AIMS: Inflammatory bowel diseases and colorectal cancer are serious intestinal disorders with continuously increasing incidence. Many aspects of etiopathogenesis still remain unclear. There is an urgent need to improve early diagnostics and markers indicating the progression of the disease. The aim of our study was to analyze the expression of matrix metalloproteinase-19 (MMP-19), and the receptor for advanced glycation end-products (RAGE) in different cell subpopulations in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) compared to the tissue in the vicinity of pathological processes. METHODS: Expression of both markers in epithelium, macrophages and vessels were evaluated in IBD and CRC groups. They were detected using immunohistochemistry in paraffin sections. RESULTS: There were significant differences between the expression of MMP-19 on macrophages and vessels among healthy and cancer tissues. In both, macrophages and vessels were significantly lower levels in cancer tissues. The expression of MMP-19 on vessels was also significantly different between peritumoral and cancer tissues (higher levels in peritumoral tissue). RAGE expression in macrophages was significantly different between healthy and cancer tissues and between peritumoral and cancer tissues. There was significantly lower expression in cancer tissues than in healthy and peritumoral tissues. Expression of RAGE in vessels was significantly different just in the comparison of healthy and peritumoral tissues (higher levels in healthy tissues). CONCLUSION: Both markers seem to be promising potential auxiliary markers in IBD and CRC diagnostics. They can also improve evaluation of disease progression.

• Klíčová slova
• colorectal cancer, inflammatory bowel disease, matrix metalloproteinase, receptor of advanced glycation end-products,
• MeSH
• biologické markery metabolismus   MeSH
• idiopatické střevní záněty * diagnóza   metabolismus   patologie   MeSH
• kolorektální nádory * diagnóza   metabolismus   patologie   MeSH
• lidé MeSH
• metaloproteinasy secernované do matrix MeSH
• receptor pro konečné produkty pokročilé glykace metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• AGER protein, human MeSH Prohlížeč
• biologické markery MeSH
• matrix metalloproteinase 19 MeSH Prohlížeč
• metaloproteinasy secernované do matrix MeSH
• receptor pro konečné produkty pokročilé glykace MeSH

PURPOSE: Tivozanib, a selective inhibitor of VEGFR-1, -2, and -3, plus mFOLFOX6 in an advanced gastrointestinal cancer phase Ib study had encouraging antineoplastic activity and a tolerable safety profile. This randomized, open-label, phase II trial of tivozanib/mFOLFOX6 versus bevacizumab/mFOLFOX6 in patients with previously untreated metastatic colorectal cancer (mCRC) evaluated tivozanib activity versus bevacizumab. EXPERIMENTAL DESIGN: Treatment-naïve patients received mFOLFOX6 every 2 weeks of each 28-day cycle plus either tivozanib orally 1.5 mg once daily for 21 days or bevacizumab intravenously 5 mg/kg every 2 weeks. Investigator-assessed progression-free survival (PFS) was the primary endpoint; some secondary endpoints included safety, overall survival, overall response rate (ORR), duration of response, time to treatment failure, and biomarker subgroup analyses. RESULTS: A prespecified interim futility analysis demonstrated that the futility boundary for superiority of tivozanib/mFOLFOX6 over bevacizumab/mFOLFOX6 for PFS in the intent-to-treat population was crossed; median PFS was 9.4 versus 10.7 months [HR = 1.091; confidence interval (CI), 0.693-1.718; P = 0.706]. Tivozanib/mFOLFOX6 resulted in PFS and ORR comparable with bevacizumab/mFOLFOX6; interim analyses biomarker results revealed no significant PFS association. Post hoc final analyses demonstrated a potential difference in tivozanib-specific PFS in patients with low neuropilin-1 (NRP-1), but not in patients with high NRP-1. Tivozanib/mFOLFOX6 was tolerable and adverse events were comparable with both bevacizumab/mFOLFOX6 and previous tivozanib studies. CONCLUSIONS: The efficacy of tivozanib/mFOLFOX6 was comparable with but not superior to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC. Since data from the prespecified interim analysis did not demonstrate superiority, this resulted in discontinuation of the study. The safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity, but these results require further validation. Clin Cancer Res; 22(20); 5058-67. ©2016 AACR.

• MeSH
• bevacizumab škodlivé účinky   terapeutické užití   MeSH
• chinoliny škodlivé účinky   terapeutické užití   MeSH
• fenylmočovinové sloučeniny škodlivé účinky   terapeutické užití   MeSH
• fluorouracil škodlivé účinky   terapeutické užití   MeSH
• inhibitory angiogeneze terapeutické užití   MeSH
• kolorektální nádory farmakoterapie   patologie   MeSH
• leukovorin škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery krev   MeSH
• neuropilin-1 krev   MeSH
• organoplatinové sloučeniny škodlivé účinky   terapeutické užití   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• progrese nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• receptory vaskulárního endoteliálního růstového faktoru antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• bevacizumab MeSH
• chinoliny MeSH
• fenylmočovinové sloučeniny MeSH
• fluorouracil MeSH
• inhibitory angiogeneze MeSH
• leukovorin MeSH
• nádorové biomarkery MeSH
• neuropilin-1 MeSH
• organoplatinové sloučeniny MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• tivozanib MeSH Prohlížeč

• MeSH
• alely MeSH
• DNA primery genetika   MeSH
• DNA vazebné proteiny genetika   MeSH
• frekvence genu MeSH
• genetická vazba MeSH
• klonování DNA MeSH
• mapování chromozomů MeSH
• mapování pomocí radiačních hybridů MeSH
• molekulární sekvence - údaje MeSH
• polymerázová řetězová reakce MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• protoonkogenní proteiny genetika   MeSH
• protoonkogeny * MeSH
• ryanodinový receptor vápníkového kanálu genetika   MeSH
• sekvence nukleotidů MeSH
• Sus scrofa genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA primery MeSH
• DNA vazebné proteiny MeSH
• protoonkogenní proteiny MeSH
• ryanodinový receptor vápníkového kanálu MeSH

Colorectal carcinoma (CRC) is characterized by wide intratumor heterogeneity with general genomic instability and there is a need for improved diagnostic, prognostic, and therapeutic tools. The liquid biopsy provides a noninvasive route of sample collection for analysis of circulating tumor cells (CTCs) and genomic material, including cell-free DNA (cfDNA), as a complementary biopsy to the solid tumor tissue. The solid biopsy is critical for molecular characterization and diagnosis at the time of collection. The liquid biopsy has the advantage of longitudinal molecular characterization of the disease, which is crucial for precision medicine and patient-oriented treatment. In this review, we provide an overview of CRC and the different methodologies for the detection of CTCs and cfDNA, followed by a discussion on the potential clinical utility of the liquid biopsy in CRC patient care, and lastly, current challenges in the field.

• Klíčová slova
• CRC, CTC, cfDNA, circulating free DNA, circulating tumor DNA, circulating tumor cell, colorectal carcinoma, ctDNA, liquid biopsy, precision medicine,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVE: Besides irreplaceable role in health, vitamin B12 is proposed to have cytoprotective role in colorectal cancer (CRC). So far, studies are inconclusive on the role dietary intake of vitamin B12 has in CRC. The aim of this study was to determine whether total dietary intake of vitamin B12 and contribution from its food sources relates to a low-risk diet and lifestyle in a population at high risk for CRC. METHODS: An observational study on 200 healthy adults from Eastern Croatia was conducted during April-May 2013. A typical diet of this population in this region is characterized with all known major dietary risk factors for CRC placing the population at high risk for CRC, yet the incidence of CRC remains relatively low. RESULTS: Diet and lifestyle characteristics of 52.2% of participants can be classified as the high-risk for CRC. Women, people in lower BMI category, and urban residents have significantly lower risk of the high-risk diet and lifestyle. Higher intake of vitamin B12 shows positive association with the low-risk diet and lifestyle. Intake of vitamin B12 from milk, dairy and fish represent independent factors for the low-risk diet and lifestyle in this population at high-risk for CRC. CONCLUSIONS: Higher intake of vitamin B12, especially intake from milk, dairy and fish are associated with the low-risk diet and lifestyle in a population at high risk for CRC. Further studies should focus on interplay between vitamin B12 and other nutrients that share the same food sources to elucidate their role in the aetiology and pathology of CRC.

• Klíčová slova
• colorectal cancer, diet and lifestyle characteristics, dietary vitamin B12, high-risk diet and lifestyle, population at high-risk for CRC,
• MeSH
• dieta statistika a číselné údaje   MeSH
• dospělí MeSH
• kolorektální nádory epidemiologie   MeSH
• lidé MeSH
• rizikové faktory MeSH
• vitamin B 12 aplikace a dávkování   MeSH
• životní styl * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Geografické názvy
• Chorvatsko epidemiologie   MeSH
• Názvy látek
• vitamin B 12 MeSH

As the current staging and grading systems are not sufficient to stratify patients for therapy and predict the outcome of the disease, there is an urgent need to understand cancer in its complexity. The mutual relationship between tumour and immune or stromal cells leads to rapid evolution and subsequent genetic and epigenetic changes. Immunoscore has been introduced as a diagnostic tool for colorectal cancer (CRC) only recently, emphasising the role of the specific tumor microenvironment in patient's prognosis and overall outcome. Despite the fact that non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), cannot be translated into proteins, they significantly affect cell's transcriptome and translatome. miRNA binding to mRNA efficiently blocks its translation and leads to mRNA destruction. On the other hand, miRNAs can be bound by lncRNAs or circular RNAs (circRNAs), which prevents them from interfering with translation. In this way, ncRNAs create a multi-step network that regulates the cell's translatome. ncRNAs are also shed by the cell as exogenous RNAs and they are also found in exosomes, suggesting their role in intercellular communication. Hence, these mechanisms affect the tumor microenvironment as much as protein signal molecules. In this review, we provide an insight into the current knowledge of the microenvironment, lncRNAs', and miRNAs' interplay. Understanding mechanisms that underlie the evolution of a tissue as complex as a tumour is crucial for the future success in therapy.

• Klíčová slova
• CAFs, CRC, colorectal cancer, lncRNA, lymphocytes, macrophages, miRNA, tumor microenvironment,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Chemoresistance has been found in all malignant tumors including colorectal carcinoma (CRC). Nowadays chemoresistance is understood as a major reason for therapy failure, with consequent tumor growth and spreading leading ultimately to the patient's premature death. The chemotherapy-related resistance of malignant colonocytes may be manifested in diverse mechanisms that may exist both prior to the onset of the therapy or after it. The ultimate function of this chemoresistance is to ensure the survival of malignant cells through continuing adaptation within an organism, therefore, the nature and spectrum of cell-survival strategies in CRC represent a highly significant target of scientific inquiry. Among these survival strategies employed by CRC cells, three unique but significantly linked phenomena stand out-epithelial-to-mesenchymal transition (EMT), autophagy, and cell death. In this mini-review, current knowledge concerning all three mechanisms including their emergence, timeline, regulation, and mutual relationships will be presented and discussed.

• Klíčová slova
• apoptosis, autophagy, chemoresistance, colorectal carcinoma (CRC), epithelial-to-mesenchymal transition (EMT),
• MeSH
• apoptóza * MeSH
• autofagie * MeSH
• chemorezistence * MeSH
• epitelo-mezenchymální tranzice * MeSH
• fenotyp MeSH
• kolorektální nádory patologie   MeSH
• lidé MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Colorectal cancer (CRC) is one of the leading cancers in both genders. TNM staging system is still the most commonly used tumor classification and prognostic system. The disadvantage of TNM is that the prognostic information it provides is incomplete, and patients with the same histological tumor stages may differ significantly in the clinical outcome. Therefore, the identification of new prognostic parameters is crucial. The carcinogenic process that gives rise to an individual tumor is unique and tumor microenviroment should be taken into consideration. In CRC, T-cell infiltration is not homogenous, and recent studies are mostly focusing on memory T-cells and CD8 cells in predicting disease-free survival (DFS) and overall survival (OS). It seems that DFS and OS are not only dependent on microsatellite instable or stable status but mostly on the levels of expression of the immune signatures. Also, patients with high infiltration of cytotoxic and memory cells have significantly better outcome. This review consolidates current knowledge and recent research about importance of immune-cell-associated proteins, specific gene profiles of immune cells and immunotherapy in CRC. We also discussed cell-specific signatures in cancer treatment.

• Klíčová slova
• Colorectal cancer (CRC), Genomic profile, Immune cells, Immunotherapy,
• MeSH
• imunoterapie MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• kolorektální nádory genetika   imunologie   patologie   MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• prognóza MeSH
• sekvenční analýza RNA MeSH
• staging nádorů MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory kontrolních bodů MeSH

OBJECTIVE: The TLR3/cGAS-STING-IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. METHODS: The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. RESULTS: Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11-2.53, P-value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07-3.84, P-value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03-2.27, P-value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5-6 risk alleles compared to those with 0-2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair-wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. CONCLUSIONS: Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.

• Klíčová slova
• CRC, interaction, polygenic-risk-score, risk,
• MeSH
• dospělí MeSH
• genetická epistáze * MeSH
• genotypizační techniky MeSH
• interferony genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• karcinogeneze genetika   MeSH
• kinasa I-kappa B genetika   MeSH
• kohortové studie MeSH
• kolon diagnostické zobrazování   patologie   MeSH
• kolonoskopie MeSH
• kolorektální nádory diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nukleotidyltransferasy genetika   MeSH
• protein-serin-threoninkinasy genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• rektum diagnostické zobrazování   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce genetika   MeSH
• studie případů a kontrol MeSH
• toll-like receptor 3 genetika   MeSH
• výpočetní biologie MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cGAS protein, human MeSH Prohlížeč
• IKBKE protein, human MeSH Prohlížeč
• interferony MeSH
• kinasa I-kappa B MeSH
• membránové proteiny MeSH
• nukleotidyltransferasy MeSH
• protein-serin-threoninkinasy MeSH
• STING1 protein, human MeSH Prohlížeč
• TBK1 protein, human MeSH Prohlížeč
• TLR3 protein, human MeSH Prohlížeč
• toll-like receptor 3 MeSH

BACKGROUND: Compared with the general population, the incidence of young-onset (YO) colorectal cancer (CRC) is increasing. However, a significant knowledge gap exists in the clinical characteristics, treatment patterns, and outcomes for these patients. MATERIALS AND METHODS: Six international tertiary cancer centers conducted a retrospective study. Patients with YO CRC (aged 18-44 years) and LO CRC (aged > 44 years) diagnosed with histologically proven colorectal adenocarcinoma from June 2003 to June 2014 were enrolled. Patients were randomly chosen from each center's database, and the patient demographics and treatment information were collected. The data were then centralized, and the final analysis was performed at a single institution. Cox proportional hazards models were used to estimate the crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for progression-free survival and mortality, and YO was compared with LO. Site-specific HRs were pooled using a random-effects meta-analysis. RESULTS: Overall, 498 patients, including 224 with YO (129 men; mean age, 37 ± 5.5 years) and 274 with LO (167 men; mean age, 64.8 ± 9.5 years) CRC, were included. At the diagnosis, 137 patients (61.2%) and 122 patients (44.5%) with YO and LO CRC had metastatic disease, respectively. For both cohorts, the 3 most common presenting symptoms were pain, hematochezia, and weight loss. Surgery was performed in 141 YO (63.0%) and 219 LO (79.9%) patients. The longitudinal noncurative treatment patterns were similar, but more biologic therapy was used for these YO patients. The pooled progression-free survival analysis results for first-line noncurative treatment favored LO (HR, 1.96; 95% CI, 1.04-3.68). The mortality analysis showed no significant differences between the 2 groups (YO: HR, 1.53; 95% CI, 0.91-2.58). CONCLUSION: Despite similar treatment patterns and survival outcomes, YO disease might be clinically more aggressive.

• Klíčová slova
• Adolescent and young adults, Metastatic colorectal cancer, Real world, Treatment pattern, Young-onset CRC,
• MeSH
• adenokarcinom epidemiologie   patologie   terapie   MeSH
• biologická terapie metody   MeSH
• dospělí MeSH
• incidence MeSH
• kolorektální nádory epidemiologie   patologie   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• mezinárodní spolupráce MeSH
• mladý dospělý MeSH
• přežití po terapii bez příznaků nemoci MeSH
• proporcionální rizikové modely MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věk při počátku nemoci MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH