Background: Organic 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). Methods: OCT1 (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. Results: Real 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. Conclusion: The downregulation of OCT1 is associated with tumor progression and a worse patient survival.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

The polyspecific organ cation transporter 1 (OCT1) is one of the most important active influx pumps for drugs like the kinase inhibitor sorafenib. The aim of this retrospective study was the definition of the role of intratumoral OCT1 mRNA expression in hepatocellular carcinoma (HCC) as a biomarker in systemic treatment with sorafenib. OCT1 mRNA expression levels were determined in biopsies from 60 primary human HCC by real time PCR. The data was retrospectively correlated with clinical parameters. Intratumoral OCT1 mRNA expression is a significant positive prognostic factor for patients treated with sorafenib according to Cox regression analysis (HR 0.653, 95 %-CI 0.430-0.992; p = 0.046). Under treatment with sorafenib, a survival benefit could be shown using the lower quartile of intratumoral OCT1 expression as a cut-off. Macrovascular invasion (MVI) was slightly more frequent in patients with low OCT1 mRNA expression (p = 0.037). Treatment-induced AFP response was not associated with intratumoral OCT1 mRNA expression levels (p = 0.633). This study indicates a promising role for intratumoral OCT1 mRNA expression as a prognostic biomarker in therapeutic algorithms in HCC. Further prospective studies are warranted on this topic.

Primary hepatic angiosarcoma (PHA) is a rare tumor entity. Radical surgical resection is currently considered the best treatment choice. The aim of this analysis is to report our experience with surgery for PHA. All resections of PHA from 01/2002 until 06/2017 were identified from our prospective institutional database. All cases were re-confirmed by a second pathologist. We analyzed completeness of resection, overall (OS) and disease-free survival (DFS). Nine patients with PHA underwent hepatic resection. Median follow-up after surgery was 15.5 months (range: 3–144). At last follow-up 4/9 patients were alive, three of them without recurrence 15, 21 and 144 months after surgery. Five patients developed PHA recurrence. Four of these died 3 to 17 months after surgery. One patient with PHA recurrence is alive 15 months after surgery. Another patient without PHA recurrence died 59 months after surgery from pancreatic cancer. Median OS and DFS after resection was 18 months (range: 3–144 months) and 10 months (range: 2–144 months), respectively. After R-0 resection (n = 8), the median OS and DFS was 59 and 11 months. Resection of PHA is the only approach to achieve complete tumor removal and offers a chance for long-term survival and should be evaluated in cases of PHA.

Background: Intrahepatic cholangiocarcinoma (ICC) is often diagnosed in advanced stage. Aim of this study was to analyse the influence of resection margins and tumor distance to the liver capsule on survival and recurrence in a single center with a high number of extended resections. Methods: From January 2008 to June 2018 data of all patients with ICC were collected and further analysed with Kaplan Meier Model, Cox regression or Chi² test for categorical data. Results: Out of 210 included patients 150 underwent curative intended resection (71.4%). Most patients required extended resections (n = 77; 51.3%). R0-resection was achieved in 131 patients (87.3%) with minimal distances to the resection margin > 1 cm in 22, 0.5-1 cm in 11, 0.1–0.5 cm in 49 patients, and < 0.1 cm in 49 patients. Overall survival (OS) for margins > 0.5 cm compared to 0.5–0.1 cm or R1 was better, but without reaching significance. All three groups had significantly better OS compared to the irresectable group. Recurrence-free survival (RFS) was also better in patients with a margin > 0.5 cm than in the < 0.5–0.1 cm or the R1-group, but even without reaching significance. Different distance to the liver capsule significantly affected OS, but not RFS. Conclusions: Wide resection margins (> 0.5 cm) should be targeted but did not show significantly better OS or RFS in a cohort with a high percentage of extended resections (> 50%). Wide margins, narrow margins and even R1 resections showed a significant benefit over the irresectable group. Therefore, extended resections should be performed, even if only narrow margins can be achieved.

For complete removal of intrahepatic cholangiocarcinoma (ICC), extended resection is often necessary. Information on the influence of visceral or vascular extension, extended resection, or postoperative morbidity on survival is scarce. The aim of this study was to show the impact of an aggressive surgical attitude on morbidity, mortality, and long-term outcome. All explorations at a high volume tertiary center between January 2008 and June 2018 with histological proof of ICC were included in this retrospective cohort study. The primary outcome was the extent of resection, secondary outcomes were postoperative morbidity, and their influence on overall survival (OS) and recurrence-free survival (RFS). Out of 210 patients, 150 underwent curative intended resection. A total of 87 extended, 26 major, and 37 minor resections were performed.In-hospital morbidity occurred in 46% of patients, with a 90-daymortality of 8%. Severity and frequency of morbidity did not differ significantly in the extended, major, or minor resection groups. If minor or major resections with visceral and/or vascular extensions were included in the extended resection group, minor (p = 0.005) and major (p = 0.042) resection had significantly better OSthan the extended resection group. All groups had significantly better OS than the exploration group. Comparing the different extended resection groups (segmental extended resection, segmental extended resection with visceral/vascular extension, minor/major resection with visceral/vascular extension), no difference was found (p = 0.977). Regarding RFSand the extent of resection, minor resection benefitted RFS, though not significantly (p = 0.051). Morbidity had no influence on RFS (p = 0.649). Extended resection results in worse OS in patients with ICC than major or minor liver resection. Minor and major resection with visceral or vascular extension should be classified as extended resection. Despite worse OS, extended resection offers a chance for long-term survival and performs significantly better than the exploration group with manageable accompanied risks.