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Glioblastoma inevitably recurs, but no standard regimen has been established for treating this recurrent disease. Several reports claim that reoperative surgery can improve survival, but the effects of reoperation timing on survival have rarely been investigated. We, therefore, evaluated the relationship between reoperation timing and survival in recurrent GBM. A consecutive cohort of unselected patients (real-world data) from three neuro-oncology cancer centers was analyzed (a total of 109 patients). All patients underwent initial maximal safe resection followed by treatment according to the Stupp protocol. Those meeting the following criteria during progression were indicated for reoperation and were further analyzed in this study: (1) The tumor volume increased by >20-30% or a tumor was rediscovered after radiological disappearance; (2) The patient's clinical status was satisfactory (KS = 70% and PS WHO = gr. 2); (3) The tumor was localized without multifocality; (4) The minimum expected tumor volume reduction was above 80%. A univariate Cox regression analysis of postsurgical survival (PSS) revealed a statistically significant effect of reoperation on PSS from a threshold of 16 months after the first surgery. Cox regression models that stratified the Karnofsky score with age adjustment confirmed a statistically significant improvement in PSS for time-to-progression (TTP) thresholds of 22 and 24 months. The patient groups exhibiting the first recurrence at 22 and 24 months had better survival rates than those exhibiting earlier recurrences. For the 22-month group, the HR was 0.5 with a 95% CI of (0.27, 0.96) and a p-value of 0.036. For the 24-month group, the HR was 0.5 with a 95% CI of (0.25, 0.96) and a p-value of 0.039. Patients with the longest survival were also the best candidates for repeated surgery. Later recurrence of glioblastoma was associated with higher survival rates after reoperation., 65269705; 00159816; 00209805; Ministerstvo Zdravotnictví Ceské Republiky, MZCR: 00098892, NU20-03-00148, NU21-03-00195, Ministry of Health of the Czech Republic [NU21-03-00195, NU20-03-00148, 00098892, 00209805, 65269705, 00159816]

Background Human papillomavirus (HPV) has been shown to adversely affect human reproduction. We aimed to evaluate the prevalence of human papillomavirus (HPV) infection in men and its correlation with semen parameters and reproductive outcomes. Methods Semen samples and penile swabs were collected from potential sperm donors (SD, n = 97) and male partners of infertile couples (IM, n = 328). The presence of HPV DNA in semen samples and penile swabs was analyzed. Associations between hrHPV positive status and fertility outcomes as well as socio-behavioral and health characteristics were evaluated using the R software package. Results High-risk HPV (hrHPV) genotypes were detected in 28.9% of SD and 35.1% of IM (P = 0.312). Penile swabs were more frequently positive for hrHPV genotypes than semen samples in both IM (32.3% vs. 11.9%, P P = 0.006). Men with hrHPV positive semen samples had lower semen volume (median volume 2.5 ml vs. 3 ml, P = 0.009), sperm concentration (median concentration 16 × 106/ml vs. 31 × 106/ml, P = 0.009) and total sperm count (median count 46 × 106 vs. 82 × 106, P = 0.009) than men with hrHPV negative samples. No association was identified between penile hrHPV status and semen parameters. Conclusions Our findings indicate that penile HPV infection is common in both potential sperm donors and men from infertile couples. Although HPV positivity is higher in penile swabs, only HPV infection in semen samples affects sperm parameters. However, there was no association between hrHPV positivity in semen and fertility outcomes including abortion rate.

Background Data about the genotype-specific human papillomavirus (HPV) prevalence in the Czech Republic is limited. We aimed to evaluate the prevalence and concordance of genotype-specific HPV infection detected in semen samples, penile swabs and cervical swabs from non-vaccinated heterosexual couples without HPV-associated disease. Methods Semen samples and penile swabs were collected from male partners and cervical swabs were collected from female partners of heterosexual couples treated for infertility (n = 195). Presence of HPV DNA in semen samples and cervical swabs was analyzed using the cobas® HPV Test and PapilloCheck®. Only the PapilloCheck® test was used to detect HPV in penile swabs. The genotype-specific prevalence and concordance of HPV infection not targeted by vaccine were evaluated using Fisher exact test. Results Both partners were infected with any HPV type in 13.8% (27/195) of couples and, of these couples, 55.6% (15/27) harbored at least one mutual genotype. High-risk HPV (hrHPV) genotypes were detected in 12.3% (24/195) of semen samples, 31.3% (61/195) of penile swabs, and 19.5% (38/195) of cervical swabs (P P P = 0.055). Conclusions This study showed that the detection of HPV infection differ by anatomic site and gender. Regardless the anatomic site, high prevalence of HPV genital infection was found in both Czech men and women.

This prospective population-based study on a group of 132 resected IDH-wildtype (IDH-wt) glioblastoma (GBM) patients assesses the prognostic and predictive value of selected genetic biomarkers and clinical factors for GBM as well as the dependence of these values on the applied therapeutic modalities. The patients were treated in our hospital between June 2006 and June 2015. Clinical data and tumor samples were analyzed to determine the frequencies of TP53, MDM2, EGFR, RB1, BCR, and CCND1 gene aberrations and the duplication/deletion statuses of the 9p21.3, 1p36.3, 19q13.32, and 10p11.1 chromosome regions. Cut-off values distinguishing low (LCN) and high (HCN) copy number status for each marker were defined. Additionally, MGMT promoter methylation and IDH1/2 mutation status were investigated retrospectively. Young age, female gender, Karnofsky scores (KS) above 80, chemoradiotherapy, TP53 HCN, and CCND1 HCN were identified as positive prognostic factors, and smoking was identified as a negative prognostic factor. Cox proportional regression models of the chemoradiotherapy patient group revealed TP53 HCN and CCND1 HCN to be positive prognostic factors for both progression-free survival and overall survival. These results confirmed the influence of key clinical factors (age, KS, adjuvant oncotherapy, and smoking) on survival in GBM IDH-wt patients and demonstrated the prognostic and/or predictive importance of CCND1, MDM2, and 22q12.2 aberrations.

As the predictive role of many risk factors for parasagittal meningioma (PM) recurrence remains unclear, the objective of the meta-analysis was to make a comprehensive assessment of the predictive value of selected risk factors in these lesions. Studies including data on selected risk factors, such as histology, tumor and sinus resection, sinus invasion, tumor localization, and immediate postoperative radiotherapy for PMs recurrence, were searched in the NCBI/NLM PubMed/MEDLINE, EBM Reviews/Cochrane Central, ProQuest, and Scopus databases, and analyzed using random effects modeling. Thirteen observational studies involving 1243 patients met the criteria for inclusion in the meta-analysis. WHO grading of meningiomas was identified as the most powerful risk factor for recurrence. WHO grade II meningiomas (OR 11.61; 95% CI 4.43–30.43; P

BACKGROUND Meningioma growth rates are highly variable, even within benign subgroups, with some remaining stable, whereas others grow rapidly. OBJECTIVE To identify molecular-genetic markers for more accurate prediction of meningioma recurrence and better-targeted therapy. METHODS Microarrays identified microRNA (miRNA) expression in primary and recurrent meningiomas of all World Health Organization (WHO) grades. Those found to be deregulated were further validated by quantitative real-time polymerase chain reaction in a cohort of 172 patients. Statistical analysis of the resulting dataset revealed predictors of meningioma recurrence. RESULTS Adjusted and nonadjusted models of time to relapse identified the most significant prognosticators to be miR-15a-5p, miR-146a-5p, and miR-331-3p. The final validation phase proved the crucial significance of miR-146a-5p and miR-331-3p, and clinical factors such as type of resection (total or partial) and WHO grade in some selected models. Following stepwise selection in a multivariate model on an expanded cohort, the most predictive model was identified to be that which included lower miR-331-3p expression (hazard ratio [HR] 1.44; P

Specific A3 adenosine receptor (A3AR) agonist, 2-chloro-N6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (2-Cl-IB-MECA), demonstrates anti-proliferative effects on various types of tumor. In the present study, the cytotoxicity of 2-Cl-IB-MECA was analyzed in a panel of tumor and non-tumor cell lines and its anticancer mechanisms in JoPaca-1 pancreatic and Hep-3B hepatocellular carcinoma cell lines were also investigated. Initially, decreased tumor cell proliferation, cell accumulation in the G1 phase and inhibition of DNA and RNA synthesis was found. Furthermore, western blot analysis showed decreased protein expression level of β-catenin, patched1 (Ptch1) and glioma-associated oncogene homolog zinc finger protein 1 (Gli1), which are components of the Wnt/β-catenin and Sonic hedgehog/Ptch/Gli transduction pathways. In concordance with these findings, the protein expression levels of cyclin D1 and c-Myc were reduced. Using a luciferase assay, it was revealed for the first time a decrease in β-catenin transcriptional activity, as an early event following 2-Cl-IB-MECA treatment. In addition, the protein expression levels of multidrug resistance-associated protein 1 and P-glycoprotein (P-gp) were reduced and the P-gp xenobiotic efflux function was also reduced. Next, the enhancing effects of 2-Cl-IB-MECA on the cytotoxicity of conventional chemotherapy was investigated. It was found that 2-Cl-IB-MECA enhanced carboplatin and doxorubicin cytotoxic effects in the JoPaca-1 and Hep-3B cell lines, and a greater synergy was found in the highly tumorigenic JoPaca-1 cell line. This provides a novel in vitro rationale for the utiliza- tion of 2-Cl-IB-MECA in combination with chemotherapeutic agents, not only for hepatocellular carcinoma, but also for pancreatic cancer. Other currently used conventional chemo- therapeutics, fluorouracil and gemcitabine, showed synergy only when combined with high doses of 2-Cl-IB-MECA. Notably, experiments with A3AR-specific antagonist, N-[9-Chloro-2-(2-furanyl)(1,2,4)-triazolo(1,5-c)quinazolin-5-yl] benzene acetamide, revealed that 2-Cl-IB-MECA had antitumor effects via both A3AR-dependent and -independent pathways. In conclusion, the present study identified novel antitumor mechanisms of 2-Cl-IB-MECA in pancreatic and hepatocellular carcinoma in vitro that further underscores the importance of A3AR agonists in cancer therapy.

Meningioma is the most common primary central nervous system neoplasm, accounting for about a third of all brain tumors. Because their growth rates and prognosis cannot be accurately estimated, biomarkers that enable prediction of their biological behavior would be clinically beneficial.To identify coding and noncoding RNAs crucial in meningioma prognostication and pathogenesis.Total RNA was purified from formalin-fixed and paraffin-embedded tumor samples of 64 patients with meningioma with distinct clinical characteristics (16 recurrent, 30 nonrecurrent with follow-up of5 years, and 18 with follow-up of5 years without recurrence). Transcriptomic sequencing was performed using the HiSeq 2500 platform (Illumina), and biological and functional differences between meningiomas of different types were evaluated by analyzing differentially expression of messenger RNA (mRNA) and long noncoding RNA (IncRNA). The prognostic value of 11 differentially expressed RNAs was then validated in an independent cohort of 90 patients using reverse transcription quantitative (real-time) polymerase chain reaction.In total, 69 mRNAs and 108 lncRNAs exhibited significant differential expression between recurrent and nonrecurrent meningiomas. Differential expression was also observed with respect to sex (12 mRNAs and 59 lncRNAs), World Health Organization grade (58 mRNAs and 98 lncRNAs), and tumor histogenesis (79 mRNAs and 76 lncRNAs). Lnc-GOLGA6A-1, ISLR2, and AMH showed high prognostic power for predicting meningioma recurrence, while lnc-GOLGA6A-1 was the most significant factor for recurrence risk estimation (1/hazard ratio = 1.31; P = .002).Transcriptomic sequencing revealed specific gene expression signatures of various clinical subtypes of meningioma. Expression of the lnc-GOLGA61-1 transcript was found to be the most reliable predictor of meningioma recurrence.

BACKGROUND MRI postcontrast nonenhanced brain tumors are found benign biologic entities with the better prognosis. The aim of this paper is to evaluate predictive features on MRI considered definite diagnosis occurrence, tumor progression, upgrading and postcontrast enhancement evolution on follow-up serial MRI. MATERIAL AND METHODS We retrospectively collected patients with the initially MRI postcontrast nonenhanced brain tumors, treated in our hospital from January 2009 to June 1, 2006. All tumors were converted into WHO 2016 IDH status classifications in accordance with current recommendations. Information about surgeries, patient clinical condition, MRI, and results of histological, immunohistochemical, molecular genetic, and cytogenetic investigations were gathered. Semiautomatic segmentations were performed using FSLeyes software (part of FSL package) on preoperative and followed-up 3D T1-w MPRAGE, T2-w or FLAIR scans. We focused on residual tumor volume, and time distribution of T2/FLAIR changes and T1-w postcontrast enhancement evolution. RESULTS Seventy-eight patients were enrolled in this study. There were 47 gliomas grade II 22 grade III and 9 grade IV. Glioma II comprised 35 diffuse astrocytomas (23 patients had IDH1 mutation). Nine gliomas grade III and 6 gliomas grade IV had IDH1 mutation. Overall survival in glioma group grade II, grade III, grade IV was 187.9 months, 71.1 months and 25.2 months, respectively. Oncotherapy underwent 14 gliomas grade II after first surgery, 13 patients had radiotherapy a 1 patient had neoadjuvant chemotherapy. Seventeen gliomas grade III were indicated to oncotherapy, 5 patients had radiotherapy and 12 had chemoradiotherapy. All patients with glioma grade IV experienced oncotherapy. Time to progression of non-contrast enhanced brain tumor was 5.8 years. Time to up-grading of non-contrast enhanced brain tumor was 16.8 months. Detailed time relations of glioma subgroup will be displayed in tables. CONCLUSION Regarding MRI postcontrast non-enhanced tumors, predominantly low grade gliomas (LGG), aggressive oncotherapy are reluctant to use but they are prone to repeat surgeries. Decision making issues are age, clinical patient status, histologic and genetic tumor characteristics, residual tumor volume, published guidelines for brain tumor treatment, and patient′s willing. Generally, hyposignal on the T1 postcontrast scans strictly relate to the better prognosis, even in HGG. Longer survival expectancy increases quality of life awareness. Prior to MRI postcontrast enhanced evolution and up-grading, T2/FLAIR changes have been demonstrated. T2/FLAIR scans considered also main role in LGG follow-up strategy. Individual tailored therapy is principal strategy. Supported by Ministry of Health of the Czech Republic, grant nr. NV19-04-00281 and grant nr. NU21-03-00195

Because of the invasiveness of examination methods as bronchoscopy for the diagnosis of lung cancer, there is currently no preventive screening for this disease. Thus, lung cancer is usually diagnosed in stage 3 or 4, when it is too late for successful treatment. However, if diagnosed early, it can be cured entirely. Therefore, it is necessary to find a suitable method to screen the high-risk populations and reveal lung cancer in the early stages. Since the mucous membranes of the respiratory tract are naturally moistened by fluids containing proteins, metabolites, chemoattractants and growth factors released by the highly active epithelium, the collection of the respiratory tract fluids can be used to diagnose malignant and benign respiratory tract diseases. The most commonly used method in this sense is bronchoalveolar lavage. However, the technique itself is not pleasant and can be accompanied by possible complications. Therefore, intensive research work is conducted to develop non-invasive methods for biomarker detection in exhaled breath, sputum, saliva or nasal secretion. We have studied an exhaled breath condensate (EBC) matrix, which is collected non-invasively and the patients are not suffering from its collection. Several studies have reported proteomic analysis of EBC while identifying low hundreds of proteins by mass spectrometry (MS). We have developed a potent gel-free MS-based approach for sample preparation and analysis. Together with a powerful search tool, we were able to identify a ten times higher number of proteins across a comparable group of individuals of about three hundred peoples’ samples. Our approach seems to be highly reproducible and applicable to various respiratory and systemic diseases. In our work focused on non-small lung cancer biomarkers compared to chronic obstructive pulmonary disease (COPD) and healthy controls, we have identified 7694 proteins and of them, 6525 proteins were quantified at least in one replicate across 296 individuals’ samples measured in triplicates. Combining univariate and multivariate statistical approaches and sensitivity analysis, we have suggested biomarkers that could distinguish lung cancer patients from COPD and healthy individuals. This research was supported by grants from the Czech Ministry of Education, Youth and Sports (EATRIS-CZ - LM2018133), European Regional Development Fund - Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868) and IGA_LF_2021_036 (Palacky University in Olomouc). Citation Format: Jana Vaclavkova, Jana Vrbkova, Pavla Kourilova, Dusan Holub, Juraj Kultan, Petr Jakubec, Ondrej Fischer, Frantisek Kopriva, Vendula Latalova, Tatiana Gvozdiakova, Marian Hajduch, Petr Dzubak. Proteomic signature in exhaled breath condensates for a non-invasive diagnostics of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2797.

Introduction: Colorectal cancer (CRC) is one of the most common cancers worldwide and metastases-related death is the main cause of its high mortality. Circulating/disseminated tumor cells (CTCs/DTCc) are considered as precursors of distant metastatic spread and can act as an independent prognostic biomarker. The impact of CTCs/DTCs presence in perioperative period on long-term cancer specific survival (CSS) was assessed. Patients and methods: The presence of CTCs/DTCs in peripheral blood, tumor-draining blood, and bone marrow of 188 colorectal cancer patients was analyzed before, immediately after, and one month after surgery using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) to detect the carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) mRNA-positive CTCs. The trial was registered at ClinicalTrials.gov (NCT 03337347), patients were followed-up and the cause of death was determined. Results: Over a median follow-up period of 116.5 months, 81 of 148 (54.7%) stage I-III CRC patients died. In total, 40.7% of them (33/81) died of cancer. The presence of CTCs/DTCs did not correlate with any conventional clinical or pathological features (tumor node metastasis (TNM) stage, grade, KRAS mutations or microsatellite instability). Patients with CTCs/DTCs in the peripheral blood and bone marrow one month after surgery had significantly shorter CSS (p=0.013, HR=2.6; resp. p=0.019, HR=2.3) than those without CTCs/DTCs. Shorter overall survival was also observed in patients with tumor-draining blood CEA mRNA-positive CTCs before surgery (p=0.014). Conclusion: The presence of CK20 mRNA-positive CTCs/DTCs in blood and bone marrow after surgery was confirmed as an independent negative prognostic factor for the long-term cancer-specific survival in stage I-III colorectal cancer patients.The study was supported by Ministry of Health of the Czech Republic (NV18-03-00470), Ministry of Education, Youth and Sport of the Czech Republic (LM2018132; LM2018133), Palacky University Olomouc (LF 2021_019) and European Regional Development Fund (ENOCH CZ.02.1.01/0.0/0.0/16_019/0000868, ACGT CZ.02.1.01/0.0/0.0/16_026/0008448). Citation Format: Josef Srovnal, Pavel Skalicky, Alona Rehulkova, Kamil Vyslouzil, Monika Vidlarova, Jana Vrbkova, Marian Hajduch. Circulating tumor cells presence shorten the cancer specific survival in colorectal cancer: 10 years follow-up study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1949.

Nanoparticles (NPs) represent an emerging platform for diagnosis and treatment of various diseases such as cancer, where they can take advantage of enhanced permeability and retention (EPR) effect for solid tumor accumulation. To improve their colloidal stability, prolong their blood circulation time and avoid premature entrapment into reticuloendothelial system, coating with hydrophilic biocompatible polymers is often essential. Most studies, however, employ just one type of coating polymer. The main purpose of this study is to head-to-head compare biological behavior of three leading polymers commonly used as &ldquo, stealth&rdquo, coating materials for biocompatibilization of NPs poly(ethylene oxide), poly(2-ethyl-2-oxazoline) and poly[N-(2-hydroxypropyl)methacrylamide] in an in vivo animal solid tumor model. We used radiolabeled biodegradable hydroxyapatite NPs as a model nanoparticle core within this study and we anchored the polymers to the NPs core by hydroxybisphosphonate end groups. The general suitability of polymers for coating of NPs intended for solid tumor accumulation is that poly(2-ethyl-2-oxazoline) and poly(ethylene oxide) gave comparably similar very good results, while poly[N-(2-hydroxypropyl)methacrylamide] was significantly worse. We did not observe a strong effect of molecular weight of the coating polymers on tumor and organ accumulation, blood circulation time, biodistribution and biodegradation of the NPs.

The main advantage of urinary biomarkers is their noninvasive character and the ability to detect multifocal prostate cancer (CaP). We have previously implemented a quadruplex assay of urinary markers into clinical practice (PCA3, AMACR, TRPM8 and MSMB with KLK3 normalization). In this study, we aimed to validate it in a larger cohort with serum PSA 2.5&ndash, 10 ng/mL and test other selected transcripts and clinical parameters, including the percentage of free prostate-specific antigen (PSA) (% free PSA) and inflammation. In the main cohort of 299 men, we tested the quadruplex transcripts. In a subset of 146 men, we analyzed additional transcripts (CD45, EPCAM, EZH2, Ki67, PA2G4, PSGR, RHOA and TBP). After a prostate massage, the urine was collected, RNA isolated from a cell sediment and qRT-PCR performed. Ct values of KLK3 (i.e., PSA) were strongly correlated with Ct values of other genes which play a role in CaP (i.e., PCA3, AMACR, TRPM8, MSMB and PSGR). AMACR, PCA3, TRPM8 and EZH2 mRNA expression, as well as % free PSA, were significantly different for BPH and CaP. The best combined model (% free PSA plus PCA3 and AMACR) achieved an AUC of 0.728 in the main cohort. In the subset of patients, the best AUC 0.753 was achieved for the combination of PCA3, % free PSA, EPCAM and PSGR. PCA3 mRNA was increased in patients with inflammation, however, this did not affect the stratification of patients indicated for prostate biopsy. In conclusion, the percentage of free PSA and urinary markers contribute to a more accurate indication for prostate biopsy.

High-risk human papillomavirus (hrHPV) infection is a cause of cervical cancer development. The addition of hrHPV testing to cervical cancer screening and monitoring of cervical intraepithelial neoplasia treatment improves the efficacy of screening and treatment, respectively. Self-sampling for hrHPV testing seems a promising tool for increasing patient participation in cervical cancer screening. In this project, 1198 cervical swabs obtained by physicians and 176 cervicovaginal swabs obtained by self-sampling (not collected in parallel) were analyzed for the presence of 14 hrHPV genotypes using three commercially available assays in comparison. HPV DNA was detected in 21.2% of all samples (21% of cervical swabs and 22.7% of cervicovaginal swabs). The cobas 4800 HPV Test was the most sensitive (0.983) and specific (0.992) for hrHPV detection overall. The PapilloCheck HPV-Screening and LMNX Genotyping Kit HPV GP had comparable specificity with that of the cobas (0.989 and 0.955, respectively), but lesser sensitivity (0.897 and 0.909, respectively). In physician-obtained cervical swabs, the cobas showed the highest sensitivity and specificity (0.980 and 0.994, respectively) for hrHPV detection, whereas in cervicovaginal swabs, the cobas had the highest sensitivity (1.00), but the PapilloCheck had the highest specificity (0.993). In conclusion, all of the detection methods evaluated were highly sensitive and specific for hrHPV detection from both clinician-collected cervical swabs and self-sampled cervicovaginal swabs.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are a promising prognostic biomarker of gliomas. The purpose of our study was to examine the clinical prognostic properties of IDH1/2 mutations in a glioma patient cohort from the Czech Republic using an improved platform for simple and reliable IDH genotyping.We retrospectively analyzed a group of 145 glioma patients by testing for the three most frequent IDH mutations, IDH1 R132H, IDH1 R132C, and IDH2 R172K, through the competitive amplification of differentially melting amplicons (CADMA) polymerase chain reaction (PCR). O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, copy number of EGFR, p53, RB1, MDM2, CDKN2A genes, and deletions in 1p, 19q and 10p chromosomal regions were also analyzed and correlated with clinical characteristics.Of 145 gliomas, 36 harbored IDH1 R132H mutation and 1 IDH1 R132C mutation. We did not detect any IDH2 R172K mutation. IDH1 mutations were positively associated with MGMT methylation (OR 3.08, 95% CI 1.387-7.282; p = 0.007), 1p/19q co-loss (OR 8.85, 95% CI 2.367-42.786; p = 0.002) and negatively associated with epidermal growth factor receptor amplification (OR 0.12, 95% CI 0.019-0.437; p = 0.006) and 10p loss (OR 0.09, 95% CI 0.005-0.436; p = 0.019). The overall survival of IDH-mutant was 25 months, but only 9 months in IDH-wild type gliomas (p = 0.035); at the same time, survival associated with methylated vs. unmethylated MGMT promoter did not significantly differ (p = 0.166).Despite IDH1 mutations being closely associated with MGMT methylation in glioma patients, IDH1 mutations in glioblastoma patients are stronger marker of overall survival than MGMT methylation and should be the marker of choice, especially when using genotyping by CADMA PCR.Key words: isocitrate dehydrogenase - polymerase chain reaction - glioma - glioblastoma.

Objective: The aims of this study were to determine the prevalence of human papillomavirus (HPV) infection in women treated for infertility and oocyte donors, and to investigate the possible influence of HPV infection on reproductive outcomes. Study design: In this observational laboratory-based study, cervical swabs were collected from oocyte donors (n = 207), and women treated for infertility (n = 945) and analysed for the presence of high-risk HPV (hrHPV) genotypes using the cobas® 4800 HPV Test and PapilloCheck® HPV-Screening. Associations between hrHPV positive status and fertility outcome or socio-behavioral and health characteristics were evaluated using R statistical software. Results: HrHPV prevalence was significantly higher in oocyte donors than in women treated for infertility (28.0% vs. 16.1%, P

Background and Objectives. Recently, we described an inverse association between cranberry supplementation and serum prostate specific antigen (PSA) in patients with negative biopsy for prostate cancer (PCa) and chronic nonbacterial prostatitis. This double blind placebo controlled study evaluates the effects of cranberry consumption on PSA values and other markers in men with PCa before radical prostatectomy. Methods: Prior to surgery, 64 patients with prostate cancer were randomized to a cranberry or placebo group. The cranberry group (n=32) received a mean 30 days of 1500 mg cranberry fruit powder. The control group (n=32) took a similar amount of placebo. Selected blood/urine markers as well as free and total phenolics in urine were measured at baseline and on the day of surgery in both groups. Prostate tissue markers were evaluated after surgery. Results: The serum PSA significantly decreased by 22.5% in the cranberry arm (n=31, P

Genetic analysis of leukemic cells significantly impacts prognosis and treatment stratification in childhood acute lymphoblastic leukemia (ALL). Our retrospective single center study of 86 children with ALL enrolled into three consecutive treatment protocols (ALL-BFM 90, ALL-BFM 95 and ALL IC-BFM 2002) between 1991 and 2007 demonstrates the importance of conventional cytogenetics and fluorescence in situ hybridization (FISH). Cytogenetic and FISH examinations were performed successfully in 82/86 (95.3%) patients and chromosomal changes were detected in 78 of the 82 (95.1%) patients: in 69/73 patients with B-cell precursor (BCP)-ALL and in 9/9 patients with T-lineage ALL (T-ALL). The most frequent chromosomal changes in subgroups divided according to WHO classification independent of treatment protocol and leukemia subtype were hyperdiploidy in 36 patients (with ≥50 chromosomes in 23 patients, with 47-49 chromosomes 13 patients) followed by translocation t(12;21) with ETV6/RUNX1 fusion detected by FISH in 18 (22%) patients. Additional changes were detected in 16/18 (88.8%) ETV6/RUNX1-positive ALL patients with predominant deletion or rearrangement of untranslocated ETV6 allele. Unique aberrations were detected in 4 patients and dicentric chromosomes in 8 patients, one with T-ALL. These results demonstrate that cytogenetics and FISH successfully provided important prognostic information and revealed not only recurrent but also new and rare rearrangements requiring further investigation in terms of prognostic significance.

Background and Aims. Erythropoiesis is closely related to iron metabolism in a balanced homeostasis. Analyses of diverse erythroid and iron metabolism disorders have shown that disrupted erythropoiesis negatively affects iron homeostasis and vice versa. The aim of this study was to characterize the relationship between erythropoietic activity and iron homeostasis in pediatric patients with erythrocyte membrane defects and thalassemia traits. Methods. Selected markers of erythropoietic activity (erythropoietin, soluble transferrin receptor - sTfR and growth differentiation factor 15) and iron status parameters (serum iron, ferritin and hepcidin) were evaluated in pediatric patients with erythrocyte membrane defects and thalassemia traits. Results. The patients with erythrocyte membrane defects and thalassemia traits had altered iron homeostasis due to disturbed erythropoiesis. In comparison with healthy controls, they had a normal to low hepcidin/ferritin ratio and concomitantly elevated sTfR. Conclusion. The findings suggest that pediatric patients with erythrocyte membrane defects and thalassemia traits are more susceptible to iron overload than the general population and that the (hepcidin/ferritin)/sTfR ratio can be used to monitor any worsening of the disease.

Objectives Significant progress in treatment strategies improves the expectations of patients with extracranial cancers. Metastases are the primary consideration in patients with cancer history. In the case of neurologic disorders, the patient should undergo brain MRI. A rationale is presented for surgery, whole-brain or stereotactic radiotherapy, or chemotherapy. Recently, we have encountered misdiagnosed primary malignant brain tumours in patients with oncologic history who had been admitted for surgery for brain metastases. The aim of our study is to evaluate the incidence of concurrent cancers, to assess the relationship between previous cancer staging and primary brain tumour evaluation as well as to determine treatment efficiency. Methods From January 2007 to December 2011, we prospectively followed up patients with concurrent history of both extracranial cancer and subsequent glioblastoma multiforme. Information was collected on the clinical condition, imaging, history of extracranial cancer, previous and present surgical and oncologic procedures, and GBM histologic, cytogenetic, and molecular genetic investigations. Results Five patients were recruited: three females and two males. The average patient age at the time of GBM diagnosis was 65.6 years. Three patients had a history of breast carcinoma, one of renal carcinoma and one of colorectal carcinoma. Following the diagnosis of carcinoma, three patients received chemotherapy and radiotherapy, one patient had radiotherapy alone, and one had no adjuvant therapy. In all the cases, surgery revealed primary GBM, with a standard occurrence of genetic abnormalities ( Table 1 ). The average time from the diagnosis of extracranial cancer to that of GBM was 4 years. Four patients underwent chemoradiotherapy and one had palliative radiotherapy. Two patients completed oncotherapy and their OS was 27 months and 19 months, respectively. One patient had post-surgical progression of hemiparesis. One patient had pulmonary embolism during oncotherapy and one had paraplegia caused by a pathological fracture of vertebras T5 due to breast carcinoma metastases. The OS was 11.8 months (range 3–27 months). All the patients succumbed to GBM progression.

Eligibility to anti-HER2 therapy for breast tumors strictly depends on demonstrating HER2 overexpression (by immunohistochemistry) or HER2 gene amplification by in situ hybridization (ISH), usually defined by the ratio of HER2 gene to chromosome 17 centromere (CEP17) copies. However, the CEP17 copy number increase (CNI) has been proven responsible for misleading HER2 FISH results and recent small cohort studies suggest that chromosome 17 polysomy is actually very rare. Here we investigated by FISH the frequency of true chromosome 17 polysomy in a consecutive cohort of 5,477 invasive breast cancer patients. We evaluated and selected the LSI 17p11.2 probe for chromosome 17 enumeration on a training cohort of 67 breast cancer samples (CEP17 ≥ 2.5). LSI 17p11.2 was used in the 297/5,477 patients from the validation cohort displaying CEP17 CNI (CEP17 ≥ 3.0). Using HER2/17p11.2 scoring criteria, 37.3%/1.5% patients initially classified as equivocal/non-amplified were reclassified as amplified. For a more accurate assessment of chromosome 17 and ploidy in the samples, we tested six markers located on chromosome 17 and centromeric regions of chromosome 8 (CEP8) and 11 (CEP11) in 67 patients with CEP17 and LSI 17p11.2 CNI. True polysomy (hyperdiploidy) according to these markers was found in 0.48% of cases (24/5,020). CEP8 and CEP11 CNI (≥3.0) was more frequent in the hyperdiploid than CEP17 non-polysomic group (55.6% vs. 6.1% and 25% vs. 2.3%, respectively). Our results suggest that chromosome 17 polysomy is a rare event found in

Background The optimal surgical strategy for treating internal carotid artery (ICA) blood blister-like aneurysms (BBAs) has remained unclear. Although some have preferred bypass surgery, others have favored less-demanding surgical methods. The aim of the present meta-analysis was to assess the efficacy, safety, and outcomes of bypass and non–bypass surgical methods when intended as primary treatment of ICA BBAs. Methods Studies reporting data on the outcomes of interest for surgically treated patients with ICA BBAs were searched for in the PubMed/MEDLINE, Evidence-Based Medicine Reviews, Cochrane Central, ProQuest, and Scopus databases. The data were analyzed using random effects modeling. Results Seven observational studies involving 140 patients met the inclusion criteria. The patients treated with bypass surgery, compared with those treated with non–bypass techniques, had lower odds of poor outcomes (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.28–2.02; P = 0.57; I2 = 0%), postoperative vasospasm (OR, 1.73; 95% CI, 0.38–7.92; P = 0.48; I2 = 19%), intraoperative bleeding (OR, 3.37; 95% CI, 0.82–13.90; P = 0.09; I2 = 0%), postoperative bleeding (OR, 1.91; 95% CI, 0.47–7.76; P = 0.36; I2 = 0%), and postoperative recurrence of BBAs (OR, 2.16; 95% CI, 0.54–8.66; P Conclusions For surgeons who use both bypass and non–bypass surgical strategies, the 2 methods seemed comparable in terms of the outcomes of interest, although the bypass technique appeared superior. However, comparisons with studies reporting bypass as the uniquely preferred technique have indicated that specialization in, and preference for, the bypass procedure has been associated with more favorable outcomes.

BACKGROUND: Glioblastoma (GBM) is the most common primary brain tumour in adults with nearly 100% mortality. Despite aggressive therapy, overall survival of GBM patients remains poor due to intrinsic or acquired resistance to maximal treatment modality based on combination of radiation and chemotherapy. The biological background behind GBM progression after first line therapy is mostly unknown and thus, there are only limited targeted therapeutic options for the second line treatment. The main goal of this study was to elucidate genetic landscape in paired samples of primary versus recurrent GBM and to validate prognostic and predictive value of the most significant differences in independent cohort of GBMs. MATERIAL AND METHODS: The cohort consists of 43 paired samples obtained during 1(st) surgery followed by radiochemotherapy (at least 54 Gy plus 3 cycles of temozolomide) and during the second palliative surgery. The analysis comprises genome copy number variations (24/43 samples) and fluorescent in situ hybridization determined gene and chromosomal region statuses for EGFR, p53, RB1, MDM2, CDKN2A and 1p, 19q, 10p. Methylation-specific PCR was used for analysis of MGMT promoter methylation and competitive amplification of differentially melting amplicons PCR for IDH1/2 mutations detection. The validation of the most relevant alterations was performed on independent cohort of non-paired 104 tumors. RESULTS: Statistically the most significant differences of GBM progression induced by combination of chemo and/or radiotherapy were: EGFR amplification, CDKN2A loss, MDM2 gain, PDGFRA gain and GSTT1 loss in primary tumors and GSTM1 gain in recurrent tumors. Univariate analysis of overall survival for significant copy number alterations proofs significantly worse prognosis for patients harboring GSTT1 deletion in primary tumor. The analysis revealed trend of better prognosis in patients with CDKN2A deletion and GSTM1 amplification in recurrent tumors. Significantly worse prognosis had GBM patients harboring GSTT1 gene aberrations and was also confirmed in independent validation cohort of unpaired GBMs in multivariate analysis adjusted for age and Karnofsky score. Full data with statistical analysis will be presented in the poster. CONCLUSION: The molecular genetic background of paired samples of primary and recurrent form of GBM revealed association with glutathione S-transferases genes. The significance of GSTT1 gene aberration was validated in independent group of GBM and thus supports the theory of in involvement of redox enzymes in GBM chemoradiation response and tumor progression. ACKNOWLEDGMENT: The financial support of grants TACR TE02000058, IGA_LF_2018_005 is gratefully acknowledged. Authors thank the collaborating neurosurgical centers from Ostrava (CGB laboratory), Brno (CEITEC) and Prague (Faculty Hospital Královské Vinohrady).

Most research on American cranberry in the prevention of urinary tract infection (UTI) has used juices. The spectrum of components in juice is limited. This study tested whether whole cranberry fruit powder (proanthocyanidin content 0.56%) could prevent recurrent UTI in 182 women with two or more UTI episodes in the last year. Participants were randomized to a cranberry (n = 89) or a placebo group (n = 93) and received daily 500 mg of cranberry for 6 months. The number of UTI diagnoses was counted. The intent-to-treat analyses showed that in the cranberry group, the UTIs were significantly fewer [10.8% vs. 25.8%, p = 0.04, with an age-standardized 12-month UTI history (p = 0.01)]. The Kaplan-Meier survival curves showed that the cranberry group experienced a longer time to first UTI than the placebo group (p = 0.04). Biochemical parameters were normal, and there was no significant difference in urinary phenolics between the groups at baseline or on day180. The results show that cranberry fruit powder (peel, seeds, pulp) may reduce the risk of symptomatic UTI in women with a history of recurrent UTIs.

Heat shock proteins hsp70 and gp96 have been confirmed as adjuvants enabling induction of cell- and antibody-mediated immunity specific to associated protein or peptide antigens due to the activation of naive dendritic cells and supporting cross-presentation of associated antigen. An efficacious vaccine preventing HIV-1 infection should induce (1) antibodies neutralizing HIV-1 Env protein, preventing virus spreading and (2) CD4(+) Th1 and CD8(+) T cells specific to viral proteins, especially gag p24, important for elimination of HIV-1 infected cells. As p24 is relatively poorly recognized by dendritic cells, its targeting to DC is important for enhancement of vaccine efficacy. In this study, a p24 protein fused to the C- or N-terminus of murine hsp70 was produced as a recombinant protein and administered without any adjuvant to experimental BALB/c mice. Consequently, p24-specific cellular and humoral immune responses were measured. To minimize the effect of bacterial endotoxin, each protein was subjected to a repeated endotoxin phase extraction until each preparation contained less than 2.5 endotoxin unit (EU) per mg of antigen. In addition, endocytosis of p24 fused to hsp70 by dendritic cells and their activation were characterized. The fusion to hsp70 protein enhanced endocytosis of p24 as well as activation of dendritic cells in vitro. After immunization of mice, hsp70-p24 fusion protein induced the strongest p24-specific CD4(+) and CD8(+) T cells (IFN-γ production) and humoral (IgG2b) responses corresponding to Th1 type dominance, whereas p24-hsp70 or p24 itself induced weaker responses.

The aim of this study was to evaluate the fatty acid (FA) profile in the plasma and erythrocyte membranes of apparently healthy men compared to male patients with various cardiovascular diseases (CVD). The plasma FA profiles were analyzed in five groups of subjects aged 37–57 years: groups 1 and 2 were male voluntary blood donors with a body mass index (BMI) 25.1 ± 1.6, (Group 1, N = 12) and a BMI 32.9 ± 4.5, (Group 2, N = 11) respectively, male patients with chronic heart failure due to dilated cardiomyopathy (Group 3, N = 10), chronic atrial fibrillation without heart failure or coronary heart disease (Group 4, N = 10) and patients after myocardial infarction (Group 5, N = 11). The FA profile in plasma and erythrocytes was measured by gas chromatography (GC) with flame ionization detection and basic plasma lipid parameters were then estimated. Deficiencies of eicosapentaenoic acid and docosahexaenoic acid were found in all the groups of CVD patients and in Group 2 (BMI 32.9 ± 4.5) of this Central European population. Unfavorable alterations in FA composition and clinical biochemistry parameters were found in patients with dilated cardiomyopathy (Group 3). Further, 75% of Group 1 (blood donors) had an average plasma PUFA level in the worst quartile for relative risk of cardiovascular events. Tailored n-3 PUFA supplementation should be recommended not only for secondary prevention in patients suffering from CVD but also for primary prevention in overweight and obese persons with a proven deficiency. Practical applications: Plasma and erythrocyte membrane n-3 polyunsaturated fatty acid (PUFA) levels are an important parameter of diet composition as well as a marker of cardiovascular risk. Regular sea fish intake or alternative supplementation with the n-3 PUFA recommendation is in all probability insufficiently realized, particularly in inland countries. In addition to contemporary guidelines and practice, research is providing data on the use of FA analysis for revealing people with an n-3 PUFA deficiency. This approach could benefit people suffering from CVD as well as for overweight and obese populations with demonstrated deficiency. Tailored n-3 PUFA supplementation should be recommended not only for secondary prevention in patients suffering from CVD but also for primary prevention in overweight and obese persons with a proven deficiency.

International audience; S28463 (S28), a ligand for Toll-like receptor 7/8, has been shown to have antiinflammatory properties in rodent models of allergic asthma. The principle goal of this study was to assess whether these antiinflammatory effects can also be observed in a nonhuman primate (NHP) model of allergic asthma. NHPs were sensitized then challenged with natural allergen, Ascaris suum extract. The animals were treated with S28 orally before each allergen challenge. The protective effect of S28 in NHPs was assessed by measuring various asthma-related phenotypes. We also characterized the metabolomic and proteomic signatures of the lung environment and plasma to identify markers associated with the disease and treatment. Our data demonstrate that clinically relevant parameters, such as wheal and flare response, blood IgE levels, recruitment of white blood cells to the bronchoalveolar space, and lung responsiveness, are decreased in the S28-treated allergic NHPs compared with nontreated allergic NHPs. Furthermore, we also identified markers that can distinguish allergic from nonallergic or allergic and drug-treated NHPs, such as metabolites, phosphocreatine and glutathione, in the plasma and BAL fluid, respectively; and inflammatory cytokines, IL-5 and IL-13, in the bronchoalveolar lavage fluid. Our preclinical study demonstrates that S28 has potential as a treatment for allergic asthma in primate species closely related to humans. Combined with our previous findings, we demonstrate that S28 is effective in different models of asthma and in different species, and has the antiinflammatory properties clinically relevant for the treatment of allergic asthma.

Background: Breast cancer (BC), the most frequent malignancy in women worldwide, is currently diagnosed in about 1.4 million female patients annually. Approximately 10-20% of BC is represented by triple negative breast cancer (TNBC) which is aggressive, the prognosis is poor and patients cannot benefit from targeted treatment based on hormonal or HER2 receptors. For this reason, search for markers that can predict the efficacy of chemotherapy in TNBC is a priority. Methods and Results: This review focuses on BCL2 protein as a prognostic marker in TNBC and its potential as a predictor of sensitivity to chemotherapy. Conclusion: BCL2 protein expression is a positive prognostic factor in BC. Better survival of patients with BCL2 positivity (BCL2+) has been explained by the correlation with estrogen receptor positive (ER+) status. BCL2+ is however not simply a surrogate marker for ER+. Moreover, BCL2 protein expression is also a positive prognostic marker in the TNBC subgroup. We and others show, that low BCL2 expression was associated with good outcome of TNBC patients treated with both adjuvant and neoadjuvant anthracycline-based chemotherapy. On the other hand, recent studies have shown that a subset of TNBC patients may benefit from the classical adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) regimen. Given the heterogeneity of TNBC there is an urgent need to find and validate the sensitivity predictors to these regimens making them usable in clinical practice. BCL2 enrichment has been described in the mesenchymal stem-like (MSL) TNBC subgroup.

A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was studied and compared with that of the parent 7-(het)aryl-7-deazaadenosine series. Several of the compounds, in particular 6-substituted 7-deazapurine derivatives bearing a furyl or ethynyl group at position 7, were significantly cytotoxic at low nanomolar concentrations whereas most were much less potent or inactive. Promising activity was observed with some compounds against Mycobacterium bovis and also against hepatitis C virus in a replicon assay.

Background Meningioma growth rates are highly variable, even within benign subgroups, causing some cases to remain stable while others grow rapidly despite radiotherapy. Biomarkers that differentiate meningiomas by aggression and enable prediction of their biological behavior would therefore be clinically beneficial. Methods Microarrays were used to identify microRNA (miRNA) expression in primary recurrent, non-recurrent and secondary meningiomas of all grades. miRNAs found to be deregulated in the microarray experiments were validated by quantitative real-time PCR using samples from a cohort of 191 patients (median age 56). Statistical analysis of the resulting dataset revealed miRNA predictors of meningioma recurrence. Results miRNAs exhibiting differential expression (independently of histological grade) in primary recurrent, non-recurrent and secondary meningiomas were identified. The most effective predictive model included miR-331-3p, extent of tumor resection and its localization as predictive markers. The model with a recurrence probability cut-off of 28% and small number of the input data (7) had a high area under the curve (AUC) (0.829), sensitivity (75%), specificity (75%), and acceptable leave-one-out cross-validation (LOOCV) test error (23.2%). miR-18a-5p, miR-130b-3p, miR-146a-5p, miR-1271-5p, age at diagnosis, gender and histological grade showed to be supportive but not predictive factors in the tested models. Conclusions This model is a novel predictor of meningioma recurrence that could facilitate optimal postoperative management. Moreover, combining this model with information on the molecular processes underpinning recurrence could enable the identification of distinct meningioma subtypes and targeted therapies. Legal entity responsible for the study The authors. Funding Ministry of Health of the Czech Republic (15-29021A); Palacky University Olomouc (LF 2019_003); Ministry of Education, Youth and Sports of the Czech Republic (LO1304, LM2015091); European Regional Development Fund (ENOCH CZ.02.1.01/0.0/0.0/16_019/0000868). Disclosure All authors have declared no conflicts of interest.

The aim of this double-blind, placebo controlled clinical trial was to assess the effects of a combination of selenium and silymarin in men with lower urinary tract symptoms, benign prostatic hyperplasia and a prostate specific antigen (PSA) ≤2.5ng/ml. The volunteers were randomized to two groups: the first one (n=26) received 240μg selenium (in the form of yeast l-selenomethionine) plus 570mg silymarin daily for 6 months and the second (n=29) received placebo. Outcome measures were changes in the International Prostate Symptom Score (IPSS), bladder volume (V), urinary flow rate, ultrasound estimated postvoid residual urine volume (RV), serum PSA, testosterone and selenium levels, safety clinical biochemistry, hematology and oxidative stress parameters at baseline and on day 180. The results showed statistically significant differences (p

UVA photons are less energetic than UVB photons but they are more abundant in solar radiation. Modern tools have shown that UVA light has serious adverse effects on the skin. We investigated the effect of consuming Lonicera caerulea berries on UVA-induced damage in SKH-1 mice. The mice were fed a diet containing L. caerulea berries (10%, w/w) for 14 days before a single UVA (30 J/cm 2 ) treatment. Effects on haematological and antioxidant parameters were evaluated 4 and 24 h after irradiation. The bioavailability of L. caerulea phenolics was also assessed. Consuming the L. caerulea berry-enriched diet caused reduced malondialdehyde production and increased catalase activity and glutathione levels were found in skin and erythrocytes. UVA-induced NADPH:quinone oxidoreductase-1 and gamma- L -glutamate- L -cysteine ligase protein in skin were reduced in mice fed L. caerulea berries. Enhanced heme oxygenase-1 level in skin, interleukin-17 in plasma and reduced interleukin-12 levels in plasma were found in the mice on the experimental diet. Histological (pyknotic) changes in the nuclei of basal cells induced by UVA exposure were reduced in L. caerulea berry consuming animals. HLPC-MS analysis showed high concentrations of hippuric acid, one of the main metabolites of aromatic amino acids and phenolic compounds, in skin, liver, urine and faeces of mice consuming the berries. Taken together, consumption of L. caerulea berries affords protection from the adverse effects of a single UVA exposure mainly via modulation of antioxidant parameters.

This study investigated the effect of one-week consumption of 165 g/day fresh blue honeysuckle berries (208 mg/day anthocyanins) in 10 healthy volunteers. At the end of intervention, levels of benzoic (median 1782 vs 4156), protocatechuic (709 vs 2417), vanillic (2779 vs 4753), 3-hydroxycinnamic (143 vs 351), p-coumaric (182 vs 271), isoferulic (805 vs 1570), ferulic (1086 vs 2395), and hippuric (194833 vs 398711 μg/mg creatinine) acids by LC/MS were significantly increased in the urine. Clinical chemistry safety markers were not altered. Oxidative stress markers, erythrocyte glutathione peroxidase (0.73 vs 0.88 U/g Hb) and catalase (2.5 vs 2.8 μkat/g Hb) activities, and erythrocyte/plasma thiobarbituric acid reactive substance (522 vs 612/33 vs 38 μmol/g Hb/protein) levels were significantly increased, without change in plasma antioxidant status. Nonsignificant changes of advanced oxidation protein products and oxidized LDL were observed. The results provide a solid base for further study of metabolite excretion and antioxidant parameters after ingestion of anthocyanins.

The modification of implant surface situated in the area of peri-implant sulcus has important role in bacterial and cell adhesion. Six different chemically and physically modified titanium discs were prepared: glazed (Tis-MALP), unglazed (Tis-O), unglazed and alkali-etched (Tis-OA), unglazed and coated with ZrN (Tis-OZ), unglazed, sand blasted, and acid etched (Tis-OPAE), and unglazed, sand blasted, acid, and alkali etched (Tis-OPAAE). Analysis of surface topography was determined using scanning electron microscopy and atomic force microscopy (AFM). Biocompatibility of gingival fibroblasts was characterized by the production of tumor necrosis factor alpha, collagen I, matrix metalloproteinase 2 (MMP-2) after 24 and 72 h and expression of α3 β1 integrin and vinculin using enzyme-linked immunosorbent assay (ELISA) or modified ELISA after 6 and 24 h. Microorganism adhesion (five bacterial strains) and biofilm formation was also evaluated. The adhesion of bacteria and gingival fibroblasts was significantly higher on titanium disc Tis-OPAAE and biofilm formation on the same surface for Streptococcus mutans, Streptococcus gordonii, and Streptococcus intermedius. The gingival fibroblasts on Tis-OPAAE disc had also significantly lower production of MMP-2. The collagen production was significantly lower on all surfaces with roughness higher than 0.2 μm. This study confirmed that the titanium disc with the surface roughness 3.39 μm (Tis-OPAAE) supported the adhesion of bacterial strains as well as gingival fibroblasts.

The alkaloids of Macleaya cordata (Papaveracae) are active components of the phytogenic feed addi- tive Sangrovit. The present study was conducted to evaluate the effects of Sangrovit on dextran sulfate sodium (DSS)-induced colitis using rats as an experimental model. Thirty-five male rats were randomly assigned to a control group (Group 1, n = 5), a Sangrovit group (Group 2, n = 20) and a DSS group (Group 3, n = 10). Group 1 received standard diet and tap water for 14 days. Group 2 received 500 ppm Sangrovit in their feed for 14 days and in the second week 5% DSS was added to the tap water. The animals in Group 3 were fed for seven days with standard diet and tap water and for the next seven days with standard diet and 5% DSS added to their tap water. The rats were sacrificed on day 14 and the following parameters were measured: disease activity (body and organ weight, colon length, presence of blood in stool), colon myeloperoxidase activity, expression of colon cyclooxygenase-2 (COx -2), hematological parameters, histological colitis score and selected parameters of oxidative stress. The animals treated with DSS for seven days (Groups 2 and 3) showed increases in liver and cecum weight, leukocyte count and colon shortening, decreases in hemoglobin and hematocrit associated with hematochezia. In compari- son with Group 3 where DSS caused mucosal edema, cellular infiltration and epithelial disruption, the Sangrovit group showed less severe damage to the colon mucosa and decreased histological colitis scores. The Sangrovit group also showed diminished expression of DSS-induced CO x -2, significantly mitigated myeloperoxidase activity in colon tissue and level of reduced glutathione in erythrocytes. In conclusion, some parameters of DSS-induced colitis were modulated by 500 ppm Sangrovit added to feed.

BACKGROUND: Regardless of GBM patient prognosis remains dire, there is a patient group, in which profit from current diagnostic methods and treatment strategies progress has yielded extension of both OS and PFS, that again recall question of recurrent GBM solution.Our work is aimed at result evaluation of our treatment strategy for the most malignant subtype of GBM - IDH wild type. MATERIAL AND METHODS: 116 consecutive patients with GBM IDH wild-type were enrolled. Recurrent GBM was defined as increasing more than 20–30% of previous, residual tumour volume, or tumour regrowing after radiologically radical surgery. We consider as a best solution repeated surgery following oncotherapy. In case unsuitable for redo-surgery, we accepted oncotherapy rechallenge. CRITERIA FOR REDO-SURGERY: Time of recurrency evolving ≥ 6 months after surgery, Clinical condition - Karnofsky score (KS) ≥ 70% and Performance status (PS) WHO ≤ gr. 2, Local recurrency, without multilocality, Option for considerable tumor volume reduction, minimally ≤ 70%; tumour location; CRITERIA FOR REPEATED ONCOTHERAPY: Time of recurrency evolving ≥ 6 motnts after prime surgery, Clinical condition - Karnofsky score (KS) ≥ 70% and Performance status (PS) WHO ≤ gr. 2, Local recurrency, without multilocality, No option for considerable tumour volume reduction, minimally ≤ 70%; tumour location. RESULTS: 23 patients met these criteria. Such treatment selection drew improvement of both PFS (10,5 months; 8.94,17.91)) and OS (19,2 months; (15.28,30.82)). A good clinical condition, longer time to the tumour recurrency commitment, primary radical surgery, following Stupp protocol a radical redo-surgery, following chemotherapy were positive clinical prognostic factors. Solely rechallenge oncotherapy (reradiation, chemotherapy/temozolomid) had lesser positive impact. Regarding cytogenetic tumour profile, based on FISH, increasing copy number P53 and CCND1 were approved as a positive prognostic factor. CONCLUSION: GBMs IDH wild-type are the most malignant subset, but these patients have relatively heterogenous life expectancy. Thera are missed relevant prognostic factors and our work attempted to change it. As emerged from this analysis, OS and PFS predominantly rely on genetic features (P53, CCND1) of certain tumour. The most important issue for successful recurrent GBM treatment was set up appropriate indication criteria. When we evaluated our patient group, the patients, who un-fulfilled criteria, underwent redo-surgery, predominantly for the patient′s and family urges.

Lower urinary tract symptoms (LUTS) are a common condition in older men. The objective of the present study was to evaluate the efficacy and tolerability of cranberry (Vaccinium macrocarpon) powder in men at risk of prostate disease with LUTS, elevated prostate-specific antigen (PSA), negative prostate biopsy and clinically confirmed chronic non-bacterial prostatitis. Forty-two participants received either 1500 mg of the dried powdered cranberries per d for 6 months (cranberry group;n21) or no cranberry treatment (control group;n21). Physical examination, International Prostate Symptom Score, quality of life (QoL), five-item version of the International Index of Erectile Function (IIEF-5), basic clinical chemistry parameters, haematology, Se, testosterone, PSA (free and total), C-reactive protein (CRP), antioxidant status, transrectal ultrasound prostate volume, urinary flow rate, ultrasound-estimated post-void residual urine volume at baseline, and at 3 and 6 months, and urineex vivoanti-adherence activity were determined in all subjects. In contrast to the control group, patients in the cranberry group had statistically significant improvement in International Prostate Symptom Score, QoL, urination parameters including voiding parameters (rate of urine flow, average flow, total volume and post-void residual urine volume), and lower total PSA level on day 180 of the study. There was no influence on blood testosterone or serum CRP levels. There was no statistically significant improvement in the control group. The results of the present trial are the first firm evidence that cranberries may ameliorate LUTS, independent of benign prostatic hyperplasia or C-reactive protein level.

Background: Glioblastoma (GBM) is the most frequent and the most malignant brain tumor in adults. Despite aggressive therapy, overall survival of GBM patients remains poor due to intrinsic or acquired resistance to combined radiation and chemotherapy. Underlying biology behind GBM progression after first line therapy is mostly unknown and thus, there are only limited targeted therapeutic options for the 2nd line treatment. The aim of this study was to investigate genetic landscape in paired samples of primary versus recurrent tumors and to validate prognostic and predictive value of the most significant differences in independent cohort of GBMs. Patients and methods: 43 paired tumor samples were obtained during the 1st surgery followed by radiochemotherapy and after tumor recurrence during the 2nd palliative surgery. 24/43 paired samples were analyzed for whole genome copy number variations (CNV), 23/43 by fluorescent in situ hybridization for determination of EGFR, p53, RB1, MDM2, CDKN2A, 1p, 19q and 10p statuses. Methylation-specific PCR was used for analysis of MGMT promoter methylation and competitive amplification of differentially melting amplicons PCR for IDH1/2 mutations detection. The impact of most relevant alterations identified in paired GBMs was then validated in independent cohort of unpaired 104 tumors. Results: The most significant differences induced by chemoradiotherapy and/or GBM progression in primary versus recurrent tumors were EGFR amplification (19/24 primary tumors, 16/24 recurrent tumors), CDKN2A loss (18/24 primary tumors, 16/24 recurrent tumors), MDM2 gain (4/24 primary tumors), PDGFRA gain (3/24 recurrent tumors) and GSTT1 loss in primary tumors (7/24) and GSTM1 gain in recurrent tumors (7/24). Univariate analysis of overall survival for significant copy number alterations shown significantly worse prognosis for patients with GSTT1 deletion (HR = 5.356, CI = 1.161-24.701, p = 0.031) in primary tumor and trend for better prognosis in patients with CDKN2A deletion (HR = 0.391, CI = 0.124-1.229, p = 0.108) and GSTM1 amplification (HR = 0.341, CI = 0.090-1.288, p = 0.112) in recurrent tumors. Significantly worse prognosis for GBM patients with aberrations of GSTT1 gene was also confirmed in independent validation cohort of unpaired GBMs in multivariate analysis adjusted for age and Karnofsky score (gain: HR = 1.95, CI = 1.116-3.260, p = 0.011; loss: HR = 2.15, CI = 1.185-3.900, p = 0.012). Conclusion: Molecular genetic profiling of 24 recurrent GBM showed association between recurrence and status of glutathione S-transferases genes. Significance of GSTT1 gene aberration was validated in independent group of glioblastomas and indicates involvement of redox enzymes in GBM chemoradiation response and tumor progression. Acknowledgment: The financial support of grants TE02000058, IGA UP LF_2017_013 is gratefully acknowledged. Citation Format: Magdalena Houdova Megova, Zuzana Sporikova, Radek Trojanec, Ondrej Kalita, Jana Vrbkova, Jiri Drabek, Vladimira Koudelakova, Marian Hajduch. Mapping of molecular landscape underlying drug resistance and recurrence in glioblastoma: Paired analysis of primary and recurrent tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3695.