Genetic causes of canine mast cell tumours (MCTs), except for mutations in the KIT gene detected in some MCTs, are generally unknown. We used whole exome sequencing to reveal mutation spectra in canine MCTs. We detected somatic mutations in 87 genes including 10 genes recognized as human cancer drivers. Besides KIT, 14 other genes were recurrently mutated. Subsequently, we performed next generation sequencing of a panel of 50 selected genes in additional MCT samples. In this group, the most frequently altered gene was GNB1 showing a recurrent dinucleotide substitution at position of Gly116 in 30% of the MCT samples (n = 6/20) and Ile80 substitution accompanied by a splice region mutation in one case. We extended the study by analysis of the above mentioned GNB1 regions in additional MCT samples by Sanger sequencing, and assessed the overall prevalence of GNB1 mutations to 17.3% (n = 14/81), which is similar to the prevalence of KIT alterations. Our results indicate that GNB1 mutations are probably involved in canine MCT pathogenesis in both cutaneous and subcutaneous MCT cases. As opposed to KIT alterations, the presence of GNB1 mutations did not negatively affect survival times, and our data even showed a trend towards positive prognosis. If our results are confirmed in a larger number of MCTs, an extension of molecular testing of canine MCTs by GNB1 analysis would help to refine the molecular stratification of MCTs, and become useful for targeted treatment strategies.

• MeSH
• mastocytární sarkom genetika   patologie   veterinární   MeSH
• mastocyty patologie   MeSH
• mutace MeSH
• nemoci psů genetika   patologie   MeSH
• proteiny vázající GTP - beta-podjednotky genetika   MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• psi MeSH
• vysoce účinné nukleotidové sekvenování veterinární   MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

V příspěvku je popsán případ multipního mastocytomu s edémem kůže a metastázami do některých vnitřních orgánů. Onemocnení začalo ve formě kožního tumoru na hrudní končetině, který byl diagnostikován jako mastocytom 1. gradu. Během krátké doby došlo k rekurenci tumoru a následnému vzniku mnohotných kožních neoplazií rozdílné velikosti a vzhledu. Navzdory intenzivní polychemoterapii Vinblastinem, Prednisonem, Lomustinem a Masivetem neoplastický proces progredoval. Postmortálním vyšetřenim byl diagnostikován nízce diferencovaný mastocytom s metastázami do plic, sleziny, jater a ledvin. Barvením podle Giemsy byla prokázána jen ojedinělá metachromatická granula ve velmi malém množství v nádorových mastocytech, ale ve všech nádorových buňkách byla výrazně pozitivní imunohistochemická reakce na průkaz c-kitu.

Multiple cutaneous mast cell tumours with marked oedema of the skin and metastases in some internal organs is described in the article. The disease began as a skin tumour on forelimb that wad diagnosed as grade I mast cell tumour. Within a short time recurrence of the tumour and the subsequent development of multiple skin tumours of different size and appearance occured. Despite of intensive polychemotherapy using Vinblastin, Prednison, Lomustin and Masivet the neoplastic process progressed. In the postmortem examination poorly differentiated mast cell tumour with metastases in the lung, spleen, liver and kidneys was diagnosed. By means of staining after Giemsa only few metachromatic granules in sporadic neoplastic mast cells were visible but in all the cells immunohistochemical reaction to c-kit was strongly positive.

• MeSH
• dermatitida MeSH
• edém MeSH
• kožní mastocytom * diagnóza   farmakoterapie   veterinární   MeSH
• kožní nemoci MeSH
• nádory kůže MeSH
• nemoci psů MeSH
• prednison farmakologie   MeSH
• protoonkogenní proteiny c-kit MeSH
• psi MeSH
• thiazoly farmakologie   MeSH
• vinblastin farmakologie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• kazuistiky MeSH

Mast cell tumours (MCTs) are the most common skin tumours in dogs. Their clinical behaviour is variable and their aetiology remains largely unknown. We performed a metaphase fluorescence in situ hybridisation (FISH) with whole chromosome painting probes, and interphase FISH with BAC probes for 14 cancer-related genes to reveal clonal structural chromosome rearrangements and copy number variants (CNVs) in canine cutaneous MCTs. The metaphase FISH performed in three MCTs revealed several clonal monosomies and trisomies and two different chromosome rearrangements. No centric fusions were detected. The interphase FISH showed a variety of low frequency CNVs for the individual cancer-related genes. The heterogeneous character of the detected abnormalities indicates increased chromosome instability in canine MCTs. The clonal gain of chromosome 11 was detected in 81% (13/16) of the MCTs. Further research is needed to evaluate the significance of this abnormality as prognostic factor for the survival time or recurrence risk assessments in canine cutaneous MCTs.

• MeSH
• chromozomální aberace * MeSH
• hybridizace in situ fluorescenční MeSH
• malování chromozomů MeSH
• mastocyty patologie   MeSH
• nádory kůže genetika   veterinární   MeSH
• nemoci psů genetika   MeSH
• psi MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• psi MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cutaneous mast cell tumours (MCT) are among the most frequent malignancies in dogs. Their clinical behaviour is highly variable and, with the exception of mutations in the c-kit gene, little is known about their genetic aetiology. The mutational status of the c-kit exons 8, 9 and 11, and exons 5-8 of the TP53 gene was analysed to find markers for molecular stratification of MCTs and predictors of clinical outcome. Mutations in the c-kit gene were detected in 19.5% (n = 8/41) samples and their presence was significantly associated with the high histopathological grade (P = 0.038). Mutations in the DNA binding domain of the TP53 gene were found in 14.6% (n = 6/41) of the analysed MCTs, and their frequency was similar in low and high grade MCTs (P > 0.05). TP53 mutations were not useful prognostic factors in this sample of canine cutaneous MCTs.

• MeSH
• frekvence genu MeSH
• kožní mastocytóza genetika   patologie   veterinární   MeSH
• mutace * MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory kůže genetika   patologie   veterinární   MeSH
• nemoci psů genetika   patologie   MeSH
• prognóza MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• psi MeSH
• stupeň nádoru veterinární   MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cutaneous and subcutaneous mast cell tumours (MCTs) are counted among the most frequent cancers in dogs. However, the genetic aetiology of their development is still mostly unknown, with the exception of KIT and tumor protein p53 (TP53 ) mutations reported in less than a half of cutaneous MCTs. In subcutaneous MCTs, no gene alterations were previously detected. We analysed KIT and TP53 mutations in cutaneous and subcutaneous MCTs, and identified methylated CpG sites in KIT and TP53 promoters and adjacent exon 1 regions. The mutation analysis focused on KIT exons 8, 9 and 11, and TP53 exons 5-8, and revealed mutations in 26% and 7% cutaneous MCT cases, respectively. Moreover, we report a first case of KIT mutation ever detected in subcutaneous MCTs. KIT exon 11 mutations and high Kiupel and Patnaik grades were associated with reduced survival in this study. Both KIT and TP53 gene were generally unmethylated in canine cutaneous MCTs. A sporadic methylation of the CpG positions in KIT promoter and adjacent exon 1 was detected in 70.4% of cutaneous and 82% of subcutaneous MCTs. A sporadic methylation of the CpG positions in the TP53 promoter and exon 1 was observed in 36.8% of the analysed cutaneous MCT samples. Only in two subcutaneous MCTs, we observed more than 30% of clones showing KIT methylation at the CpG positions 13 or 14. The CpG position 14 is involved in a predicted binding site for Sp1 transcription factor. However, the significance of KIT promoter methylation at this specific position needs further evaluation.

• MeSH
• kožní mastocytóza genetika   chirurgie   veterinární   MeSH
• mutace MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory kůže genetika   chirurgie   veterinární   MeSH
• nemoci psů genetika   chirurgie   MeSH
• pilotní projekty MeSH
• přežití MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• psi MeSH
• subkutánní tkáň MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Žírné buňky jsou v obecném povědomí spojovány především s uvolňováním histaminu během alergických reakcí, mají však velmi významnou roli v řadě dalších fyziologických i patologických reakcí organismu. K méně známým patří jejich úloha při ukončení těhotenství a zahájení porodu, kdy jsou považovány za zprostředkovatele vlivu endokrinních signálů na místní reakce v děloze. Řada látek produkovaných žírnými buňkami má angiogenní účinky, známé především u nádorového bujení, ovlivňují ale i embryonální a postnatální růst či proces hojení ran. Podílejí se též na řadě kompenzačních reakcí, jimiž tkáň reaguje na mechanickou zátěž, hypoxii či zánět (remodelace dýchacích cest u astmatu, plicních cév při chronické hypoxii, hypertrofie myokardu, jaterní cirhóza, chronická pankreatitida). Tento přehled je věnován novým poznatkům o jejich úloze během porodu, nenádorové angiogenezi a v remodelaci plicních cév při chronické hypoxii.

Mast cells are well known as the producers of histamine and major effectors of type1 hypersensitivity. They play however an important role in many other physiological and pathological processes. Lesser-known is their role in the processes such as a termination of pregnancy and initiation of delivery. The mast cells are considered as the modulators of endocrine signals on the local reactions in uterus. Many substances produced by the mast cells have the angiogenic effects known primarily for their role in tumour growth, but they influence also embryonal and postnatal growth or process of wound healing. Mast cells also participate in a number of compensatory reactions in the tissue response to the mechanical load, hypoxia or inflammation (airway remodelling in asthma, remodelling of pulmonary vessels in chronic hypoxia, myocardial hypertrophy, liver cirrhosis, chronic pancreatitis). This review describes recent concepts of their role in labour, non-cancerous angiogenesis and remodelling of pulmonary vasculature during chronic hypoxia. Key words: mast

• Klíčová slova
• mediátory, angiogeneze, remodelace, plicní cévy,
• MeSH
• hypoxie MeSH
• lidé MeSH
• mastocyty fyziologie   MeSH
• porod MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• přehledy MeSH

Pomerne dlho pretrvávali predstavy, že nádor je tvorený iba transformovanými bunkami, pre ktoré je typická hyperproliferácia, invazívnosť a imortalizácia buniek. Terapeutické stratégie boli preto zamerané na autonómnu proliferáciu a prežívanie nádorových buniek. Ide o vlastnosti podmienené aktiváciou onkogénov a inaktiváciou tumor-supresorových génov. Vedecké sledovania priniesli poznanie, že samotný rast nádoru je komplexným dejom. Okrem toho potvrdili účasť heterotypických multicelulárnych interakcií v nádorovom tkanive. Komplexita ako charakteristika sa priraďuje k tým dejom, ktoré nevykazujú vlastnosti lineárnych systémov. V priebehu nádorového rastu sú určité zákonitosti, ktoré nie je možné presne usporiadať z hľadiska trvania a následnosti. Preto ho môžeme považovať za dej so znakmi komplexity. Pri takomto pohľade nádorové prostredie tvoria viaceré druhy buniek, ako sú endotelové bunky a ich progenitorové bunky, pericyty, fibroblasty, fibroblasty asociované s nádorom, myofibroblasty, hladkosvalové bunky, žírne bunky, T- a B-lymfocyty, neutrofily, eozinofily, bazofily, NK-bunky a niekoľko foriem makrofágov. V súčasnosti sa opodstatnene predpokladá, že hlboké štúdium vnútorného prostredia nádorov môže viesť k formovaniu nových základov nádorovej biológie ako aj terapeutických postupov. Štúdium detailov mikroprostredia nádorov je potrebné z hľadiska vedeckého poznania a následne aj pre definovanie biomarkerov charakterizujúcich nádory. Ich sledovanie prehĺbi molekulovú diagnostiku. Biomarkery sa budú využívať v širokom meradle pre monitorovanie priebehu rastu nádorov a aj priebehu liečby. Sledovanie kombinácie biomarkerov umožní bližšie charakterizovať mikroprostredie nádorov. Okrem receptorov, signálnych molekúl, rastových faktorov, molekúl akcelerujúcich apoptózu to môžu byť nielen molekuly samotné, ale aj ich kombinácie, alebo charakteristiky neoangiogenézy, alebo inervácie nádorov. Komplexita nádorov zahrňuje nielen intracelulárne prostredie, ale aj intercelulárne vzťahy a vzťahy buniek s extracelulárnymi súčasťami nádorov. K doteraz známym skutočnostiam pribudne sledovanie cirkulujúcich nádorových buniek. Pre ich detekciu sa s veľkou pravdepodobnosťou budú využívať nízkomolekulové fluoreskujúce farbivá. Možno očakávať, že cirkulujúce nádorové bunky budú markerom prognózy i ukazovateľom progresie malignity a liečby. Vedecké bádanie prehĺbi individuálnu terapiu pacientov s nádorovými chorobami. V prehľadovej štúdii sme sa pokúsili analyzovať vedecké poznatky z pozície akceptácie zložitostí a heterogénnosti každého nádoru. Spracovanie obrovského množstva literatúry sme považovali za zmysluplné z hľadiska akceptácie nových poznatkov a teoretickej prípravy na očakávané zmeny diagnostiky a liečby nádorov. Predpokladáme, že prezentované poznatky sú užitočným krokom pre ucelený pohľad do mikroprostredia nádorov.

It was believed for rather a long time that the only components of tumour tissue are transformed cells characterised by hyper- proliferation, invasivity and immortalisation. Therapeutic strategies thus focused on autonomous proliferation and tumour cell survival. These result from oncogene activation and inactivation of tumour-suppressor genes. Research studies showed that tumour growth itself is a complex process. In addition, studies confi rmed involvement of heterotypical multicellular interactions in tumour tissue. Complexity as a characteristic is one of the processes that do not demonstrate attributes of linear systems. The process of tumour growth involves certain patterns that cannot be classified according to duration and sequence. Consequently, tumour growth can be viewed as a process with features typical for complexity. From this perspective, tumour environment consists of a range of cells, such as endothelial cells and their progenitor cells, pericytes, fi broblasts, tumour-associated fi broblasts, myofi broblasts, smooth muscle cells, mast cells, T- and B-lymphocytes, neutrophils, eosinophils, basophils, NK-cells and several different forms of macrophages. At present, well-founded assumptions exist that in-depth study of intra-tumour environment might lead to formulation of new principles in tumour bio logy as well as introduction of new therapeutic strategies. Research into details of tumour microenvironment is needed to expand scientifi c knowledge as well as to, subsequently, defi ne tumour bio markers. Monitoring of these bio markers will facilitate molecular diagnostics. Biomarkers will be widely used to monitor tumour growth as well as to monitor the process of treatment. Monitoring of combinations of bio markers will enable more detailed characterisation of tumour microenvironment. These might include, apart from receptors, signal molecules, growth factors and molecules accelerating apoptosis, specifi c molecules as well as their combinations or neoangiogenesis or tumour innervation parameters. Tumour complexity involves not just intracellular environment but also intracellular relationships and associations between cells and extracellular tumour components. Detection of circulating tumour cells represents another parameter to be monitored. Low-molecular weight fl uorescent dyes will very likely be used for their detection. It can be assumed that circulating tumour cells will be used as markers of prognosis as well as indicators of malignity progression and treatment. Scientifi c advances in this area will facilitate individua lised therapy of patients suffering from cancers. The aim of the present review study was to analyze scientifi c knowledge from the perspective of acceptance of complexity and heterogeneity of each tumour. We perceived processing of the vast amounts of literature as meaningful with respect to recognition of new knowledge and theoretical preparation for expected changes in diagnostics and treatment of tumours. We believe that the presented fi ndings are a useful step towards achievement of comprehensive insight into tumour microenvironment.

• MeSH
• lidé MeSH
• nádory imunologie   patofyziologie   MeSH
• patologická angiogeneze MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

Dendritic cell (DC) immunotherapy is capable of generating tumour-specific immune responses. Different maturation strategies were previously tested to obtain DC capable of anti-cancer responses in vitro, usually with limited clinical benefit. Mutual comparison of currently used maturation strategies and subsequent complex evaluation of DC functions and their stimulatory capacity on T cells was performed in this study to optimize the DC vaccination strategy for further clinical application. DC were generated from monocytes using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, pulsed with whole tumour cell lysate and then matured with one of five selected maturation strategies or cultured without additional maturation stimulus. DC were characterized with regard to their surface marker expression, cytokine profiles, migratory capacity, allogeneic and autologous T cell stimulatory capacity as well as their specific cytotoxicity against tumour antigens. We were able to demonstrate extensive variability among different maturation strategies currently used in DC immunotherapeutic protocols that may at least partially explain limited clinical benefit of some clinical trials with such DC. We identified DC matured with interferon-γ and lipopolysaccharide as the most attractive candidate for future clinical trials in cancer immunotherapy.

• MeSH
• biologické markery metabolismus   MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky imunologie   MeSH
• faktor stimulující granulocyto-makrofágové kolonie metabolismus   farmakologie   MeSH
• imunoterapie metody   MeSH
• interleukin-10 metabolismus   MeSH
• interleukin-12 metabolismus   MeSH
• interleukin-4 metabolismus   farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• monocyty cytologie   MeSH
• nádorové buněčné linie MeSH
• nádory imunologie   terapie   MeSH
• pohyb buněk MeSH
• T-lymfocyty imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mastocytosis is a clonal hematopoietic disorder characterized by proliferation of abnormal mast cells in various organs including the skin, digestive system, lymph nodes, and bone marrow. We report on a 75-year-old woman presenting with abdominal pain, vomiting, diarrhoea, myalgia, and weight loss. Abdominal CT showed hepatosplenomegaly with heterogeneous splenic parenchyma, lymphadenopathy, and osteopenia with areas of osteosclerosis but no primary tumour. An 18F-FDG PET/CT revealed an overall low metabolic activity of the lesions with a diffuse bone marrow involvement raising suspicion of a haematological neoplasm. Subsequently, bone marrow and peripheral blood examinations confirmed the diagnosis of aggressive systemic mastocytosis.

• MeSH
• fluorodeoxyglukosa F18 * MeSH
• kostní dřeň diagnostické zobrazování   MeSH
• lidé MeSH
• PET/CT MeSH
• pozitronová emisní tomografie MeSH
• senioři MeSH
• systémová mastocytóza * diagnostické zobrazování   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• MeSH
• klasifikace MeSH
• nádory diagnóza   MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• patologie
• onkologie