Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker.

BACKGROUND: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease. METHODS: We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany. RESULTS: We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs. CONCLUSIONS: By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.

[The German Transplant Registry - An Analysis of Legacy Data 2006-2016]. / Das Deutsche Transplantationsregister ­ eine Analyse der Altdaten 2006­2016.

INTRODUCTION: In 2018, medical transplant data from three institutions were merged to create a German transplant registry. Since June 2021, access to data of the registry has been available. It was planned to analyze the registry data in order to compare special allocation rules with regular allocation for heart, liver, lung, and kidney transplantation. Our approach led to a quality analysis of the registry. METHODS: Upon request, legacy data (2006-2016) of the registry was provided, divided into 61 elements. From these elements, the user had to compile the required dataset. Data checks were performed for completeness, correct allocation of information, and consistency among different sources. Software used for these tasks included R, SQL, and Excel. RESULTS: The initial elements ("waiting list" elements) of the four types of transplantations contained data from a total of 80,259 originally listed patients. However, these patients were only partially present in other elements resulting in complete datasets reflecting waiting time in only 23%, 30%, 50%, and 96%, and for post-transplantation outcomes in 14%, 11%, 38%, and 13% (heart, liver, lung, and kidney transplantation, respectively). The linking of urgency information with clinical data was successful in only a small proportion, with only 6% for heart transplantation. Incorrect and thus implausible allocations in the case of special allocation rules indicated incorrect entries in the registry. Data from different data providers were inconsistent. DISCUSSION: The incompleteness and incorrect data allocation raise doubts about the reliability of scientific studies based on the transplant registry. The complex structure also hinders the compilation of a reliable dataset, which is uncommon internationally. New data (acquisition since 2017) has only been available since December 2023. CONCLUSION: The transplant registry urgently needs restructuring. Competent clinical data management, involving transplant medical expertise, and continuous quality controls are essential in this process.

Microvascular invasion of hepatocellular carcinoma predicts microvascular invasion of its recurrence: potential implications for salvage liver transplantation?

Background: Microvascular invasion (MVI) can only be assessed on a full surgical specimen. We aimed at evaluating, whether the histology of the primary tumor is predictive of MVI in a hepatocellular carcinoma (HCC) recurrence. Methods: Patients, who underwent liver resection or orthotopic liver transplantation (OLT) for recurrent HCC from January 2001 until June 2018 were eligible for this retrospective analysis. Resected specimens were evaluated for HCC subtype/morphology, vessels encapsulating tumor clusters (VETC)-pattern and MVI. Dichotomous parameters were analyzed using χ2-test and ϕ-values, with P values <0.05 being considered significant. Results: Of 230 HCC recurrences, 37 (16.1%) underwent repeated liver resection (n=22) or OLT (n=15). Of these, 67.6% initially exceeded the Milan criteria. MVI correlated Milan criteria (P=0.005), tumor size (P=0.015) and VETC-pattern (P=0.034) in the primary specimen. The recurrences shared many features of the primary HCC such as tumor grade (P=0.002), VETC-pattern (P=0.035), and MVI (P=0.046). In recurrences, however, only the concordance with the Milan criteria correlated with MVI (P=0.018). No patient without MVI in the primary HCC revealed MVI on early recurrence (<2 years) (P=0.035). Conclusions: HCC recurrences share many biological features of the primary tumor. Moreover, early recurrences of MVI-negative HCC never revealed MVI. This finding offers novel concepts, e.g., patient selection for salvage OLT.

Transjugular Portosystemic Stent Shunt: Impact of Right Atrial Pressure on Portal Venous Hemodynamics Within the First Week.

PURPOSE: Porto-systemic pressure gradient is used to prognosticate rebleeding and resolution of ascites after TIPS. This study investigates the reliability of portal pressure characteristics as quantified immediately after TIPS placement and at short-term control. PATIENTS AND METHODS: Portal venous pressure (PVP) and right atrial pressure (RAP) were prospectively obtained before and after TIPS as well as ≥ 48 h after TIPS procedure. Porto-systemic pressure gradients (PSG) and pressure changes were calculated. A multivariate regression analysis was performed to predict portal hemodynamics at short-term control. RESULTS: The study included 124 consecutive patients. Indications for TIPS were refractory ascites, variceal bleeding or combinations of both. Pre- and post-interventional PSG yielded 16.4 ± 5.3 mmHg and 5.9 ± 2.7 mmHg, respectively. At that time, 105/124 patients (84.7%) met the target (PSG ≤ 8 mmHg). After 4 days (median), PSG was 8.5 ± 3.5 mmHg and only 66 patients (53%) met that target. In patients exceeding the target PSG at follow-up, PVP was significantly higher and RAP was lower resulting in the increased PSG. The highly variable changes of RAP were the main contributor to different pressure gradients. In the multivariate regression analysis, PVP and RAP immediately after TIPS were predictors for PSG at short-term control with moderately predictive capacity (AUC = 0.75). CONCLUSION: Besides the reduction of portal vein pressure, the highly variable right atrial pressure was the main contributor to different pressure gradients. Thus, immediate post-TIPS measurements do not reliably predict portal hemodynamics during follow-up. These findings need to be further investigated with respect to the corresponding clinical course of the patients.

High pretreatment static and dynamic alpha-fetoprotein values predict reduced overall survival in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha-fetoprotein (AFP) is a well-established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static AFP values is limited and the clinical potential is a matter of ongoing scientific discussion. OBJECTIVE: We here evaluated the prognostic impact of pretreatment static and dynamic AFP variables on overall survival of hepatocellular carcinoma patients in a Western cohort. METHODS: Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenberg University Mainz between 1998 and 2014 and two available pretreatment AFP-values (AFP-slope) were retrospectively analysed. Clinicopathological baseline parameters, pretreatment static values and AFP-slope were assessed. Prognostic impact was determined by Kaplan-Meier analyses and Cox regression models. RESULTS: High static and dynamic AFP variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child-Pugh B (p < 0.01) and C stage (p < 0.001), portal vein thrombosis (p < 0.001) and extrahepatic spread (p < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic AFP variable resulted in higher time-dependent area under the curves. Notably, in patients with more favourable prognosis, AFP-slope prior to therapy was a slightly stronger predictor for overall survival compared with static AFP values. CONCLUSION: Static and dynamic AFP variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP-slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis.

Liver transplantation and BCLC classification: Limitations impede optimum treatment.

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) system has been endorsed by international guidelines as a staging algorithm of hepatocellular carcinoma. This analysis was performed to assess the outcome of liver transplantation in patients treated against the BCLC recommendations. METHODS: The data of 198 patients who underwent liver transplantation for hepatocellular carcinoma were extracted from a prospectively maintained database to classify the patients according to the BCLC system. RESULTS: BCLC staging was as follows: 0, n = 5; A, n = 77; B, n = 41; C, n = 53; and D, n = 22. Accordingly, liver transplantation was performed in the majority of patients against BCLC recommendations. Surgery (n = 16), radiofrequency ablation (n = 15) and transarterial chemoembolization (n = 151) preceded liver transplantation in 182 patients. Sixteen patients were transplanted without pretreatment. The1-, 5- and 10-year survival rates were 83.8%, 62.4% and 45.9%, and 1-, 5-, and 10-year recurrence rates were 7.7%, 22.7% and 26.7%. The BCLC classification did neither impact survival (P = 0.796) nor recurrence (P = 0.693). In the Cox analysis, RECIST tumor progression and initial alpha fetoprotein were independent predictors of outcome. CONCLUSIONS: Neither the oncological nor the functional stratification imposed by the BCLC system was of importance for outcome. Lack of flexibility and disregard of biological parameters hamper its clinical applicability in liver transplantation.

Decision making for transjugular intrahepatic portosystemic stent shunt in refractory ascites and variceal bleeding: MELD, or not MELD, that is the question.

PURPOSE: The model of end-stage liver disease (MELD) score has been shown to predict 3-month prognosis following transjugular intrahepatic portosystemic stent shunt (TIPS) in liver cirrhosis; however, that score was derived from a mixed cohort, including patients with refractory ascites and variceal bleeding. This study re-evaluates the role of the MELD score and focuses on differences between both groups of patients. METHODS: A total of 301 patients (192 male and 109 female) received TIPS, 213 because of refractory ascites and 88 because of variceal bleeding. Univariate and multivariate Cox analyses were performed to identify predictors of mortality and area under the receiver operator characteristics (AUROC) were used to assess the prognostic capacity of the MELD score and of the results of predictors of the multivariate analyses. RESULTS: In refractory ascites, age, bilirubin and albumin were independent predictors of mortality. In variceal bleeding, emergency TIPS during ongoing bleeding, concomitant grade III ascites, history of hepatic encephalopathy, spontaneous bacterial peritonitis, bilirubin and platelet count proved significant. AUROCs of the MELD score for 3-month survival yielded 0.543 and 0.836 for refractory ascites and variceal bleeding, respectively (P < 0.001). For 1-year survival, the respective AUROCs yielded 0.533 and 0.767 (P < 0.001). In contrast to MELD, the AUROCs based on the calculated risk scores of this study resulted in 0.660 and 0.876 for 3-month survival, and 0.665 and 0.835 for 1-year survival in patients with ascites and variceal bleeding, respectively. CONCLUSION: In refractory ascites, the prognostic capability of MELD is significantly inferior compared to variceal bleeding. The results of our multivariate analyses and AUROC calculations corroborate the impact of different prognostic variables in patients undergoing TIPS for ascites and variceal bleeding.

High pre-treatment static and dynamic alpha-fetoprotein values predict reduced overall survival in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha-fetoprotein is a well-established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static alpha-fetoprotein values is limited and the clinical potential is a matter of ongoing scientific discussion. OBJECTIVE: We here evaluated the prognostic impact of pre-treatment static and dynamic alpha-fetoprotein variables on overall survival of hepatocellular carcinoma patients in a Western cohort. METHODS: Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenberg-University Mainz between 1998 and 2014 and two available pre-treatment alpha-fetoprotein-values (AFP-slope) were retrospectively analysed. Clinico-pathological baseline parameters, pre-treatment static values and AFP-slope were assessed. Prognostic impact was determined by Kaplan-Meier analyses and Cox regression models. RESULTS: High static and dynamic alpha-fetoprotein variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child-Pugh B (p < 0.01) and C stage (p < 0.001), portal vein thrombosis (p < 0.001) and extrahepatic spread (p < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic alpha-fetoprotein variable resulted in higher time-dependent area under the curves. Notably, in patients with more favourable prognosis, AFP-slope prior to therapy was a slightly stronger predictor for overall survival compared with static alpha-fetoprotein values. CONCLUSION: Static and dynamic alpha-fetoprotein variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP-slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis.

Charting the Path Forward for Risk Prediction in Liver Transplant for Hepatocellular Carcinoma: International Validation of HALTHCC Among 4,089 Patients.

Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out [25.2%]) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre-LT levels of alpha-fetoprotein, Model for End-Stage Liver Disease Sodium score, and tumor burden score was recalibrated among a randomly selected cohort (n = 1,021) and validated in the remainder (n = 3,068). This study demonstrated significant heterogeneity by site and year, reflecting practice trends over the last decade. On explant pathology, both vascular invasion (VI) and poorly differentiated component (PDC) increased with increasing HALTHCC score. The lowest-risk patients (HALTHCC 0-5) had lower rates of VI and PDC than the highest-risk patients (HALTHCC > 35) (VI, 7.7%[ 1.2-14.2] vs. 70.6% [48.3-92.9] and PDC:4.6% [0.1%-9.8%] vs. 47.1% [22.6-71.5]; P < 0.0001 for both). This trend was robust to MC status. This international study was used to adjust the coefficients in the HALTHCC score. Before recalibration, HALTHCC had the greatest discriminatory ability for overall survival (OS; C-index = 0.61) compared to all previously reported scores. Following recalibration, the prognostic utility increased for both recurrence (C-index = 0.71) and OS (C-index = 0.63). Conclusion: This large international trial validated and refined the role for the continuous risk metric, HALTHCC, in establishing pre-LT risk among candidates with HCC worldwide. Prospective trials introducing HALTHCC into clinical practice are warranted.

Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre.

Background: The recurrence of hepatocellular carcinoma (HCC) is the strongest survival-limiting factor after liver transplantation (LT) in patients with HCC. In the face of donor organ shortage, it is necessary to identify factors associated with HCC recurrence in order to maximize the utility of the available grafts. Objective: To study the phenomenon of HCC recurrence after LT at a European transplantation centre over the past 20 years. Methods: Data from 304 HCC patients who underwent LT were prospectively recorded. Clinical and pathological factors were assessed for their association with recurrence. Results: Fifty-one patients (16.8%) had HCC recurrence after LT. Patients exceeding the Milan criteria developed HCC recurrence more frequently. The time point of recurrence did not affect survival after recurrence. Furthermore, there was no difference in survival between patients with intra- and extrahepatic recurrence. However, patients with recurrence due to needle tract seeding had a significantly better outcome than patients with other sites of recurrence. Conclusion: Our data support a restrictive use of patient selection criteria to help identify patients who have an increased risk of HCC recurrence after LT, and highlight the need to improve patient selection before LT in order to minimize the rate of HCC recurrence.

Hepatocellular carcinoma recurrence after acute liver allograft rejection treatment: A multicenter European experience.

BACKGROUND: During the last decades, several risk factors for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) have been investigated. However, the impact of two important drivers of oncogenesis, namely the immunosuppression and the treatment of acute cellular rejection (ACR) have been marginally addressed. This study aimed at investigating the impact of ACR treatment on the incidence of tumor recurrence in a large European HCC-LT population. METHODS: Seven hundred and eighty-one adult patients transplanted between February 1, 1985 and June 30, 2016 were retrospectively analyzed. After propensity score match, 116 patients treated for ACR using steroid boluses were compared with 115 patients who did not present any ACR or a histologic but clinical irrelevant ACR. RESULTS: Steroid boluses treated patients had a 18-fold higher overall incidence of HCC recurrence than those non-treated patients (16.4% vs. 0.9%; P<0.0001). At multivariate Cox regression analysis, steroid boluses used to treat ACR were an independent risk factor for HCC recurrence (HR=14.2; 95% CI: 1.8-110.4; P = 0.010). CONCLUSIONS: The decision to treat ACR as well as to reinforce immunosuppression load should be cautiously taken in view of the presented results. Prospective studies are needed to further elucidate the clinical impact of immunosuppression on HCC recurrence after transplantation.

The Intention-to-Treat Effect of Bridging Treatments in the Setting of Milan Criteria-In Patients Waiting for Liver Transplantation.

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria (MC), the benefit of locoregional therapies (LRTs) in the context of liver transplantation (LT) is still debated. Initial biases in the selection between treated and untreated patients have yielded conflicting reported results. The study aimed to identify, using a competing risk analysis, risk factors for HCC-dependent LT failure, defined as pretransplant tumor-related delisting or posttransplant recurrence. The study was registered at www.clinicaltrials.gov (identification number NCT03723304). In order to offset the initial limitations of the investigated population, an inverse probability of treatment weighting (IPTW) analysis was used: 1083 MC-in patients (no LRT = 182; LRT = 901) were balanced using 8 variables: age, sex, Model for End-Stage Liver Disease (MELD) value, hepatitis C virus status, hepatitis B virus status, largest lesion diameter, number of nodules, and alpha-fetoprotein (AFP). All the covariates were available at the first referral. After the IPTW, a pseudo-population of 2019 patients listed for LT was analyzed, comparing 2 homogeneous groups of untreated (n = 1077) and LRT-treated (n = 942) patients. Tumor progression after LRT was the most important independent risk factor for HCC-dependent failure (subhazard ratio [SHR], 5.62; P < 0.001). Other independent risk factors were major tumor diameter, AFP, MELD, patient age, male sex, and period of wait-list registration. One single LRT was protective compared with no treatment (SHR, 0.51; P < 0.001). The positive effect was still observed when 2-3 treatments were performed (SHR, 0.66; P = 0.02), but it was lost in the case of ≥4 LRTs (SHR, 0.80; P = 0.27). In conclusion, for MC-in patients, up to 3 LRTs are beneficial for success in intention-to-treat LT patients, with a 49% to 34% reduction in failure risk compared with untreated patients. This benefit is lost if more LRTs are required. A poor response to LRT is associated with a higher risk for HCC-dependent transplant failure.

Expression and prognostic significance of insulin­like growth factor-2 receptor in human hepatocellular carcinoma and the influence of transarterial chemoembolization.

Hepatocellular carcinoma (HCC) is one of the most common human malignancies, the incidence of which is growing worldwide. The prognosis of HCC is very poor and it is often accompanied by a high rate of recurrence. Conventional chemotherapeutic approaches are largely inefficient. In order to develop novel effective methods for the early detection and prognosis of HCC, novel markers and therapeutic targets are urgently required. The present study focused on the effects of the expression of the tumor suppressor gene insulin­like growth factor­2 receptor (IGF2R) on patient survival and tumor recurrence in patients with HCC; this study paid specific attention to the influence of transarterial chemoembolization (TACE) prior to surgery. The mRNA expression levels of IGF2R were measured in primary human HCC and corresponding non­neoplastic tumor­surrounding tissue (TST) by reverse transcription­polymerase chain reaction (RT­PCR) (n=92). Subsequently, the associations between IGF2R expression and clinicopathological parameters, outcomes of HCC and TACE pretreatment prior to surgery were determined. Furthermore, the effects of the IGF2R gene polymorphisms rs629849 and rs642588 on susceptibility and on clinicopathological features of HCC were investigated. RT­PCR demonstrated that the mRNA expression levels of IGF2R were downregulated in HCC compared with in TST samples (P=0.004), which was associated with a worse recurrence­free survival of patients with HCC (P=0.002) and a lower occurrence of cirrhosis (P=0.05). TACE­pretreated patients with HCC (n=26) exhibited significantly higher IGF2R mRNA expression in tumor tissues (P=0.019). In addition, significantly more patients with HCC in the TACE­pretreated group exhibited upregulated IGF2R mRNA expression compared with in the non­treated patients (P=0.032). The IGF2R SNPs rs629849 and rs642588 were not significantly associated with HCC risk, whereas a homozygous IGF2R rs629849 GG genotype was associated with a significantly elevated risk of non­viral liver cirrhosis (P=0.05). In conclusion, these data suggested an important role for IGF2R expression in HCC, particularly with regards to TACE treatment prior to surgery.

Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study.

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met) and 23 DR-patients. DR symptoms referred to post-DLT only, while those of FAP patients were both pre- and post-transplantation. Symptoms of TTR-amyloidosis in Val30Met and Non-Val30Met patients pre- and post-LT were similarly distributed. Biopsy-proven de novo amyloidosis occurred in 4/23 DR after a mean observation of 10 years. Analysis for manifestations of amyloidosis only included patients with available 5-year follow-up data (n = 13 FAP, n = 12 DR). Compared to Val30Met FAP patients pre-LT, Val30Met DR patients had better NCV (P = 0.04) and HRV (P = 0.015). In the Non-Val30Met group no differences were found between DR and FAP patients pre-LT. TTR-amyloidosis symptoms showed no differences in FAP patients pre- and 5 years post-LT, irrespective of Val30Met status. In DR patients, de novo amyloidosis occurred earlier than expected. Therefore, recipients for DLT need to be carefully selected and followed.

Recipient liver function before liver transplantation influences post-transplantation survival in patients with HCC.

BACKGROUND: Liver transplantation (LT) is a complex yet curative treatment for a subset of patients with hepatocellular carcinoma (HCC). Due to donor organ shortage, patients with HCC need to be carefully selected for LT. In European countries, selection of patients is based on the Milan criteria, and donor organs are allocated by Eurotransplant. In order to optimize the utilization of available liver grafts, the outcome of HCC patients after LT needs to be closely monitored and evaluated. METHODS: We assessed the outcome of 304 HCC patients who underwent LT at a tertiary medical center over a period of nearly 20 years (February 1998 until June 2017). RESULTS: The 5-, 10- and 15-year survival rates were 62, 47 and 30%, respectively. The strongest survival-determining factor was tumour recurrence. Apart from a high tumour grading, the pre-LT MELD score was significantly and negatively associated with survival after LT. CONCLUSION: Our results confirm the importance of recurrence for the outcome of HCC patients after LT and highlight the relevance of HCC patients' liver function before LT. Our findings encourage efforts to identify prognostically relevant factors for LT in HCC with the overall goal of refining the organ allocation system and maximizing the survival benefit after LT.

Donor Shortage in Germany: Impact on Short- and Long-Term Results in Liver Transplantation.

With slightly more than 10 donors per million inhabitants, Germany belongs to the underdeveloped countries in Europe with regard to organ donation. Organ shortage is supposed to promote the usage of organs which are declined in case of less pronounced scarcity. This may result in deteriorated graft and patient survival. In the light of this situation, data on the centers' procedures and outcome of liver transplantation in Germany is presented based upon reports of Eurotransplant, the German Institutions for Quality Assessment, and the Deutsche Stiftung Organtransplantation. Surprisingly, along with an increasing organ scarcity, the outcome during waiting time and after transplantation has been improved. The 1- and 3-year patient survival improved by 7 and 9%, respectively. Reasons for this unexpected development are discussed.

Liver Preservation by Aortic Perfusion Alone Compared With Preservation by Aortic Perfusion and Additional Arterial Ex Situ Back-Table Perfusion With Histidine-Tryptophan-Ketoglutarate Solution: A Prospective, Randomized, Controlled, Multicenter Study.

BACKGROUND: Arterial ex situ back-table perfusion (BP) reportedly reduces ischemic-type biliary lesion after liver transplantation. We aimed to verify these findings in a prospective investigation. METHODS: Our prospective, randomized, controlled, multicenter study involved livers retrieved from patients in 2 German regions, and compared the outcomes of standard aortic perfusion to those of aortic perfusion combined with arterial ex situ BP. The primary endpoint was the incidence of ischemic-type biliary lesions over a follow-up of 2 years after liver transplantation, whereas secondary endpoints included 2-year graft survival, initial graft damage as reflected by transaminase levels, and functional biliary parameters at 6 months after transplantation. RESULTS: A total of 75 livers preserved via standard aortic perfusion and 75 preserved via standard aortic perfusion plus arterial BP were treated using a standardized protocol. The incidence of clinically apparent biliary lesions after liver transplantation (n = 9 for both groups; P = 0.947), the 2-year graft survival rate (standard aortic perfusion, 74%; standard aortic perfusion plus arterial BP, 68%; P = 0.34), and incidence of initial graft injury did not differ between the 2 perfusion modes. Although 33 of the 77 patients with cholangiography workups exhibited injured bile ducts, only 10 had clinical symptoms. CONCLUSIONS: Contrary to previous findings, the present study indicated that additional ex situ BP did not prevent ischemic-type biliary lesions or ischemia-reperfusion injury after liver transplantation. Moreover, there was considerable discrepancy between cholangiography findings regarding bile duct changes and clinically apparent cholangiopathy after transplantation, which should be considered when assessing ischemic-type biliary lesions.

Intention-to-treat survival benefit of liver transplantation in patients with hepatocellular cancer.

The debate about the best approach to select patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still ongoing. This study aims to identify the best variables allowing to discriminate between "high-" and "low-benefit" patients. To do so, the concept of intention-to-treat (ITT) survival benefit of LT has been created. Data of 2,103 adult HCC patients consecutively enlisted during the period 1987-2015 were analyzed. Three rigorous statistical steps were used in order to create the ITT survival benefit of LT: the development of an ITT LT and a non-LT survival model, and the individual prediction of the ITT survival benefit of LT defined as the difference between the median ITT survival with (based on the first model) and without LT (based on the second model) calculated for each enrolled patient. Four variables (Model for End-Stage Liver Disease, alpha-fetoprotein, Milan-Criteria status, and radiological response) displayed a high effect in terms of delta benefit. According to these risk factors, four benefit groups were identified. Patients with three to four factors ("no-benefit group"; n = 405 of 2,103; 19.2%) had no benefit of LT compared to alternative treatments. Conversely, patients without any risk factor ("large-benefit group"; n = 108; 5.1%) yielded the highest benefit from LT reaching 60 months. CONCLUSION: The ITT transplant survival benefit presented here allows physicians to better select HCC patients waiting for LT. The obtained stratification may lead to an improved and more equitable method of organ allocation. Patients without benefit should be de-listed, whereas patients with large benefit ratio should be prioritized for LT. (Hepatology 2017;66:1910-1919).

Detection of benign hilar bile duct stenoses - A retrospective analysis in 250 patients with suspicion of Klatskin tumour.

INTRODUCTION: The aim of this study was to identify clinical, laboratory and radiological parameters to distinguish benign from malignant stenoses of the proximal bile duct. METHODS: Between 1997 and 2011, 250 patients were referred to our clinic with hilar bile duct stenoses suspicious for Klatskin tumour. Medical histories, clinical data, pre-interventional laboratory tests, imaging findings, as well as therapeutic approach and patient outcome were compared to final histological results. All data were retrieved from our prospectively maintained database and analysed retrospectively. RESULTS: We found benign bile duct lesions in 34 patients (13.6%). Among the entire study population, uni- and multivariate analyses of 18 clinicopathological parameters revealed that patient age, serum alkaline phosphatase, tumour marker CA19-9 and presence of tumour mass in computed tomography were independent predictors for malignant biliary stenoses (p < 0.05). Receiver operator characteristic curve showed that a CA19-9 serum level of 61.2 U/ml or more has a sensitivity, specificity and diagnostic accuracy for predicting the malignant nature of the hilar biliary stenoses of 74.6%, 80.0% and 83.5%, respectively. Surgical resection could be avoided by preoperative work-up and surgical exploration in 10 out of 34 patients with benign lesions. Rates of major liver resections performed were 66.7% in the benign lesion group and 90.7% in the Klatskin tumour group. CONCLUSION: Despite improvements of preoperative diagnostics, it remains difficult to differentiate between benign and malignant hilar bile duct stenosis. Even explorative laparotomy was not able to safely exclude Klatskin tumour in all cases and therefore major liver resection was inevitable.