Transarteriální chemoembolizace (TACE) je jednou ze základních metod endovaskulární léčby nádorů. Je využívána především u hy-pervaskularizovaných nádorů jater, které jsou na rozdíl od normálního jaterního parenchymu dominantně zásobené arteriální krví. TACE využívá kombinace ischemizace nádorového ložiska a vysoké lokální koncentrace současně podávaného chemoterapeutika. Nejstarším agens vhodným k chemoembolizace je lipiodol, až v posledních 25 letech se objevily částice vázající a uvolňující chemoterapeutikum a degradabilní částice. Jednotlivé částice se liší především velikostí, způsobem vazby chemoterapeutika a degradabilitou. Na trhu je k dispozici několik druhů částic vhodných k chemoembolizaci, dosud ale není jednoznačně prokázána vyšší efektivita některého typu částic. V závislosti na velikosti nádoru, selektivitě přístupu a stavu pacienta ale může úspěšnost a nežádoucí účinky léčby ovlivnit volba správné velikosti částic a použití permanentních nebo degradabilních částic, přičemž degradabilní částice je možné použít i neselektivně a u pacientů s rizikovými faktory.

Transarterial chemoembolization (TACE) is one of the basic methods of endovascular treatment of cancer. It is mainly used in hypervascularized liver tumors, which are predominantly supplied with arterial blood in contrast to normal liver parenchyma. TACE uses a combination of ischemia of the tumor and high local concentration of the simultaneously administered chemotherapeutic agent. The oldest agent suitable for chemoembolization is lipiodol. In the last 25 years emerged drug eluting particles and degradable particles. Individual particles differ mainly in size, binding of the chemotherapeutic agent and degradability. Several types of particles suitable for chemoembolization are available on the market, but the superior efficacy of any type of particle has not yet been clearly demonstrated. However, depending on the size of the tumour, the selectivity of the arterial approach and the patient ́s condition, the choice of the correct particle size and the choice of permanent or degradable particles may influence the success and side effects of treatment, while degradable particles can also be used non-selectively and in patients with risk factors.

• MeSH
• Chemoembolization, Therapeutic * methods   instrumentation   MeSH
• Doxorubicin therapeutic use   MeSH
• Carcinoma, Hepatocellular drug therapy   therapy   MeSH
• Humans MeSH
• Drug Liberation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Úvod: Incidence HCC celosvětově stoupá. Resekce a transplantace jater jsou radikálními léčebnými metodami, které lze však využít jen u 25 % nemocných. TACE je pak metodou paliativní léčebné volby u nemocných primárně chirurgicky neřešitelných. Materiál a metoda: 35 nemocných (27 mužů a 8 žen) průměrného věku 73,4?7,2 roku s HCC o kumulativním průměru 83,8?36,3 mm bylo léčeno TACE DEB s doxorubicinem. 28krát se jednalo o solitární, 7krát o mnohočetný HCC. 31 nemocných bylo klasifikováno jako Child A, 4 jako Child B. Hodnotili jsme celkové, tumor specifické a bezpříznakové přežívání nemocných jeden rok po výkonu a jejich korelaci s věkem, pohlavím, počtem a celkovým průměrem nádorových ložisek a komplikací výkonu. Výsledky: 30denní mortalita, morbidita byla 0, resp. 8,6 %. U 25,7 % nemocných se objevil po výkonu tzv. postembolizační syndrom. Opakované TACE jsme provedli u 14 (40 %) nemocných z důvodu progrese HCC. U dvou nemocných (5,7 %) jsme po TACE provedli resekci jater. Dle RECIST kritérií nedošlo u žádného nemocného ke kompletní odpovědi po TACE, k částečné odpovědi došlo u 17,1 % a stabilní onemocnění bylo u 37,1 % nemocných. U 25,7 % nemocných došlo k progresi HCC. Jednoroční celkové přežití, tumor specifické a bezpříznakové přežití po TACE bylo 69,7 %, resp. 88,9 a 49,3 % nemocných. Lepší přežívání (p<0,02) bylo u osob mladších 75 let v porovnání se staršími nemocnými. U ostatních sledovaných parametrů jsme nenalezli statistické rozdíly. Horší bezpříznakové přežívání (p<0,01) měli nemocní s komplikacemi po výkonu. Závěr: TACE je metodou paliativní léčebné volby u nemocných s HCC radikálně chirurgicky neřešitelným. V prvním roce po TACE nedochází až u poloviny nemocných k progresi HCC. Lepší výsledky jsou dosaženy u nemocných mladších věkových skupin a tam, kde nejsou komplikace výkonu.

Introduction: The incidence of HCC is growing all over the word. Liver resection and transplantation are the methods of choice in only 25% of patients, representing radical treatment approaches. TACE is a method of palliative treatment in patients with primary unresectable disease. Material and methods: 35 patients (27 men and 8 women) of an average age of 73.4 ? 7.2 years with HCC of average cumulative diameter 83.8 ? 36.3 mm were treated by TACE DEB with Doxorubicin. Solitary and multiple lesions were presented in 28 and 7 patients, respectively. 31 patients were classified as Child A, and 4 as Child B. One year overall survival, disease-specific, disease-free interval and their correlation with patients’ age, gender, as well as the number and cumulative diameter of tumours and complications after procedure were evaluated. Results: 30-day mortality and morbidity rate was 0 and 8.6%, respectively. The so-called postembolization syndrome developed in 25.7% of patients. Repeated TACE was performed in 14 (40%) patients due to tumour progression. In two patients (5.7%) we performed liver resection after TACE. According to the RECIST criteria there was no complete response, partial response was presented in 17.1, stable disease in 37.1 and progression of disease in 25.7% of patients. One year overall survival, tumour-specific survival and disease-free survival was 69.7%, 88.9 and 49.3%, respectively. Better overall survival (p < 0.02) was achieved in patients < 75 years old. Worse disease-free interval was observed in patients with complication after TACE (p < 0.01). No significant differences were found in the other evaluated parameters. Conclusion: TACE is the method of palliative treatment in patients with unresectable HCC. There is no progression of HCC in one-half of patients after TACE. Better results are achieved in younger patients and in patients with no complications of procedure.

• Keywords
• postembolizační syndrom,
• MeSH
• Survival Analysis MeSH
• Chemoembolization, Therapeutic * methods   statistics & numerical data   MeSH
• Doxorubicin therapeutic use   MeSH
• Carcinoma, Hepatocellular * therapy   MeSH
• Remission Induction MeSH
• Topoisomerase II Inhibitors therapeutic use   MeSH
• Kaplan-Meier Estimate MeSH
• Humans MeSH
• Liver Neoplasms * therapy   MeSH
• Palliative Care MeSH
• Postoperative Complications MeSH
• Disease-Free Survival MeSH
• Disease Progression MeSH
• Antibiotics, Antineoplastic therapeutic use   MeSH
• Reoperation statistics & numerical data   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Statistics as Topic MeSH
• Age Factors MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH

Spojená resekce jater a podvaz portální žíly (associated liver partition and portal vein ligation for staged hepatectomy – ALPPS) je nový postup s rostoucí řadou vědeckých a klinických studií, a jak se ukazuje, je to účinná a bezpečná metoda pro vybranou skupinu pacientů. Představujeme první případ ALPPS provedené po dvojité TACE proceduře u 64leté pacientky s rozsáhlým hepatocelulárním karcinomem pravého jaterního laloku. Postup byl úspěšný a zbytek jater vykázal značnou 90% hypertrofii, což dokazuje, že ALPPS někdy může být provedena po paliativních postupech u jaterních malignit. Klíčová slova: hepatocelulární karcinom – spojená resekce jater a podvaz portální žíly (ALPPS) – transhepatální arteriální chemoembolizace (TACE) – játra – resekce – hypertrofie Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy. Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů. Obdrženo: 17. 10. 2015 Přijato: 10. 11. 2015

The associating liver partition and portal vein ligation (ALPPS) is a novel procedure with increasing number of scientific and clinical studies, and by now, it showed to be efficient and safe procedure in selected group of patients. Here we present the first case of ALPPS done after double TACE procedure in a 64-years-old female patient with extensive hepatocellular carcinoma of the right liver lobe. The procedure was successful and liver remnant showed significant 90% hypertrophy which proves that ALPPS sometimes can be performed after palliative procedures in liver malignancies.

• MeSH
• Chemoembolization, Therapeutic adverse effects   MeSH
• Hepatectomy * methods   MeSH
• Carcinoma, Hepatocellular * surgery   MeSH
• Middle Aged MeSH
• Humans MeSH
• Pancreatitis MeSH
• Tomography, X-Ray Computed MeSH
• Sepsis MeSH
• Portal Vein * surgery   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires TACE (also called ADAM17), which cleaves TNF from its transmembrane tether. The trafficking of TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. This identified a novel protein, that we name iTAP (iRhom Tail-Associated Protein) that binds to iRhoms, enhancing the cell surface stability of iRhoms and TACE, preventing their degradation in lysosomes. Depleting iTAP in primary human macrophages profoundly impaired TNF production and tissues from iTAP KO mice exhibit a pronounced depletion in active TACE levels. Our work identifies iTAP as a physiological regulator of TNF signalling and a novel target for the control of inflammation.

• MeSH
• Cell Line MeSH
• Cytoskeletal Proteins genetics   metabolism   MeSH
• Endosomes metabolism   MeSH
• Fibroblasts cytology   metabolism   MeSH
• HEK293 Cells MeSH
• HeLa Cells MeSH
• Humans MeSH
• Macrophages cytology   metabolism   MeSH
• Membrane Proteins genetics   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Primary Cell Culture MeSH
• ADAM17 Protein genetics   metabolism   MeSH
• Proteolysis MeSH
• RAW 264.7 Cells MeSH
• Gene Expression Regulation MeSH
• Amino Acid Sequence MeSH
• Sequence Homology, Amino Acid MeSH
• Sequence Alignment MeSH
• Signal Transduction MeSH
• Tumor Necrosis Factor-alpha genetics   metabolism   MeSH
• Carrier Proteins genetics   metabolism   MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Hydroxámová funkčná skupina je významným štruktúrnym prvkom pre účinok inhibítorov na metaloproteinázy. Selektivita inhibítorov k jednotlivým metaloproteinázam závisí nielen od štruktúry nosnej časti molekuly, ale aj od rôznych substituentov. Kombinácia tradičných prístupov založených na štruktúre a mechanizmoch účinku s novými metódami, akými sú racionálne projektovanie liečiv a kombinatorická chémia, bude nevyhnutná pre ďalší rozvoj špecifických inhibítorov proteáz. V blízkej budúcnosti môžeme očakávať úspech pri klinickom skúšaní nových inhibítorov hydroxámového typu.

The hydroxamic acid moiety is the key structural element for the potency of the inhibitors against metalloprotease enzymes. However, the selectivity of the inhibitors towards various metalloproteases depends on the structures of the templates or scaffolds as well as the variations of the substituents. A combination of the traditional substrate- and mechanism-based approaches and the new technologies, such as the structural-based drug design as well as combinatorial chemistry, will be essential for the future development of specific protease inhibitors. Success in a clinical trial of new hydroxamic acid-based inhibitors is expected soon.

• MeSH
• Financing, Organized MeSH
• Matrix Metalloproteinase Inhibitors MeSH
• Hydroxamic Acids pharmacokinetics   chemistry   MeSH
• Humans MeSH
• Matrix Metalloproteinases therapeutic use   MeSH
• ADAM Proteins antagonists & inhibitors   pharmacokinetics   MeSH
• Amyloid Precursor Protein Secretases antagonists & inhibitors   adverse effects   therapeutic use   MeSH
• Tumor Necrosis Factor-alpha antagonists & inhibitors   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH

• MeSH
• Biological Therapy MeSH
• Chemoembolization, Therapeutic methods   utilization   MeSH
• Carcinoma, Hepatocellular * diagnosis   drug therapy   therapy   MeSH
• Antibodies, Monoclonal, Humanized administration & dosage   therapeutic use   MeSH
• Humans MeSH
• Meta-Analysis as Topic MeSH
• Disease-Free Survival MeSH
• Neoplasm Grading classification   MeSH
• Check Tag
• Humans MeSH

• Publication type
• Meeting Abstract MeSH

Several membrane-anchored signal mediators such as cytokines (e.g. TNFα) and growth factors are proteolytically shed from the cell surface by the metalloproteinase ADAM17, which, thus, has an essential role in inflammatory and developmental processes. The membrane proteins iRhom1 and iRhom2 are instrumental for the transport of ADAM17 to the cell surface and its regulation. However, the structure-function determinants of the iRhom-ADAM17 complex are poorly understood. We used AI-based modelling to gain insights into the structure-function relationship of this complex. We identified different regions in the iRhom homology domain (IRHD) that are differentially responsible for iRhom functions. We have supported the validity of the predicted structure-function determinants with several in vitro, ex vivo and in vivo approaches and demonstrated the regulatory role of the IRHD for iRhom-ADAM17 complex cohesion and forward trafficking. Overall, we provide mechanistic insights into the iRhom-ADAM17-mediated shedding event, which is at the centre of several important cytokine and growth factor pathways.

• MeSH
• Cell Membrane metabolism   MeSH
• Cytokines metabolism   MeSH
• Membrane Proteins * metabolism   MeSH
• Models, Structural MeSH
• ADAM17 Protein metabolism   MeSH
• Carrier Proteins * genetics   metabolism   MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Chronic venous disease (CVD) is a common disorder of lower extremities. OBJECTIVES: The study was scheduled to investigate the relationship between polymorphisms in major proinflammatory genes TNF α (-238 A/G; -308 A/G), TNF β (NcoI), IL-1β (+3953 T/C); IL-6 (-174 G/C; -596 G/C) and ADAM17 (3'TACE) and CVD risk. Genotype-phenotype study was calculated to test possible association between examined genotypes and phenotypes of CVD. METHODS: Finally, 150 CVD patients and 227 control subjects were enrolled to the study. Genotypes in proinflammatory gene polymorphisms were identified from isolated DNA by PCR method and restriction analysis. RESULTS: Significant differences in genotype distribution/allelic frequencies in TNF β gene, IL-1 β gene and in ADAM17 gene polymorphisms were found between CVD women and control ones. In the genotype-phenotype study, identified genotypes were associated with arterial hypertension (ADAM17, IL-6-men), ischaemic heart disease (TNF α and β genes), diabetes mellitus (ADAM17-women, TNF β-men), age of CVD onset (TNF α and IL-6), ulceration (ADAM17), duration of ulceration (ADAM17), ulceration recurrence (ADAM17-women), home care necessity (TNF α), varices surgery (TNF α), erysipelas development (ADAM17-men) and tumour development (TNF α). CONCLUSION: Studying of these polymorphisms associations can help us better identify patients at higher risk of developing severe CVD.

• MeSH
• Chronic Disease MeSH
• Gene Frequency MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Interleukin-1beta genetics   MeSH
• Interleukin-6 genetics   MeSH
• Polymorphism, Single Nucleotide MeSH
• Cardiovascular Diseases * genetics   MeSH
• Humans MeSH
• Lymphotoxin-alpha genetics   MeSH
• ADAM17 Protein genetics   MeSH
• Tumor Necrosis Factor-alpha * genetics   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Carbonic anhydrase IX (CA IX) is a hypoxia-induced enzyme regulating tumour pH and facilitating cell migration/invasion. It is primarily expressed as a transmembrane cell-surface protein, but its ectodomain can be shed by ADAM17 to extracellular space. This study aims to elucidate the impact of CA IX shedding on cancer cells. METHODS: We generated a non-shed CA IX mutant by deletion of amino acids 393-402 from the stalk region and studied its phenotypic effects compared to full-length, shedding-competent CA IX using a range of assays based on immunodetection, confocal microscopy, in vitro real-time cell monitoring and in vivo tumour cell inoculation using xenografted NMRI and C57BL/6J female mice. RESULTS: We demonstrated that the impairment of shedding does not alter the ability of CA IX to bind ADAM17, internalise, form oligomers and regulate pH, but induces cancer-promoting changes in extracellular proteome. Moreover, it affects intrinsic properties of cells expressing the non-shed variant, in terms of their increased ability to migrate, generate primary tumours and form metastatic lesions in lungs. CONCLUSIONS: Our results show that the ectodomain shedding controls pro-tumorigenic and pro-metastatic roles of the cell-associated CA IX and suggest that this phenomenon should be considered when developing CA IX-targeted therapeutic strategies.

• MeSH
• Phenotype MeSH
• Neoplasm Invasiveness pathology   MeSH
• Carbonic Anhydrase IX metabolism   MeSH
• Carcinogenesis metabolism   pathology   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Neoplasms metabolism   pathology   MeSH
• ADAM17 Protein metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH