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Simple Summary: For patients undergoing multimodal treatment for colorectal liver metastases (CLM), the development of sinusoidal obstruction syndrome (SOS) as a side effect of oxaliplatin-based chemotherapy may endanger the prospects after liver resection. In this study, we aimed to investigate possible protective effects of an additional preoperative inhibition of vascular endothelial growth factor (VEGF) on the occurrence of SOS and its implications on liver function and regeneration after liver resection. After successful establishment of a novel murine model of SOS, we were able to show a reduced incidence of SOS after additive treatment with a VEGF inhibitor. Changes in the VEGF pathway, namely in the expression of VEGF receptor-2 (VEGF-R2), may be responsible for these findings. By preventing the incidence of SOS, the inhibition of VEGF may help to reduce morbidity after liver resection for patients with CLM. Further clinical studies are needed to corroborate our results. Abstract: (1) Background: Sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy is associated with unfavorable outcomes after partial hepatectomy for colorectal liver metastases (CLM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), may prevent SOS development. We investigated the impact of VEGF-inhibition on the development of SOS in a murine model. (2) Methods: Male wild-type and CD39-null mice received oxaliplatin, additional anti-VEGF (OxAV), or controls, and were sacrificed or subjected to major partial hepatectomy (MH). Specimen were used for histological analysis of SOS. Liver damage was assessed by plasma transaminases. The VEGF pathway was elucidated by quantitative PCR of liver tissue and protein analysis of plasma. (3) Results: Mice treated with oxaliplatin developed SOS. Concomitant anti-VEGF facilitated a reduced incidence of SOS, but not in CD39-null mice. SOS was associated with increased plasma VEGF-A and decreased hepatocyte growth factor (HGF). After OxAV treatment, VEGF-R2 was upregulated in wild-type but downregulated in CD39-null mice. Oxaliplatin alone was associated with higher liver damage after MH than in mice with concomitant VEGF-inhibition. (4) Conclusions: We established a murine model of oxaliplatin-induced SOS and provided novel evidence on the protective effect of VEGF-inhibition against the development of SOS that may be associated with changes in the pathway of VEGF and its receptor VEGF-R2.

Simple Summary: Oncological follow-up after liver transplantation for cholangiocellular carcinoma must consider the risk of recurrence. Immunosuppressive medication with so-called mTOR inhibitors seems to have a tumor-suppressive effect, as improved survival has been shown under this medication for patients with recurrent hepatocellular carcinoma after liver transplantation. The aim of our study was to investigate recurrence and survival in relation to tumor type and type of immunosuppression for cholangiocellular carcinoma after liver transplantation. The time from liver transplantation to recurrence and survival after cancer recurrence were endpoints of the study. Significant improvement in survival for recurrent cholangiocellular carcinoma was seen after surgical resection and reduction in immunosuppression, while N1 status at transplantation and histological Grading >1 were associated with worse outcomes. Abstract: Liver transplantation (LT) for cholangiocarcinoma (CCA), or biliary tract cancer (BTC), remains controversial regarding high recurrence rates and poor prognosis. Oncological follow-up may benefit from tumor-inhibiting properties of mTOR inhibitors (mTORI), shown with improved survival for recurrent hepatocellular carcinoma (HCC) patients after LT. The aim of this study was to investigate the recurrence and survival in relation to tumor type and type of immunosuppression (IS). LT patients with CCA or mixed HCC/CCA (mHCC/CCA) (n = 67) were retrospectively analyzed. Endpoints were the time from LT to recurrence (n = 44) and survival after recurrence. Statistically significant impairment in survival for recurrent CCA (rCCA) was shown in patients not eligible for surgical resection (HR 2.46 (CI: 1.2-5.1; p = 0.02). Histological proven grading >1 and N1 status at initial transplantation were associated with impaired survival (HR 0.13 (CI: 0.03-0.58); p < 0.01 and HR 3.4 (CI: 1.0-11.65); p = 0.05). Reduced IS after tumor recurrence improved survival (HR 4.2/CI: 1.3-13.6; p = 0.02). MTORI initiation before recurrence or after had no significant impact on survival. Our data thereby indicate, similar to findings in recurrent HCC after LT, that patients with rCCA after LT benefit from a reduction in IS upon recurrence.

Additional file 1: Figure S1. Englisch translation of digital quality management document. QM documents are prospectively collected on the day of discharge and validated daily by a group of senior consultant surgeons. It includes the indication for surgical treatment (blue), complications which occurred during the inpatient stay (red) and the necessary procedure for complication management (green). Complications are classified either as medical or organizational. Medical complications are further classified into renal, post pancreatic surgery, central nervous system, post vascular surgery, cardiovascular, systemic, or surgical site infections, bleeding, post organ transplantation, pulmonary, gastrointestinal, and hepatobiliary complications. Finally, complications are classified according to Clavien-Dindo.

Background: Minimally invasive liver surgery (MILS) has a high variance in the type of resection and complexity, which has been underestimated in learning curve studies in the past. The aim of this work was to evaluate complexity-adjusted learning curves over time for laparoscopic liver resection (LLR) and robotic liver resection (RLR). Methods: Cumulative sum analysis (CUSUM) and complexity adjustment were performed using the Iwate score for LLR and RLR (n = 647). Lowest point of smoothed data was used to capture the cutoff of the increase in complexity. Data were collected retrospectively at the Department of Surgery of the Charité-Universitätsmedizin Berlin. Results: A total of 132 RLR and 514 LLR were performed. According to the complexity-adjusted CUSUM analysis, the initial learning phase was reached after 117 for LLR and 93 procedures for RLR, respectively. With increasing experience, the rate of (extended) right hemihepatectomy multiplied from 8.4% to 18.9% for LLR (P = 0.031) and from 21.6% to 58.3% for RLR (P < 0.001). Complication rates remained comparable between both episodes for LLR and RLR (T1 vs T2, P > 0.05). The complexity-adjusted CUSUM analysis demonstrated for blood transfusion, conversion, and operative time an increase during the learning phase (T1), while a steady state was reached in the following (T2). Conclusions: The learning phase for MILS after adjusting for complexity is about 4 times longer than assumed in previous studies, which should urge caution.

Background Although Bismuth-Corlette (BC) type 4 perihilar cholangiocarcinoma (pCCA) is no longer considered a contraindication for curative surgery, few data are available from Western series to indicate the outcomes for these patients. This study aimed to compare the short- and long-term outcomes for patients with BC type 4 versus BC types 2 and 3 pCCA undergoing surgical resection using a multi-institutional international database. Methods Uni- and multivariable analyses of patients undergoing surgery at 20 Western centers for BC types 2 and 3 pCCA and BC type 4 pCCA. Results Among 1138 pCCA patients included in the study, 826 (73%) had BC type 2 or 3 disease and 312 (27%) had type 4 disease. The two groups demonstrated significant differences in terms of clinicopathologic characteristics (i.e., portal vein embolization, extended hepatectomy, and positive margin). The incidence of severe complications was 46% for the BC types 2 and 3 patients and 51% for the BC type 4 patients (p = 0.1). Moreover, the 90-day mortality was 13% for the BC types 2 and 3 patients and 12% for the BC type 4 patients (p = 0.57). Lymph-node metastasis (N1; hazard-ratio [HR], 1.62), positive margins (R1; HR, 1.36), perineural invasion (HR, 1.53), and poor grade of differentiation (HR, 1.25) were predictors of survival (all p ≤0.004), but BC type was not associated with prognosis. Among the N0 and R0 patients, the 5-year overall survival was 43% for the patients with BC types 2 and 3 pCCA and 41% for those with BC type 4 pCCA (p = 0.60). Conclusions In this analysis of a large Western multi-institutional cohort, resection was shown to be an acceptable curative treatment option for selected patients with BC type 4 pCCA although a more technically challenging surgical approach was required.

Safak Gül-Klein,1 Henriette Hegermann,1 Robert Röhle,2– 4 Moritz Schmelzle,1 Frank Tacke,5 Wenzel Schöning,1 Robert Öllinger,1 Tomasz Dziodzio,1 Patrick Maier,1 Julius M Plewe,1 David Horst,6 Igor Maximilian Sauer,2 Johann Pratschke,1 Nils Lachmann,7 Dennis Eurich1 1Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany; 2Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany; 3Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Coordinating Center for Clinical Studies, Berlin, Germany; 4Berlin Institute of Health (BIH), Berlin, Germany; 5Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hepatology & Gastroenterology, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany; 6Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany; 7Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, HLA Laboratory, Institute of Transfusion Medicine, Histocompatibility and Immunogenetics, Charité - Universitätsmedizin, Berlin, GermanyCorrespondence: Safak Gül-KleinDepartment of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, GermanyTel +49 30 450 652 195Fax +49 30 450 552 900Email safak.guel@charite.deBackground: Donor-specific antibodies (DSA) against donor human leukocyte antigen after liver transplantation, which are associated with histological changes, have been widely studied with respect to their sustained impact on transplant function. However, their long-term impact after liver transplantation remains unclear.Methods: We performed a cross-sectional analysis from June 2016 to July 2017 that included all patients who presented themselves for scheduled follow-up after receiving a liver transplantation between September 1989 and December 2016. In addition to a liver protocol biopsy, patients were screened for human leukocyte antigen antibodies (HLAab) and donor-specific antibodies. Subsequently, the association between human leukocyte antigen antibodies, donor-specific antibodies, histologic and clinical features, and immunosuppression was analyzed.Results: Analysis for human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was performed for 291 and 271 patients. A significant association between higher inflammation grades and the presence of human leukocyte antigen antibodies and donor-specific antibodies was detected, while fibrosis stages remained unaffected. These results were confirmed by multivariate logistic regression for inflammation showing a significant increase for presence of human leukocyte antigen antibodies and donor-specific antibodies (OR: 4.43; 95% CI: 1.67– 12.6; p=0.0035). Furthermore, the use of everolimus in combination with tacrolimus was significantly associated with the status of negative human leukocyte antigen antibodies and donor-specific antibodies. Viral etiology for liver disease, hepatocellular carcinoma (HCC) and higher steatosis grades of the graft were significantly associated with a lower rate of human leukocyte antigen antibodies. The impact of human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was associated with higher levels of laboratory parameters, such as transaminases and bilirubin.Conclusion: Donor-specific antibodies against donor human leukocyte antigen are associated with histological and biochemical graft inflammation after liver transplantation, while fibrosis seems to be unaffected. Future studies should validate these findings for longer observation periods and specific subgroups.Keywords: human leukocyte antigen antibodies, donor-specific antibodies, liver biopsy, liver transplantation

Safak Gül-Klein,1 Anika Kästner,1 Philipp Konstantin Haber,1 Felix Krenzien,1 Simon Wabitsch,1 Alexander Krannich,2 Andreas Andreou,3 Dennis Eurich,1 Frank Tacke,4 David Horst,5 Johann Pratschke,1 Moritz Schmelzle1 1Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Berlin, Germany; 2Clinical Study Center, Clinical Trial Office, Charité—Universitätsmedizin Berlin, Berlin, Germany; 3Division of Acute Care Surgery, Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, Bern, Switzerland; 4Department of Hepatology/Gastroenterology, Charité—Universitätsmedizin Berlin, Berlin, Germany; 5Institute of Pathology, Charité—Universitätsmedizin Berlin, Berlin, GermanyCorrespondence: Safak Gül-KleinDepartment of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, GermanyEmail safak.guel@charite.dePurpose: The impact of acute rejection (AR) after liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient outcome is uncertain. This aim of this study is to investigate whether AR is associated with HCC relapse and overall survival.Patients and Methods: Patients undergoing LT for HCC between 2001 and 2015 were retrospectively analyzed with regard to histopathological proven AR within the median time until recurrence. Cox’s regression analysis was conducted revealing risk factors for HCC recurrence.Results: HCC recurred in 47 of 252 analyzed patients with a median time to recurrence of 20 months. Patients with AR (28.6%) had a significantly higher frequency of recurrence compared to patients without AR (13.0%, p=0.002). Multiple Cox regression analyses identified AR within 20 months to be an independent risk factor for HCC recurrence both as dichotomized (HR=2.91, 95%CI: 1.30– 6.53; p=0.009) and as a continuous variable (HR=1.81, 95%CI: 1.28– 2.54; p=0.001). HCC recurrence and AR were associated with higher grades of liver fibrosis one year after LT, when compared to patients without AR (p=0.019).Conclusion: Our results demonstrate an association of AR with HCC recurrence after LT with implications for intervals of monitoring in tumor surveillance. Graft fibrosis and immune mechanisms are potentially related and causal interactions are worth further investigation.Keywords: histology, protocol liver biopsy, graft fibrosis, immunological mechanisms, predictors of tumor relapse

Background/Aims Long-term survival of liver transplant recipients is endangered by tumorigenesis at different sites. Little is known about primary de novo tumors developing in the graft. Methods We analyzed the follow-up data of 2731 liver recipients that were transplanted between 1988 and 2019 at our institution (Charité - Universitätsmedizin Berlin, Department of Surgery). All cases with new intrahepatic tumors during follow-up were identified. Results A total of nine patients were diagnosed at a median of 16 years (range, 2-24 years) after surgery. Eight patients presented with hepatocellular carcinoma (HCC), and one patient presented with epithelioid hemangioendothelioma (EHE). All eight HCC patients had a recurrence of the initial disease that had caused liver failure before transplantation. This was associated with viral reinfection with either HCV or HBV in seven cases. Of the nine patients, three underwent surgical resection and only one patient was alive at data abstraction. Conclusion Intrahepatic de novo neoplasms in the liver graft need to be considered in the long-term follow-up of liver recipients and were strongly associated with recurrent viral hepatitis in our study. Although prognosis of this rare complication is generally poor, patients may benefit from surgical resection of localized disease.

BACKGROUND/AIM Esophagectomy is crucial for achieving long-term survival in patients with esophageal cancer, while being associated with a significant risk of complications. Aiming to reduce invasiveness and morbidity, total minimal-invasive esophagectomy (MIE) has been gradually implemented worldwide. The aim of the study was to compare MIE to open Ivor-Lewis esophagectomy (OE) for esophageal cancer or cancer of the gastroesophageal junction (GEJ), in terms of postoperative and oncological outcomes. PATIENTS AND METHODS Clinicopathological data of patients undergoing oncologic transthoracic esophagectomy (Ivor Lewis procedure) between 2010 and 2019 were assessed. Postoperative outcomes and long-term survival of patients undergoing OE were compared to those after MIE using 1:1 propensity score matching. RESULTS After excluding hybrid and robotic procedures, 90 patients who underwent MIE were compared with a matched cohort of 90 patients who underwent OE. MIE was associated with lower major postoperative morbidity (31% vs. 46%, p=0.046) and lower 90-day mortality (2% vs. 12%, p=0.010) compared to OE. MIE showed non-inferior 3-year overall (65% vs. 52%, p=0.019) and comparable disease-free survival rates (49% vs. 51%, p=0.851) in comparison to OE. CONCLUSION Our data suggest that MIE should be preferably performed in patients with esophageal cancer or cancer of the GEJ.

Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in these patients, however, the impact of immunosuppression is unknown. Methods: All patients diagnosed with rHCC in the follow-up after LT were identified from a database of liver recipients transplanted between 1988 and 2019 at our institution (Charité Universitätsmedizin Berlin, Germany). Based on the immunosuppressive regimen following diagnosis of rHCC and the oncological treatment approach, survival analysis was performed. Results: Among 484 patients transplanted for HCC, 112 (23.1%) developed rHCC in the follow-up. Recurrent HCC was diagnosed at a median interval of 16.0 months (range 1.0–203.0), with the majority presenting early after transplantation (63.0%, &lt, 2 years). Median survival after rHCC diagnosis was 10.6 months (0.3–228.7). Reduction of immunosuppression was associated with improved survival, particularly in patients with palliative treatment (8.4 versus 3.0 months). In addition, greater reduction of immunosuppression seemed to be associated with greater prolongation of survival. Graft rejection after reduction was uncommon (n = 7, 6.8%) and did not result in any graft loss. Patients that underwent surgical resection showed improved survival rates (median 19.5 vs. 8.7 months). Conclusion: Reduction of immunosuppressive therapy after rHCC diagnosis is associated with prolonged survival in LT patients. Therefore, reduction of immunosuppression should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.

Background Rodent models of liver resection have been used to investigate and evaluate the liver’s complex physiology and pathology since 1931. First documented by Higgins and Anderson, such models were created to understand liver regeneration mechanisms to improve outcomes in patients undergoing extensive liver resection for liver cancer or other underlying liver diseases. Methods A systematic search was conducted using Pubmed, gathering publications up to January 2019, which engaged with the mouse model of extended liver resection as a method itself. The results of this search were filtered according to their language, novelty, and relevancy. Results The Boolean search found 3741 articles on Pubmed, with 3130 publications remaining when filtered by language and the presence of a full text. In total, 21 of these publications examined the key themes of the animal model described. The mortality varied from 0 to 50% depending on the surgeon's experience and the resection method. The liver resection was mainly performed with classic sutures (14 out of 21 publications) and isoflurane was used for anaesthesia (10 out of 21 publications) in combination with analgesics (buprenorphine or ketamine/xylazine). The most used mouse strain was C57BL/6 (7 of 21 publications) which was on average 11 weeks old with a weight of 23 g. Conclusion Through the overview, laid out in the selected publications, this paper reviews the shift of the extended liver resection model from rat to the mouse, describes the state of the art in the experimental setting, and discusses the possible limitations and pitfalls. Clearly, the extended liver resection in mice is a reproducible, practical and easy to learn method.

Background: Transplantation of the liver entails a state of altered recipient immunologic competence. There are only scarce data concerning the impact of host immunologic factors on the outcome of liver transplant recipients in the context of hepatocellular carcinoma (HCC). Material/Methods: Our study focused on evaluating the presence of tumor necrosis and frequency levels of angiopoietins and monocytes/macrophages subtypes in the host liver prior to liver transplantation (LTX) and their association with recurrence, graft rejection, survival, and clinical prognosis after LTX. Formation of tumor necrosis and tissue densities of angiopoietins and cellular immunologic infiltrates – CD68+ and CD163+ macrophages (TAMs) and TIE2-expressing monocytes (TEMs) – were quantified in recipient HCC specimens. The densities were then matched with clinicopathologic variables and patient survival after LTX (n=88). Some patients were treated prior to LTX by neoadjuvant transarterial chemoembolization (TACE, n=55). Results: Recipient hepatic infiltration with TEMs and CD68+ TAMs was associated with decreased 1-, 3-, and 5-year survival, as well as metastatic and recurrent HCC after LTX (all p

Although more than one million liver transplantations have been carried out worldwide, the literature on liver resections in transplanted livers is scarce. We herein report a total number of fourteen patients, who underwent liver resection after liver transplantation (LT) between September 2004 and 2017. Hepatocellular carcinomas and biliary tree pathologies were the predominant indications for liver resection (n = 5 each), other indications were abscesses (n = 2), post-transplant lymphoproliferative disease (n = 1) and one benign tumor. Liver resection was performed at a median of 120 months (interquartile range (IQR): 56.5&ndash, 199.25) after LT with a preoperative Model for End-Stage Liver Disease (MELD) score of 11 (IQR: 6.75&ndash, 21). Severe complications greater than Clavien&ndash, Dindo Grade III occurred in 5 out of 14 patients (36%). We compared liver resection patients, who had a treatment option of retransplantation (ReLT), with actual ReLTs (excluding early graft failure or rejection, n = 44). Bearing in mind that late ReLT was carried out at a median of 117 months after first transplantation and a median of MELD of 32 (IQR: 17.5&ndash, 37), three-year survival following liver resection after LT was similar to late ReLT (50.0% vs. 59.1%, p = 0.733). Compared to ReLT, liver resection after LT is a rare surgical procedure with significantly shorter hospital (mean 25, IQR: 8.75&ndash, 49, p = 0.034) and ICU stays (mean 2, IQR: 1&ndash, 8, p &lt, 0.001), acceptable complications and survival rates.

Additional file 3: Table S1. Antibodies and reagents used for immunohistology. Table S2. Association of the presence of liver steatosis with clinicopathological characteristics of patients with hepatocellular carcinoma as determined by the chi-squared (χ2) test. The Fischer test was applied when the number of patients in the subgroups was less than five (n

Nicotinamide adenine dinucleotide (NAD), a prominent member of the pyridine nucleotide family, plays a pivotal role in cell-oxidation protection, DNA repair, cell signalling and central metabolic pathways, such as beta oxidation, glycolysis and the citric acid cycle. In particular, extracellular NAD(+) has recently been demonstrated to moderate pathogenesis of multiple systemic diseases as well as aging. Herein we present an assaying method, that serves to quantify extracellular NAD(+) in human heparinised plasma and exhibits a sensitivity ranging from the low micromolar into the low nanomolar domain. The assay achieves the quantification of extracellular NAD(+) by means of a two-step enzymatic cycling reaction, based on alcohol dehydrogenase. An albumin modified revised simulated body fluid was employed as standard matrix in order to optimise enzymatic activity and enhance the linear behaviour and sensitivity of the method. In addition, we evaluated assay linearity, reproducibility and confirmed long-term storage stability of extracellular NAD(+) in frozen human heparinised plasma. In summary, our findings pose a novel standardised method suitable for high throughput screenings of extracellular NAD(+) levels in human heparinised plasma, paving the way for new clinical discovery studies.

Background: Tumour angiogenesis is modulated on both an epigenetic and protein level and has potential implications for immune cell responses. However, the importance of related angiogenic biomarkers in cholangiocarcinoma (CCA) is unknown. This study assessed human CCA samples for the expression of angiogenesisassociated microRNAs, angiopoietins (Angs) and monocytes expressing the Angreceptor, TIE2, with regards to prognostic significance after liver resection. Methods: Angiogenic miRNAs were analysed in frozen samples of intrahepatic CCA (iCC; n = 43) and hilar CCA (HC; n = 45). Ang-1 and Ang-2, as well as TIE2- expressing monocytes (TEMs), were detected in paraffin-embedded iCC sections (n = 88). MiRNA expression and the abundance of TEMs and Angs were correlated with clinicopathological characteristics and survival. Results: MiR-126 was downregulated in 76.7% of all CCA samples, with high relative expression associated with smaller tumours and reduced lymph node metastasis. High Ang-1 expression was associated with less lymphangiosis carcinomatosa and better histological grading (all p < 0.05). The absence of TEMs in iCC correlated with elevated CA19-9 levels. High relative miR-126 and low miR-128 levels were associated with improved survival in iCC and HC, respectively (all p < 0.05). High miR-126, low miR-128 and TEMs were independent prognostic factors for recurrence-free and overall survival (all p < 0.05). Conclusions: These results suggest that angiogenic miRNAs, Angs and TEMs are of prognostic value in CCA. In addition to the possible functional links between angiogenic miRNA expression profiles, Angs and immune-cell responses by TEMs, these data have clinical implications as novel diagnostic tools.

Additional file 1: Table S1. Comparison of MP levels in ascites and blood according to baseline parameters at index paracentesis. Values are displayed in median (range) separated according to the presence or absence of parameters. Figure S1. Flow cytometry in ascitic fluid: Gating strategy and examples for different antigen expression profiles on ascites microparticles. Figure S2. Individual values for microparticles in plasma and ascites.

Background Liver Retransplantation (Re-LT) procedures are associated with an increased risk of morbidity and mortality. Up to date, there is no knowledge on the health-related quality of life and the mental status of these patients. Methods Health-Related Quality of Life (HRQoL) was assessed by using the Short Form 36 (SF-36) Health Survey and Mental Status was assessed by using the Hospital Anxiety and Depression Scale (HADS). The patients were examined in different assessments: During regular check-up examinations in the LT outpatient department in 2011 (Survey 1) and in a postal survey in 2013 (Survey 2). Their medical data was collected by using an established database. Results We received eligible surveys of 383 patients (55.6%) with a history of LT, of which 15 (3.9%) had undergone Re-LT (Re-LT group). These patients were compared to a group of 60 patients who had undergone only one LT. With regard to their HRQoL, the Re-LT group had significantly lower scores on the scales of physical function (PF, p = 0.026), their role-physical (RP, p = 0.008), their vitality (VIT, p = 0.040), and their role-emotional (RE, p = 0.005). The scores for anxiety and depression did not differ significantly between the groups. In a multiple regression analysis, chronic kidney disease was found to be an independent risk factor for decreased scores of PF (p = 0.023). Conclusions Patients who have to undergo Re-LT procedures are faceing impairments in physical aspects of a HRQoL. Together with clinical results from other studies, the findings of the present examination underline the need for an optimized organ distribution strategy since not all patients listed for Re-LT appear to benefit from it.

Additional file 1. Quality of life survey in German

Additional file 2. Quality of life survey in English