BACKGROUND: The prognostic significance of mast cells and different phenotypes of macrophages in the microenvironment of hepatocellular carcinoma (HCC) following resection is unclear. We aimed in this study to assess the local distribution of infiltrating macrophages and mast cells of specific phenotypes in tissues of HCC and to evaluate their prognostic values for survival of post-surgical patients. METHODS: The clinicopathological and follow-up data of 70 patients with HCC, who underwent curative resection of tumor from 1997 to 2019, were collected. The infiltration of CD68+ and CD163+ macrophages and CD117+ mast cells was assessed immunohistochemically in representative resected specimens of HCC and adjacent tissues. The area fraction (AF) of positively stained cells was estimated automatically using QuPath image analysis software in several regions, such as tumor center (TC), inner margin (IM), outer margin (OM), and peritumor (PT) area. The prognostic significance of immune cells, individually and in associations, for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: High AF of CD68+ macrophages in TC and IM and high AF of mast cells in IM and PT area were associated with a longer DFS. High AF of CD163+ macrophages in PT area correlated with a shorter DFS. Patients from CD163TChigh & CD68TClow group had a shorter DFS compared to all the rest of the groups, and cases with CD163IMlow & CD68IMhigh demonstrated significantly longer DFS compared to low AF of both markers. Patients from CD68IMhigh & CD163PTlow group, CD117IMhigh & CD163PTlow group, and CD117PThigh & CD163PTlow group had a significantly longer DFS compared to all other combinations of respective cells. CONCLUSIONS: The individual prognostic impact of CD68+ and CD163+ macrophages and mast cells in the microenvironment of HCC after resection depends on their abundance and location, whereas the cumulative impact is built upon combination of different cell phenotypes within and between regions.
Kazuistika prezentuje děvčátko s rekurentními anafylaxemi. Zpočátku byl spouštěčem potíží stres, navozený rozvodem rodičů dítěte. Po zklidnění rodinné situace následovala půlroční remise, ale pak opět začaly ataky anafylaxe každé 2 měsíce. Pro podezření na neceliakální glutenovou intoleranci a histaminovou intoleranci byla nasazena bezlepková a histamin šetřící dieta. Na této dietě měla dva roky ataky méně často a s mírnějším průběhem. Velké zhoršení nastalo v pubertě, ataky se vyskytovaly až 3× měsíčně, 1–3 hodiny po jídle a projevovaly se bolestivými křečemi žaludku i střev, prudkým zvracením, průjmy, cefalgií, generalizovanou urtikárií s angioedémem obličeje a následnou únavou a slabostí. V rámci prevence vzniku anafylaxí byla bez efektu podávána antihistaminika, ketotifen, kombinace H1 + H2 blokátorů, omeprazol, montelukast, dinatrium-chromoglykát. Podrobné alergologické vyšetření, včetně multiplex metody ALEX 2, nepřispělo ke zjištění příčiny potíží. Diagnózu stanovila až gastroskopie a kolonoskopie s biopsiemi a histochemickým vyšetřením, které prokázaly přítomnost mastocytární enterokolitidy. Syndrom aktivace mastocytů byl potvrzen průkazem zvýšené sérové tryptázy v atace. Pacientka zůstává nadále v naší péči, prognóza dalšího vývoje nemoci je nejistá.
This case report presents a girl with recurrent anaphylaxis. Initially, her systemic reactions were triggered by the stress induced by the divorce of the child’s parents. After the family situation calmed down, a six-month remission followed, but then the anaphylaxis attacks began again every 2 months. Because of a suspected non-celiac gluten intolerance and histamine intolerance, she was put on a gluten- free and low histamine diet. She followed this diet for the next 2 years, her attacks were less frequent and with a milder course. A major deterioration occurred in adolescence, with attacks occurring up to 3 times a month, 1–3 hours after meals. Symptoms manifested as painful cramps in the stomach and intestines, violent vomiting, diarrhea, cephalgia, generalized urticaria with facial angioedema and subsequent fatigue and weakness. Antihistamines, ketotifen, a combination of H1 + H2 blockers, omeprazole, montelucast, disodium cromoglycate were administered without effect to prevent anaphylaxis. Detailed allergy examination including multiplex method ALEX 2 did not reveal the cause. The diagnosis was established by gastroscopy and colonoscopy with biopsies, histochemistry revealed presence of mastocytic enterocolitis. MCAS/ mast cell activation syndrome has been confirmed by a substantial increase in serum tryptase level during an attack over the patient's baseline tryptase. The patient remains in our care and the prognosis of further course of the disease is uncertain.
- Klíčová slova
- mastocytární enterokolitida,
- MeSH
- anafylaxe * etiologie farmakoterapie MeSH
- dítě MeSH
- enterokolitida * diagnóza farmakoterapie MeSH
- gastroskopie MeSH
- kolonoskopie MeSH
- lidé MeSH
- mastocyty * patologie MeSH
- progrese nemoci MeSH
- psychický stres MeSH
- rozvod MeSH
- syndrom aktivace žírných buněk * diagnóza farmakoterapie terapie MeSH
- terapie neúspěšná MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The immune checkpoint inhibitors have revolutionized cancer immunotherapy. These inhibitors are game changers in many cancers and for many patients, sometimes show unprecedented therapeutic efficacy. However, their therapeutic efficacy is largely limited in many solid tumors where the tumor-controlled immune microenvironment prevents the immune system from efficiently reaching, recognizing, and eliminating cancer cells. The tumor immune microenvironment is largely orchestrated by immune cells through which tumors gain resistance against the immune system. Among these cells are mast cells and dendritic cells. Both cell types possess enormous capabilities to shape the immune microenvironment. These capabilities stage these cells as cellular checkpoints in the immune microenvironment. Regaining control over these cells in the tumor microenvironment can open new avenues for breaking the resistance of solid tumors to immunotherapy. In this review, we will discuss mast cells and dendritic cells in the context of solid tumors and how these immune cells can, alone or in cooperation, modulate the solid tumor resistance to the immune system. We will also discuss how this modulation could be used in novel immunotherapeutic modalities to weaken the solid tumor resistance to the immune system. This weakening could then help other immunotherapeutic modalities engage against these tumors more efficiently.
- MeSH
- dendritické buňky patologie MeSH
- imunoterapie MeSH
- inhibitory kontrolních bodů MeSH
- lidé MeSH
- mastocyty * patologie MeSH
- nádorové mikroprostředí MeSH
- nádory * patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels <125 ng/mL.
- MeSH
- dospělí MeSH
- kostní dřeň metabolismus patologie MeSH
- kožní nemoci patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mastocytóza diagnóza epidemiologie metabolismus MeSH
- mastocyty metabolismus patologie MeSH
- míra přežití MeSH
- následné studie MeSH
- prognóza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- systémová mastocytóza diagnóza epidemiologie metabolismus MeSH
- tryptasy metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of de novo synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.
- MeSH
- buněčná membrána imunologie metabolismus mikrobiologie patologie MeSH
- buněčná smrt MeSH
- buněčné mikroprostředí MeSH
- cholesterol metabolismus MeSH
- cytokiny metabolismus MeSH
- cytotoxiny metabolismus MeSH
- degranulace buněk MeSH
- grampozitivní bakteriální infekce imunologie metabolismus mikrobiologie patologie MeSH
- grampozitivní bakterie imunologie metabolismus MeSH
- interakce hostitele a patogenu MeSH
- lidé MeSH
- mastocyty imunologie metabolismus mikrobiologie patologie MeSH
- mediátory zánětu metabolismus MeSH
- vápníková signalizace MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Mastocytosis is a rare neoplasm characterized by the expansion and accumulation of mast cells in various organ systems. Systemic mastocytosis (SM) may or may not present with cutaneous lesions. To examine the frequency and clinical impact of cutaneous involvement, data on 1,510 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis were analyzed. Cutaneous involvement was found in 1,195 of 1,510 patients (79.1%). Of these, 286 had cutaneous mastocytosis, and 721 had SM with skin involvement. Adult patients with skin involvement who did not have a bone marrow examination (n = 188) were defined as having mastocytosis in the skin. In 315 patients, SM without skin involvement was found. The percentage of cases with cutaneous involvement was higher in indolent SM (100%) and smoldering SM (87.9%) compared to aggressive SM (46.8%) or mast cell leukemia (38.5%). After a median follow-up of 5.6 years, no patient with cutaneous mastocytosis had died, but 2.6% of the patients with mastocytosis in the skin, 5.7% of the patients with SM with skin involvement, and 28.95% of the patients with SM without skin involvement had died. Overall survival was longer in patients with skin involvement (cutaneous mastocytosis and/or mastocytosis in the skin and/or SM with skin involvement) than in patients with SM without skin involvement (P < 0.0001). These data argue for a thorough examination of both the skin and bone marrow in adult patients with mastocytosis.
- MeSH
- analýza přežití MeSH
- biopsie MeSH
- časové faktory MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- kostní dřeň patologie MeSH
- kožní mastocytóza diagnóza epidemiologie patologie MeSH
- kůže patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mastocyty patologie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- prognóza MeSH
- registrace statistika a číselné údaje MeSH
- senioři MeSH
- systémová mastocytóza diagnóza mortalita patologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
Chronic inflammation of adipose tissue is associated with the pathogenesis of cardiovascular diseases. Mast cells represent an important component of the innate defense system of the organism. In our work, we quantified mast cell number in epicardial adipose tissue (EAT), subcutaneous adipose tissue (SAT), and right atrial myocardium (RA) in patients undergoing open heart surgery (n=57). Bioptic samples of EAT (n=44), SAT (n=42) and RA (n=17) were fixed by 4 % paraformaldehyde and embedded into paraffin. An anti-mast cell tryptase antibody was used for immunohistochemical detection and quantification of mast cells. We also demonstrated immunohistochemically the expression of CD117 and chymase markers. In EAT of patients with coronary artery disease (CAD), higher incidence of mast cells has been found compared to patients without CAD (3.7±2.6 vs. 2.1±1.2 cells/mm(2)). In SAT and RA, there was no difference in the number of mast cells in CAD and non-CAD patients. Mast cells in SAT, EAT and RA expressed CD117 and chymase. An increased incidence of mast cells in EAT of CAD patients may indicate the specific role of these inflammatory cells in relation to EAT and coronary arteries affected by atherosclerosis.
- MeSH
- biologické markery metabolismus MeSH
- dospělí MeSH
- kardiochirurgické výkony škodlivé účinky metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- mastocyty metabolismus patologie MeSH
- myokard metabolismus patologie MeSH
- nemoci koronárních tepen metabolismus patologie MeSH
- perikard metabolismus patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- tuková tkáň metabolismus patologie MeSH
- zánět etiologie metabolismus patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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
T-2 toxin, A trichothecenes mycotoxin, is immunotoxic to animals and humans. Although it is highly cardiotoxic, the pathogenesis of cardiomyopathy caused by T-2 toxin is not entirely clear. Hence, in our research, cardiomyopathy was induced by a single injection of T-2 mycotoxin (0.23 mg/kg s.c., 1 LD50) to Wistar rats. The cardiac tissue was carefully examinated by using basic histopathology, semiquantitative (tissue grading score scales) and imaging (a total number of mast cells - MCs) analyses on days 1, 7, 14, 21, 28 and 60 of the study. The most intensive myocardial alterations (cardiac damage score, CDS = 4.20-4.40), irregular glycogen distribution (glycogen distribution score, GDS = 4.07-4.17), haemorrhagic foci (vascular damage score, VDS = 4.57-4.90), diffuse accumulation and degranulation of MCs were observed on day 28 and 60 after treatment (p < 0.001 vs. control and 1st T-2-toxin-treated group, respectively). Besides, statistically significant positive correlations were obtained regarding myocardial injury, glycogen distribution and intensity of haemorrhage, and a negative correlation was found in the case of MCs. Obtained results are essential and crucial for further in vivo experimental studies, including the development of medications able to reduce T-2 toxin-induced cardiotoxicity.
- MeSH
- glykogen metabolismus MeSH
- kardiomyocyty metabolismus MeSH
- kardiomyopatie chemicky indukované etiologie patologie MeSH
- kardiotoxicita etiologie patologie MeSH
- mastocyty patologie MeSH
- myokard metabolismus patologie MeSH
- potkani Wistar MeSH
- T-2 toxin toxicita MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
