Biomarkers as prognostic and predictive factors in patients with hepatocellular carcinoma undergoing radiological oncological interventions.

BACKGROUND: Hepatocellular carcinoma is the most common malignant liver tumor in adults and thermal ablation and transarterial embolization are important methods of therapy. Thermal ablation can be used in early stages. Methods based on the transarterial approach, especially transarterial chemoembolization, play an important role in intermediate stage diseases. The success of procedures depends not only on the biological nature and the size of the tumor, on the technical design of the procedure and on the patient's response to treatment, but also on the molecular changes associated with these procedures. In addition to classic predictive and prognostic factors including age, patient comorbidities, Child-Pugh score, tumor characteristics, presence of large surrounding vessels, and portal vein thrombosis, molecular prognostic and predictive factors (serum biomarkers) are often mentioned in studies. Currently, only a-fetoprotein is routinely used as a prognostic biomarker; however, there are studies referring to new serum biomarkers that can potentially help to classical markers and imaging methods to determine the cancer prognosis and predict the success of therapy. These biomarkers most often include g-glutamyltranspeptidase, des- g-carboxyprothrombin, some types of microRNAs, inflammatory and hypoxic substances, whose serum levels are changed by the intervention therapies. Evaluation of these molecules could lead to the optimization of the medical intervention (choice of therapy method, timing of treatment) or change the management of patient follow-up after interventions. Although several biomarkers have shown promising results, most serum biomarkers still require validation in phase III studies. PURPOSE: The aim of this work is to present a comprehensive overview of classical and molecular biomarkers that could potentially help in the prognostic stratification of patients and better predict the success and effect of radiological intervention methods.

Dynamic Changes in Circulating MicroRNA Levels in Liver Cancer Patients Undergoing Thermal Ablation and Transarterial Chemoembolization.

BACKGROUND: Hepatic cancer patients who cannot undergo surgical resection of tumour are candidates for methods of interventional radiology - transarterial chemoembolization (TACE) or thermal ablative (TA) therapy. Both methods are causing characteristic changes in liver tissue (inflammatory immune response, hypoxia, elevated temperature, tissue destruction) which are accompanied with systemic secretion of cytokines or microRNAs (miRNAs). The aim of our study was to investigate whether the level of circulating miRNAs related to hypoxia (miR-21 and miR-210), liver injury (miR-122) and epithelial-mesenchymal transition (miR-200a) could reflect systemic effect of these intervention techniques. MATERIALS AND METHODS: Study consisted of 10 primary hepatocellular carcinoma patients treated with TACE and 10 patients with liver metastases of colorectal cancer treated with TA. Thermal ablation was performed using the radiofrequency or microwave generator (RITA, Microsulis, AngioDynamics,Inc), for TACE drug eluting beads (DCBeads, Biocompatibles Ltd.) were used. Tumours were evaluated using RECIST (Response Evaluation Criteria in Solid Tumours), mRECIST (modified RECIST) criterion and volumetry. For all patients we determined concentrations of miRNA in blood plasma samples from four time points (before intervention, immediately after intervention, 24 hours after intervention, 1 week after intervention) using TaqMan® Assays and quantitative real time polymerase chain reaction method. RESULTS: After both intervention techniques we observed changes in circulating miRNA levels. In TA cases we observed significant increase of miR-122 and miR-200a concentrations immediately after intervention, on the contrary in TACE we observed increase in miRNA concentration at time point 24 hours after intervention (miR-21, miR-210, miR-122, miR-200a). Increased concentration of circulating miRNA was followed by subsequent decline to initial level. These changes were consistent with presumed biological effect of TA and TACE on tumour tissue. CONCLUSION: Data of this pilot study show potential usage of circulating miRNA for monitoring of systemic effect of thermal ablative and intraarterial therapies. This work was created at Masaryk University as part of the project MUNI/A/1574/2018 and it was supported by Czech Ministry of Health grants No. 15-32484A, 16-31765A and 16-31314A. The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 4. 3. 2019.

[Pilot Study on MicroRNAs as Biomarkers of Response to Sunitinib Treatment in Patients with Metastatic Renall Cell Carcinoma]. / MikroRNA jako biomarkery odpovedi na lécbu sunitinibem u pacientu s metastatickým karcinomem ledvin - pilotní studie.

BACKGROUND: Renal cell carcinoma (RCC) accounts for 2-3% of all malignant tumours. Metastatic RCC (mRCC) is commonly treated with tyrosine kinase inhibitors (TKI). Effective TKIs administration can be achieved only by accurate prediction of therapeutical response. Therefore, the aim of this study was to analyse papers concerning predictive potential of microRNA (miRNA). MATERIAL AND METHODS: We chose seven candidate miRNAs and analysed their expression on 44 patients divided into cohort with poor and good response to sunitinib treatment. Patients were divided into two groups according to progression-free survival. RNA from tissue samples was isolated and expression of selected miRNAs was measured using quantitative PCR with miRNA-specific TaqMan probes. RESULTS: We successfully validated two miRNAs to be differentially expressed in responding and non-responding patients to sunitinib treatment. Other analysed miRNAs have not shown predictive potential. CONCLUSION: From miRNAs studied so far, two miRNAs had predictive value according to present study.Key words: microRNA - renal cell carcinoma - sunitib The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Supported by Ministry of Health of the Czech Republic, grant No. 15-34678A. All rights reserved.Submitted: 19. 3. 2018Accepted: 20. 3. 2018.

[Urinary MicroRNAs as Potential Biomarkers of Bladder Cancer]. / Mocové mikroRNA jako potenciální biomarkery karcinomu mocového mechýre.

BACKGROUND: Currently, there are no urinary-based tumour markers with sufficient sensitivity and specificity to replace cystoscopy in the detection of bladder cancer (BCA). Urinary microRNAs are emerging as clinically useful class of biomarkers for early and non-invasive detection of urologic malignancies. PATIENTS AND METHODS: In this study, 155 patients with BCA and 83 healthy controls were enrolled. Expression profiles of urinary miRNAs were obtained using Affymetrix miRNA microarrays and candidate miRNAs further validated in independent cohort using specific TaqMan assays and quantitative real-time polymerase chain reaction method. RESULTS: Whole-genome profiling identified miRNA signature with significantly different concentrations in urine of BCA compared to controls (p < 0.01). In the independent validation phase of the study, three miRNAs were confirmed to have significantly higher levels in urine of patients with BCA in comparison with control groups (p < 0.0001). In addition, we observed significant decrease in two miRNAs (p < 0.01) concentrations in the urinary samples collected 3 months after surgery compared to pre-operative samples. CONCLUSION: We identified and validated miRNAs to have significantly higher concentrations in urine of patients with BCA in comparison with controls. Our data have shown that urinary miRNAs could serve as sensitive and specific biomarkers enabling non-invasive detection of BCA.Key words: urinary microRNAs - biomarkers - bladder cancer The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. This study was supported by Ministry of Health of the Czech Republic, grant No. 15-31071A. All rights reserved.Submitted: 19. 3. 2018Accepted: 20. 3. 2018.

[Triple-negative breast cancer: analysis of patients diagnosed and/or treated at the Masaryk Memorial Cancer Institute between 2004 and 2009]. / Triple-negativní karcinom prsu: analýza souboru pacientek diagnostikovaných a/nebo lécených v Masarykove onkologickém ústavu v letech 2004 az 2009.

BACKGROUND: Triple-negative breast cancer (TNBC) represents a heterogeneous group of breast cancers that do not express ER-α, PgR and Her-2 receptors. Generally, these tumors are aggressive and more common in younger women, in which an association of TNBC with mutations in the BRCA1 gene was documented. The aim of our study was to create a representative group of patients with TNBC, which could be analyzed and the data gathered to build basic epidemiological, molecular and clinical characteristics of Czech patients with TNBC. PATIENTS AND METHODS: We performed basic clinical-pathologic correlations in a group of 335 patients diagnosed and/or treated for TNBC at the Masaryk Memorial Cancer Institute between 2004 and 2009. We also performed immunohistochemical examination of expression of cytokeratin 5/6, cytokeratin 14 and EGFR to identify the basal-like subset of TNBC. RESULTS: The median age of patients with TNBC was 56 years, range 25-88 years. A total of 9.25% of TNBC cases were diagnosed in patients under the age of 34, and another 15.22% of cases were in the age group of 35 to 44 years. 'Basal-like' carcinomas accounted for 75% of TNBC. We confirmed the aggressive nature of this disease: in the follow-up period we observed a relapse in 25% of patients: 55% of deaths due to disease progression occured within 2 years after diagnosis of the disease. Treatment strategies include chemotherapy, in most cases (88.4%). Chemotherapy was mostly based on regimens with anthracyclines or in combination with taxanes. The most important negative prognostic factors in relation to OS (disease specific OS) were: higher clinical stage (p < 0.0001), pN - positive status (p < 0.0001), high proliferative activity (as measured by Ki-67, cut-off 50%, HR = 0.4740, p = 0.0411) and positive expression of CK5/6 (HR = 0.4274, p = 0.0338). In relation to DFS, the negative prognostic significance was found for these factors: higher clinical stage (p < 0.0001), pN positive status (p < 0.0001), high proliferative activity (Ki-67, cut-off 50%, HR = 0.04993, p = 0.0240). DFS was longer in patients with a higher number of applied cycles of anthracycline-based chemotherapy (> 4 cycles, HR = 1.7273, p = 0.0467). CONCLUSION: TNBC is an aggressive form of breast cancer, which may occur in patients of all ages, but more frequently in younger patients. Only early detection of disease and intensive treatment gives a high chance of cure. Unfortunately, no reliable predictive factors have been identified so far. Better therapeutic results can be expected from targeted therapy.