Nature and outcomes of the increased incidence of colorectal malignancy after liver transplantation in Australasia.

OBJECTIVES: To examine whether incidence of colorectal malignancy is increased in Australasian liver transplant recipients compared with the general population of Australia, and to assess the characteristics and outcomes of colorectal malignancy in this patient group. DESIGN, SETTING AND PATIENTS: Data on patients who underwent orthotopic liver transplantation (OLTx) and had a diagnosis of de-novo colorectal malignancy after transplantation during the period 1985-2011 were obtained from the Australia and New Zealand Liver Transplant Registry, and these data were compared with colorectal malignancy data from the Australian Institute of Health and Welfare. MAIN OUTCOME MEASURES: Time from OLTx to diagnosis of colorectal malignancy, stage of colorectal malignancy at diagnosis, patient survival, and standardised incidence ratio (SIR) for colorectal malignancy. RESULTS: Forty-eight of 3735 recipients (1.3%) were diagnosed with colorectal malignancy at a median of 7.3 years after OLTx. More advanced colorectal malignancy (regional or metastatic disease) was evident at diagnosis in 20 of the 48 patients; these patients tended to be younger than patients with less advanced malignancy (P = 0.01) and diagnosed sooner after OLTx (P = 0.005). Despite treatment predominantly with surgery, 19 of the 48 patients died from the malignancy. The overall SIR for colorectal malignancy liver transplant recipients compared with the general population of Australia was 2.80 (95% CI, 2.06-3.71). CONCLUSIONS: The incidence of colorectal malignancy is increased in liver transplant recipients in comparison with the general population. Of concern is the tendency for advanced malignancy to be diagnosed in younger patients. These data highlight the importance of considering whether specific guidelines for colorectal malignancy screening in the Australasian adult liver transplant population are needed.

Poorer survival in patients whose explanted hepatocellular carcinoma (HCC) exceeds Milan or UCSF Criteria. An analysis of liver transplantation in HCC in Australia and New Zealand.

BACKGROUND: Milan and University of California San Francisco (UCSF) Criteria have been used for selection of patients with hepatocellular carcinoma (HCC) for liver transplantation (LTx). The aims of this study were to analyse the results of LTx for HCC in Australia and New Zealand with emphasis on the effects of discordance between pre-LTx radiological and post-LTx pathological staging. METHODS: A total of 186 LTx for HCC carried out between July 1985 and August 2003 were included. Patients were categorized according to the Milan and UCSF Criteria. RESULTS: The median follow-up was 6.55 years (range 2.96-20.93 years). Pre-LTx factors associated with better survival include tumour size < or = 5 cm, number of tumours < or = 3, staging within Milan and UCSF Criteria and more recent transplantation (1996-2003). In all, 14 patients had a pre-LTx stage outside the Milan but within the UCSF Criteria. One- and 5-year patient survival rates were, respectively, 88% and 74% within the Milan Criteria, and 87% and 73% within the UCSF Criteria. Vascular invasion, capsular invasion, lymph node invasion and pathological stage outside UCSF Criteria were associated with poor outcome. Of patients within the Milan and UCSF Criteria pre-LTx, 24% and 18%, respectively, were outside the same criteria post-LTx. These patients had poorer survival rates. CONCLUSIONS: The use of the UCSF Criteria in this cohort increased the number of patients eligible for LTx without compromising 5-year survival rates. Patients whose explant tumours were outside the Milan or UCSF Criteria had poorer outcomes compared with those whose explants remained within these criteria.

Undetected hepatocellular carcinoma in patients undergoing liver transplantation: is associated with favorable outcome.

BACKGROUND/AIMS: The aim of the study was to define the clinical characteristics and outcome of patients found to have undetected hepatocellular carcinomas (HCC) at liver transplantation. Patients who underwent liver transplantation and were unexpectedly found to have a HCC despite prior workup showing normal alpha-fetoprotein levels and/or no visible radiological lesion were defined as having an undetected HCC. METHODOLOGY: Thirty-two of these patients had a histological diagnosis of HCC in the explanted liver. Undetected HCC was defined as a carcinoma found only on pathological evaluation of the explanted liver, with a pre-OLT workup showing a normal serum alpha-fetoprotein (AFP) level (<20 ng/mL) and/or no suspicious lesion on preoperative radiological evaluation. RESULTS: Nine patients had a tumor that met the criteria for an undetected HCC. The most common cause for transplantation was cryptogenic cirrhosis (44.4%). Tumor size was 2 cm or less in all patients, vascular invasion was detected in 11.1% of the patients, and tumor, node, metastasis (TNM) classification was stage I in 77.8%. Eight patients (88.9%) remained alive at the cessation of the analysis with a mean follow-up of 60 +/- 30.4 months. There was no tumor recurrence in any patient. Statistical analysis showed significant differences between undetected and detected HCCs when causes of pretransplantation liver disease, peak AFP level, tumor size, number of tumors, presence of vascular invasion or pathological differentiation were compared. Undetected HCCs were associated with a better survival rate after liver transplantation (p = 0.008). CONCLUSIONS: Patients with undetected HCCs at OLT have a favorable outcome with tumor-free survival. Most patients had small, early-stage HCCs, but the possibility of finding tumors greater than 2 cm, multifocal lesions, and vascular invasion exist despite thorough investigation. An exhaustive histopathological search of the explant for malignancy will allow for greater accuracy in prognosis.

[Liver transplantation for primary biliary cirrhosis: retrospective analysis of 52 patients in QLTS].

OBJECTIVE: Retrospectively analyzing post-transplant primary biliary cirrhosis patients to document the actual survival time, the cause of post-transplant death, and recurrences after liver transplantation in patients followed up by the Queensland Liver Transplant Service (QLTS). METHODS: The case notes of all post-piggyback liver transplantation patients followed up by QLTS were reviewed. We analyzed the clinical characteristics of the PBC patients, post-transplant actual survival rates, the causes of post-transplant death, and risk factors of recurrence, and compared the survival rates between patients with and without liver transplantation using a European model. RESULTS: Fifty-two post-transplant patients with 54 transplantations were identified with an average age of 53 years and a mean follow-up time of 55 months. The actual survival times of PBC patients with grafts for 1 years, 5 years and 10 years were 88.4%, 80.1%, 76.9% and 80.9%, 65.4%, 19.8%. The causes of death were MOF intra-abdominal bleeding, renal failure, sepsis and cardiovascular diseases. Comparing the survival rates between with and without transplantation, 8.5% of PBC patients have recurrences with an average recurrent time of 34 months. CONCLUSION: (1) Liver transplantation could improve survival rates, but the optimum time for transplantation should be focused on; (2) A long-term and larger follow-up sampling should be done to understand the effects of recurrences on patient's long-term survival; (3) CsA may play a more important role in preventing recurrence of PBC than Tacrolimus

Increased mononuclear cell activation and apoptosis early after human liver transplantation is associated with a reduced frequency of acute rejection.

Experimental models of orthotopic liver transplantation (OLT) have shown that the very early events post-OLT are critical in distinguishing immunogenic and tolerogenic reactions. In rodents, increased leukocyte apoptosis and cytokine expression have been demonstrated in tolerogenic strain combinations. Information from human OLT recipients is less abundant. The aim of this study was to determine the amount of early leukocyte activation and apoptosis following human OLT, and to correlate this with subsequent rejection status. Peripheral blood mononuclear cells (PBMC) were isolated from 76 patients undergoing OLT - on the day prior, 5 hrs after reperfusion (day 0), and 18-24 hrs post-OLT (day 1). The mean level of apoptotic PBMCs on post OLT day 1 was higher than healthy recipients (0.9% +/- 0.2 vs. 0.2% +/- 0.1, p=0.013). Apoptosis was greater in nonrejecting (NR) (1.1% +/- 0.3) compared with acutely-rejecting (R) (0.3% +/- 0.1, p=0.021) patients. On day 1, PBMC from NR patients had increased expression of IFN-gamma (p=0.006), IL-10 (p=0.016), and CD40 ligand (p=0.02) compared with R. Donor cell chimerism on day 1 did not differ between the groups indicating that this was unlikely to account for increased PBMC apoptosis in the NR group. Interestingly, the level of chimerism on day 0 was significantly higher in NR (3.8% +/- 0.6) compared with R (1.2% +/- 0.4, p=0.004) patients and there was a close correlation between chimerism on day 0 and cytokine expression on day 1. These results imply that similar mechanisms are occurring in the human liver to promote graft acceptance as in the experimental models of liver transplantation and suggest that strategies that promote liver transplant acceptance in rodents might be applicable to humans.

The influence of viral genotypes and rejection episodes on the recurrence of hepatitis C after liver transplantation.

PURPOSE: The aim of this study was to report the influence of hepatitis C virus (HCV) genotype and rejection episodes on the outcome of orthotopic liver transplantation (OLT), hepatitis recurrence, and progression to graft cirrhosis after OLT. METHODS: Fifty-three patients who all had undergone OLT for end-stage liver cirrhosis were selected for this study. Hepatitis C genotype was determined. Recurrent hepatitis and rejection were diagnosed based on elevated liver function tests and a liver biopsy. RESULTS: The patients were followed up for a mean of 51.9 +/- 34.3 months. The cumulative survival rate was no different in OLT for hepatitis C and OLT for all other liver diseases. After OLT, serum HCV RNA was detected in 93%. Histological recurrence occurred in 85% of all patients. The 1-, 3-, and 5-year recurrence rates were 48%, 77%, and 85%, respectively. Of the 41 patients with recurrent hepatitis C, 4 (10%) had cirrhosis, 18 (44%) had hepatitis with fibrosis, and 91 (46%) had hepatitis without fibrosis at the end of follow-up. A total of 32% of the patients were infected by HCV genotype 1b and 68% by other HCV genotypes. The recurrence rates were significantly higher in patients infected with genotype 1b than in those with other genotypes ( p = 0.04). Twenty of 48 patients (42%) experienced acute rejection. There was a strong association between the number of rejection episodes and the incidence of HCV-related cirrhosis ( p < 0.01). CONCLUSION: Our findings showed the genotype 1b to result in a higher recurrence rate after OLT. On the other hand, rejection episodes were associated with a more rapid progression to graft cirrhosis.

Lymphocyte apoptosis and cell replacement in human liver allografts.

BACKGROUND: Apoptosis of graft-infiltrating T cells has been described after rodent liver transplantation. The aim of this study was to assess lymphocyte apoptosis in human allografts. Additionally, kinetics of leukocyte turnover were studied to determine whether apoptotic cells were likely to be of donor or recipient origin. METHODS: Liver biopsy specimens (n=36) taken between days 3 and 1855 were stained with terminal deoxynucleotidyl transferase dUTP nick end-labeling and anti-CD3 to detect apoptotic lymphocytes. Renal allograft and hepatitis C biopsy specimens served as controls. Donor cell turnover was studied in sex-mismatched grafts using Y-chromosome in situ hybridization to detect recipient cells and double immunostaining for leukocyte phenotyping. RESULTS: T-cell apoptosis was prominent in hepatic sinusoids (72% of biopsy specimens) as early as day 3. It ranged from 0% to 18.2% of CD3+ cells (mean 5.28+/-0.82%) and persisted for >14 days, including time points >1 year. There was no difference between biopsy specimens with or without rejection (6.34+/-1.14% and 4.61+/-1.13%, P=NS). Apoptotic cells in portal tracts were less frequent (33% of biopsy specimens) and less abundant (1.13+/-0.36%, P<0.0001). No lymphocyte apoptosis was seen in renal allograft biopsy specimens or hepatitis C biopsy specimens, indicating that it is a distinctive feature of the liver allograft. Persisting lymphocyte apoptosis even after donor lymphocytes had been replaced suggests that recipient lymphocyte deletion must occur. Donor Kupffer cells persisted for many months. CONCLUSIONS: Our results suggest that the sinusoidal microenvironment promotes recipient lymphocyte apoptosis, which may account for the improved outcome of liver grafts compared with other organ allografts.

Liver transplantation as a therapeutic option for hepatocellular carcinoma.

Better outcomes of the patients receiving liver transplantation for viral hepatitis and hepatocellular carcinoma (HCC) are achieved by improved patient selection and perioperative treatment with antiviral agents including lamivudine, ribavirin and interferon. Patient selection is accomplished by high-quality imaging as well as exclusion of patients with large tumors, obvious extrahepatic disease or macroscopic vascular invasion. Using such criteria, a 5-year survival of 92% has been reached in the Queensland Liver Transplant Service on a small number of highly selected patients with HCC. The treatment algorithm of Makuuchi has guided us in recommending resection, estimating to what extent the liver resection can be performed safely, and timing liver transplantation when it is the only option. Adult-to-adult living-donor liver transplantation is being performed safely in many centers worldwide. The transplantation of liver from living donors to HCC patients, when standard criteria for the likelihood of good outcomes are fulfilled, will increase in Japan in the near future.