Bayesian modelling of time series data (BayModTS)-a FAIR workflow to process sparse and highly variable data.

MOTIVATION: Systems biology aims to better understand living systems through mathematical modelling of experimental and clinical data. A pervasive challenge in quantitative dynamical modelling is the integration of time series measurements, which often have high variability and low sampling resolution. Approaches are required to utilize such information while consistently handling uncertainties. RESULTS: We present BayModTS (Bayesian modelling of time series data), a new FAIR (findable, accessible, interoperable, and reusable) workflow for processing and analysing sparse and highly variable time series data. BayModTS consistently transfers uncertainties from data to model predictions, including process knowledge via parameterized models. Further, credible differences in the dynamics of different conditions can be identified by filtering noise. To demonstrate the power and versatility of BayModTS, we applied it to three hepatic datasets gathered from three different species and with different measurement techniques: (i) blood perfusion measurements by magnetic resonance imaging in rat livers after portal vein ligation, (ii) pharmacokinetic time series of different drugs in normal and steatotic mice, and (iii) CT-based volumetric assessment of human liver remnants after clinical liver resection. AVAILABILITY AND IMPLEMENTATION: The BayModTS codebase is available on GitHub at https://github.com/Systems-Theory-in-Systems-Biology/BayModTS. The repository contains a Python script for the executable BayModTS workflow and a widely applicable SBML (systems biology markup language) model for retarded transient functions. In addition, all examples from the paper are included in the repository. Data and code of the application examples are stored on DaRUS: https://doi.org/10.18419/darus-3876. The raw MRI ROI voxel data were uploaded to DaRUS: https://doi.org/10.18419/darus-3878. The steatosis metabolite data are published on FairdomHub: 10.15490/fairdomhub.1.study.1070.1.

Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4.

There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies.

Approaching Thrombospondin-1 as a Potential Target for Mesenchymal Stromal Cells to Support Liver Regeneration after Partial Hepatectomy in Mouse and Humans.

Extended liver resection carries the risk of post-surgery liver failure involving thrombospondin-1-mediated aggravation of hepatic epithelial plasticity and function. Mesenchymal stromal cells (MSCs), by interfering with thrombospondin-1 (THBS1), counteract hepatic dysfunction, though the mechanisms involved remain unknown. Herein, two-thirds partial hepatectomy in mice increased hepatic THBS1, downstream transforming growth factor-ß3, and perturbation of liver tissue homeostasis. All these events were ameliorated by hepatic transfusion of human bone marrow-derived MSCs. Treatment attenuated platelet and macrophage recruitment to the liver, both major sources of THBS1. By mitigating THBS1, MSCs muted surgery-induced tissue deterioration and dysfunction, and thus supported post-hepatectomy regeneration. After liver surgery, patients displayed increased tissue THBS1, which is associated with functional impairment and may indicate a higher risk of post-surgery complications. Since liver dysfunction involving THBS1 improves with MSC treatment in various animal models, it seems feasible to also modulate THBS1 in humans to impede post-surgery acute liver failure.

Portal venous contrast enhancement ratio of the adrenal glands and spleen as prognostic marker of mortality in patients with acute mesenteric ischemia.

PURPOSE: Contrast enhancement of the adrenal gland defined by computed tomography (CT) was previously analyzed as a prognostic factor for critically ill patients in various diseases. However, no study investigated this quantitative parameter in patients with acute mesenteric ischemia. Therefore, the aim of this study was to evaluate the prognostic value of the contrast enhancement of the adrenal glands in patients with clinically suspected AMI. METHODS: All patients with clinically suspected AMI were retrospectively assessed between 2016 and 2020. All patients underwent surgical exploration after CT imaging. Overall, 134 patients (52 female patients, 38.8%) with a mean age of 69.2 ± 12.4 years were included into the present analysis. For all patients, the preoperative CT was used to calculate the contrast media enhancement of the adrenal glands and the spleen. RESULTS: A total of 27 patients (18.5%) died within the first 24 h and over the following 30-day 94 patients (68.6%) died. There were statistically significant differences regarding the mean values for adrenal-to-spleen ratio for 24-h mortality (p = 0.001) and 30-day mortality (p = 0.004), whereas the radiodensity of the inferior vena cava and the radiodensity of the spleen was statistically significant between survivors and non-survivors after 30 days (p = 0.037 and p = 0.028, respectively). In Cox regression analysis, mean adrenal radiodensity was associated with 24-h mortality (HR 1.09, 95% CI 1.02-1.16, p = 0.01) but not with 30-day mortality (HR 1.03, 95% CI 0.99-1.07, p = 0.13). CONCLUSION: The contrast media enhancement of the adrenal gland is associated with the 24-h and 30-day mortality in patients with AMI. However, the prognostic relevance for translation into clinical routine needs to be validated in other cohorts.

Quantifying fat zonation in liver lobules: an integrated multiscale in silico model combining disturbed microperfusion and fat metabolism via a continuum biomechanical bi-scale, tri-phasic approach.

Metabolic zonation refers to the spatial separation of metabolic functions along the sinusoidal axes of the liver. This phenomenon forms the foundation for adjusting hepatic metabolism to physiological requirements in health and disease (e.g., metabolic dysfunction-associated steatotic liver disease/MASLD). Zonated metabolic functions are influenced by zonal morphological abnormalities in the liver, such as periportal fibrosis and pericentral steatosis. We aim to analyze the interplay between microperfusion, oxygen gradient, fat metabolism and resulting zonated fat accumulation in a liver lobule. Therefore we developed a continuum biomechanical, tri-phasic, bi-scale, and multicomponent in silico model, which allows to numerically simulate coupled perfusion-function-growth interactions two-dimensionally in liver lobules. The developed homogenized model has the following specifications: (i) thermodynamically consistent, (ii) tri-phase model (tissue, fat, blood), (iii) penta-substances (glycogen, glucose, lactate, FFA, and oxygen), and (iv) bi-scale approach (lobule, cell). Our presented in silico model accounts for the mutual coupling between spatial and time-dependent liver perfusion, metabolic pathways and fat accumulation. The model thus allows the prediction of fat development in the liver lobule, depending on perfusion, oxygen and plasma concentration of free fatty acids (FFA), oxidative processes, the synthesis and the secretion of triglycerides (TGs). The use of a bi-scale approach allows in addition to focus on scale bridging processes. Thus, we will investigate how changes at the cellular scale affect perfusion at the lobular scale and vice versa. This allows to predict the zonation of fat distribution (periportal or pericentral) depending on initial conditions, as well as external and internal boundary value conditions.

Critical Evaluation of Discarded Donor Livers in the Eurotransplant Region: Potential Implications for Machine Perfusion.

BACKGROUND There are still many offered donor livers that are declined during the allocation process. Machine perfusion offers the option to evaluate (especially marginal) donor organs and to better decide whether a graft has the potential of being transplanted or not. There is a lack of clear detailed data on why organs are declined and how many donor livers would have the potential of being evaluated in the machine. MATERIAL AND METHODS We retrospectively reviewed 1356 donor livers between 2016 and 2018, which were offered by Eurotransplant and were declined during the allocation process; 284 grafts were from donor after cardiac death (DCD) and 1072 donations were from after brain death (DBD). The analysis was performed independently and blinded by senior transplant surgeons. RESULTS There were 904 (66.6%) donor livers with potential to be evaluated as suitable grafts in machine perfusion, whereas 417 (30.8%) organs were definitely not-transplantable, mainly due to liver cirrhosis, (untreated) donor malignancy, cardiac diseases of the donor leading to a hepatic congestion, and/or systemic infections in the donor. Donors in blood group "AB" were disproportionally often rejected. Due to missing data, 35 (2.6%) organs could not be sufficiently evaluated. CONCLUSIONS Our data suggest that many declined donor livers have potential of being evaluated by machine perfusion. Comprehensive use of machine perfusion is necessary and useful to improve the current organ shortage.

[Liver transplantation in aged patients]. / Lebertransplantation bei alten Patient:innen.

Due to the demographic changes and the increasing incidence of chronic, especially nutritively toxic liver diseases, the number of patients over 65 years of age with indications for liver transplantation is rising considerably. Patient age alone is not a contraindication for organ transplantation; however, in order to ensure the postoperative outcome, a structured interdisciplinary assessment is necessary, especially in older potential organ recipients. With knowledge of comorbidities, individualized prehabilitation enables the perioperative risk to be minimized. The postoperative morbidity in aged patients appears to be comparable to that of younger patients, especially after careful evaluation. Overall, there is a clear survival advantage compared with the best conservative treatment for liver disease. In addition to the perioperative procedure, differences in follow-up care and long-term outcome should also be considered. In this context, predominantly the pharmacological peculiarities, such as polypharmacy and the mutual influence of immunosuppression and comorbidities, have to be taken into account. In addition to old organ recipients, livers from old donors (so-called marginal organs) increasingly play a crucial role in transplantation medicine due to the organ shortage. These are more susceptible to ischemia reperfusion injury and thus put the recipient at a higher risk for delayed or lack of organ function recovery. New ethical issues are raised by the increasing age of donors and recipients, complicating decision making about organ acceptance or rejection for the transplantation physician.

Blocking autophagy with chloroquine aggravates lipid accumulation and reduces intracellular energy synthesis in hepatocellular carcinoma cells, both contributing to its anti-proliferative effect.

PURPOSE: The autophagy inhibitor chloroquine enhances the effect of targeted therapy using tyrosine kinase inhibitor in liver cancer. We would like to further understand the specific mechanism by which chloroquine inhibits the proliferation of tumor cells. METHODS: We used a human hepatocarcinoma cell line (HepG2) as cell culture model. In contrast to the control groups (treated only with complete medium), cells in experimental groups were treated either with complete medium + 40 ng/ml Hepatocyte growth factor (HGF), or with complete medium + 60 µM chloroquine or with complete medium + 40 ng/ml HGF + 60 µM chloroquine for 24 h. Cell number and ATP content were investigated using spectrophotometric assays. Cell proliferation and apoptosis were detected by immunohistochemistry. Cell morphological alterations were examined by Giemsa and H&E staining. Cellular lipid content was determined by Oil Red O staining and Triglyceride quantification assay. Autophagy-related proteins (LC3B and p62) and hepatocyte proliferation-related protein (S6K1) were examined using western blot. The autophagic flux of cells was assessed by mRFP-EGFP-LC3 transfection assay. RESULTS: We found that chloroquine inhibited the proliferation of HepG2 cells, as evidenced by a decrease in cellular ATP content, Ki-67 and S6K1 protein expression and a reduction in cell number. This finding was associated with an increase in lipid content. As expected, chloroquine inhibited autophagy of HepG2 cells, as evidenced by the accumulation of LC3B-II and the significant upregulation of p62. mRFP-EGFP-LC3 transfection assay showed that indeed chloroquine blocked the autophagic flux in HepG2 cells. CONCLUSION: Chloroquine impaired proliferation of HepG2 cells might be due to intracellular accumulation of lipids and inhibition of energy synthesis.

[Multimodal therapy for liver metastases of colorectal carcinoma in curative intention]. / Multimodale Therapie bei Lebermetastasen kolorektaler Karzinome in kurativer Intention.

Depending on the patient's constitution, the biological conditions of the primary tumor, the metastases and the liver function and perfusion, a variety of therapeutic options are available. The basis of metastatic surgery of the liver is partial liver resection. Multimodal therapies with local and systemic approaches are used in functionally or oncologically borderline situations. They are intended to improve long-term success and allow curative treatment in more patients. In recent years, for isolated lesions that cannot be removed by partial liver resection, an R0 situation is achieved in selected patients by liver transplantation with good long-term success. The large number of treatment options and the increasing individualization of therapy require treatment planning in the interdisciplinary tumor board. Also, in view of promising studies, for example, in the field of liver transplantation as well as regional therapy methods, the range of treatment options has not yet been exhausted.

When is it safe for the liver donor to be discharged home and prevent unnecessary re-hospitalizations? - A systematic review of the literature and expert panel recommendations.

BACKGROUND: Few data are available on discharge criteria after living liver donation (LLD). OBJECTIVES: To identify the features for fit for discharge checklist after LLD to prevent unnecessary re-hospitalizations and to provide international expert recommendations. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. The critical outcomes included were complications rates and liver function (defined by elevated bilirubin and INR) (CRD42021260725). RESULTS: Total 57/1710 studies were included in qualitative analysis and 28/57 on the final analysis. No randomized controlled trials were identified. The complications rate was reported in 20/28 studies and ranged from 7.8% to 71.2%. Post hepatectomy liver function was reported in 13 studies. The Quality of Evidence (QoE) was Low and Very-Low for complications rate and liver function test, respectively. CONCLUSIONS: Monitoring and prevention of donor complications should be crucial in decision making of discharge. Pain and diet control, removal of all drains and catheters, deep venous thrombosis prophylaxis, and use routine imaging (CT scan or liver ultrasound) before discharge should be included as fit for discharge checklist (QoE; Low | GRADE of recommendation; Strong). Transient Impaired liver function (defined by elevated bilirubin and INR), a prognostic marker of outcome after liver resection, usually occurs after donor right hepatectomy and should be monitored. Improving trends for bilirubin and INR value should be observed by day 5 post hepatectomy and be included in the fit for discharge checklist. (QoE; Very-Low | GRADE; Strong).

Hepatectomy-Induced Alterations in Hepatic Perfusion and Function - Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function.

Liver resection causes marked perfusion alterations in the liver remnant both on the organ scale (vascular anatomy) and on the microscale (sinusoidal blood flow on tissue level). These changes in perfusion affect hepatic functions via direct alterations in blood supply and drainage, followed by indirect changes of biomechanical tissue properties and cellular function. Changes in blood flow impose compression, tension and shear forces on the liver tissue. These forces are perceived by mechanosensors on parenchymal and non-parenchymal cells of the liver and regulate cell-cell and cell-matrix interactions as well as cellular signaling and metabolism. These interactions are key players in tissue growth and remodeling, a prerequisite to restore tissue function after PHx. Their dysregulation is associated with metabolic impairment of the liver eventually leading to liver failure, a serious post-hepatectomy complication with high morbidity and mortality. Though certain links are known, the overall functional change after liver surgery is not understood due to complex feedback loops, non-linearities, spatial heterogeneities and different time-scales of events. Computational modeling is a unique approach to gain a better understanding of complex biomedical systems. This approach allows (i) integration of heterogeneous data and knowledge on multiple scales into a consistent view of how perfusion is related to hepatic function; (ii) testing and generating hypotheses based on predictive models, which must be validated experimentally and clinically. In the long term, computational modeling will (iii) support surgical planning by predicting surgery-induced perfusion perturbations and their functional (metabolic) consequences; and thereby (iv) allow minimizing surgical risks for the individual patient. Here, we review the alterations of hepatic perfusion, biomechanical properties and function associated with hepatectomy. Specifically, we provide an overview over the clinical problem, preoperative diagnostics, functional imaging approaches, experimental approaches in animal models, mechanoperception in the liver and impact on cellular metabolism, omics approaches with a focus on transcriptomics, data integration and uncertainty analysis, and computational modeling on multiple scales. Finally, we provide a perspective on how multi-scale computational models, which couple perfusion changes to hepatic function, could become part of clinical workflows to predict and optimize patient outcome after complex liver surgery.

Prediction of Survival After Partial Hepatectomy Using a Physiologically Based Pharmacokinetic Model of Indocyanine Green Liver Function Tests.

The evaluation of hepatic function and functional capacity of the liver are essential tasks in hepatology as well as in hepatobiliary surgery. Indocyanine green (ICG) is a widely applied test compound that is used in clinical routine to evaluate hepatic function. Important questions for the functional evaluation with ICG in the context of hepatectomy are how liver disease such as cirrhosis alters ICG elimination, and if postoperative survival can be predicted from preoperative ICG measurements. Within this work a physiologically based pharmacokinetic (PBPK) model of ICG was developed and applied to the prediction of the effects of a liver resection under various degrees of cirrhosis. For the parametrization of the computational model and validation of model predictions a database of ICG pharmacokinetic data was established. The model was applied (i) to study the effect of liver cirrhosis and liver resection on ICG pharmacokinetics; and (ii) to evaluate the model-based prediction of postoperative ICG-R15 (retention ratio 15 min after administration) as a measure for postoperative outcome. Key results are the accurate prediction of changes in ICG pharmacokinetics caused by liver cirrhosis and postoperative changes of ICG-elimination after liver resection, as validated with a wide range of data sets. Based on the PBPK model, individual survival after liver resection could be classified, demonstrating its potential value as a clinical tool.

Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-ß.

Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-ß (TGF-ß) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-ß, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-ß signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-ß.

Application of Magnetic Resonance Imaging in Liver Biomechanics: A Systematic Review.

MRI-based biomechanical studies can provide a deep understanding of the mechanisms governing liver function, its mechanical performance but also liver diseases. In addition, comprehensive modeling of the liver can help improve liver disease treatment. Furthermore, such studies demonstrate the beginning of an engineering-level approach to how the liver disease affects material properties and liver function. Aimed at researchers in the field of MRI-based liver simulation, research articles pertinent to MRI-based liver modeling were identified, reviewed, and summarized systematically. Various MRI applications for liver biomechanics are highlighted, and the limitations of different viscoelastic models used in magnetic resonance elastography are addressed. The clinical application of the simulations and the diseases studied are also discussed. Based on the developed questionnaire, the papers' quality was assessed, and of the 46 reviewed papers, 32 papers were determined to be of high-quality. Due to the lack of the suitable material models for different liver diseases studied by magnetic resonance elastography, researchers may consider the effect of liver diseases on constitutive models. In the future, research groups may incorporate various aspects of machine learning (ML) into constitutive models and MRI data extraction to further refine the study methodology. Moreover, researchers should strive for further reproducibility and rigorous model validation and verification.

Simultaneous right-sided nephrectomy with orthotopic liver and kidney transplantation-An alternative method for patients with autosomal dominant polycystic liver and kidney disease.

PURPOSE: In patients suffering from autosomal dominant polycystic liver and kidney disease (ADPLKD), combined organ transplantation often poses a technical challenge due to the large volume of both organs. To simplify the transplantation procedure by improving the exposure of anatomical structures, we introduce a novel surgical technique of orthotopic liver and kidney transplantation. METHODS: The modified simultaneous liver and kidney transplantation technique via a right-sided L-incision included three steps: (1) right-sided nephrectomy in the recipient followed by (2) orthotopic liver transplantation in cava replacement technique and (3) the orthotopic kidney transplantation with arterial reconstruction to the right common iliac artery. RESULTS: In total, seven patients with ADPLKD were transplanted by using the modified transplantation technique. The mean operation time was 342.43 min (±68.77). Postoperative patients were treated for 6.28 days (±2.50) in the intensive care unit and were discharged from the surgical ward approximately 28 days (±5.66) after the operation with normal graft function. Complications associated with the use of the modified technique, such as bleeding, anastomotic stenosis, biloma, or urinoma, did not occur. CONCLUSION: Modified simultaneous liver and kidney transplantation is a safe alternative for patients with ADPLKD. By combining right-sided nephrectomy and orthotopic graft transplantation, the approach optimizes the exposure of anatomical structures and simplifies the transplantation procedure. Additionally, the modified transplantation technique does not require a particular organ explantation procedure and can be applied for all liver and kidney grafts.

Dynamic PET/CT with the Hepatobiliary Tracer [68Ga]Ga-Tmos-DAZA for Characterization of a Hepatic Tumor.

Established imaging modalities for the characterization of liver tumors are computed tomography (CT), magnetical resonance (MR) imaging, sonography, and hepatobiliary scintigraphy. In some cases, their results may be inconclusive or certain examinations not possible due to contraindications. Positron emission tomography (PET)/CT has the capability of dynamic imaging with high temporal resolution. With radiolabeled tri-alkoxysalicyl-1,4-diazepan-6-amine (TAoS-DAZA) tracers, imaging of liver perfusion and hepatobiliary function is possible in a single examination. In the presented case, the PET/CT was performed in a patient with suspected hepatocellular carcinoma and atypical CT findings. PET imaging characteristics were consistent with a hepatocellular carcinoma (HCC). PET with DAZA ligands may be a supplemental method for liver tumor characterization in difficult cases.

Modulation of Autophagy: A Novel "Rejuvenation" Strategy for the Aging Liver.

Aging is a natural life process which leads to a gradual decline of essential physiological processes. For the liver, it leads to alterations in histomorphology (steatosis and fibrosis) and function (protein synthesis and energy generation) and affects central hepatocellular processes (autophagy, mitochondrial respiration, and hepatocyte proliferation). These alterations do not only impair the metabolic capacity of the liver but also represent important factors in the pathogenesis of malignant liver disease. Autophagy is a recycling process for eukaryotic cells to degrade dysfunctional intracellular components and to reuse the basic substances. It plays a crucial role in maintaining cell homeostasis and in resisting environmental stress. Emerging evidence shows that modulating autophagy seems to be effective in improving the age-related alterations of the liver. However, autophagy is a double-edged sword for the aged liver. Upregulating autophagy alleviates hepatic steatosis and ROS-induced cellular stress and promotes hepatocyte proliferation but may aggravate hepatic fibrosis. Therefore, a well-balanced autophagy modulation strategy might be suitable to alleviate age-related liver dysfunction. Conclusion. Modulation of autophagy is a promising strategy for "rejuvenation" of the aged liver. Detailed knowledge regarding the most devastating processes in the individual patient is needed to effectively counteract aging of the liver without causing obvious harm.

[Surgical treatment of hepato-pancreatic metastases from renal cell carcinoma]. / Chirurgische Therapie von Leber- und Pankreasmetastasen von Nierenzellkarzinomen.

BACKGROUND: The role of surgical treatment of hepato-pancreatic metastases from renal cell carcinoma is still under discussion. MATERIAL AND METHODS: We report about 52 patients of whom 33 underwent surgery for liver metastases and 19 for pancreatic metastases from 1995 to 2018. RESULTS: The 5­year survival rate of all patients with partial liver resection was statistically significantly lower (38%, median survival time 34 months) than with pancreas resection (69%, median survival time 69 months, p = 0.017). Of the patients 21 survived the resection of metastases longer than 5 years and 4 patients longer than 10 years. In R0 resected patients, recurrences were observed in 13 cases after liver resection and in 9 cases after pancreas resection. The cumulative recurrence rate after 5 years was 38% for the liver and 57% for the pancreas. In R0 partial liver resections, an interval <24 months between nephrectomy and liver resection as well as multiple metastases were negative prognostic factors. CONCLUSION: In spite of high recurrence rates, surgical treatment for hepato-pancreatic metastases from renal cell carcinoma yielded very good long-term results, in particular with complete resection of solitary metachronous metastases. Repeated surgery for completely resectable metastases, resulted in long tumor-free intervals and thus contributed to good long-term results.

Liver Transplant Due to Flupirtine-Induced Acute Liver Failure.

OBJECTIVES: Acute drug-induced liver failure is a rare indication for liver transplant. There is only one case of flupirtine-induced liver failure requiring transplant in the literature. In February 2018, the European Medicines Agency issued a withdrawal of approval for flupirtine medication in European countries as a result of the risk of acute liver failure. MATERIALS AND METHODS: The aim of this study was a German-wide collection of data regarding patients with liver transplant as a result of flupirtine-associated liver failure. RESULTS: A total of 9 patients received transplants. All patients were women with a mean age of 43 years. Indication for flupirtine medication was musculoskeletal symptoms and migraine headache. The medication was taken over a period of approximately 3 months. All patients developed progressive acute liver failure, and no patient had previous chronic liver disease or cirrhosis. The mean laboratory Model for End Stage Liver Disease score for the patients was 31 ± 7 at time of transplant. Eight of the 9 patients were listed as "high urgency" for transplant. After transplant, they had an uneventful course with a prolonged mean intensive care unit stay of 13 ± 8.7 days. The whole hospitalization time was 43 ± 21 days. CONCLUSIONS: This is the largest published series of patients who received liver transplant after a drug-induced acute liver failure from flupirtine medication.

Milan criteria in the MELD era-is it justifiable to extend the limits for orthotopic liver transplantation?

BACKGROUND: The Milan criteria (MC) are widely used for the indication of liver transplantation (LTx) in hepatocellular carcinoma (HCC). Good long-term results have also been reported following LTx for patients exceeding the MC. In this article, we compare the overall and recurrence-free survival of our patients fulfilling and exceeding the MC according to the post-transplant histopathological results. PATIENTS AND METHODS: Data from 120 patients with HCC (22 females and 98 males) were analyzed. The median patient age was 61 years (Q1, Q3 54.7, 65.4), and the median MELD score was 11 (Q1, Q3 8, 15). The median follow-up period was 53 months (Q1, Q3 16.6, 78). Patients were categorized into established criteria (MC, up-to-seven (UTS), Asan criteria, AFP score), and the outcome of the individual groups was compared. RESULTS: Seventy-four of 120 patients fulfilled the MC, 86 patients met the UTS criteria, 85 patients fulfilled the Asan criteria, and 79 patients had an AFP score less than or equal to 2. The 1- and 5-year survival rates of all patients were 76.7% and 55.6%, respectively. In total, 14.2% of all patients (5.4% of patients who met the MC, 7% of patients who met the UTS criteria, 5.9% of patients who met the Asan criteria, and 6.3% of patients who had an AFP score less than 2) experienced recurrence. CONCLUSIONS: The outcomes of the patients were comparable to those reported in the current literature. In our population, similar recurrence and survival rates of the patients were noted for patients fulfilling the UTS criteria irrespective of fulfilling or exceeding the MC. Consequently, we consider using UTS criteria as the extended criterion for LTx indication.