compared with 1.4% in the other groups combined (P < 0.01). The elevated TnT group had a much higher mortality rate when compared with those in the intermediate group (P < 0.0001). Conclusion. TnT may accurately help risk stratify patients in the early postoperative setting to better predict cardiovascular complications.

Liver Transplantation for Hepatocellular Carcinoma: Impact of Wait Time at a Single Center

ABSTRACT Introduction and aim. Liver transplantation (LT) provides durable survival for hepatocellular carcinoma (HCC). However, there is continuing debate concerning the impact of wait time and acceptable tumor burden on outcomes after LT. We sought to review outcomes of LT for HCC at a single, large U.S. center, examining the influence of wait time on post-LT outcomes. Material and methods. We reviewed LT for HCC at Mayo Clinic in Florida from 1/1/2003 until 6/30/2014. Follow up was updated through 8/1/ 2015. Results. From 2003-2014,978 patients were referred for management of HCC. 376 patients were transplanted for presumed HCC within Milan criteria, and the results of these 376 cases were analyzed. The median diagnosis to LT time was 183 days (8 - 4,337), and median transplant list wait time was 62 days (0 -1815). There was no statistical difference in recurrence-free or overall survival for those with wait time of less than or greater than 180 days from diagnosis of HCC to LT. The most important predictor of long term survival after LT was HCC recurrence (HR: 18.61, p < 0.001). Recurrences of HCC as well as survival were predicted by factors related to tumor biology, including histopathological grade, vascular invasion, and pre-LT serum alpha-fetoprotein levels. Disease recurrence occurred in 13%. The overall 5-year patient survival was 65.8%, while the probability of 5-year recurrence-free survival was 62.2%. Conclusions. In this large, single-center experience with long-term data, factors of tumor biology, but not a longer wait time, were associated with recurrence-free and overall survival.

Liver transplantation using young pediatric donor grafts in adults with hepatitis C infection.

BACKGROUND: The impact of using grafts from donor's age less than or equal to 13 years on adult hepatitis C virus (HCV) recipients in terms of survival and HCV recurrence is undefined. To determine if adults undergoing liver transplantation for HCV who receive a graft from a donor age less than or equal to 13 years have similar outcomes to recipients of organs from 18- to 35-year-old donors. METHODS: Records from adult HCV patients undergoing liver transplantation between April 1998 and April 2004 who received whole grafts from non-HCV donors less than 35 years old after brain death were reviewed. Patients with donor age less than or equal to 13 years (group 1) and 18 to 35 years (group 2) were compared for patient and graft survival, allograft rejection, biliary complications, and HCV recurrence. RESULTS: Fifty-one HCV patients were analyzed. The two groups were similar except that group 1 donors and recipients were smaller in size. One year patient and graft survival for groups 1 vs. 2 were 93% vs. 94% and 93% vs. 83%, respectively (P=NS). Biliary complications, HCV recurrence, and advanced fibrosis free survival were not significantly different. CONCLUSION: Whole liver grafts from donors age less than or equal to 13 years can potentially be used in selected size-matched adult HCV patients in the absence of an acceptable pediatric recipient.

Liver retransplantation of patients with hepatitis C infection is associated with acceptable patient and graft survival.

Infection with hepatitis C virus (HCV) is the leading cause of liver transplantation (LT), while liver retransplantation (RT) for HCV is controversial as a result of concerns over poor outcomes. We sought to compare patient and graft survival after RT in patients with and without HCV. We performed a retrospective chart review of all patients undergoing RT at our center between February 1998 and April 2004. Indications for RT, HCV status, patient, and donor characteristics, laboratory values, and hospitalization status at RT were collected. A total of 108 patients (48 HCV and 60 non-HCV) underwent RT during the study period, with mean post-RT follow-up of 1,096 days (range, 0-2,888 days). Grafts from donors aged>60 years were used less frequently in HCV patients at RT (6%) compared with LT (47%), P<0.001. There was no difference between HCV vs. non-HCV patients in 1- and 3-year patient survival (respectively, 79% vs. 63%, and 71% vs. 63%) and graft survival (respectively, 67% vs. 66%, and 59% vs. 56%). Post-RT mortality and graft failure in HCV patients occurred within the first year in 89% of patients, and 83% were unrelated to HCV recurrence. We conclude that patients should not be excluded from consideration for retransplantation solely on the basis of a diagnosis of HCV.

Peritonitis after liver transplantation: Incidence, risk factors, microbiology profiles, and outcome.

Peritonitis occurring after liver transplantation (PLT) has been poorly characterized to date. The aims of this study were to define the incidence, risk factors, microbiology profiles, and outcome of nonlocalized PLT. This was a retrospective study of 950 cadaveric liver transplantation (LT) procedures in 837 patients, followed for a mean of 1,086 days (range, 104-2,483 days) after LT. PLT was defined as the presence of at least one positive ascitic fluid culture after LT. There were 108 PLT episodes in 91 patients occurring at a median of 14 days (range, 1-102 days) after LT. Significant risk factors associated with the development of PLT by multivariate analysis included pre-LT model for end-stage liver disease score, duration of LT surgery, Roux-en-Y biliary anastomosis, and renal replacement therapy after LT. Biliary complications, intra-abdominal bleeding, and bowel leak/perforation were associated with 34.3%, 26.9%, and 18.5% of episodes, respectively. Multiple organisms, gram-positive cocci, fungus, and multidrug-resistant bacteria were isolated in 61.1%, 92.6%, 25.9%, and 76.9% of ascitic fluid cultures, respectively. The 28 fungal PLT episodes were associated with bowel leak/perforation and polymicrobial peritonitis. Patients who developed PLT after their first LT had a significantly greater risk of graft loss or mortality compared to unaffected patients. Parameters significantly associated with these adverse outcomes by multivariate analysis were recipient age at LT and bowel leak or perforation after LT. In conclusion, PLT is a serious infectious complication of LT, associated with significant intra-abdominal pathology and reduced recipient and graft survival.

Use of stable isotopically labeled tracers to measure very low density lipoprotein-triglyceride turnover.

Tracer methods for VLDL-TG kinetics vary in their ability to account for the effect of tracer recycling, which can influence the calculation of VLDL-TG fractional catabolic rates (FCRs). We evaluated a novel approach, involving stable isotopically labeled glycerol or palmitate tracers in conjunction with compartmental modeling, for measuring VLDL-TG kinetics in normolipidemic human subjects. When administered as a bolus simultaneously, both tracers provided identical VLDL-TG FCRs when the data were analyzed by a compartmental model that accounted for hepatic lipid tracer recycling, but not by non-compartmental analysis. The model-derived FCR was greater than that determined using a non-compartmental approach, and was 2- to 3-fold higher than that usually reported by using a bolus of radioactive [3H]glycerol. When palmitate tracer was given as a constant infusion, VLDL-TG turnover appeared 5-fold slower, because tracer recycling through hepatic lipid pools could not be resolved with the infusion protocol. We conclude that accounting for tracer recycling, particularly the contribution of hepatic glycerolipid pools, is essential to accurately measure VLDL-TG kinetics, and that bolus injection of stable isotopically labeled glycerol or palmitate tracers in conjunction with compartmental modeling analysis offers a reliable approach for measuring VLDL-TG kinetics.

Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is an immune mediated chronic liver disease with a prevalence of 17 cases/100,000. Resistance to the standard treatment of AIH (prednisone and azathioprine) occurs in 15% to 20%. There is currently no standard treatment of patients with steroid refractory AIH. GOALS: Determine the efficacy of tacrolimus in the treatment of steroid refractory AIH. METHODS: This is a retrospective study evaluating the efficacy of Tacrolimus in the treatment of steroid refractory AIH. RESULTS: Between October 1998 and February 2002, 11 patients with steroid refractory AIH were treated with tacrolimus. Mean age was 63 years. Median duration of steroid treatment before starting tacrolimus was 9 months. Median duration of tacrolimus treatment was 25 months. Median follow-up period was 16 months. Median baseline ALT, AST were 77 U/L and 68 U/L and became 21 U/L and 32 U/L respectively at end of follow-up (P = 0.005 and 0.01 respectively). Significant weight reduction was seen in all patients (P = 0.02). Tacrolimus treatment was safe and well tolerated. CONCLUSION: Use of low dose tacrolimus led to successful biochemical and histologic remission and weaning off prednisone in patients with steroid refractory AIH. This data supports further studies in evaluating the use of tacrolimus in the treatment of AIH.