Criteria to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT) are based on tumor size and number of nodules rather than on tumor biology. The present study was undertaken to assess the role of transarterial chemoembolization (TACE) in selecting patients with tumors suitable for LT. Ninety-six consecutive patients with HCC were treated by repeatedly performed TACE, 62 of them exceeding the Milan criteria. Patients meeting the Milan criteria were immediately listed, and patients beyond the listing criteria were listed upon downstaging of the tumor following successful TACE. Fifty patients were finally transplanted. Of these 50 patients, 34 exceeded the Milan criteria. In these 96 patients, overall 5-year survival was 51.9%. However, it was 80.9% for patients undergoing LT and 0% for patients without transplantation (P Ͻ 0.0001). Tumor recurrence was primarily influenced by the control of the disease through continued TACE during the waiting time. Freedom from recurrence after 5 years was 94.5% in patients (n ϭ 39) with progression-free TACE during the waiting time. Tumor recurrence was significantly higher in patients (n ϭ 11) who after initial response to TACE progressed again before LT (freedom from recurrence 35.4%; P ϭ 0.0017). Progression-free course of TACE during the waiting time (P ϭ 0.006; risk ratio, 8.95), and a limited number of tumor nodules as assessed in the surgical specimen (P ϭ 0.025; risk ratio, 0.116) proved to be significant predictors for freedom from recurrence in the multivariate analysis. Milan criteria were without impact on recurrence. Our data suggest that sustained response to TACE is a better selection criterion for LT than the initial assessment of tumor size or number.

BackgroundWe investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).MethodsIn a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint.ResultsRecurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874).ConclusionsSirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Arterial steal syndromes (ASSs) after orthotopic liver transplantation (OLT) are characterized by arterial hypoperfusion of the graft caused by shifting of blood flow into the splenic or gastroduodenal artery. Despite their potentially devastating consequences, such as ischemic biliary tract destruction or graft failure, ASSs have received little attention to date. We report the incidence, diagnosis, and treatment of ASS among 1,250 consecutive OLTs. ASS was observed in 69 patients (5.9%). All these patients presented with elevated liver enzyme levels, impaired graft function, or cholestasis. Treatment consisted of splenectomy (n ‫؍‬ 18), coil embolization of the splenic or gastroduodenal artery (n ‫؍‬ 29), or reduction in splenic artery blood flow through administration of an artificial stenosis (banding; n ‫؍‬ 9). Mild symptoms of ASS did not warrant treatment in 13 patients. However, 3 of these patients developed ischemic biliary destruction requiring re-OLT. Serious complications also were observed after splenectomy and coil embolization, requiring re-OLT in 18%. Conversely, no complications were observed after banding the splenic artery. Prophylactic banding of the splenic artery was performed in 97 patients and was associated with a complication rate of 4%. In summary, the incidence of ASS is similar to that of other vascular complications. Untreated ASSs may lead to serious complications in more than 30% of patients. Of a variety of treatment options, banding the splenic artery was associated with the lowest complication rate. Banding also may be performed prophylactically in selected patients to prevent the development of ASS after OLT. (Liver Transpl 2003;9: 596-602.)

Complications involving the portal vein or the vena cava, are rare after orthotopic liver transplantation. We report on the incidence and treatment of venous complications following 1000 orthotopic liver transplantations in 911 patients. Twenty-six of the adult patients (2.7%) suffered from portal complications after transplantation, whereas complications of the vena cava were observed in only 17 patients (1.8%). Technical problems or recurrence of the underlying disease (e.g. Budd-Chiari syndrome) accounted for the majority of complications of the vena cava, whereas alteration of the vessel wall or splenectomy during transplantation could be identified as important risk factors for portal vein complications. In patients undergoing modification of the standard end-to-end veno-venous anastomosis of the portal vein due to pathological changes of the vessel wall, complications occurred in 8.3%, whereas only 2.4% of patients who received a standard anastomosis of the portal vein experienced complications of the portal vein. Furthermore, splenectomy during transplantation was also associated with an increased incidence of portal vein complications (10.5 vs. 2.2% in patients without splenectomy). Treatment was dependent on the signs and symptoms of the patients, and varied considerably between patients with portal vein complications and patients suffering from complications of the vena cava. Complications of the vena cava led to retransplantation in about one-third of the patients, whereas in patients with occlusion of the portal vein, retransplantation was necessary in only 15%, and more than half of the patients suffering from portal vein complications did not require any treatment at all. Usually, treatment of patients with portal vein complications only became necessary when additional complications such as arterial occlusion or bile duct injuries occurred.

Ischemic-type biliary lesions (ITBL) belong to a group of biliary disorders that are regarded as the major complication in patients with orthotopic liver transplantation (OLT). We performed histological evaluation of donor common bile ducts received during OLT to find morphological clues to the pathomechanisms of ITBL. We investigated 93 grafts of 92 patients (recipients: mean age, 56.5 years; underlying disease: hepatocellular carcinoma (n = 45), alcoholic cirrhosis (n = 16), viral hepatitis with cirrhosis (n = 9), retransplantations (n = 9), others (n = 14); donors: mean age, 53.2 years). Donor common bile ducts were received after recirculation of the hepatic artery prior to biliary end-to-end anastomosis and routinely processed. Statistical evaluation was performed by chi-square analysis and multivariate analysis using a logistic regression model. With regard to ITBL (observed in 19.4 %), the following phenomena were found to be statistically relevant: necrosis of the bile duct wall, arteriolonecrosis, vascular lesions (such as subintimal edema), and intramural bleeding (P < 0.001, P < 0.001, P = 0.029, and P = 0.031, respectively). In logistic regression analysis, arteriolonecrosis was the only parameter with significance (P = 0.001). Based on these results on the morphology of the donor common bile duct, we conclude that these phenomena of vascular damage, reflecting microangiopathy, play a major role in the pathogenesis of ITBL.

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Despite striking differences in local tumor recurrence and shorter time to progression, survival in patients with early CRLM does not depend on the mode of primary hepatic treatment.

BackgroundOrganic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).MethodsOCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs.ResultsReal time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p ≤ 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression.In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC.ConclusionThe downregulation of OCT1 is associated with tumor progression and a worse patient survival.