Nejvíce citovaný článek - PubMed ID 21895872
MiR-195, miR-196b, miR-181c, miR-21 expression levels and O-6-methylguanine-DNA methyltransferase methylation status are associated with clinical outcome in glioblastoma patients
BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. The treatment of GBM consists of a combination of surgery and subsequent oncological therapy, i.e., radiotherapy, chemotherapy, or their combination. If postoperative oncological therapy involves irradiation, magnetic resonance imaging (MRI) is used for radiotherapy treatment planning. Unfortunately, in some cases, a very early worsening (progression) or return (recurrence) of the disease is observed several weeks after the surgery and is called rapid early progression (REP). Radiotherapy planning is currently based on MRI for target volumes definitions in many radiotherapy facilities. However, patients with REP may benefit from targeting radiotherapy with other imaging modalities. The purpose of the presented clinical trial is to evaluate the utility of 11C-methionine in optimizing radiotherapy for glioblastoma patients with REP. METHODS: This study is a nonrandomized, open-label, parallel-setting, prospective, monocentric clinical trial. The main aim of this study was to refine the diagnosis in patients with GBM with REP and to optimize subsequent radiotherapy planning. Glioblastoma patients who develop REP within approximately 6 weeks after surgery will undergo 11C-methionine positron emission tomography (PET/CT) examinations. Target volumes for radiotherapy are defined using both standard planning T1-weighted contrast-enhanced MRI and PET/CT. The primary outcome is progression-free survival defined using RANO criteria and compared to a historical cohort with REP treated without PET/CT optimization of radiotherapy. DISCUSSION: PET is one of the most modern methods of molecular imaging. 11C-Methionine is an example of a radiolabelled (carbon 11) amino acid commonly used in the diagnosis of brain tumors and in the evaluation of response to treatment. Optimized radiotherapy may also have the potential to cover those regions with a high risk of subsequent progression, which would not be identified using standard-of-care MRI for radiotherapy planning. This is one of the first study focused on radiotherapy optimization for subgroup of patinets with REP. TRIAL REGISTRATION: NCT05608395, registered on 8.11.2022 in clinicaltrials.gov; EudraCT Number: 2020-000640-64, registered on 26.5.2020 in clinicaltrialsregister.eu. Protocol ID: MOU-2020-01, version 3.2, date 18.09.2020.
- Klíčová slova
- 11C-methionine, Clinical trial, Glioblastoma, Positron emission tomography, Radiopharmaceutical, Radiotherapy, Rapid early progression,
- MeSH
- dospělí MeSH
- glioblastom * diagnostické zobrazování terapie diagnóza radioterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- methionin * MeSH
- nádory mozku * diagnostické zobrazování terapie radioterapie diagnóza MeSH
- PET/CT metody MeSH
- plánování radioterapie pomocí počítače metody MeSH
- progrese nemoci * MeSH
- prospektivní studie MeSH
- radiofarmaka terapeutické užití MeSH
- radioizotopy uhlíku MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- Názvy látek
- methionin * MeSH
- radiofarmaka MeSH
- radioizotopy uhlíku MeSH
The aim of this retrospective study is to provide real-world evidence in glioblastoma treatment and to compare overall survival after Stupp's regimen treatment today and a decade ago. A current consecutive cohort of histologically confirmed glioblastoma irradiated from 1/2014 to 12/2017 in our cancer center was compared with an already published historical control of patients treated in 1/2003-12/2009. A total of new 155 patients was analyzed, median age 60.9 years, 61% men, 58 patients (37%) underwent gross total tumor resection. Stupp's regimen was indicated in 90 patients (58%), 65 patients (42%) underwent radiotherapy alone. Median progression-free survival in Stupp's regimen cohort was 6.7 months, median OS 16.0 months, and 2-year OS 30.7%. OS was longer if patients were able to finish at least three cycles of adjuvant chemotherapy (median 23.3 months and 43.9% of patients lived at 2 years after surgery). Rapid early progression prior to radiotherapy was a negative prognostic factor with HR 1.87 (p = 0.007). The interval between surgery and the start of radiotherapy (median 6.7 weeks) was not prognostically significant (p = 0.825). The median OS in the current cohort was about 2 months longer than in the historical control group treated 10 years ago (16 vs. 13.8 months) using the same Stupp's regimen. Taking into account differences in patient's characteristics between current and historical cohorts, age, extent of resection, and ECOG patient performance status adjusted HR (Stupp's regimen vs. RT alone) for OS was determined as 0.45 (p = 0.002).
- Klíčová slova
- chemotherapy, glioblastoma, overall survival, radiotherapy, rapid early progression, real-world evidence,
- Publikační typ
- časopisecké články MeSH
Glioblastoma stem-like cells (GSCs) are critical for the aggressiveness and progression of glioblastoma (GBM) and contribute to its resistance to adjuvant treatment. MicroRNAs (miRNAs) are small, non-coding RNAs controlling gene expression at the post-transcriptional level, which are known to be important regulators of the stem-like features. Moreover, miRNAs have been previously proved to be promising diagnostic biomarkers in several cancers including GBM. Using global expression analysis of miRNAs in 10 paired in-vitro as well as in-vivo characterized primary GSC and non-stem glioblastoma cultures, we identified a miRNA signature associated with the stem-like phenotype in GBM. 51 most deregulated miRNAs classified the cell cultures into GSC and non-stem cell clusters and identified a subgroup of GSC cultures with more pronounced stem-cell characteristics. The importance of the identified miRNA signature was further supported by demonstrating that a Risk Score based on the expression of seven miRNAs overexpressed in GSC predicted overall survival in GBM patients in the TCGA dataset independently of the IDH1 status. In summary, we identified miRNAs differentially expressed in GSCs and described their association with GBM patient survival. We propose that these miRNAs participate on GSC features and could represent helpful prognostic markers and potential therapeutic targets in GBM.
- MeSH
- analýza přežití MeSH
- glioblastom genetika MeSH
- isocitrátdehydrogenasa genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA genetika MeSH
- mutace MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové buňky kultivované MeSH
- nádorové kmenové buňky chemie MeSH
- nádory mozku genetika MeSH
- nestin MeSH
- regulace genové exprese u nádorů MeSH
- senioři MeSH
- stanovení celkové genové exprese metody MeSH
- transkripční faktory SOXB1 genetika MeSH
- transplantace nádorů MeSH
- zvířata MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- IDH1 protein, human MeSH Prohlížeč
- isocitrátdehydrogenasa MeSH
- mikro RNA MeSH
- NES protein, human MeSH Prohlížeč
- nestin MeSH
- SOX2 protein, human MeSH Prohlížeč
- transkripční faktory SOXB1 MeSH
High-grade gliomas (HGGs) are malignant primary brain tumors of glial cell origin. Despite optimal course of treatment, including maximal surgical resection followed by adjuvant chemo- and/or radiotherapy, the prognosis still remains poor. The main reason is the commonly occurring chemo- and radioresistance of these tumors. In recent years, several signaling pathways, especially PI3K/AKT and ATM/CHK2/p53, have been linked to the resistance of gliomas. Moreover, additional studies have shown that these pathways are significantly regulated by microRNAs (miRNAs), short endogenous RNA molecules that modulate gene expression and control many biological processes including apoptosis, proliferation, cell cycle, invasivity, and angiogenesis. MiRNAs are not only highly deregulated in gliomas, their expression signatures have also been shown to predict prognosis and therapy response. Therefore, they present promising biomarkers and therapeutic targets that might overcome the resistance to treatment and improve prognosis of glioma patients. In this review, we summarize the current knowledge of the functional role of miRNAs in gliomas resistance to chemo- and radiotherapy.
- MeSH
- apoptóza MeSH
- ATM protein MeSH
- checkpoint kinasa 2 MeSH
- chemorezistence genetika MeSH
- DNA vazebné proteiny metabolismus MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- gliom * farmakoterapie genetika radioterapie MeSH
- invazivní růst nádoru MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- nádorové supresorové proteiny metabolismus MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory mozku farmakoterapie genetika radioterapie MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- proteiny buněčného cyklu metabolismus MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- tolerance záření genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- ATM protein, human MeSH Prohlížeč
- ATM protein MeSH
- checkpoint kinasa 2 MeSH
- CHEK2 protein, human MeSH Prohlížeč
- DNA vazebné proteiny MeSH
- mikro RNA MeSH
- nádorové supresorové proteiny MeSH
- nádorový supresorový protein p53 MeSH
- protein-serin-threoninkinasy MeSH
- proteiny buněčného cyklu MeSH
- protoonkogenní proteiny c-akt MeSH
- TP53 protein, human MeSH Prohlížeč
BACKGROUND: Rectal cancer accounts for approximately one third of all colorectal cancers (CRC), which belong among leading causes of cancer deaths worldwide. Standard treatment for locally advanced rectal cancer (cT3/4 and/or cN+) includes neoadjuvant chemoradiotherapy with fluoropyrimidines (capecitabine or 5-fluorouracil) followed by radical surgical resection. Unfortunately, a significant proportion of tumors do not respond enough to the neoadjuvant treatment and these patients are at risk of relapse. MicroRNAs (miRNAs) are small non-coding RNAs playing significant roles in the pathogenesis of many cancers including rectal cancer. MiRNAs could present the new predictive biomarkers for rectal cancer patients. METHODS: We selected 20 patients who underwent neoadjuvant chemoradiotherapy for advanced rectal cancer and whose tumors were classified as most sensitive or resistant to the treatment. These two groups were compared using large-scale miRNA expression profiling. RESULTS: Expression levels of 8 miRNAs significantly differed between two groups. MiR-215, miR-190b and miR-29b-2* have been overexpressed in non-responders, and let-7e, miR-196b, miR-450a, miR-450b-5p and miR-99a* have shown higher expression levels in responders. Using these miRNAs 9 of 10 responders and 9 of 10 non-responders (p < 0.05) have been correctly classified. CONCLUSIONS: Our pilot study suggests that miRNAs are part of the mechanisms that are involved in response of rectal cancer to the chemoradiotherapy and that miRNAs may be promising predictive biomarkers for such patients. In most miRNAs we identified (miR-215, miR-99a*, miR-196b, miR-450b-5p and let-7e), the connection between their expression and radioresistance or chemoresistance to inhibitors of thymidylate synthetase was already established.
- MeSH
- adenokarcinom genetika metabolismus patologie chirurgie terapie MeSH
- antimetabolity antitumorózní farmakologie terapeutické užití MeSH
- capecitabinum MeSH
- chemoradioterapie * MeSH
- chemorezistence genetika MeSH
- deoxycytidin analogy a deriváty farmakologie terapeutické užití MeSH
- dospělí MeSH
- fluorouracil analogy a deriváty farmakologie terapeutické užití MeSH
- kombinovaná terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA biosyntéza genetika MeSH
- nádorové proteiny antagonisté a inhibitory fyziologie MeSH
- nádory rekta genetika metabolismus patologie chirurgie terapie MeSH
- neoadjuvantní terapie * MeSH
- pilotní projekty MeSH
- regulace genové exprese u nádorů * MeSH
- retrospektivní studie MeSH
- RNA nádorová biosyntéza genetika MeSH
- senioři MeSH
- stanovení celkové genové exprese MeSH
- thymidylátsynthasa antagonisté a inhibitory fyziologie MeSH
- tolerance záření genetika MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- antimetabolity antitumorózní MeSH
- capecitabinum MeSH
- deoxycytidin MeSH
- fluorouracil MeSH
- mikro RNA MeSH
- nádorové proteiny MeSH
- RNA nádorová MeSH
- thymidylátsynthasa MeSH
PURPOSE: MicroRNA-21 (miR-21) is one of the miRNAs that are frequently and highly overexpressed in tumor tissue of colorectal cancer (CRC) patients; however, only a little is known about its functional role in CRC. METHODS: We examined the expression level of miR-21 in 44 paired samples of tumoral and non-tumoral colon tissues diagnosed for CRC using TaqMan real-time PCR method. Furthermore, we used miR-21 inhibitor (anti-miR-21) to transient knockdown of miR-21 in DLD-1 colon cancer cells and examined the effects of miR-21 silencing on viability, apoptosis, chemosensitivity, cell cycle, and migration of DLD1 cells. RESULTS: The expression levels of miR-21 were significantly increased in CRC tumor tissue (P < 0.0001). Significant differences in miR-21 levels were observed also between CRC tissues of patients with CRC in different clinical stages: I vs. II (P = 0.033) and I vs. IV (P = 0.021). Kaplan-Meier analysis proved that the miR-21 expression levels are correlated to shorter overall survival of CRC patients (P = 0.0341). MiR-21 silencing in DLD1 cell line had no effect on the cell viability; however, when combined with chemotherapeutics (5-FU, L-OHP, and SN38), it contributed to the decrease of cell viability. Suppression of miR-21 decreased cell migration ability of DLD-1 cells by nearly 30 % (P = 0.016). CONCLUSION: We have confirmed the overexpression of miR-21 in CRC samples and its correlation with advanced disease and shorter overall survival. These findings could be described in part by the fact that CRC cells with increased expression of miR-21 have higher migration ability.
- MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- apoptóza účinky léků genetika MeSH
- buněčný cyklus účinky léků genetika MeSH
- Kaplanův-Meierův odhad MeSH
- kolorektální nádory farmakoterapie genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA antagonisté a inhibitory genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory tračníku genetika patologie MeSH
- pohyb buněk účinky léků genetika MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- viabilita buněk účinky léků genetika MeSH
- Check Tag
- 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
- Názvy látek
- antitumorózní látky MeSH
- mikro RNA MeSH
- MIRN21 microRNA, human MeSH Prohlížeč
For the many years, the central dogma of molecular biology has been that RNA functions mainly as an informational intermediate between a DNA sequence and its encoded protein. But one of the great surprises of modern biology was the discovery that protein-coding genes represent less than 2% of the total genome sequence, and subsequently the fact that at least 90% of the human genome is actively transcribed. Thus, the human transcriptome was found to be more complex than a collection of protein-coding genes and their splice variants. Although initially argued to be spurious transcriptional noise or accumulated evolutionary debris arising from the early assembly of genes and/or the insertion of mobile genetic elements, recent evidence suggests that the non-coding RNAs (ncRNAs) may play major biological roles in cellular development, physiology and pathologies. NcRNAs could be grouped into two major classes based on the transcript size; small ncRNAs and long ncRNAs. Each of these classes can be further divided, whereas novel subclasses are still being discovered and characterized. Although, in the last years, small ncRNAs called microRNAs were studied most frequently with more than ten thousand hits at PubMed database, recently, evidence has begun to accumulate describing the molecular mechanisms by which a wide range of novel RNA species function, providing insight into their functional roles in cellular biology and in human disease. In this review, we summarize newly discovered classes of ncRNAs, and highlight their functioning in cancer biology and potential usage as biomarkers or therapeutic targets.
- MeSH
- lidé MeSH
- nádory genetika MeSH
- nekódující RNA genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- nekódující RNA MeSH