Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Tumor microenvironment plays an important role in progression, metastasis and therapeutic resistance. Microenvironment of glioblastoma multiforme (GBM) often contains observable hypoxic regions contributing to malignant phenotype, resulting in poor patient survival prognosis and responsiveness to therapy. The proposed project will aim 1) to determine the expression patterns of markers of hypoxia and invasiveness contributing to GBM progression in tumor samples obtained from particular patients 2) retrospective and prospective analyses of clinical data (overall survival, progression-free survival, response rate) in selected GBM patients related to their previous therapy. The outcomes of the project include determination of expression of the above-mentioned molecules in GBM patients treated with different therapeutic protocols, definition of correlation between hypoxia and responsiveness of patients to the therapeutic protocols. Furthermore, amongst analyzed molecules the project seeks to identify potential biomarker(s) of GBM progression applicable in clinical diagnostics and therapy.
Mikroprostředí nádoru hraje důležitou roli v jeho progresi, metastazování a terapeutické rezistenci. Součástí mikroprostředí glioblastoma multiforme (GBM) jsou často pozorované hypoxické oblasti přispívající k vysoce malignímu fenotypu těchto nádorů, což zhoršuje jak prognózu přežití, tak odpovídavost na terapii. Projekt se bude zabývat 1) stanovením exprese vybraných hypoxických markerů a markerů invazivity v rámci relevantních signálních drah podílejících se na progresi GBM z odebraného vzorku u konkrétních pacientů, 2) retrospektivním a prospektivním zhodnocením klinických dat (overall survival, progression-free survival, response rate) vybraných pacientů s diagnózou GBM s ohledem na předchozí léčbu. Výstupem projektu bude stanovení přítomnosti a úrovně exprese výše uvedených molekul u GBM pacientů léčených odlišnými terapeutickými přístupy a určení korelace mezi signalizací indukovanou hypoxií a odpovídavostí pacientů na konkrétní terapeutické protokoly. Mezi stanovovanými molekulami identifikovat potenciální biomarker(y) progrese GBM použitelné v klinické diagnostice a praxi.
- Klíčová slova
- signalizace, diagnostika, mikroprostředí, microenvironment, diagnostics, Glioblastoma multiforme, signaling, hypoxie, Hypoxia, glioblastoma multiforme, invazivita, prognostické a prediktivní markery, invasiveness, prognostic and predictive markers,
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Selection during metastasizing may shift molecular patterns by which colorectal cancer liver metastases retain their unique molecular profile. Colorectal tumors originating from the left side of colon harbor distinct molecular properties and prognosis and consequently should be treated differently from those in the right side. Genomic alterations in solid cancers can be characterized by next generation sequencing of DNA and RNA to monitor patient’s reaction to therapy. We aim to monitor genomic evolution of cancer in relation to the specific therapy by a whole exome and transcriptome sequencing of primary and metastatic colon cancer patients. The main aim is to identify mutations associated with therapy outcome. We will compare obtained outcomes between good and poor responders to chemotherapy originating from left- or right-side of CRC. The presence of mutations will be independently validated on a larger set of patients from both Czech Republic and Colorectal Consortia. The significance of the project lays on improvement of the therapy efficacy in colon cancer patients.
Selekce během metastázování vede k posunu molekulárních profilů u jaterních metastáz kolorektálního karcinomu (CRLM) v porovnáni s primárním karcinomem tlustého střeva (CRC). CRC, které pocházejí z levé strany tlustého střeva, vykazují odlišné molekulární vlastnosti a prognózu a měli by být léčeni odlišně než pacienti s CRC pocházející z pravé strany. Genomové změny v solidních nádorech mohou umožnit prostřednictvím simultánního sekvenování DNA a RNA izolované z primárních a metastatických CRC sledování reakce pacienta na terapii. Hlavním cílem je identifikovat mutace spojené s předpovědí na léčbu. Získané výsledky budou porovnávany mezi CRC pacienty s dobrou a špatnou odpovědí na chemoterapii u pacientů s nádorem v levé nebo pravé části tlustého střeva. Přítomnost mutací bude nezávisle ověřena na větším počtu pacientů s CRC z České republiky i celosvětových konsorcií zaměřených na výzkum CRC. Význam projektu spočívá v zlepšení účinnosti léčby u pacientů s CRC.
- Klíčová slova
- rezistence, resistance, Metastasis, targeted therapy, cílená léčba, chemoterapie, chemotherapy, metastáza, colon cancer, karcinom střeva, specifická mutace, imunologický přístup, specific mutation, immunological approach,
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
Cíl: Retrospektivní audit z urologického centra zaměřený na urologické píštěle, které vznikly v přímé souvislosti s léčbou gynekologické malignity. Podrobněji diskutované jsou ureteroarteriální píštěle, tedy patologické komunikace mezi močovodem a tepnou. Materiál: Jedná se retrospektivní analýzu případů v 10letém období (2011–2020), kdy bylo diagnostikováno a léčeno na našem pracovišti celkem 47 onkogynekologických pacientek s diagnózou močové píštěle. Jednalo se o případy, které byly na naši kliniku odeslány z lokálních, ale i ostatních pracovišť ČR. V rámci tohoto retrospektivního auditu zaměřeného na urologickou toxicitu onkogynekologické léčby jsme komplikaci ve formě ureteroarteriální píštěle zaznamenali celkem 3krát. Výsledky: Z celkového počtu 64 případů močových píštělí, které jsme za 10 let zaznamenali, bylo 47 pacientek (73,4 %) v přímé souvislosti s onkogynekologickou léčbou. Ve skupině s gynekologickými nádory jsme se setkali u třech pacientek (6,4 %) s diagnózou ureteroarteriální píštěle, přičemž dvě z nich v souvislosti s touto komplikací zemřely (exsangvinace). Ve všech případech se jednalo o pacientky léčené pro karcinom děložního čípku. Tyto ženy podstoupily v průběhu léčby radioterapii. Závěr: Ureteroarteriální píštěle jsou dnes těmi nejzávažnějšími komplikacemi, které mohou v medicíně vůbec nastat. Tato práce potvrzuje, že se s těmito případy setkáváme reálně i v dnešní době. U takto postižených pacientek bývá management extrémně náročný a vyžaduje víceoborovou spolupráci. Metody endovaskulární intervence umožňují v urgentních situacích nechirurgickým přístupem kontrolu krvácení. Zpravidla ale bývají prvním krokem k definitivnímu chirurgickému řešení.
Aim: A retrospective audit from a urological center focused on urological fistulas that directly connect with the treatment of gynecological malignancy. Ureteroarterial fistulas, i.e., pathological communication between the ureter and the artery, are discussed in more detail. Materials and methods: Over a period of ten years, from 2011 to 2020, a group of 47 patients with a diagnosis of urinary fistula was retrospectively evaluated. These patients, with a history of treatment for gynecological malignancy, were sent to our clinic from local and non-regional departments in the Czech Republic. We found three cases of ureteroarterial fistula in the presented analysis that focused on urological toxicity of oncogynecological treatment. Results: Within the mentioned period of ten years, we recorded 64 cases of urinary fistulas, and 47 patients (73.4%) were directly related to oncogynecological treatment. In the group with gynecological tumors, we found three patients (6.4%) with a diagnosis of ureteroarterial fistula, two of whom died directly related to this complication (exsanguination). These patients were treated for cervical cancer. All of them underwent radiotherapy during the treatment. Conclusion: Ureteroarterial fistulas are the most severe complications that can occur in medicine. This work confirms that we have encountered these cases even recently. Management is highly demanding for patients affected in this way and requires multidisciplinary cooperation. Endovascular intervention methods can control bleeding in emergency situations with non-surgical approaches. However, they are usually the first step towards a definitive surgical solution.
BACKGROUND: The optimal radiotherapy technique for cardiac sparing in left-sided early breast cancer (EBC) is not clear. In this context, the aim of our dosimetric study was to compare cardiac and lung doses according to the type of radiotherapy - whole breast irradiation (WBI), external partial breast irradiation (PBI), and multicatheter interstitial brachytherapy-accelerated partial breast irradiation (MIB-APBI). The dosimetric results with the WBI and PBI were calculated with and without DIBH. MATERIALS AND METHODS: Dosimetric study of 23 patients treated with WBI, PBI, with and without DIBH, or MIB-APBI. The prescribed dose was 40 Gy in 15 fractions for WBI and PBI and 34 Gy in 10 fractions (bid) for MIB-APBI. Doses to the organs-at-risk (OAR) - heart, left anterior descending coronary artery (LAD), left ventricle (LV), and left lung - were recalculated to the equivalent dose in 2-Gy fractions (EQD2). RESULTS: The addition of DIBH significantly reduced EQD2 doses to all OARs (except for the left lung maximal dose) in WBI and PBI. MHD values were 0.72 Gy for DIBH-WBI, 1.01 Gy for MIB-APBI and 0.24 Gy for DIBH-PBI. There were no significant differences in cardiac doses between WBI with DIBH and PBI without DIBH. DIBH-PBI resulted in significantly lower mean doses to all OARs (except for maximum lung dose) compared to MIB-APBI. Conclusions: These results show that the use of DIBH significantly reduces cardiac doses in patients with left EBC. Partial irradiation techniques (PBI, MIB-APBI) significantly reduced cardiac doses due to the smaller clinical target volume. The best results were obtained with DIBH-PBI.
- Publikační typ
- časopisecké články MeSH
Background: Although several prognostic factors for survival have been identified in glioblastoma, there are numerous other potential markers (such as hemoglobin) whose role has not yet been confirmed. The aim of this study was to evaluate a wide range of potential prognostic factors, including HIF-1α and hemoglobin levels, for survival in glioblastoma. A secondary aim was to determine whether hemoglobin levels were associated with HIF-1α expression. Methods: A retrospective study of 136 patients treated for glioblastoma at our institution between 2012 and 2021 was performed. Cox univariate and multivariate analyses were carried out. Kaplan-Meier survival curves were generated. In addition, bivariate non-parametric correlation analyses were performed for key variables. Results: Median survival was 11.9 months (range: 0-119.4). According to the univariate analysis, 13 variables were significantly associated with survival: age, performance status, extent of surgery, tumor depth, tumor size, epilepsy, postoperative chemoradiotherapy, IDH mutations, CD44, HIF-1α, HIF-1β, vimentin, and PDFGR. According to the multivariate regression analysis, only four variables remained significantly associated with survival: age, extent of surgery, epilepsy, and HIF-1α expression. No significant association was observed between hemoglobin levels (low <120 g/L in females or <140 g/L in males vs. high ≥120 or ≥140 g/L) and survival or HIF-1α/HIF-1β expression. Conclusions: In this retrospective study of patients with glioblastoma, four variables-age, extent of surgery, HIF-1α expression, and epilepsy-were significant prognostic factors for survival. Hemoglobin levels were not significantly associated with survival or HIF-1α expression. Although hypoxia is a well-recognized component of the glioblastoma microenvironment, more research is needed to understand the pathogenesis of onset tumor hypoxia and treatment implication.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Glioblastoma is a malignant and aggressive type of central nevous system malignancy characterized by many distinct biological features including extensive hypoxia. Hypoxia in glioblatoma associates with complex signaling patterns including activation of several pathways such as MAPK, PI3K-AKT/mTOR and IL-6/JAK/STAT3 with the master regulator HIF-1, which in turn drive particular tumor behaviors determining, in the end, treatment outcomes and patients fate. Thus, the present study was designed to investigate the expression of selected hypoxia related factors including STAT3 in a small set of long-term surviving glioma patients. METHODS: The expression of selected hypoxia related factors including STAT3 was evaluated in a time series of formalin fixed paraffin embedded and cryopreserved glioma samples from repeatedly resected patients. In addition, comparative studies were also conducted on primary glioma cells derived from original patient samples, stabilized glioma cell lines and tumor-xenograft mice model. Obtained data were correlated with clinical findings too. RESULTS: Glioblastoma samples of the analyzed patients displayed heterogeneity in the expression of hypoxia- related and EMT markers with most interesting trend being observed in pSTAT3. This heterogeneity was subsequently confirmed in other employed models (primocultures derived from glioblastoma tissue resections, cryopreserved tumor specimens, stabilized glioblastoma cell line in vitro and in vivo) and concerned, in particular, STAT3 expression which remained stable. In addition, subsequent studies on the role of STAT3 in the context of glioblastoma hypoxia demonstrated opposing effects of its deletion on cell viability as well as the expression of hypoxia and EMT markers. CONCLUSIONS: Our results suport the importance of STAT3 expression and activity in the context of hypoxia in malignant glioblastoma long-term surviving glioma patients while emphasizing heterogeneity of biological outcomes in varying employed tumor models.
- MeSH
- dospělí MeSH
- glioblastom metabolismus patologie genetika MeSH
- gliom * metabolismus patologie genetika MeSH
- hypoxie metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- myši MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory mozku metabolismus patologie genetika MeSH
- regulace genové exprese u nádorů MeSH
- senioři MeSH
- transkripční faktor STAT3 * metabolismus MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The role of postmastectomy radiotherapy and regional nodal irradiation after radical mastectomy is defined in high-risk patients with locally advanced tumors, positive margins, and unfavorable biology. The benefit of postmastectomy radiotherapy in intermediate-risk patients (T3N0 tumors) remains a matter of controversy. It has been demonstrated that radiotherapy after breast-conserving surgery lowers the locoregional recurrence rate compared with surgery alone and improves the overall survival rate. In patients with four or more positive lymph nodes or extracapsular extension, regional lymph node irradiation is indicated regardless of the surgery type (breast-conserving surgery or mastectomy). Despite the consensus that patients with more than three positive lymph nodes should be treated with radiotherapy, there is controversy regarding the recommendations for patients with one to three involved lymph nodes. In patients with N0 disease with negative findings on axillary surgery, there is a trend to administer regional lymph node irradiation in patients with a high risk of recurrence. In patients treated with neoadjuvant systemic therapy and mastectomy, adjuvant radiotherapy should be administered in cases of clinical stage III and/or ≥ypN1. In patients treated with neoadjuvant systemic therapy and breast-conserving surgery, postoperative radiotherapy is indicated irrespective of pathological response.
- MeSH
- adjuvantní radioterapie MeSH
- lidé MeSH
- lokální recidiva nádoru patologie MeSH
- mastektomie MeSH
- nádory prsu * farmakoterapie MeSH
- segmentální mastektomie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Histological identification of dispersed glioma cells in small biopsies can be challenging, especially in tumours lacking the IDH1 R132H mutation or alterations in TP53. We postulated that immunohistochemical detection of proteins expressed preferentially in gliomas (EGFR, MEOX2, CD34) or during embryonal development (SOX11, INSM1) can be used to distinguish reactive gliosis from glioma. Tissue microarrays of 46 reactive glioses, 81 glioblastomas, 34 IDH1-mutant diffuse gliomas, and 23 gliomas of other types were analysed. Glial neoplasms were significantly more often (p < 0.001, χ2) positive for EGFR (34.1% vs. 0%), MEOX2 (49.3% vs. 2.3%), SOX11 (70.5% vs. 20.4%), and INSM1 (65.4% vs. 2.3%). In 94.3% (66/70) of the glioblastomas, the expression of at least two markers was observed, while no reactive gliosis showed coexpression of any of the proteins. Compared to IDH1-mutant tumours, glioblastomas showed significantly higher expression of EGFR, MEOX2, and CD34 and significantly lower positivity for SOX11. Non-diffuse gliomas were only rarely positive for any of the five markers tested. Our results indicate that immunohistochemical detection of EGFR, MEOX2, SOX11, and INSM1 can be useful for detection of glioblastoma cells in limited histological samples, especially when used in combination.
- Publikační typ
- časopisecké články MeSH
Telomeric sequences, the structures comprised of hexanucleotide repeats and associated proteins, play a pivotal role in chromosome end protection and preservation of genomic stability. Herein we address telomere length (TL) dynamics in primary colorectal cancer (CRC) tumour tissues and corresponding liver metastases. TL was measured by multiplex monochrome real-time qPCR in paired samples of primary tumours and liver metastases along with non-cancerous reference tissues obtained from 51 patients diagnosed with metastatic CRC. Telomere shortening was observed in the majority of primary tumour tissues compared to non-cancerous mucosa (84.1%, p < 0.0001). Tumours located within the proximal colon had shorter TL than those in the rectum (p < 0.05). TL in liver metastases was not significantly different from that in primary tumours (p = 0.41). TL in metastatic tissue was shorter in the patients diagnosed with metachronous liver metastases than in those diagnosed with synchronous liver metastases (p = 0.03). The metastatic liver lesions size correlated with the TL in metastases (p < 0.05). Following the neoadjuvant treatment, the patients with rectal cancer had shortened telomeres in tumour tissue than prior to the therapy (p = 0.01). Patients with a TL ratio between tumour tissue and the adjacent non-cancerous mucosa of ≥ 0.387 were associated with increased overall survival (p = 0.01). This study provides insights into TL dynamics during progression of the disease. The results show TL differences in metastatic lesions and may help in clinical practice to predict the patient's prognosis.
Modern communication and information technologies are rapidly being deployed at health care institutions around the world. Although these technologies offer many benefits, ensuring data protection is a major concern, and implementation of robust data protection measures is essential. In this context, health care providers and medical care facilities must frequently make difficult decisions and compromises between the need to provide effective medical care and the need to ensure data security and patient privacy. In the present paper, we describe and discuss key issues related to data protection systems in the setting of cancer care hospitals in Europe. We provide real-life examples from two European countries-Poland and the Czech Republic-to illustrate data protection issues and the steps being taking to address these questions. More specifically, we discuss the legal framework surrounding data protection and technical aspects related to patient authentication and communication.
- Publikační typ
- časopisecké články MeSH
