Recurrent Liver Transplantation Research Articles

"No-Touch" Left Approach for Recipient Hepatectomy: A Promising Strategy to Minimize Hepatocellular Carcinoma Recurrence in Liver Transplantation.

Managing hepatocellular carcinoma (HCC) presents significant clinical challenges, often necessitating orthotopic liver transplantation (OLT). To mitigate the risk of iatrogenic metastasis during OLT and reduce posttransplantation recurrence (PTR), we introduced the "no-touch" left (NTL) approach for recipient hepatectomy in OLT. In this retrospective cohort study, our aim was to compare the safety and PTR rates in patients undergoing OLT via either the NTL technique or the conventional approach for recipient hepatectomy. We included 106 patients who met the Hangzhou criteria and exhibited a high tumor burden in the right lobe, with 50 patients assigned to the NTL group and 56 to the conventional group. The primary endpoint was the 1-y PTR rate, whereas secondary endpoints encompassed the safety of the NTL approach, PTR rates at 2 and 5 y, and overall survival. Baseline demographics and clinical characteristics showed no significant differences between the groups. The NTL approach exhibited major surgical outcomes similar to those of the conventional approach. The cumulative PTR rates at 1, 2, and 5 y were 14.0% in the NTL group, compared with 24.5%, 35.8%, and 35.8% in the conventional group (P = 0.013). Cumulative overall survival rates at 1, 2, and 5 y were 94.0%, 91.9%, and 89.7% in the NTL group and 88.7%, 75.5%, and 72.5% in the conventional group (P = 0.03). This innovative surgical technique enhances safety and significantly reduces the risk of PTR, leading to improved long-term survival. Further prospective studies with larger cohorts and longer follow-up periods are needed to validate our findings and establish the NTL approach as a standard practice in OLT.

Effect of statins on the recurrence of hepatocellular carcinoma after liver transplantation: An illusion revealed by exposure density sampling.

Statins have been reported to reduce overall death and hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT) recipients. However, previous retrospective studies have significant flaws in immortal time bias. Using data from 658 patients who received LT for HCC, we matched 140 statin users with statin nonusers in a 1:2 ratio at the time of the first statin administration after LT using the exposure density sampling (EDS). The propensity score, calculated using baseline variables (including explant pathology), was used for EDS to equilibrate both groups. HCC recurrence and overall death were compared after adjusting for information at the time of sampling. Among statin users, the median time to statin start was 219 (IQR 98-570) days, and intensity of statins was mainly moderate (87.1%). Statin users and nonusers sampled using EDS showed well-balanced baseline characteristics, including detailed tumour pathology, and similar HCC recurrence with cumulative incidences of 11.3% and 11.8% at 5 years, respectively (p = .861). In multivariate Cox models (HR 1.04, p = .918) and subgroup analyses, statins did not affect HCC recurrence. Conversely, statin users showed a significantly lower risk of overall death than nonusers (HR 0.28, p < .001). There was no difference in the type and intensity of statin usage between statin users who experienced HCC recurrence and those who did not. Upon controlling immortal time bias by EDS, statins did not affect HCC recurrence but reduced mortality after LT. Statin usage is encouraged for survival benefits but not for preventing HCC recurrence in LT recipients.

Impact of donor sex on hepatocellular carcinoma recurrence in liver transplantation after brain death.

Hepatocellular carcinoma (HCC) is predominantly seen in males but has a better prognosis in females. No prior studies have investigated HCC recurrence based on sex combination following liver transplant donated after brain death (DBDLT). This study sought to elucidate the effects of donor and recipient sex on HCC recurrence rates. 9232 adult recipients from the United Network for Organ Sharing (UNOS) database who underwent DBDLT for HCC from 2012 to 2018 were included. Donor-recipient pairs were divided into (1) female donor/female recipient (F-F) (n=1089); (2) male donor/female recipient (M-F) (n=975); (3) female donor/male recipient (F-M) (n=2691); (4) male donor/male recipient (M-M) (n=4477). The primary prognostic outcome was HCC recurrence. A multivariable competing risk regression analysis was used to assess prognostic influences. The median recipient age and model for end-stage liver disease (MELD) scores were similar among the four groups. Livers of male recipients demonstrated greater in size and number of HCC (both p-values were <.0001). There was also a higher rate of vascular invasion in male recipients compared to female (p<.0001). Competing risk analyses showed that the cumulative HCC recurrence rate was significantly lower in the M-F group (p=.013). After adjusting for tumor characteristics, liver grafts from male donors were associated with a lower HCC recurrence rate in female recipients (HR: .62 95%CI: .42-.93) (p=.021). In DBDLT, male donor to female recipient pairing exhibited lower HCC recurrence rates. Lowest rates of HCC recurrence were confirmed among the female recipients of male donor grafts group in the deceased donor LT cohort. A competing risk multivariable regression analysis demonstrated that male donor sex was significantly associated with low HCC recurrence in female but not male recipients.

Preoperative Coagulation Assessment with Thromboelastography to Predict Hepatocellular Carcinoma Recurrence in Liver Transplantation Recipients

INTRODUCTION: Hepatocellular carcinoma (HCC) recurrence in liver transplantation portends to poor survival. Recent studies have used tumor burden, microvascular invasion, and α-fetoprotein to predict recurrence. However, the use of thromboelastographs (TEGs) to predict recurrence has not been evaluated. The objective of this study was to identify if TEGs can predict HCC recurrence in liver transplant recipients. METHODS: Thromboelastographs were measured preoperatively in HCC patients who underwent liver transplant between March 2008 and September 2021. Receiver operating characteristic curve was used to find specific TEG indices associated with recurrence using Youden index for variables with a p value of <0.1. Disease-free survival time was compared in patients with and without coagulation risk factors for recurrent HCC (Figure). RESULTS: Twenty-three of 280 transplant patients with HCC had recurrence (8%). Reaction time (R-time) was significantly longer in patients with recurrence (p = 0.048) with a Youden index >5.8 minutes. Maximum amplitude (MA) also met criteria for inclusion (p = 0.059) with an inflection point of >53 mm. The combination of MA >53 mm and R-time >5.8 minutes was associated with a 19% HCC recurrence rate vs 1.6% (p = 0.001). When controlling for age >65 (hazard ratio of 2.782, p = 0.017), having 2 or more risk factors was associated with an odds ratio of 17.2 for recurrence (95% CI 2.1 to 143, p = 0.008). CONCLUSION: The combination of R-time >5.8 minutes and MA >53 mm was significantly associated with HCC recurrence. These measurements may help identify patients who are candidates for liver transplant with HCC that are beyond Milan and UCSF criteria and help with screening of recurrent disease in patients undergoing liver transplantation.Figure

A Pre-TACE Radiomics Model to Predict HCC Progression and Recurrence in Liver Transplantation: A Pilot Study on a Novel Biomarker.

Despite transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), a significant number of patients will develop progression on the liver transplant (LT) waiting list or disease recurrence post-LT. We sought to evaluate the feasibility of a pre-TACE radiomics model, an imaging-based tool to predict these adverse outcomes. We analyzed the pre-TACE computed tomography images of patients waiting for a LT. The primary endpoint was a combined event that included waitlist dropout for tumor progression or tumor recurrence post-LT. The radiomic features were extracted from the largest HCC volume from the arterial and portal venous phase. A third set of features was created, combining the features from these 2 contrast phases. We applied a least absolute shrinkage and selection operator feature selection method and a support vector machine classifier. Three prognostic models were built using each feature set. The models' performance was compared using 5-fold cross-validated area under the receiver operating characteristic curves. . Eighty-eight patients were included, of whom 33 experienced the combined event (37.5%). The median time to dropout was 5.6 mo (interquartile range: 3.6-9.3), and the median time for post-LT recurrence was 19.2 mo (interquartile range: 6.1-34.0). Twenty-four patients (27.3%) dropped out and 64 (72.7%) patients were transplanted. Of these, 14 (21.9%) had recurrence post-LT. Model performance yielded a mean area under the receiver operating characteristic curves of 0.70 (±0.07), 0.87 (±0.06), and 0.81 (±0.06) for the arterial, venous, and the combined models, respectively. A pre-TACE radiomics model for HCC patients undergoing LT may be a useful tool for outcome prediction. Further external model validation with a larger sample size is required.

Post liver transplant recurrence in patients with hepatocellular carcinoma: not necessarily the end of the road!

Post liver transplant recurrence in patients with hepatocellular carcinoma: not necessarily the end of the road!

Hypothermic Oxygenated Liver Perfusion (HOPE) Prevents Tumor Recurrence in Liver Transplantation From Donation After Circulatory Death.

The aim of this study was to investigate tumor recurrence after liver transplantation for hepatocellular carcinoma (HCC), with and without hypothermic oxygenated liver perfusion (HOPE) before transplantation. We analyzed all liver recipients with HCC, transplanted between January 2012 and September 2019 with donation after circulatory death (DCD) livers after previous end-ischemic HOPE-treatment (n = 70, Center A). Tumor parameters and key confounders were compared to consecutive recipients with HCC, transplanted during the same observation period with an unperfused DBD liver (n = 70). In a next step, we analyzed unperfused DCD (n = 70) and DBD liver recipients (n = 70), transplanted for HCC at an external center (Center B). Tumor parameters were not significantly different between HOPE-treated DCD and unperfused DBD liver recipients at Center A. One-third of patients were outside established tumor thresholds, for example, Milan criteria, in both groups. Despite no difference in tumor load, we found a 4-fold higher tumor recurrence rate in unperfused DBD livers (25.7%, 18/70), compared to only 5.7% (n = 4/70) recipients with tumor recurrence in the HOPE-treated DCD cohort (P = 0.002) in Center A. The tumor recurrence rate was also twice higher in unperfused DCD and DBD recipients at the external Center B, despite significant less cases outside Milan. HOPE-treatment of DCD livers resulted therefore in a 5-year tumor-free survival of 92% in HCC recipients, compared to 73%, 82.7%, and 81.2% in patients receiving unperfused DBD or DCD livers, from both centers. We suggest that a simple machine liver perfusion approach appears advantageous to protect from HCC recurrence after liver transplantation, despite extended tumor criteria.

Delta PD-1 Expressed M2 Macrophages Promote Liver Tumor Recurrence after Transplantation

Introduction Hepatocellular Carcinoma (HCC) is one of the dominant malignancies worldwide and become the primary cause for liver transplantation. Despite its effectiveness, tumor recurrence remains to be a challenge for liver transplantation especially in patients received living donor grafts. Macrophages are key immune cells mediating the inflammatory responses during injuries. Our group previously reported that a subpopulation of macrophages (M2) enhanced tumor metastasis and contributed to poor relapse free survival in HCC patients received curative hepatectomy. Currently, the implications as well as activation mechanisms of these cells in liver transplantation are unknown. Our preliminary evidences indicated the accumulation of a subset of M2 macrophages, expressed with Δ42PD-1, a natural isoform of a immune regulator PD-1, in the post-transplant tissues. We hypothesized that liver graft injury during transplantation activate M2 macrophages, via Δ42PD-1 mechanism, leads to tumor recurrence and poor outcome in HCC patients. Materials and Methods A clinical cohort of 100 HCC patients who underwent deceased (DDLT) and living (LDLT) donor liver transplantation were included. To understand its clinical implications, the expression level of tissue M2 macrophages with and without Δ42PD-1+ were examined followed by the association analyses with patients post-transplant outcomes. To investigate its roles in recurrence, Δ42PD-1+ populations isolated from patients were studied in rat tumor transplant model and in vitro co-cultivation system with HCC cells (Figure 1). Results and Discussion Clinically, 2.1 fold elevation of intra-hepatic M2 macrophages were found in living donor graft compared to deceased graft during the early phase of post-transplantation (P<0.01)(Figure 2). In addition, we identified the increased of Δ42PD-1 expressed in the elevated M2 sub-population (Figure 3). Further analysis indicated the M2 macrophages contributed to the higher recurrence incidences and shorter relapse free survival in patients (P=0.036)(Figure 4A and 4B). In vivo study showed that liver graft injuries significantly induced the accumulation of M2 macrophages after transplantation and resulted in larger tumor volume in the rat transplant tumor model. We showed that that Δ42PD-1[high] macrophages expressed characteristic M2 phenotypes including pro-tumor cytokine secretory profiles compared to Δ42PD-1[low] cells. Co-cultivation of Δ42PD-1[high] population with HCC cells significant increased tumor cells proliferation. Conclusion Here we revealed a novel cellular mechanism in promoting the post-transplant recurrence in liver transplantation. Liver graft injury induced the accumulation and activation of tumor promoting Δ42PD-1 M2 macrophages. Targeting the specific immune population and the regulatory mechanism represent a potential therapeutic strategy in attenuating tumor recurrence in HCC.

Short Course of Postoperative Hepatitis B Immunoglobulin Plus Antivirals Prevents Reinfection of Liver Transplant Recipients.

Hepatitis B immune globulin (HBIG) has been an integral component of prophylaxis against hepatitis B virus (HBV) recurrence in liver transplantation (LT) recipients, but HBIG is costly and inconvenient to administer, prompting consideration of alternative regimens. In this retrospective cohort, we report on the success of antiviral therapy combined with a short course (in hospital only) HBIG in liver transplant recipients with HBV DNA less than 100 IU/mL pre-LT. A total of 42 hepatitis B surface antigen (HBsAg) positive, human immunodeficiency virus and hepatitis D virus-negative patients with pretransplant HBV DNA undetectable to 100 IU/mL who received HBIG 5000 IU in anhepatic phase and daily for 5 days together with nucleos(t)ide analogues indefinitely yielded 1- and 3-year cumulative incidences of recurrence, defined by positive serum HBsAg, of 2.9% (upper 95% confidence interval, 19%). One patient had HBV viremia 16 months post-LT without detectable HBsAg. Both patients with either HBsAg positivity or viremia had recurrent hepatocellular carcinoma diagnosed within a month of detection. Post-LT survival was 98% and 94% at 1 and 5 years, respectively. We conclude that a very short course of HBIG combined with long-term antiviral therapy is highly effective in preventing HBV recurrence and should be the preferred strategy for LT recipients with undetectable or low-level viremia at time of LT.

Bi-directional roles of IRF-1 on autophagy diminish its prognostic value as compared with Ki67 in liver transplantation for hepatocellular carcinoma.

The prognostic values of IRF-1 and Ki-67 for liver transplantation (LT) of hepatocellular carcinoma (HCC) were investigated, as well as the mechanisms of IRF-1 in tumor suppression. Adult orthotropic liver transplantation cases (N = 127) were involved in the analysis. A significant decreased recurrence free survival (RFS) was found in the Ki-67 positive groups. Ki-67, tumor microemboli, the Milan and UCSF criteria were found to be independent risk factors for RFS. In LT for HCC beyond the Milan criteria, a significant decrease in RFS was found in the IRF-1 negative groups. In SK-Hep1 cells, an increase in apoptosis and decrease in autophagy were observed after IFN-γ stimulation, which was accompanied with increasing IRF-1 levels. When IRF-1 siRNA or a caspase inhibitor were used, reductions in LC3-II were diminished or disappeared after IFN-γ stimulation, suggesting that IFN-γ inhibited autophagy via IRF-1 expression and caspase activation. However, after IRF-1 siRNA was introduced, a reduction in LC3-II was found. Thus basic expression of IRF-1 was also necessary for autophagy. IRF-1 may be used as a potential target for HCC treatment based on its capacity to affect apoptosis and autophagy. Ki-67 shows great promise for the prediction of HCC recurrence in LT and can be used as an aid in the selection of LT candidates.

Prognosis after recurrence of hepatocellular carcinoma in liver transplantation: predictors for successful treatment and survival.

There are no established prognostic factors or standardized therapies for hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT). The aim of this study was to investigate impact of underlying patient condition on treatment and outcomes of recurrence of HCC after LT. The medical records of 268 LT patients with HCC were evaluated. Potential prognostic factors for survival after recurrence were evaluated, including recurrent tumor characteristics, medical/radiological/surgical therapies for recurrence, and an inflammatory marker (neutrophil/lymphocyte ratio). Laboratory tests at recurrence, including albumin, absolute lymphocyte count (ALC), prognostic nutritional index (PNI: ALC(/μL) × 0.005 + Albumin(g/dL) × 10), were evaluated as surrogate markers for underlying patient conditions. A total of 51 (19%) patients developed HCC recurrence. The use of sirolimus and sorafenib significantly improved outcome (p = 0.007 and 0.04), and better nutritional status (PNI ≥ 40) enhanced their efficacy. On multivariate analysis, low ALC (<500/μL) and albumin (<2.8 g/L) remained independent prognostic factors (p = 0.03 and 0.02; hazard ratio = 3.61 [Ref. >1000/μL] and 4.97 [Ref. >3.5 g/dL], respectively). Low PNI (<40) showed significantly lower survival rate after adjusting the risk (p = 0.006, hazard ratio = 3.29). Underlying patient conditions and nutritional status, represented by ALC and albumin, are important to successful cancer treatment and strong prognostic markers for survival after HCC recurrence.

Lack of a 5.9 kDa peptide C-terminal fragment of fibrinogen α chain precedes fibrosis progression in patients with liver disease.

Early detection of fibrosis progression is of major relevance for the diagnosis and management of patients with liver disease. This study was designed to find non-invasive biomarkers for fibrosis in a clinical context where this process occurs rapidly, HCV-positive patients who underwent liver transplantation (LT). We analyzed 93 LT patients with HCV recurrence, 41 non-LT patients with liver disease showing a fibrosis stage F≥1 and 9 patients without HCV recurrence who received antiviral treatment before LT, as control group. Blood obtained from 16 healthy subjects was also analyzed. Serum samples were fractionated by ion exchange chromatography and their proteomic profile was analyzed by SELDI-TOF-MS. Characterization of the peptide of interest was performed by ion chromatography and electrophoresis, followed by tandem mass spectrometry identification. Marked differences were observed between the serum proteome profile of LT patients with early fibrosis recurrence and non-recurrent LT patients. A robust peak intensity located at 5905 m/z was the distinguishing feature of non-recurrent LT patients. However, the same peak was barely detected in recurrent LT patients. Similar results were found when comparing samples of healthy subjects with those of non-LT fibrotic patients, indicating that our findings were not related to either LT or HCV infection. Using tandem mass-spectrometry, we identified the protein peak as a C-terminal fragment of the fibrinogen α chain. Cell culture experiments demonstrated that TGF-β reduces α-fibrinogen mRNA expression and 5905 m/z peak intensity in HepG2 cells, suggesting that TGF-β activity regulates the circulating levels of this protein fragment. In conclusion, we identified a 5.9 kDa C-terminal fragment of the fibrinogen α chain as an early serum biomarker of fibrogenic processes in patients with liver disease.

Antiviral interventions for liver transplant patients with recurrent graft infection due to hepatitis C virus.

Antiviral therapy for recurrent hepatitis C infection after liver transplantation is controversial due to unresolved balance between benefits and harms. To compare the therapeutic benefits and harms of different antiviral regimens in patients with hepatitis C re-infected grafts after liver transplantation. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2013), MEDLINE, EMBASE, and Science Citation Index Expanded to February 2013. We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing various antiviral therapies (alone or in combination) in the treatment of hepatitis C virus recurrence in liver transplantation for the review. Two authors collected the data independently. We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) using the fixed-effect and the random-effects models based on available case-analysis. In the presence of only trials for a dichotomous outcome, we performed the Fisher's exact test. Overall, 17 trials with 736 patients met the inclusion criteria for this review. All trials had high risk of bias. Five hundred and one patients randomised in 11 trials provided information for various comparisons in this systematic review after excluding post-randomisation drop-outs and patients from trials that did not report any of the outcomes of interest for this review. The comparisons for which outcomes were available included pegylated (peg) interferon versus control; peg interferon plus ribavirin versus control; ribavirin plus peg interferon versus peg interferon; peg interferon (1.5 μg/kg/week) plus ribavirin versus peg interferon (0.5 μg/kg/week) plus ribavirin; amantadine plus peg interferon plus ribavirin versus peg interferon plus ribavirin; interferon versus control; interferon plus ribavirin versus control; ribavirin versus interferon; and ribavirin versus placebo. Long-term follow-up was not available in these trials. There were no significant differences in mortality, retransplantation, graft rejections requiring retransplantation or medical treatment, or fibrosis worsening between the groups in any of the comparisons in which these outcomes were reported. Quality of life and liver decompensation were not reported in any of the trials. There was a significantly higher proportion of participants who developed serious adverse events in the ribavirin plus peg interferon combination therapy group than in the peg interferon monotherapy group (1 trial; 56 participants; 17/28 (60.7%) in the intervention group versus 5/28 (17.9%) in the control group; RR 3.40; 95% CI 1.46 to 7.94). There was no significant difference in proportion of participants who developed serious adverse events or in the number of serious adverse events between the intervention and control groups in the other comparisons that reported serious adverse events. Considering the lack of clinical benefit, there is currently no evidence to recommend or refute antiviral treatment for recurrent liver graft infection with hepatitis C virus. Further randomised clinical trials with low risk of bias and low risk of random errors with adequate duration of follow-up are necessary.

A novel immunological approach to prevent HCV recurrence in liver transplantation

A novel immunological approach to prevent HCV recurrence in liver transplantation

Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver

Liver transplantation (LT) is a cure for many liver diseases. Blood chimerism of donor origin can develop after LT, which raises the possibility of the existence of hematopoietic stem/progenitor cells (HSPCs) in the liver. We characterized the blood chimerism in a large cohort of 249 LT patients and analyzed putative HSPCs in adult human livers. The overall incidence of chimerism was 6.43%, of which 11.11% was among short-term (1 day to 6 months) and 3.77% was among long-term (6 months to 8 years) LT patients. Hematopoietic Lin(-) CD34(+) CD38(-) CD90(+) populations have been demonstrated to generate long-term lymphomyeloid grafts in transplantations. In human adult livers, we detected Lin(-) CD34(+) CD38(-) CD90(+) populations accounting for 0.03% ± 0.017% of the total single liver cells and for 0.05% ± 0.012% of CD45(+) liver cells. Both Lin(-) CD34(+) and Lin(-) CD45(+) liver cells, from extensively perfused human liver grafts, were capable of forming hematopoietic myeloid-lineage and erythroid-lineage methylcellulose colonies. More importantly, Lin(-) CD45(+) or CD45(+) liver cells could be engrafted into hematopoietic cells in an immunodeficient mouse model. These results are the first evidence of the presence of putative HSPC populations in the adult human liver, where the liver is a good ectopic niche. The discovery of the existence of HSPCs in the adult liver have implications for the understanding of extramarrow hematopoiesis, liver regeneration, mechanisms of tolerance in organ transplantation, and de novo cancer recurrence in LT patients. The human adult liver contains a small population of HSPCs. In LT patients, there are two types of chimerisms: transient chimerism, resulting from mature leucocytes, and long-term chimerism, derived from putative HSPCs in the liver graft.

Circulating Tumor Cells in Hepatocellular Carcinoma: Detection Techniques, Clinical Implications, and Future Perspectives

Hepatocellular carcinoma (HCC) is a primary liver cancer with a huge challenge in terms of its complex etiology and its management. The fact that the most common site of early tumor recurrence in liver transplantation for HCC is the transplanted allograft strongly suggests that circulating tumor cells (CTCs) are really an active source of HCC metastasis or recurrence. In the past decade, with the tremendous progress in the technology of CTC detection, there is convincing evidence that CTCs have great potential as a marker for metastatic disease and poor prognosis in patients with a malignancy. Currently some interesting and encouraging results have been achieved in HCC CTC detection, although the knowledge about its clinical relevance in HCC is lagging behind other major tumor types. Here we will review existing and developing methodologies for CTC detection, discuss future perspectives, and describe the potential clinical impact of the identification and molecular characterization of CTC subset or circulating cancer stem cells in HCC patients. Particular attention is given to the results based on the HCC CTC study.

Influence of Immunosuppressive Drugs on the Recurrence of Hepatocellular Carcinoma After Liver Transplantation: A Gap Between Basic Science and Clinical Evidence

Effects of immunosuppressive drug on tumor development in transplantation are understudied. Tumors are especially concerning when liver transplantation recipients have a pretransplant hepatocellular carcinoma (HCC). Because immunosuppressive drugs likely influence HCC recurrence, with mammalian target of rapamycin inhibitors showing antineoplastic properties especially experimentally, we sought for practical medical guidance from published clinical studies. Although the current literature review revealed 14 studies regarding immunosuppression in this context, suggesting antitumor effects for mammalian target of rapamycin inhibitors, the quality of evidence is low. Therefore, randomized controlled trials investigating effects of immunosuppression on HCC recurrence in liver transplantation are lacking, exposing a gap between basic science knowledge and clinical evidence.

Prediction of Tumor Recurrence by 18F-FDG PET in Liver Transplantation for Hepatocellular Carcinoma

Although several prognostic factors are used to predict recurrence and to select adequate candidates for liver transplantation for hepatocellular carcinoma (HCC), these prognostic factors have some clinical limitations. The purpose of this study was to evaluate (18)F-FDG PET as a prognostic factor and to optimize its ability to predict tumor recurrence in liver transplantation for HCC. The study included a total of 59 HCC patients (45 men and 15 women; mean age +/- SD, 56 +/- 8 y) who underwent (18)F-FDG PET and subsequent orthotopic liver transplantation. All patients were followed up for more than 1 y (mean, 29 +/- 17 mo), and recurrence of tumor was monitored. Three PET parameters-maximal standardized uptake value (SUV(max)), ratio of tumor SUV(max) to normal-liver SUV(max) (T(SUVmax)/L(SUVmax)), and ratio of tumor SUV(max) to normal-liver mean SUV (T(SUVmax)/L(SUVmean))-were tested as prognostic factors and compared with conventional prognostic factors. Among the 3 parameters tested, T(SUVmax)/L(SUVmax) was the most significant in the prediction of tumor recurrence, with a cutoff value of 1.15. In a multivariate analysis of various prognostic factors including T(SUVmax)/L(SUVmax), serum alpha-fetoprotein, T stage, size of tumor, and vascular invasion of tumor, T(SUVmax)/L(SUVmax) was the most significant, and only vascular invasion of tumor had additional significance. According to T(SUVmax)/L(SUVmax), the 1-y recurrence-free survival rate above the cutoff was markedly different from the rate below the cutoff (97% vs. 57%, P < 0.001). In this study, (18)F-FDG PET was an independent and significant predictor of tumor recurrence. In liver transplantation for HCC, (18)F-FDG PET can provide effective information on the prognosis for tumor recurrence and the selection of adequate candidates for liver transplantation.

P.399 Hepatitis C recurrence in liver transplantation in University Hospital “Merkur”, Zagreb

P.399 Hepatitis C recurrence in liver transplantation in University Hospital “Merkur”, Zagreb

Preliminary Results of a “Prope” Tolerogenic Regimen with Thymoglobulin Pretreatment and Hepatitis C Virus Recurrence in Liver Transplantation

Recent reports demonstrate the efficacy of induction immunosuppression with Thymoglobulin, a potent antithymocyte polyclonal antibody, in allowing acquired tolerance by means of a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression. The effect of this novel approach on recurrence of hepatitis C viral disease after liver transplantation has never been investigated. We report the preliminary results of a retrospective analysis aimed at discovering any relationship between Thymoglobulin immunosuppression and the pattern of recurrence of hepatitis C. Thymoglobulin induction plus tacrolimus monotherapy was used in a group of 22 hepatitis C virus (HCV)+ patients receiving liver transplantation; 30 HCV+ patients receiving transplants within the same year received conventional tacrolimus plus steroid immunosuppression and represented the comparison group. Patient survival and acute rejection rate did not differ between the two groups. Significantly lower dosages and levels of tacrolimus were possible with Thymoglobulin, and a progressive weaning of tacrolimus monotherapy was accomplished in most patients, without major rejection complications. The HCV recurrence rate was similar in both groups, although significantly lower HCV RNA loads were obtained with Thymoglobulin pretreatment. The mean time to histologic recurrence was shorter in Thymoglobulin-treated patients; however, no significant difference was observed in mean Ishak's histologic grading and staging of HCV recurrence. In our preliminary experience, a "prope" tolerogenic regimen with Thymoglobulin pretreatment and low-dose immunosuppression in liver-transplant recipients gave good protection against rejection and permitted lower HCV viral loads, whose significance in the long-term outcome of HCV patients deserves further investigation.