Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas represents a rare subtype of pancreatic ductal adenocarcinoma (PDAC). Despite a distinct morphology and specific clinical behavior, UCOGCs exhibit unexpected similarities in regard to DNA mutational profiles with conventional PDAC. Treating pancreatic ductal adenocarcinoma is particularly challenging, with limited prospects for cure. As with many other malignant neoplasms, the exploration of microRNAs (miRNAs, miRs) in regulating the biological characteristics of pancreatic cancer is undergoing extensive investigation to enhance tumor diagnostics and unveil the therapeutic possibilities. Herein, we evaluated the expression of miR-21, -96, -148a, -155, -196a, -210, and -217 in UCOGCs and poorly differentiated (grade 3, G3) PDACs. The expression of miR-21, miR-155, and miR-210 in both UCOGCs and G3 PDACs was significantly upregulated compared to the levels in normal tissue, while the levels of miR-148a and miR-217 were downregulated. We did not find any significant differences between cancerous and normal tissues for the expression of miR-96 and miR-196a in G3 PDACs, whereas miR-196a was slightly, but significantly, downregulated in UCOGCs. On the other hand, we have not observed significant differences in the expression of the majority of miRNAs between UCOGC and G3 PDAC, with the exception of miR-155. UCOGC samples demonstrated lower mean levels of miR-155 in comparison with those in G3 PDACs.
- Publikační typ
- časopisecké články MeSH
Pancreatic cancer is a severe malignancy with increasing incidence and high mortality due to late diagnosis and low sensitivity to treatments. Search for the most appropriate drugs and therapeutic regimens is the most promising way to improve the treatment outcomes of the patients. This study aimed to compare (1) in vitro efficacy and (2) in vivo antitumor effects of conventional paclitaxel and the newly synthesized second (SB-T-1216) and third (SB-T-121605 and SB-T-121606) generation taxanes in KRAS wild type BxPC-3 and more aggressive KRAS G12V mutated Paca-44 pancreatic cancer cell line models. In vitro, paclitaxel efficacy was 27.6 ± 1.7 nM, while SB-Ts showed 1.7-7.4 times higher efficacy. Incorporation of SB-T-121605 and SB-T-121606 into in vivo therapeutic regimens containing paclitaxel was effective in suppressing tumor growth in Paca-44 tumor-bearing mice at small doses (≤3 mg/kg). SB-T-121605 and SB-T-121606 in combination with paclitaxel are promising candidates for the next phase of preclinical testing.
- Publikační typ
- časopisecké články MeSH
The aim of this study was to investigate the prognostic significance of membranous β-catenin and cytoplasmic β-catenin expression in pancreatic cancer patients (pts). One hundred pts with histologically verified exocrine pancreatic ductal adenocarcinoma were retrospectively studied. The membranous β-catenin, cytoplasmic β-catenin, and cell nucleus β-catenin expression were immunohistochemically evaluated. The expression of membranous β-catenin was <5% in none of the pts, 5-25% in one patient, 26-50% in 2 pts, 51-75% in 14 pts, and >75% in 81 pts. The expression of cytoplasmic β-catenin was <5% in 34 pts, 5-25% in 42 pts, 26-50% in 18 pts, 51-75% in 3 pts, and >75% in one patient. The expression of β-catenin in the cell nucleus was negative in all pts. At the time of the last follow-up, 21 pts were alive and 79 pts had died. Median OS was 1.3 (0.4-2.3) years in pts with membranous β-catenin expression ≤75% and 1.7 (1.3-2.1) years in pts with membranous β-catenin expression >75% (p=0.045). Median OS was (1.3-2.0) 1.6 years in pts with cytoplasmic β-catenin expression ≤25% and 0.9 (0.5-1.2) years in pts with cytoplasmic β-catenin expression >25% (p=0.040). In the univariate Cox proportional hazard models HR (95% CI) was 0.556 (0.311-0.995) in pts with membranous β-catenin expression >75% (p=0.048) and 2.200 (1.216-3.980) in pts with cytoplasmic β-catenin expression >25% (p=0.009). The present results indicate a favorable prognostic significance of membranous β-catenin expression in pancreatic cancer.
Úvod: Karcinom pankreatu je závažné onkologické onemocnění se stále se zvyšující incidencí a vysokou mírou morbidity a mortality. Terapeutické možnosti jsou limitované a pětileté přežití je 7–20 %, v závislosti na možnosti chirurgické resekce a časnosti záchytu onemocnění. Většina nemocných s touto diagnózou umírá v důsledku rezistence nádorových buněk a mikroprostředí vůči používané léčbě. Metody: V naší práci jsme se zaměřili na zavedení dvou typů in vivo modelů, kterými jsou cell-line derived xenograft (CDX) a patient derived xenograft (PDX). Tyto dva modely se navzájem výrazně liší metodologicky, náročností technickou i finanční, ale i dosaženými výsledky. Výsledky: V pilotní studii se nám podařilo úspěšně zavést CDX model s velmi agresivní a rezistentní linií PaCa-44 karcinomu pankreatu o celkovém počtu 30 jedinců NU/NU myší. Dále jsme vytvořili tři PDX modely s různými subtypy karcinomu pankreatu, pacientů operovaných na Chirurgické klinice FNKV, s jejich následnou retransplantací do dalších generací o celkovém počtu 23 jedinců kmene NOD/SCID a 47 jedinců kmene NU/NU. Zavedené CDX i PDX modely pak slouží k porovnání jak konvenčních, tak experimentálních chemoterapeutických režimů. Závěr: Dalšími kroky bude vyhodnocení vlivu léčebných režimů pomocí zobrazovacích i molekulárně genetických metod a optimalizace celého procesu pro využití v rámci precizní personalizované léčby pacientů s karcinomem pankreatu. Nadcházejícím cílem je vytvořit knihovnu PDX modelů nejčastějšího duktálního adenokarcinomu pankreatu a dalších vzácných subtypů karcinomu pankreatu.
Introduction: Pancreatic cancer is a severe oncological disease with an ever-increasing incidence and a high rate of morbidity and mortality. Therapeutic options are limited and the five-year overall survival rate is 7–20%, depending on the possibility of surgical resection and the earliness of detection. Most patients with this diagnosis die due to the resistance of tumour cells and their microenvironment to the used treatment regimes. Methods: In our study, we focused on the implementation of two in vivo models, which are the cell-line derived xenograft (CDX) and the patient-derived xenograft (PDX). These two models differ significantly from each other methodologically, technically, financially, but also in their achieved results. Results: In a pilot study, we managed to successfully implement the CDX model with a very aggressive and resistant PaCa-44 line of pancreatic cancer in a total of 30 NU/NU strain mice. Furthermore, we created three PDX models with various subtypes of pancreatic cancer from patients operated at the University Hospital Kralovske Vinohrady, Department of General Surgery. These tumours were re-transplanted into subsequent generations of 23 individuals of NOD/SCID strain and 47 NU/NU strain mice. The established CDX and PDX models are then used to compare conventional and experimental chemotherapy regimens. Conclusion: The next steps will be to evaluate the effects of treatment regimens by using imaging and molecular genetic methods and to optimise the entire process for further use in precise personalised medicine for patients with pancreatic cancer. The upcoming goal is to create a library of PDX models of the most common pancreatic ductal adenocarcinoma and other rare subtypes of pancreatic cancer.
- MeSH
- modely nemocí na zvířatech MeSH
- myši nahé MeSH
- nádory slinivky břišní * chirurgie terapie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Pancreatic ductal adenocarcinoma represents a disease with increasing incidence. Its prognosis is the worst among all malignancies despite the aggressive combined multimodal treatment across all stages. In metastatic disease, median survival is approximatelly one year. The mainstay of treatment is chemotherapy (neo/adjuvant, palliative) and in selected subgroups of patients even radiotherapy. Nevertheless, nowadays there are very few prognostic and/or predictive biomarkers available that can be used to identify and better stratify patients based on risk to tailored treatment. Potentially, promising areas of research are circulating tumor cells and circulating tumor DNA, which can be easily obtained from peripheral blood - so called liquid biopsy. They may serve as a tool to assess response to applied treatment, and to detect the emergence of treatment-resistant clones or early disease relapse. Moreover, their study may allow identification of potentially tumor-specific alterations, which may serve as target structures for targeted (tailored) therapy. Alternatively, different prognostic indexes/scores calculated by analysis of selected parameters of blood and/or biochemistry can be used to better stratify patients based on risk and better predict prognosis. The aim of this mini-review is to provide a basic overview of the current state of the art in this area and its potential significance for clinical practice.
- MeSH
- cirkulující nádorová DNA * genetika MeSH
- duktální karcinom slinivky břišní * diagnóza genetika terapie MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- nádorové biomarkery genetika MeSH
- nádorové cirkulující buňky * MeSH
- nádory slinivky břišní * diagnóza genetika terapie MeSH
- prognóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) still represents one of the most aggressive cancers. Understanding of the epithelial-mesenchymal crosstalk as a crucial part of the tumor microenvironment should pave the way for therapies to improve patient survival rates. Well-established cell lines present a useful and reproducible model to study PDAC biology. However, the tumor-stromal interactions between cancer cells and cancer-associated fibroblasts (CAFs) are still poorly understood. MATERIALS AND METHODS: We studied interactions between four PDAC cell lines (Panc-1, CAPAN-2, MIAPaCa-2, and PaTu-8902) and conditioned media derived from primary cultures of normal fibroblasts/PDAC-derived CAFs (PANFs). RESULTS: When the tested PDAC cell lines were stimulated by PANF-derived conditioned media, the most aggressive behavior was acquired by the Panc-1 cell line (increased number and size of colonies, remaining expression of vimentin and keratin 8 as well as increase of epithelial-to-mesenchymal polarization markers), whereas PaTu-8902 cells were rather inhibited. Of note, administration of the conditioned media to MIAPaCa-2 cells resulted in an inverse effect on the size and number of colonies, whereas CAPAN-2 cells were rather stimulated. To explain the heterogeneous pattern of the observed PDAC crosstalk at the in vitro level, we further compared the phenotype of primary cultures of cells derived from ascitic fluid with that of the tested PDAC cell lines, analyzed tumor samples of PDAC patients, and performed gene expression profiling of PANFs. Immuno-cyto/histo-chemical analysis found specific phenotype differences within the group of examined patients and tested PDAC cell lines, whereas the genomic approach in PANFs found the key molecules (IL6, IL8, MFGE8 and periostin) that may contribute to the cancer aggressive behavior. CONCLUSION: The desmoplastic patient-specific regulation of cancer cells by CAFs (also demonstrated by the heterogeneous response of PDAC cell lines to fibroblasts) precludes simple targeting and development of an effective treatment strategy and rather requires establishment of an individualized tumor-specific treatment protocol.
- MeSH
- duktální karcinom slinivky břišní metabolismus patologie MeSH
- epitelo-mezenchymální tranzice MeSH
- fibroblasty asociované s nádorem metabolismus patologie MeSH
- fibroblasty metabolismus patologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí MeSH
- nádory slinivky břišní metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Aortoezofageální píštěl (AEP) je definována jako patologická komunikace mezi aortou a jícnem. Toto onemocnění je zatíženo vysokou mortalitou a morbiditou. Pro AEP je charakteristický soubor příznaků, který se nazývá Chiariho triáda a zahrnuje bolest na hrudi či dysfagii, krvácení do trávicí trubice a masivní krvácení nastupující po bezpříznakovém období. Rozlišujeme dva typy AEP - primární a sekundární. Mezi nejčastější příčiny primárních AEP patří aneurysmata hrudní aorty, polknutí cizích těles, tumory jícnu, traumatická poranění aorty či tuberkulóza. Sekundární AEP vzniká jako komplikace endovaskulární implantace stentgraftu (TEVAR) či chirurgických výkonů na aortě, příp. jícnu. V současné době je pro detekci AEP nejvíce preferovanou diagnostickou metodou CT angiografie, případně endoskopie, a to jednak z důvodu dostupnosti, ale také pro její vysoké rozlišení. Vzhledem k fulminantnímu průběhu je ovšem AEP často diagnostikována až post mortem. Terapií AEP je urgentní endovaskulární léčba ve formě implantace stentgraftu, který může zabránit okamžité exsangvinaci pacienta. Článek popisuje případ pacienta s AEP a uvádí základní přehled o tomto vzácném, ale závažném onemocnění.
Aortoesophageal fistula (AEP) is defined as a pathological communication between the aorta and the esophagus. This condition is associated with high mortality and morbidity. AEP is characterized by a set of symptoms called the Chiari Triad. Typical symptoms are chest pain or dysphagia, gastrointestinal bleeding, and massive hematemesis occurring after a symptom-free period. There are two types of AEP - primary and secondary. The most common causes of the primary AEP are thoracic aortic aneurysms, foreign bodies swallowing, esophagus tumors, traumatic aortic injuries, and TB. The secondary AEP arises as a complication of thoracic endovascular aortic repair (TEVAR), surgery on the aorta, resp. esophagus. Currently, CT angiography and endoscopy diagnostic methods are most preferred for AEP detection. The main reasons for using these methods are availability and high-resolution ability. The detection of AEP is often diagnosed post-mortem due to fulminant progress. A therapy of AEP is an urgent endovascular treatment in the form of stent-graft implantation, which can prevent immediate exsanguination of the patient. This paper describes a patient with AEP and introduces a basic overview of this rare but severe disease.
- MeSH
- adherence pacienta MeSH
- aorta thoracica patologie MeSH
- aortální aneurysma diagnóza patologie MeSH
- bolesti na hrudi etiologie MeSH
- cévní píštěle * diagnóza etiologie klasifikace MeSH
- cévní protézy MeSH
- CT angiografie MeSH
- disekce aorty * diagnóza patologie MeSH
- elektrokardiografie MeSH
- ezofágus diagnostické zobrazování patologie MeSH
- fatální výsledek MeSH
- hemoragický šok etiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- odmítnutí terapie pacientem MeSH
- srdeční chlopně umělé MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Karcinom z Merkelových buněk je vzácným maligním kožním nádorem s agresivním chováním, který ve většině případů bývá asociovaný s infekcí polyomavirem karcinomu z Merkelových buněk (MCPyV). Ve výjimečných případech se nádor manifestuje jako metastáza do lymfatické uzliny bez jednoznačného průkazu primárního kožního ložiska. V této práci prezentujeme případ 42letého pacienta s tříselnou lymfadenopatií, s histologickým nálezem karcinomu z Merkelových buněk. Imunohistochemicky byla v nádoru prokázána exprese chromograninu-A, synaptofyzinu a tečkovitá pozitivita cytokeratinu 20. Molekulárně genetickým vyšetřením byla pomocí metody real-time PCR detekována přítomnost genomu MCPyV v nádorových buňkách. Dermatologické vyšetření ani staging pomocí PET CT ložisko primárního nádoru v jiné lokalizaci u pacienta neprokázalo.
Merkel cell carcinoma is a rare cutaneous tumor with an aggressive clinical course. In most cases it is associated with Merkel cell polyomavirus infection. Exceptionally, the tumor can present as a lymph node metastasis without a discernible cutaneous primary. In this report we present the case of a 42 year-old man with inguinal lymphadenopathy, histologically consistent with Merkel cell carcinoma. Tumor cells expressed immunohistochemically chromogranin-A, synaptophysin and displayed dot-like positivity for cytokeratin 20. The genome of MCPyV in neoplastic cells was detected using real-time PCR. A cutaneous primary has not been identified neither during the dermatologic examination, nor with PET CT scan.
- MeSH
- dospělí MeSH
- imunohistochemie MeSH
- lidé MeSH
- lymfatické uzliny anatomie a histologie diagnostické zobrazování chirurgie patologie MeSH
- Merkelův nádor * diagnóza terapie MeSH
- metastázy nádorů MeSH
- prognóza MeSH
- radioterapie MeSH
- třísla chirurgie patologie účinky záření MeSH
- výsledek terapie MeSH
- vzácné nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
Germ cell tumors and particularly seminomas reflect the epigenomic features of their parental primordial germ cells (PGCs), including genomic DNA hypomethylation and expression of pluripotent cell markers. Because the DNA hypomethylation might be a result of TET dioxygenase activity, we examined expression of TET1-3 enzymes and the level of their product, 5-hydroxymethylcytosine (5hmC), in a panel of histologically characterized seminomas and non-seminomatous germ cell tumors. Expression of TET dioxygenase mRNAs was quantified by real-time PCR. TET1 expression and the level of 5hmC were examined immunohistochemically. Quantitative assessment of 5-methylcytosine (5mC) and 5hmC levels was done by the liquid chromatography-mass spectroscopy technique. We found highly increased expression of TET1 dioxygenase in most seminomas and strong TET1 staining in seminoma cells. Isocitrate dehydrogenase 1 and 2 mutations were not detected, suggesting the enzymatic activity of TET1. The levels of 5mC and 5hmC in seminomas were found decreased in comparison to non-seminomatous germ cell tumors and healthy testicular tissue. We propose that TET1 expression should be studied as a potential marker of seminomas and mixed germ cell tumors and we suggest that elevated expression of TET dioxygenase enzymes is associated with the maintenance of low DNA methylation levels in seminomas. This "anti-methylator" phenotype of seminomas is in contrast to the CpG island methylator phenotype (CIMP) observed in a fraction of tumors of various types.
- MeSH
- 5-methylcytosin analogy a deriváty analýza MeSH
- dioxygenasy analýza genetika MeSH
- DNA vazebné proteiny analýza genetika MeSH
- dospělí MeSH
- lidé MeSH
- metylace DNA * MeSH
- oxygenasy se smíšenou funkcí analýza genetika MeSH
- protoonkogenní proteiny analýza genetika MeSH
- regulace genové exprese u nádorů MeSH
- seminom genetika patologie MeSH
- testikulární nádory genetika patologie MeSH
- testis metabolismus patologie MeSH
- upregulace MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- autoimunitní nemoci diagnóza imunologie patologie MeSH
- diferenciální diagnóza MeSH
- hormony kůry nadledvin MeSH
- imunoglobulin G krev MeSH
- lidé MeSH
- nádory slinivky břišní MeSH
- obstrukční žloutenka etiologie MeSH
- pankreas diagnostické zobrazování patologie MeSH
- pankreatitida * diagnóza imunologie patologie MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
