PURPOSE:For primary and secondary liver tumors oncological resection remains a chance of cure. Augmentation of functional liver tissue may be necessary to preserve sufficient future liver remnant (FLR). Clinical decision-making on liver augmentation techniques and indications may differ internationally. Thus, this study aims to identify standards of liver augmentation in hepato-pancreatico-biliary (HPB) centers in Germany, Switzerland, and Austria. METHODS:Using a web-based survey, 48 hospitals in Germany, Switzerland, and Austria were invited to report their surgical indication, standard procedures, and results of liver augmentation. RESULTS:Forty (83.3%) of the hospitals invited participated. Most of the hospitals were certified liver centers (55%), performing complex surgeries such as liver transplantation (57.5%) and ALPPS (80%). The standard liver augmentation technique in all countries was portal vein embolization (PVE; 56%), followed by ALPPS (32.1%) in Germany or PVE with hepatic vein embolization (33.3%) in Switzerland and Austria. Standard procedure for liver augmentation did not correlate with certification as liver center, performance of liver transplantation or ALPPS. Surgical indication for PVE varied depending on tumor entity. Most hospitals rated the importance of PVE before resection of cholangiocarcinoma or colorectal metastases as high, while PVE for hepatocellular carcinoma was rated as low. CONCLUSION:The survey gives an overview of the clinical routine in HPB centers in Germany, Austria, and Switzerland. PVE seems to dominate as standard technique to increase the FLR. However, there is a variety in the main indication for liver augmentation. Further studies are necessary evaluating the differing PVE techniques for liver augmentation.

Background: Postoperative liver failure (PLF) is a severe complication after major liver resection (MLR). To increase the safety of patients, clinical bedside tests are of great importance. However, limitations of their applicability and validity impair their value. Methods: Preoperative measurements of the liver maximum capacity (LiMAx) were performed in n = 40 patients, who underwent MLR (≥3 segments). Matched postoperative LiMAx was measured in n = 21 patients. Liver function was compared between pretreated patients (n = 11 with portal vein embolisation (PVE) and n = 19 patients with preoperative chemotherapy) and therapy naïve patients. The LiMAx values were compared with liver-specific blood parameters and volumetric analysis. Results: In total, n = 40 patients were enrolled in this study. The majority of patients (n = 33; 82.5%) had high preoperative LiMAx values (>315 µg/kg/h), while only seven patients (17.5%) had medium values (140–315 µg/kg/h), and none of the patients had low values (<140 µg/kg/h). A comparison of pretreated patients (with PVE and/or chemotherapy) and therapy naïve patients showed no significant difference in the preoperative LiMAx values (p > 0.05). The preoperative LiMAx values were significantly higher than the matched postoperative values on postoperative day 1 (p < 0.0001). A comparison between the expected and measured postoperative LiMAx showed a difference (≥10%) in 7 out of 13 patients (53.8%). After an initial postoperative decrease in the LiMAx, the patients without complications (n = 12) showed a continuous increase until 14 days after surgery. In the patients with postoperative complications, a decrease in the LiMAx was associated with a prolonged recovery. Conclusions: For patients undergoing MLR within the 0.5% rule, which is the clinical gold standard, the LiMAx values do not offer any additional information. Additionally, the LiMAx may have reflected liver function, but it did not deliver additional information regarding postoperative liver recovery. The clinical use of LiMAx might be relevant in selected patients beyond the 0.5% rule.

Ischemic reperfusion injury (IRI) after liver transplantation is a common cause of early allograft dysfunction with high mortality. The purpose of this case report series is to highlight an unusual clinical course in which complete recovery can occur following the identification of severe hepatic IRI post-transplantation and the implications of this finding on management strategies in patients with IRI post-transplant. Here, we include three cases of severe IRI following liver transplantation that are putatively resolved without retransplantation or definitive therapeutic intervention. All patients recovered until their final follow-up visits to our institution and developed no significant complications from their injury throughout the course of patient care by our institution after discharge from the hospital.

The shortage of organs for transplantation remains a global problem. The retransplantation of a previously transplanted kidney might be a possibility to expand the pool of donors. We provide our experience with the successful reuse of transplanted kidneys in the Eurotransplant region.

Background: Liver metastases (LM) occur in about 50% of patients with colorectal cancer. Besides the multimodal treatment of the primary tumor, the only way to cure patients with colorectal LM (CRLM) is complete resection. Different surgical procedures for this purpose are available depending on location, size, and number of LM. Additional concepts for patients with primary unresectable LM exist, ranging from Chemotherapy to induction of liver hypertrophy and even liver transplantation. This review intends to provide an overview of the surgical approach. Summary: Surgical options in the treatment of CRLM are defined and limited by their intraparenchymal location and their proximity to major vessels and intrahepatic bile ducts. Lesions located in the periphery can be excised in a parenchymal sparing fashion with a small tumor-surrounding resection margin of healthy liver parenchyma. If this is not possible, anatomical resections based on segmental boundaries are performed. In these cases, a sufficient functional volume of liver parenchyma after resection (future liver remnant volume [FLRV]) has to be preserved. This FLRV depends on various factors such as bodyweight and possible preexisting liver damage, such as cirrhosis, fibrosis, or chemotherapy-induced liver impairment. Liver hypertrophy via partial occlusion of the portal venous system is a standard procedure for patients with primary unresectable LM to increase FLRV. Furthermore, discussion of liver transplantation in cases of unresectable LM is gaining importance again. A combination of surgery and adjuvant and/or neoadjuvant chemotherapy may be indicated in individual cases, but general evidence-based recommendations cannot be given without further studies. Key Messages: Surgical removal of all metastases represents the only option of a potentially curative treatment of UICC stage IV colorectal carcinoma with liver involvement. An interdisciplinary approach consisting of chemotherapeutical downsizing and hypertrophy of the FLRV offers potential curative treatment for patients with initially unresectable metastases. For all others, liver transplantation is seeing a revival showing promising results in overall survival compared to chemotherapy alone.

Abstract Background Postoperative liver failure (PLF) is a serious complication of extended liver surgery. The need for clinical bedside tests to predict sufficient liver function in the remnant liver tissue after surgery and to monitor liver function and its potential for regeneration is vital to increase the safety of patients in the perioperative setting. Methods The liver maximum capacity (LiMAx) test was prospectively applied both preoperatively (n = 40) and postoperatively (n = 19) for 40 patients who underwent extended liver surgery (≥3 segments). LiMAx values were correlated with liver-specific blood parameters as well as with volumetric analysis regarding their potential as predictors of the clinical outcome and for monitoring the liver functional capacity. Results The majority of patients (n = 33; 82.5%) had high preoperative LiMAx values (> 315 µg/kg/h), while only seven patients (17.5%) had medium values (140–315 µg/kg/h), and none of the patients had low values (< 140 µg/kg/h). According to the LiMAx algorithm and preoperative volumetry, expected and measured postoperative LiMAx were compared. They differed in 7 out of 13 patients (53.8%) with a cut-off ≥10%. After surgery, patients with an uneventful recovery (n = 12) showed a typical trend in the LiMAx values, with a drop after surgery followed by an increase until 14 days after surgery. This course was reflected similarly by blood-based tests (e.g., prothrombin time). In patients with postoperative complications, a decrease in LiMAx was associated with a prolonged recovery. Conclusions For patients undergoing extended liver surgery within the 0.5% rule, which is the clinical gold standard, LiMAx values do not offer any additional information. Additionally, LiMAx may reflect liver recovery but it did not deliver additional information regarding postoperative liver recovery. The clinical use of LiMAx might be relevant in selected patients beyond the 0.5% rule.

Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3-6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation.

BACKGROUND Postoperative pulmonary embolism following liver transplantations is still one of the most fatal complications, especially during the early postoperative phase. The use of a thrombolytic agent such as the recombinant tissue-type plasminogen activator (rtPA) is considered a contraindication early after major abdominal surgery such as liver transplantation. However, thrombolysis after major surgery in the early postoperative period carries a substantial risk of surgical site hemorrhage. CASE REPORT A 55-year-old patient presented with a hepatic mass diagnosed as a combined cholangio/hepatocellular carcinoma. Following the criteria of the University of San Francisco, California (UCSF) for liver transplantation, the case was selected for liver transplantation. The patient received neoadjuvant therapy. After the liver transplantation, on the second postoperative day, an acute, severe dyspnea with sudden onset occurred on the surgical ward. A computed tomography angiography showed a drawn-out embolus, which sprawled into both pulmonary main arteries and occluded them subtotally. A thrombolysis with rtPA was started. Within the first 60 minutes of administration of rtPA, the circulation stabilized effectively, so that epinephrine could be tapered down to zero and the patient was promptly extubated. About 6 hours after administration of rtPA, a sudden and pronounced bleeding via one of the intraperitoneal drains occurred, hemoglobin concentration dropped from 9.7 g/dL to 6.4 g/dL. After immediate re-laparotomy, circulation and hemoglobin concentration were absolutely stable. CONCLUSIONS Even with anticipated high risk of bleeding, thrombolysis with rtPA can be used as a life-savings treatment in a case of pulmonary embolism after liver transplantation.

Introduction: Combined hepatocellular-cholangiocarcinoma is rare and comprises features of hepatocellular carcinoma and cholangiocarcinoma. The treatment of choice has not yet been defined. The aim of the study was to analyze outcomes of patients with combined hepatocellular-cholangiocarcinoma, who underwent liver transplantation. Material and Methods: All patients with combined hepatocellular-cholangiocarcinoma, who underwent liver transplantation, from January 2001 to August 2018 were identified. Pre-, intra- and postoperative data were retrospectively assessed. A univariate analysis was performed to identify prognostic factors. Results: A total number of 19 patients were included to this study. Perioperative death was seen in two patients (10.5%). Recurrent disease was reported in 11 patients (64.7%) within the median time of 4 months. One and three years survival rates were 57.1% (CI 0.301-1) and 38.1% (CI 0.137-1). Factors associated mortality were tumor size >3 cm, presence of lymphatic invasion, and prolonged ICU stay. Patients with mixed HCC-CC lesions have significantly better survival compared to patients with separate lesions of HCC and CCC in one liver (p = .025). Conclusion: Although overall survival rates are clearly decreased compared to HCC patients, liver transplantation should be taken under consideration for selected patients with early stage and real mixed HCC-CC, who are likely to benefit from liver transplantation.

Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. Conclusion. There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.

Background: Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany. The data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients a very scarce. Methods: The authors performed a single center analysis in liver transplant recipients on the effect of pantoprazole on the serum trough levels of different immunosuppressants. The trough levels were compared over a period of 1 year before and after start or stop of a continuous oral co-administration of 40 mg pantoprazole once daily. Results: The serum trough levels of tacrolimus (n = 30), everolimus (n = 7), or sirolimus (n = 3) remain constant during an observation period of at least 1 year before and after co-administration of pantoprazole. None of the included patients needed a change of dosage of the observed immunosuppressants during the observation period. Conclusions: The oral co-administration of pantoprazole is safe in immunosuppressed liver transplant recipients according to the serum trough levels of tacrolimus, everolimus, and sirolimus. This analysis provides first data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients.

Progression of chronic kidney disease associated with progressive fibrosis and impaired tubular epithelial regeneration is still an unmet biomedical challenge because, once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. Prompted by various studies across multiple organs demonstrating that preconditioning regimens to induce endogenous regenerative mechanisms protect various organs from later incurring acute injuries, we here aimed to gain insights into the molecular mechanisms underlying successful protection and to explore whether such pathways could be utilized to inhibit progression of chronic organ injury. We identified a protective mechanism controlled by the transcription factor ARNT that effectively inhibits progression of chronic kidney injury by transcriptional induction of ALK3, the principal mediator of antifibrotic and proregenerative bone morphogenetic protein-signaling (BMP-signaling) responses. We further report that ARNT expression itself is controlled by the FKBP12/YY1 transcriptional repressor complex and that disruption of such FKBP12/YY1 complexes by picomolar FK506 at subimmunosuppressive doses increases ARNT expression, subsequently leading to homodimeric ARNT-induced ALK3 transcription. Direct targeting of FKBP12/YY1 with in vivo morpholino approaches or small molecule inhibitors, including GPI-1046, was equally effective for inducing ARNT expression, with subsequent activation of ALK3-dependent canonical BMP-signaling responses and attenuated chronic organ failure in models of chronic kidney disease, and also cardiac and liver injuries. In summary, we report an organ-protective mechanism that can be pharmacologically modulated by immunophilin ligands FK506 and GPI-1046 or therapeutically targeted by in vivo morpholino approaches.

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 μg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial.We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups.Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome.Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.

Alcoholic liver disease (ALD) is the second most common diagnosis among patients undergoing liver transplantation (LT). The recovery results of patients transplanted for ALD are often at least as good as those of patients transplanted for other diagnoses and better than those suffering from hepatitis C virus, cryptogenic cirrhosis, or hepatocellular carcinoma. In the case of medically non-responding patients with severe acute alcoholic hepatitis or acute-on chronic liver failure, the refusal of LT is often based on the lack of the required alcohol abstinence period of six months. The obligatory abidance of a period of abstinence as a transplant eligibility requirement for medically non-responding patients seems unfair and inhumane, since the majority of these patients will not survive the six-month abstinence period. Data from various studies have challenged the 6-mo rule, while excellent survival results of LT have been observed in selected patients with severe alcoholic hepatitis not responding to medical therapy. Patients with severe advanced ALD should have legal access to LT. The mere lack of pre-LT abstinence should not be an obstacle for being listed.