Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and its mortality is third among all solid tumors, behind carcinomas of the lung and the colon. Despite continuous ...advancements in the management of this disease, the prognosis for HCC remains inferior compared to other tumor entities. While orthotopic liver transplantation (OLT) and surgical resection are the only two curative treatment options, OLT remains the best treatment strategy as it not only removes the tumor but cures the underlying liver disease. As the applicability of OLT is nowadays limited by organ shortage, major liver resections ⁻ even in patients with underlying chronic liver disease ⁻ are adopted increasingly into clinical practice. Against the background of the oftentimes present chronical liver disease, locoregional therapies have also gained increasing significance. These strategies range from radiofrequency ablation and trans-arterial chemoembolization to selective internal radiation therapy and are employed in both curative and palliative intent, individually, as a bridging to transplant or in combination with liver resection. The choice of the appropriate treatment, or combination of treatments, should consider the tumor stage, the function of the remaining liver parenchyma, the future liver remnant volume and the patient's general condition. This review aims to address the topic of multimodal treatment strategies in HCC, highlighting a multidisciplinary treatment approach to further improve outcome in these patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This editorial aims to summarize the 13 scientific articles published in the Special Issue entitled "New Frontiers in Organ Preservation and Hepatoprotection" ....
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In the face of a critical organ shortage in the Western world, various strategies are employed to expand the donor pool for orthotopic liver transplantation (OLT). Among them is the transplantation ...of organs from extended criteria donors, a valuable source of liver allografts, however, characterized by potential risks for post‐OLT complications and inferior outcomes. In recent years, machine perfusion (MP) of the explanted donor liver as well as regional perfusion techniques has witnessed significant advancements. Here, we aim to discuss different modes of dynamic organ preservation in OLT. These include hypothermic and normothermic MP, hypothermic oxygenated machine perfusion (HOPE), controlled oxygenated rewarming as well as regional perfusion protocols. Over recent years, multiple feasibility trials have demonstrated the clinical prospects of MP. In the context of OLT using organs from extended criteria donors, MP has numerous advantages compared to conventional cold storage, some of which include the preservation and reconditioning of borderline transplantable organs and the viability assessment of high‐risk donor allografts. This review aims to address the topic of liver allograft MP, highlighting particularly the current trends in clinical applications and future perspectives. Furthermore, different approaches of liver storage and reconditioning are reviewed in the context of ongoing research.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Abdominal infections including cholangitis represent a major problem in patients with perihilar cholangiocarcinoma (pCCA). Thus, we investigated bacterial colonization of the bile ducts and ...determined its impact on postoperative outcome focusing on abdominal infections. A cohort of 95 pCCA patients who underwent surgery between 2010 and 2019 with available intraoperative microbial bile cultures were analyzed regarding bile duct colonization and postoperative abdominal infection by group comparisons and logistic regressions. 84.2% (80/95) showed bacterial colonization of the bile ducts and 54.7% (52/95) developed postoperative abdominal infections. Enterococcus faecalis (38.8%, 31/80), Enterococcus faecium (32.5%, 26/80), Enterobacter cloacae (16.3%, 13/80) and Escherichia coli (11.3%, 9/80) were the most common bacteria colonizing the bile ducts and Enterococcus faecium (71.2%, 37/52), Enterococcus faecalis (30.8%, 16/52), Enterobacter cloacae (25.0%, 13/52) and Escherichia coli (19.2%, 10/52) the most common causes of postoperative abdominal infection. Further, reduced susceptibility to perioperative antibiotic prophylaxis (OR = 10.10, p = .007) was identified as independent predictor of postoperative abdominal infection. Bacterial colonization is common in pCCA patients and reduced susceptibility of the bacteria to the intraoperative antibiotic prophylaxis is an independent predictor of postoperative abdominal infections. Adapting antibiotic prophylaxis might therefore have the potential to improve surgical outcome pCCA patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Muscle wasting and alterations of body composition are linked to clinical outcomes in numerous medical conditions. The role of myosteatosis in posttransplant outcomes remains to be determined. Here ...we investigated skeletal muscle mass and myosteatosis as prognostic factors in patients undergoing orthotopic liver transplantation (OLT). The data of 225 consecutive OLT recipients from a prospective database were retrospectively analyzed (May 2010‐December 2017). Computed tomography–based skeletal‐muscle‐index (muscle mass), visceral‐fat‐area (visceral adiposity), and mean skeletal‐muscle‐radiation‐attenuation (myosteatosis) were calculated using a segmentation tool. Cut‐off values of myosteatosis resulted in a good stratification of patients into low‐ and high‐risk groups in terms of morbidity (Clavien‐Dindo ≥3b). Patients with myosteatosis had significantly higher complication rates (90‐day Comprehensive Complication Index 68 ± 32 vs 44 ± 30, P < .001) and also displayed significantly longer intensive care (18 ± 25 vs 11 ± 21 days, P < .001) and hospital stay (56 ± 55 vs 33 ± 24 days, P < .001). Estimated costs were 44% higher compared to patients without myosteatosis. Multivariable analysis identified myosteatosis as an independent prognostic factor for major morbidity (odds ratio: 2.772, confidence interval: 1.516‐5.066, P = .001). Adding myosteatosis to the well‐established Balance‐of‐Risk‐(BAR) score resulted in an increased prognostic value compared to the original BAR score. Myosteatosis may be a useful parameter to predict perioperative outcome in patients undergoing OLT, supporting the role of muscle quality (myosteatosis) over quantity (muscle mass) in this setting.
This study demonstrates the association of myosteatosis with inferior perioperative outcome in patients undergoing orthotopic liver transplantation, supporting the role of muscle quality (myosteatosis) over quantity (muscle mass) in this setting.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological ...events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular-pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and associated with a dismal prognosis due to the lack of an efficient systemic therapy. In contrast to other cancers, new ...immunotherapies have demonstrated unsatisfactory results in clinical trials, underlining the importance of a deeper understanding of the special tumor microenvironment of CCA and the role of immune cells interacting with the tumor. Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy. Therefore, the aim of this systemic review is to summarize the current literature focusing on the proportions and distribution, molecular pathogenesis, prognostic significance of TILs and their role in immunotherapy for CCA patients.In CCA, CD8+ and CD4+ T lymphocytes represent the majority of TILs and are mostly sequestered around the cancer cells. CD20+ B lymphocytes and Natural Killer (NK) cells are less frequent. In contrast, Foxp3+ cells (regulatory T cells, Tregs) are observed to infiltrate into the tumor. In the immune microenvironment of CCA, cancer cells and stromal cells such as TAMs, TANs, MSDCs and CAFs inhibit the immune protection function of TILs by secreting factors like IL-10 and TGF-β. With respect to molecular pathogenesis, the Wnt/-catenin, TGF-signaling routes, aPKC-i/P-Sp1/Snail Signaling, B7-H1/PD-1Pathway and Fas/FasL signaling pathways are connected to the malignant potential and contributed to tumor immune evasion by increasing TIL apoptosis. Distinct subtypes of TILs show different prognostic implications for the long-term outcome in CCA. Although there are occasionally conflicting results, CD8+ and CD4+ T cells, and CD20+ B cells are positively correlated with the oncological prognosis of CCA, while a high number of Tregs is very likely associated with worse overall survival. TILs also play a major role in immunotherapy for CCA.In summary, the presence of TILs may represent an important marker for the prognosis and a potential target for novel therapy, but more clinical and translationaldata is needed to fully unravel the importance of TILs in the treatment of CCA.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Body composition and myosteatosis affect clinical outcomes in orthotopic liver transplantation (OLT). Here we aimed to compare the value and limitations of various selection criteria to ...define pre-transplant myosteatosis in the assessment of short- and long-term outcomes following OLT. We retrospectively analyzed the data of 264 consecutive recipients who underwent deceased donor OLT at a German university medical centre. Myosteatosis was evaluated by preoperative computed-tomography-based segmentation. Patients were stratified using muscle radiation attenuation of the whole muscle area (L3Muslce-RA), psoas RA (L3Psoas-RA) and intramuscular adipose tissue content (IMAC) values. L3Muslce-RA, L3Psoas-RA and IMAC performed well without major differences and identified patients at risk for inferior outcomes in the group analysis. Quartile-based analyses, receiver operating characteristic curve and correlation analyses showed a superior association of L3Muslce-RA with perioperative outcomes when compared to L3Psoas-RA and L3IMAC. Long-term outcome did not show any major differences between the used selection criteria. This study confirms the prognostic role of myosteatosis in OLT with a particularly strong value in the perioperative phase. Although, based on our data, L3Muscle-RA might be the most suitable and recommended selection criterion to assess CT-based myosteatosis when compared to L3Psoas-RA and L3IMAC, further studies are warranted to validate these findings.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Machine perfusion (MP) is often referred to as one of the most promising advancements in liver transplantation research of the last few decades, with various techniques and modalities being evaluated ...in preclinical studies using animal models. However, low scientific rigor and subpar reporting standards lead to limited reproducibility and translational potential, hindering progress. This pre-registered systematic review (PROSPERO: CRD42021234667) aimed to provide a thematic overview of the preclinical research landscape on MP in liver transplantation using in vivo transplantation models and to explore methodological and reporting standards, using the ARRIVE (Animal Research: Reporting of In Vivo Experiments) score. In total 56 articles were included. Studies were evenly distributed across Asia, Europe, and the Americas. Porcine models were used in 57.1% of the studies, followed by rats (39.3%) and dogs (3.6%). In terms of graft type, 55.4% of the studies used donation after cardiac death grafts, while donation after brain death grafts accounted for 37.5%. Regarding MP modalities, the distribution was as follows: 41.5% of articles utilized hypothermic MP, 21.5% normothermic MP, 13.8% subnormothermic MP, and 16.9% utilized hypothermic oxygenated MP. The stringent documentation of ARRIVE elements concerning precise experimental execution, group size and selection, the choice of statistical methods, as well as adherence to the principles of the 3Rs, was notably lacking in the majority of publications, with less than 30% providing comprehensive details. Postoperative analgesia and antibiotics treatment were not documented in 82.1% of all included studies. None of the analyzed studies fully adhered to the ARRIVE Guidelines. In conclusion, the present study emphasizes the importance of adhering to reporting standards to promote reproducibility and adequate animal welfare in preclinical studies in machine perfusion. At the same time, it highlights a clear deficiency in this field, underscoring the need for further investigations into animal welfare-related topics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In an attempt to further improve liver allograft utilization and outcome in orthotopic liver transplantation (OLT), a variety of clinical scoring systems have been developed. Here we aimed to ...comparatively investigate the association of the Balance-of-Risk (BAR), Survival-Outcomes-Following-Liver-Transplant (SOFT), Preallocation-Survival-Outcomes-Following-Liver-Transplant (pSOFT), Donor-Risk-Index (DRI), and the Eurotransplant-Donor-Risk-Index (ET-DRI) scores with short- and long-term outcome following OLT.
We included 338 consecutive patients, who underwent OLT in our institution between May 2010 and November 2017. For each prognostic model, the optimal cutoff values were determined with the help of the Youden-index and their diagnostic accuracy for 90-day post OLT-mortality and major postoperative complications was measured by the area under the receiver operating characteristic curve (AUROC). Patient- and graft survival were analyzed using the Kaplan-Meier method and the log-rank test. Morbidity was assessed using the Clavien-Dindo classification and the Comprehensive-Complication-Index.
BAR, SOFT, and pSOFT performed well above the conventional AUROC-threshold of 0.70 with good prediction of early mortality. Only BAR showed AUC>0.70 for both mortality and major morbidity. With the cutoffs of 14, 31, and 22 respectively for BAR, SOFT, and pSOFT, subgroup analysis showed significant differences (p<0.001) in morbidity and mortality, length of intensive care- and hospital-stay and early allograft dysfunction rates. Five-years patient survival was inferior in the high BAR, pSOFT, and SOFT groups.
Out of all scores tested, the BAR-score had the best value in predicting both 90-day morbidity and mortality after OLT showing the highest AUCs. The pSOFT and SOFT scores demonstrated an acceptable accuracy in predicting 90-day morbidity and mortality. The used BAR, SOFT, and pSOFT cutoffs allowed the identification of patients at risk in terms of five-year patient survival. The DRI and ET-DRI scores have failed to predict recipient outcomes in the present setting.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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