In liver surgery, biliary obstruction can lead to secondary biliary cirrhosis, a life-threatening disease with liver transplantation as the only curative treatment option. Mesenchymal stromal cells (MSC) have been shown to improve liver function in both acute and chronic liver disease models. This study evaluated the effect of allogenic MSC transplantation in a large animal model of repeated biliary obstruction followed by partial hepatectomy. MSC transplantation supported the growth of regenerated liver tissue after 14 days (MSC group, n = 10: from 1087 ± 108 (0 h) to 1243 ± 92 mL (14 days); control group, n = 11: from 1080 ± 95 (0 h) to 1100 ± 105 mL (14 days), p = 0.016), with a lower volume fraction of hepatocytes in regenerated liver tissue compared to resected liver tissue (59.5 ± 10.2% vs. 70.2 ± 5.6%, p < 0.05). Volume fraction of connective tissue, blood vessels and bile vessels in regenerated liver tissue, serum levels of liver enzymes (AST, ALT, ALP and GGT) and liver metabolites (albumin, bilirubin, urea and creatinine), as well as plasma levels of IL-6, IL-8, TNF-α and TGF-β, were not affected by MSC transplantation. In our novel, large animal (pig) model of repeated biliary obstruction followed by partial hepatectomy, MSC transplantation promoted growth of liver tissue without any effect on liver function. This study underscores the importance of translating results between small and large animal models as well as the careful translation of results from animal model into human medicine.

• Klíčová slova
• hepatectomy, mesenchymal stromal cell, pig model, quantitative histology, secondary biliary cirrhosis,
• MeSH
• cholestáza komplikace   MeSH
• mezenchymální kmenové buňky MeSH
• modely nemocí na zvířatech * MeSH
• nemoci jater etiologie   patologie   terapie   MeSH
• prasata MeSH
• transplantace mezenchymálních kmenových buněk metody   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The aim of this review is to describe current possibilities of gene therapy in liver tumours. The authors discuss the following methods which were used in experimental clinical trials: tumour suppressor genes, suicide gene therapy, immunogene therapy and use of oncolytic viruses. The results from these first clinical trials were encouraging. However, because of the present limitations, such as safe transport and selective expression of genes in the malignant cells, gene therapy cannot be used as a definitive treatment for liver tumours.

• MeSH
• genetická terapie * MeSH
• lidé MeSH
• nádory jater terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Portal vein embolization (PVE) and PVE with autologous mesenchymal stem cell application (PVE-MSC) increases future liver remnant volume (FLRV). The aim of this study was to compare both methods from the aspect of FLRV growth, progression of colorectal liver metastases (CLM), CLM resectability and long-term results. PATIENTS AND METHODS: Fifty-five patients with CLM and insufficient FLRV were included in the study. FLVR growth and CLM volume were evaluated using computed tomography. Liver resection was performed in patients with FLVR >30% of total liver volume. RESULTS: In the PVE (N=27) group, FLRV growth was observed in 23 patients (85.2%) and in 100% of patients in the PVE-MSC (N=28) group (p<0.05). The rapidity of FLRV and CLM growth did not differ between groups. R0 resection was performed in 14 (51.8%) and 24 (85.7%) patients from the PVE and PVE-MSC (p<0.02) groups, respectively. The 3-year overall and progression-free survival rates were 85.75% and 9.3% in the PVE group and 68.7% and 17.1% in the PVE-MSC group, respectively (p<0.67 and p<0.84, respectively). CONCLUSION: PVE-MSC allows for more effective growth of FLRV and resectability of CLM compared to PVE. The two methods do not differ in their long-term results.

• Klíčová slova
• Colorectal liver metastases, future liver remnant volume, portal vein embolization, stem cells,
• MeSH
• časové faktory MeSH
• Kaplanův-Meierův odhad MeSH
• kolorektální nádory mortalita   patologie   MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory jater mortalita   sekundární   terapie   MeSH
• přežití bez známek nemoci MeSH
• regenerace jater * MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• terapeutická embolizace škodlivé účinky   metody   MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   mortalita   MeSH
• transplantace mezenchymálních kmenových buněk * škodlivé účinky   mortalita   MeSH
• vena portae * MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

BACKGROUND/AIMS: Alteration of cancer cell redox status has been recognized as a promising therapeutic implication. In recent years, the emerged field of non-thermal plasma (NTP) has shown considerable promise in various biomedical applications, including cancer therapy. However, understanding the molecular mechanisms procuring cellular responses remains incomplete. Thus, the aim of this study was a rigorous biochemical analysis of interactions between NTP and liver cancer cells. METHODS: The concept was validated using three different cell lines. We provide several distinct lines of evidence to support our findings; we use various methods (epifluorescent and confocal microscopy, clonogenic and cytotoxicity assays, Western blotting, pharmacological inhibition studies, etc.). RESULTS: We assessed the influence of NTP on three human liver cancer cell lines (Huh7, Alexander and HepG2). NTP treatment resulted in higher anti-proliferative effect against Alexander and Huh7 relative to HepG2. Our data clearly showed that the NTP-mediated alternation of mitochondrial membrane potential and dynamics led to ROS-mediated apoptosis in Huh7 and Alexander cells. Interestingly, plasma treatment resulted in p53 down-regulation in Huh7 cells. High levels of Bcl-2 protein expression in HepG2 resulted in their resistance in response to oxidative stress- mediated by plasma. CONCLUSION: We show thoroughly time- and dose-dependent kinetics of ROS accumulation in HCC cells. Furthermore, we show nuclear compartmentalization of the superoxide anion triggered by NTP. NTP induced apoptotic death in Huh7 liver cancer cells via simultaneous downregulation of mutated p53, pSTAT1 and STAT1. Contrary, hydrogen peroxide treatment results in autophagic cell death. We disclosed detailed mechanisms of NTP-mediated alteration of redox signalling in liver cancer cells.

• Klíčová slova
• Apoptosis, Non-thermal plasma, Oxidative stress, Reactive oxygen species, Stress resistance, p53,
• MeSH
• buněčná smrt účinky léků   MeSH
• buňky Hep G2 MeSH
• down regulace účinky léků   MeSH
• hepatocelulární karcinom farmakoterapie   genetika   metabolismus   patologie   MeSH
• lidé MeSH
• nádorový supresorový protein p53 biosyntéza   genetika   MeSH
• nádory jater farmakoterapie   genetika   metabolismus   patologie   MeSH
• oxidace-redukce účinky léků   MeSH
• plazmové plyny farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH
• plazmové plyny MeSH
• reaktivní formy kyslíku MeSH
• TP53 protein, human MeSH Prohlížeč

Radiological methods and procedures have become not only an inseparable part of the diagnosis of primary and secondary liver tumors, but also therapy and disease management of patients with colorectal cancer. The most common primary liver cancer, hepatocellular carcinoma, can be treated with curative intent by surgical approach as well as navigational radiological interventions. Palliative methods include transarterial chemoembolization, which is suitable for more than half of patients during treatment. extends treatment options even in patients with metastatic colorectal cancer who fail at standard therapies. In addition to thermal ablation in oligometastatic disease, intravascular procedures (chemoembolization and regional chemotherapy, preoperative portal vein embolization) can be used. By modern intervention approaches in patients with malignant biliary tract stenosis, we are able to refine and accelerate the diagnosis, to improve quality of life and to extend patients' survival.

• Klíčová slova
• liver tumors, thermal ablation chemoembolization.,
• MeSH
• chemoembolizace * MeSH
• hepatocelulární karcinom * terapie   MeSH
• intervenční radiologie * MeSH
• kvalita života MeSH
• lidé MeSH
• nádory jater * terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: In patients with colorectal liver metastases, the possibility for radical liver resection can be limited by oxaliplatin-induced sinusoidal obstruction syndrome (SOS). This study investigates the potential of mesenchymal stem cells (MSC) to improve the outcome of liver resections in pigs with SOS. MATERIALS AND METHODS: SOS was induced in all animals (n=20) on day 0. Animals in the experimental group (n=8) received allogeneic MSC on day 7. Liver resection was performed in all animals on day 14 and the animals were observed until day 28. Ultrasound volumetry, biochemical analysis and histological examination of liver parenchyma was performed during the follow-up period. RESULTS: Six animals from the control group died prematurely, while all animals survived in the experimental group. According to histology, biochemical analysis and ultrasound volumetry, there were no significant differences between the groups documenting the effect of MSC. CONCLUSION: Single dose allogeneic MSC administration improved survival of animals with SOS undergoing partial liver resection. Further experiments with different timing of liver resection and MSC administration should be performed to investigate the effect of MSC in more detail.

• Klíčová slova
• Sinusoidal obstruction syndrome, colorectal cancer, liver metastases, liver resection, mesenchymal stem cells, monocrotaline,
• MeSH
• biologické markery MeSH
• hepatektomie * metody   MeSH
• imunofenotypizace MeSH
• imunohistochemie MeSH
• jaterní žilní okluze etiologie   patologie   terapie   MeSH
• kolorektální nádory patologie   MeSH
• kombinovaná terapie MeSH
• mezenchymální kmenové buňky * cytologie   MeSH
• modely nemocí na zvířatech MeSH
• nádory jater komplikace   sekundární   MeSH
• prasata MeSH
• transplantace mezenchymálních kmenových buněk * MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH

BACKGROUND: Sunitinib and pazopanib are both oral small molecule multityrosine kinase inhibitors (MTKI) used in the treatment of renal cell carcinoma (RCC). Hepatotoxicity or "liver injury" is the most important adverse effect of pazopanib administration, but little is known about the underlying mechanism. Liver injury may also occur in patients treated with sunitinib, but severe toxicity is extremely rare. Herein we report two new cases of severe liver injury induced by MTKI. Both cases are unique and exceptional. We assessed both cases for drug-induced liver injury (DILI) using the updated score Roussel Uclaf causality assessment method (RUCAM). The literature on potential pathogenic mechanisms and precautionary measures is reviewed. CASE PRESENTATION: A case of a metastatic RCC (mRCC) patient treated with pazopanib who had manifestation of severe liver injury is presented. These manifestations consisted of grade 4 alanine aminotransferase (ALT) increase and grade 4 hyperbilirubinemia. Alternate causes of acute or chronic liver disease were excluded. The patient gradually recovered from the liver injury and refused any further therapy for mRCC. The patient was diagnosed with acute myeloid leukemia (AML) two years later and eventually succumbed to the disease. The second case describes a mRCC patient treated with sunitinib for 3,5 years and fatal liver failure after 2 weeks of clarithromycin co-medication for acute bronchitis. CONCLUSIONS: Liver injury has been commonly observed in TKI-treated patients with unpredictable course. Management requires regular routine liver enzyme-monitoring and the collaboration of medical oncologist and hepatologist. There is an unmet medical need for a risk stratification and definition of predictive biomarkers to identify potential genetic polymorphisms or other factors associated with TKI-induced liver injury. Any potential unrecommended concomitant therapy has to be avoided.

• Klíčová slova
• Clarithromycin, Drug induced liver injury (DILI), Fatal liver failure, Hepatotoxicity, Renal cell carcinoma, Roussel Uclaf causality assessment method (RUCAM), TKI,
• MeSH
• chronické poškození jater způsobené chemickými látkami * MeSH
• karcinom z renálních buněk * farmakoterapie   MeSH
• lékové postižení jater * etiologie   MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   MeSH
• tyrosin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH
• Názvy látek
• tyrosin MeSH

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the fourth most frequent cause of cancer-related death worldwide. Sorafenib is the first line recommended therapy for patients with locally advanced/metastatic HCC. The low response rate is attributed to intrinsic resistance of HCC cells to Sorafenib. The potential resistance to Sorafenib-induced cell death is multifactorial and involves all hallmarks of cancer. However, the presence of sub-therapeutic dose can negatively influence the antitumoral properties of the drug. In this sense, the present study showed that the sub-optimal Sorafenib concentration (10 nM) was associated with activation of caspase-9, AMP-activated protein kinase (AMPK), sustained autophagy, peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α) and mitochondrial function in HepG2 cells. The increased mitochondrial respiration by Sorafenib (10 nM) was also observed in permeabilized HepG2 cells, but not in isolated rat mitochondria, which suggests the involvement of an upstream component in this regulatory mechanism. The basal glycolysis was dose dependently increased at early time point studied (6 h). Interestingly, Sorafenib increased nitric oxide (NO) generation that played an inhibitory role in mitochondrial respiration in sub-therapeutic dose of Sorafenib. The administration of sustained therapeutic dose of Sorafenib (10 µM, 24 h) induced mitochondrial dysfunction and dropped basal glycolysis derived acidification, as well as increased oxidative stress and apoptosis in HepG2. In conclusion, the accurate control of the administered dose of Sorafenib is relevant for the potential prosurvival or proapoptotic properties induced by the drug in liver cancer cells.

• Klíčová slova
• AMPK, Apoptosis, Autophagy, Mitochondria, Reactive oxygen species,
• MeSH
• autofagie účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• buňky Hep G2 MeSH
• chemorezistence účinky léků   MeSH
• hepatocelulární karcinom metabolismus   patologie   MeSH
• jaterní mitochondrie účinky léků   metabolismus   MeSH
• kaspasa 9 metabolismus   MeSH
• lidé MeSH
• nádory jater metabolismus   patologie   MeSH
• oxid dusnatý metabolismus   MeSH
• potkani Wistar MeSH
• PPARGC1A metabolismus   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• sorafenib farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kaspasa 9 MeSH
• oxid dusnatý MeSH
• PPARGC1A protein, human MeSH Prohlížeč
• PPARGC1A MeSH
• proteinkinasy aktivované AMP MeSH
• protinádorové látky MeSH
• sorafenib MeSH

The effect of foetal liver cells on GVH reaction with the parental lymphocytes in F1 hybrid mice was studied. The GVH reaction was induced in newborn (CBA X C3H)F1 and in 10-day-old (CBA X C57BL/6)F1 hybrid mice. Foetal liver cells did not induce a GVH reaction. The GVH reaction of CBA spleen cells in (CBA X C3H)F1 hybrid mice was demonstrable, although weak. Foetal liver cells suppressed the GVH reaction, in dependence on cell concentration, in (CBA x C3H)F1 but not in (CBA X C57BL/6)F1 hybrid mice. The possibility to induce transplantation tolerance with foetal liver cells is discussed.

• MeSH
• imunosupresivní léčba * MeSH
• inbrední kmeny myší MeSH
• játra embryologie   MeSH
• křížení genetické MeSH
• myši MeSH
• novorozená zvířata MeSH
• plod MeSH
• reakce štěpu proti hostiteli * MeSH
• slezina imunologie   MeSH
• těhotenství MeSH
• transfuze lymfocytů * MeSH
• transplantace jater * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Only 15-20 % of patients with liver tumours can undergo radical surgery. Insufficient future liver remnant volume (FLRV) is one of the main causes of tumours unresectability. Portal vein embolization (PVE) together with administration of haematopoietic stem cells (HSC) may expand the operability of primary unresectable liver tumours. METHODS: In this pilot study, the authors reported on five patients (1 hepatocellular carcinoma, 4 colorectal cancer metastases) with FLRV <30 %, who underwent PVE on the side of the tumour with a subsequent application of HSC to the non-embolized branch of portal vein. RESULTS: PVE with HSC application was without any complications. In three patients, a sufficient increase of FLRV occurred within 2-4 weeks followed by a liver resection. All patients were between 5-12 months after the surgery in good condition; one of them was diagnosed with pulmonary metastasis after nine months that was successfully treated with laser metastasectomy. In one patient with hepatocellular carcinoma, an increase of FLRV and progression of the tumour in the liver occurred following the PVE with administration of HSC and the patient was treated only symptomatically. Despite an adequate increase of FLRV, severe intraabdominal adhesions hampered liver resection in one patient. CONCLUSIONS: Combination of PVE with HSC administration appeared to be a promising method that stimulated growth of FLRV with a subsequent possibility of an early radical liver resection. The issue is a danger of tumour progression in the liver parenchyma following the PVE with HSC. The current randomized study should answer these questions (Tab. 1, Fig. 4, Ref. 38).

• MeSH
• autologní transplantace MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory jater terapie   MeSH
• pilotní projekty MeSH
• prospektivní studie MeSH
• senioři MeSH
• terapeutická embolizace * MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• vena portae * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH