BACKGROUND & AIMS: Despite strong evidence for improved preservation of donor livers by machine perfusion, longer post-transplant follow-up data are urgently needed in an unselected patient population. We aimed to assess long-term outcomes after transplantation of hypothermic oxygenated machine perfusion (HOPE)-treated donor livers based on real-world data (i.e., IDEAL-D stage 4). METHODS: In this international, multicentre, observational cohort study, we collected data from adult recipients of HOPE-treated livers transplanted between January 2012 and December 2021. Analyses were stratified by donation after brain death (DBD) and donation after circulatory death (DCD), sub-divided by their respective risk categories. The primary outcome was death-censored graft survival. Secondary outcomes included the incidence of primary non-function (PNF) and ischaemic cholangiopathy (IC). RESULTS: We report on 1,202 liver transplantations (64% DBD) performed at 22 European centres. For DBD, a total number of 99 benchmark (8%), 176 standard (15%), and 493 extended-criteria (41%) cases were included. For DCD, 117 transplants were classified as low risk (10%), 186 as high risk (16%), and 131 as futile (11%), with significant risk profile variations among centres. Actuarial 1-, 3-, and 5-year death-censored graft survival rates for DBD and DCD livers were 95%, 92%, and 91%, vs. 92%, 87%, and 81%, respectively (log-rank p = 0.003). Within DBD and DCD strata, death-censored graft survival was similar among risk groups (log-rank p = 0.26, p = 0.99). Graft loss due to PNF or IC was 2.3% and 0.4% (DBD), and 5% and 4.1% (DCD). CONCLUSIONS: This study shows excellent 5-year survival after transplantation of HOPE-treated DBD and DCD livers with low rates of graft loss due to PNF or IC, irrespective of their individual risk profile. HOPE treatment has now reached IDEAL-D stage 4, which further supports its implementation in routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05520320. IMPACT AND IMPLICATIONS: This study demonstrates the excellent long-term performance of hypothermic oxygenated machine perfusion (HOPE) treatment of donation after circulatory and donation after brain death liver grafts irrespective of their individual risk profile in a real-world setting, outside the evaluation of randomised-controlled trials. While previous studies have established safety, feasibility, and efficacy against the current standard, according to the IDEAL-D evaluation framework, HOPE treatment has now reached the final IDEAL-D stage 4, which further supports its implementation in routine clinical practice.

• MeSH
• dárci tkání statistika a číselné údaje   MeSH
• dospělí MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• perfuze * metody   přístrojové vybavení   MeSH
• přežívání štěpu * MeSH
• senioři MeSH
• terapeutická hypotermie metody   MeSH
• transplantace jater * metody   škodlivé účinky   MeSH
• uchovávání orgánů * metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH

BACKGROUND: While 4 randomized controlled clinical trials confirmed the early benefits of hypothermic oxygenated machine perfusion (HOPE), high-level evidence regarding long-term clinical outcomes is lacking. The aim of this follow-up study from the HOPE-ECD-DBD trial was to compare long-term outcomes in patients who underwent liver transplantation using extended criteria donor allografts from donation after brain death (ECD-DBD), randomized to either HOPE or static cold storage (SCS). METHODS: Between September 2017 and September 2020, recipients of liver transplantation from 4 European centers receiving extended criteria donor-donation after brain death allografts were randomly assigned to HOPE or SCS (1:1). Follow-up data were available for all patients. Analyzed endpoints included the incidence of late-onset complications (occurring later than 6 months and graded according to the Clavien-Dindo Classification and the Comprehensive Complication Index) and long-term graft survival and patient survival. RESULTS: A total of 46 patients were randomized, 23 in both arms. The median follow-up was 48 months (95% CI: 41-55). After excluding early perioperative morbidity, a significant reduction in late-onset morbidity was observed in the HOPE group (median reduction of 23 Comprehensive Complication Index-points [p=0.003] and lower incidence of major complications [Clavien-Dindo ≥3, 43% vs. 85%, p=0.009]). Primary graft loss occurred in 13 patients (HOPE n=3 vs. SCS n=10), resulting in a significantly lower overall graft survival (p=0.029) and adverse 1-, 3-, and 5-year survival probabilities in the SCS group, which did not reach the level of significance (HOPE 0.913, 0.869, 0.869 vs. SCS 0.783, 0.606, 0.519, respectively). CONCLUSIONS: Our exploratory findings indicate that HOPE reduces late-onset morbidity and improves long-term graft survival providing clinical evidence to further support the broad implementation of HOPE in human liver transplantation.

• MeSH
• lidé MeSH
• mozková smrt MeSH
• následné studie MeSH
• perfuze metody   MeSH
• přežívání štěpu MeSH
• transplantace jater * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Hepatic in vitro models that accurately replicate phenotypes and functionality of the human liver are needed for applications in toxicology, pharmacology and biomedicine. Notably, it has become clear that liver function can only be sustained in 3D culture systems at physiologically relevant cell densities. Additionally, drug metabolism and drug-induced cellular toxicity often follow distinct spatial micropatterns of the metabolic zones in the liver acinus, calling for models that capture this zonation. We demonstrate the manufacture of accurate liver microphysiological systems (MPS) via engineering of 3D stereolithography printed hydrogel chips with arrays of diffusion open synthetic vasculature channels at spacings approaching in vivo capillary distances. Chip designs are compatible with seeding of cell suspensions or preformed liver cell spheroids. Importantly, primary human hepatocytes (PHH) and hiPSC-derived hepatocyte-like cells remain viable, exhibit improved molecular phenotypes compared to isogenic monolayer and static spheroid cultures and form interconnected tissue structures over the course of multiple weeks in perfused culture. 3D optical oxygen mapping of embedded sensor beads shows that the liver MPS recapitulates oxygen gradients found in the acini, which translates into zone-specific acet-ami-no-phen toxicity patterns. Zonation, here naturally generated by high cell densities and associated oxygen and nutrient utilization along the flow path, is also documented by spatial proteomics showing increased concentration of periportal- versus perivenous-associated proteins at the inlet region and vice versa at the outlet region. The presented microperfused liver MPS provides a promising platform for the mesoscale culture of human liver cells at phenotypically relevant densities and oxygen exposures. STATEMENT OF SIGNIFICANCE: A full 3D tissue culture platform is presented, enabled by massively parallel arrays of high-resolution 3D printed microperfusion hydrogel channels that functionally mimics tissue vasculature. The platform supports long-term culture of liver models with dimensions of several millimeters at physiologically relevant cell densities, which is difficult to achieve with other methods. Human liver models are generated from seeded primary human hepatocytes (PHHs) cultured for two weeks, and from seeded spheroids of hiPSC-derived human liver-like cells cultured for two months. Both model types show improved functionality over state-of-the-art 3D spheroid suspensions cultured in parallel. The platform can generate physiologically relevant oxygen gradients driven by consumption rather than supply, which was validated by visualization of embedded oxygen-sensitive microbeads, which is exploited to demonstrate zonation-specific toxicity in PHH liver models.

• MeSH
• hepatocyty * metabolismus   MeSH
• hydrogely metabolismus   MeSH
• játra * MeSH
• kyslík metabolismus   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• dítě MeSH
• péče o pacienty v kritickém stavu MeSH
• terapie náhlých příhod MeSH
• Check Tag
• dítě MeSH

• Konspekt
• Pediatrie
• NLK Obory
• pediatrie
• urgentní lékařství
• NLK Publikační typ
• kolektivní monografie

Reconfiguring the structure and selectivity of existing chemotherapeutics represents an opportunity for developing novel tumor-selective drugs. Here, as a proof-of-concept, the use of high-frequency sound waves is demonstrated to transform the nonselective anthracycline doxorubicin into a tumor selective drug molecule. The transformed drug self-aggregates in water to form ≈200 nm nanodrugs without requiring organic solvents, chemical agents, or surfactants. The nanodrugs preferentially interact with lipid rafts in the mitochondria of cancer cells. The mitochondrial localization of the nanodrugs plays a key role in inducing reactive oxygen species mediated selective death of breast cancer, colorectal carcinoma, ovarian carcinoma, and drug-resistant cell lines. Only marginal cytotoxicity (80-100% cell viability) toward fibroblasts and cardiomyocytes is observed, even after administration of high doses of the nanodrug (25-40 μg mL-1 ). Penetration, cytotoxicity, and selectivity of the nanodrugs in tumor-mimicking tissues are validated by using a 3D coculture of cancer and healthy cells and 3D cell-collagen constructs in a perfusion bioreactor. The nanodrugs exhibit tropism for lung and limited accumulation in the liver and spleen, as suggested by in vivo biodistribution studies. The results highlight the potential of this approach to transform the structure and bioactivity of anticancer drugs and antibiotics bearing sono-active moieties.

• MeSH
• doxorubicin chemie   farmakologie   MeSH
• lidé MeSH
• nádory vaječníků * MeSH
• nanočástice * chemie   MeSH
• protinádorová antibiotika chemie   MeSH
• tkáňová distribuce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A convenient geometrical description of the microvascular network is necessary for computationally efficient mathematical modelling of liver perfusion, metabolic and other physiological processes. The tissue models currently used are based on the generally accepted schematic structure of the parenchyma at the lobular level, assuming its perfect regular structure and geometrical symmetries. Hepatic lobule, portal lobule, or liver acinus are considered usually as autonomous functional units on which particular physiological problems are studied. We propose a new periodic unit-the liver representative periodic cell (LRPC) and establish its geometrical parametrization. The LRPC is constituted by two portal lobulae, such that it contains the liver acinus as a substructure. As a remarkable advantage over the classical phenomenological modelling approaches, the LRPC enables for multiscale modelling based on the periodic homogenization method. Derived macroscopic equations involve so called effective medium parameters, such as the tissue permeability, which reflect the LRPC geometry. In this way, mutual influences between the macroscopic phenomena, such as inhomogeneous perfusion, and the local processes relevant to the lobular (mesoscopic) level are respected. The LRPC based model is intended for its use within a complete hierarchical model of the whole liver. Using the Double-permeability Darcy model obtained by the homogenization, we illustrate the usefulness of the LRPC based modelling to describe the blood perfusion in the parenchyma.

• MeSH
• anatomické modely * MeSH
• biologické modely MeSH
• játra anatomie a histologie   krevní zásobení   MeSH
• lidé MeSH
• mikrocirkulace MeSH
• ověření koncepční studie MeSH
• perfuze MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: The aim of this study was to evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD). BACKGROUND: HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT). METHODS: Between September 2017 and September 2020, 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n = 23) or SCS (n = 23). Peak-ALT levels within 7 days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications [Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)], length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD). RESULTS: Demographics were equally distributed between both groups [donor age: 72 (IQR: 59-78) years, recipient age: 62 (IQR: 55-65) years, labMELD: 15 (IQR: 9-25), 38 male and 8 female recipients]. HOPE resulted in a 47% decrease in serum peak ALT [418 (IQR: 221-828) vs 796 (IQR: 477-1195) IU/L, P = 0.030], a significant reduction in 90-day complications [44% vs 74% CD grade ≥3, P = 0.036; 32 (IQR: 12-56) vs 52 (IQR: 35-98) CCI, P = 0.021], and shorter ICU- and hospital-stays [5 (IQR: 4-8) vs 8 (IQR: 5-18) days, P = 0.045; 20 (IQR: 16-27) vs 36 (IQR: 23-62) days, P = 0.002] compared to SCS. A trend toward reduced EAD was observed for HOPE (17% vs 35%; P = 0.314). CONCLUSION: This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.

• MeSH
• alografty MeSH
• dárci tkání zásobování a distribuce   MeSH
• design vybavení MeSH
• incidence MeSH
• lidé středního věku MeSH
• lidé MeSH
• perfuze přístrojové vybavení   MeSH
• pooperační komplikace epidemiologie   prevence a kontrola   MeSH
• přežívání štěpu MeSH
• senioři MeSH
• terapeutická hypotermie přístrojové vybavení   MeSH
• transplantace jater metody   MeSH
• uchovávání orgánů přístrojové vybavení   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Evropa MeSH

Colorectal cancer is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Despite advances in improving resectability, most patients present with non-resectable colorectal liver metastases requiring palliative systemic therapy and locoregional disease control strategies. There is a growing interest in the use of liver transplantation to treat non-resectable colorectal liver metastases in well selected patients, leading to a surge in the number of studies and prospective trials worldwide, thereby fuelling the emerging field of transplant oncology. The interdisciplinary nature of this field requires domain-specific evidence and expertise to be drawn from multiple clinical specialities and the basic sciences. Importantly, the wider societal implication of liver transplantation for non-resectable colorectal liver metastases, such as the effect on the allocation of resources and national transplant waitlists, should be considered. To address the urgent need for a consensus approach, the International Hepato-Pancreato-Biliary Association commissioned the Liver Transplantation for Colorectal liver Metastases 2021 working group, consisting of international leaders in the areas of hepatobiliary surgery, colorectal oncology, liver transplantation, hepatology, and bioethics. The aim of this study was to standardise nomenclature and define management principles in five key domains: patient selection, evaluation of biological behaviour, graft selection, recipient considerations, and outcomes. An extensive literature review was done within the five domains identified. Between November, 2020, and January, 2021, a three-step modified Delphi consensus process was undertaken by the workgroup, who were further subgrouped into the Scientific Committee, Expert Panel, and Transplant Centre Representatives. A final consensus of 44 statements, standardised nomenclature, and a practical management algorithm is presented. Specific criteria for clinico-patho-radiological assessments with molecular profiling is crucial in this setting. After this, the careful evaluation of biological behaviour with bridging therapy to transplantation with an appropriate assessment of the response is required. The sequencing of treatment in synchronous metastatic disease requires special consideration and is highlighted here. Some ethical dilemmas within organ allocation for malignant indications are discussed and the role for extended criteria grafts, living donor transplantation, and machine perfusion technologies for non-resectable colorectal liver metastases are reviewed. Appropriate immunosuppressive regimens and strategies for the follow-up and treatment of recurrent disease are proposed. This consensus guideline provides a framework by which liver transplantation for non-resectable colorectal liver metastases might be safely instituted and is a meaningful step towards future evidenced-based practice for better patient selection and organ allocation to improve the survival for patients with this disease.

• MeSH
• adenokarcinom diagnóza   sekundární   chirurgie   MeSH
• delfská metoda MeSH
• klinické rozhodování metody   MeSH
• kolorektální nádory patologie   MeSH
• lidé MeSH
• nádory jater diagnóza   sekundární   chirurgie   MeSH
• prognóza MeSH
• transplantace jater metody   normy   MeSH
• výběr pacientů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• konsensus - konference MeSH
• směrnice pro lékařskou praxi MeSH

Cíl: Cílem studie bylo posoudit, zda přidání výpočtu frakce arteriálního sycení (arterial enhancement fraction - AEF) k hodnocení vícefázové výpočetní tomografie (CT) zlepší detekci viabilní nádorové tkáně po lokální léčbě nádoru jater u různě zkušených hodnotitelů. Metodika: Dva mladí radiologové s rozdílně dlouhou praxí v CT diagnostice (3 a 1 rok) hodnotili nezávisle CT obrazy pacientů, kteří splnili kritéria studie. CT dokumentace byla hodnocena nejprve samostatně a poté v kombinaci s barevnými mapami AEF. Hodnotitelé posuzovali přítomnost rezidua viabilní nádorové tkáně, při pozitivním nálezu měřili jeho velikost. Stejnou obrazovou dokumentaci hodnotili dva zkušení radiologové (s praxí více než 10 let). Jeden z nich provedl shodné hodnocení jako mladí radiologové, druhý hodnotil pouze CT s AEF a přihlížel ke klinickému obrazu a dalšímu vývoji onemocnění. Oba zkušení hodnotitelé srovnali výsledky svého hodnocení a z jejich shody vzešla referenční hodnota, s níž byly porovnány nálezy mladých radiologů. Výsledky byly statisticky analyzovány. Výsledky: Hodnocena byla dokumentace 70 pacientů. Reziduum nádorové tkáně po prodělané lokální léčbě bylo detekováno u 40 osob. Přidání AEF ke standardní CT dokumentaci mírně zvýšilo senzitivitu pro detekci viabilní nádorové tkáně u obou mladších hodnotitelů, signifikantně však zvýšilo specificitu nálezu, u radiologa s tříletou praxí (z 56,6 % na 96,6 %, p = 0,0004) a začátečníka (z 36,7 % na 73,7 %, p = 0,0089). Podobně se zvýšila přesnost měření velikosti tumoru. Závěr: Použití AEF jako součásti hodnocení CT dokumentace zvyšuje schopnost detekovat přítomnost rezidua po lokální léčbě jaterních nádorů a zvyšuje přesnost jeho měření. Největší efekt byl patrný u nejméně zkušeného hodnotitele. Výpočet AEF lze provést z vícefázového CT bez výrazného navýšení radiační dávky.

Objectives: We investigated whether the use of arterial enhancement fraction (AEF) during the evaluation of multiphasic contrast-enhanced computed tomography (CECT) improves the assessment of viable tumor tissue after locoregional therapy in liver tumors. We tested how the use of the AEF influences the accuracy of tumor residue detection in differently experienced evaluators. Methods: Two differently experienced radiologists independently evaluated CT images of patients who met the criteria of our study. CT documentation was evaluated first separately and then in combination with AEF color maps. The evaluators assessed the presence of a residue of viable tumor tissue, and measured it, in case of a positive finding. The same documentation was evaluated by two experienced radiologists (with more than 10 years of experience). One of them performed the same evaluation as young radiologists, the other evaluated only CT with AEF and took into account the clinical information and further development of the disease. Both experienced evaluators compared the results of their evaluation and their agreement resulted in a reference value to which the findings of young radiologists were compared. The results were statistically analyzed. Results: The documentation of 70 patients was evaluated. Viable tumor tissue was detected in 40 of them. The addition of AEF to the standard CT documentation slightly increased the sensitivity in both young evaluators, but significantly increased the specificity in intermedialy experienced radiologist (from 56.6% to 96.6%, p = 0.0004) in novice (36.7% to 73,7%, p = 0.0089). Similarly, the precision of tumor size measurement has improved significantly for both. Conclusion: Using AEF as a part of CECT in monitoring after locoregional treatment of liver tumor increases the detection capability and accuracy of viable tumor tissue measurement. The greatest effect was seen in a low-experienced radiologist. AEF is calculated from triphasic CECT examination without increasing radiation dose and its assesment is not time-consuming.

• MeSH
• lidé MeSH
• multidetektorová počítačová tomografie metody   MeSH
• nádorové biomarkery MeSH
• nádory jater * diagnóza   MeSH
• perfuze MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH

Technecium-99m methoxyisobutylisonitril (99mTc-MIBI) je radiofarmakum, které se běžně používá ve spojení s fyzickou nebo farmakologickou zátěží pro perfuzní scintigrafii myokardu. Toto vyšetření poskytuje informaci bud‘ ke stanovení diagnózy s podezřením na ischemickou chorobu srdeční anebo pomáhá určit prognózu pacientů s již známou diagnózou. Interpretace výsledků těchto studií zahrnuje systematické vizuální hodnocení nezpracovaných rotujících projekčních obrazů k určení velikosti srdce a přítomnosti pohybových nebo zeslabovacích artefaktů. Hodnocení nasnímaných dat za účelem kontroly kvality může příležitostně vést k náhodným extrakardialním nálezům, které naznačují přítomnost jiného primárně nekardiálního onemocnění. V této kazuistice popisujeme případ 58leté ženy, která podstoupila zátěžovou perfuzní scintigrafii myokardu pro atypické levostranné bolesti na hrudi. Nasnímaná data ukázala velkou fotopenickou oblast v pravém horním epigastriu. Na následně provedeném Low Dose CT břicha vykazovala fotopenická oblast nízkou denzitu a byla konzistentní s jaterní cystou detekovanou na provedeném ultrazvukovém vyšetření. Dále uvádíme diferenciálně diagnostickou rozvahu, přehled nefyziologické akumulace extrakardiální aktivity identifikované na nasnímaných datech u perfuzní scintigrafie myokardu a důležitost rutinní analýzy těchto obrazů pro náhodné nekardiální nálezy.

Technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) is a radiopharmaceutical routinely used in conjunction with exercise or pharmacologic stress for myocardial perfusion scintigraphy. This procedure provides information for the diagnosis and prognosis in patients with suspected coronary artery disease. Interpretation of these studies includes systematic review of unprocessed rotating projectional images for evaluation of cardiac size as well as the presence of motion or attenuation artifacts. Inspection of raw data for the purpose of quality control may occasionally yield up incidental extracardiac findings that suggest the presence of another primary noncardiac disease. We present a case of 58 year old woman who underwent 99mTc-MIBI myocardial perfusion scintigraphy due to atypical left-sided chest pain. The raw data in cine mode showed an incidental large photopenic area in the right upper abdominal quadrant. The photopenic area corresponded to the location of a large intrahepatic cyst on consequential abdominal SPECT/LDCT and was consistent with hepatic cyst found on performed ultrasonography. We review the differential diagnosis of non-physiological accumulation of extra-cardiac activity identified on myocardial perfusion scintigraphy raw data and the importance of routinely analyzing these images for incidental non-cardiac findings.

• Klíčová slova
• nekardiální nálezy,
• MeSH
• játra diagnostické zobrazování   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhodný nález * MeSH
• PET/CT metody   MeSH
• senioři MeSH
• zobrazování myokardiální perfuze * metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH