R Demlová

Masaryk Memorial Cancer Institute, Brünn, South Moravian, Czech Republic

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Publications (19)25.63 Total impact

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    ABSTRACT: Objective: Individuals with decreased thiopurine methyltransferase (TPMT) activity are at risk of adverse effects of thiopurine administration whereas its increased activity may inactivate drugs faster. We evaluated genotype-phenotype correlations in patients with suspected hematological malignancies and inflammatory bowel disease from our region based on findings of nonlinear TPMT enzyme kinetics previously unreported. Patients and Methods: The study group comprised 267 individuals. They were screened for the most common variants of low TPMT activity. TPMT activity was measured in erythrocytes using the HPLC rate-blanked method. Results: Thirty-three patients (12.4%) were heterozygous (26 were TPMT*1/*3A, 5 TPMT*1/*2, 2 TPMT *1/*3C) and 1 was a compound heterozygote (*2/*3A). Normal and low normal TPMT activities substantially overlapped in wild-type and heterozygous individuals, whereas high activities were found in 29 wild-type genotyped patients. Extreme and life-threatening toxicity was observed in the compound heterozygote patient. Conclusion: Activity measurement performed at diagnosis provides clinicians with information on immediate pharmacokinetic-related adverse events and/or hypermetabolism, and genotyping may indicate the rate of pharmacodynamic thioguanine nucleotide accumulation due to slower overall thiopurine metabolism. © 2014 S. Karger AG, Basel.
    Oncology 03/2014; 86(3):152-158. · 2.17 Impact Factor
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    ABSTRACT: Vitamin D is the third steroid hormone playing important bio-logical roles in the development of breast cancer. Decreased plasma levels of its 25- hydroxyderivative, 25OHD, display robust associations with higher incidence of breast cancer and shorter overall survival. Although no consensus exists, most authors agree that optimal plasma levels shall be within 75- 150 nmol/ l whereas levels higher than 375 nmol/ l can be potentially toxic with higher risk of hypercalcemia. To date, no data are available on the optimal levels of vitamin D related to the risk of breast cancer development, its phenotype features and the course of the disease. Published studies mostly describe associations among higher levels of 25OHD and lower bio-logically aggressiveness of the tumor. The polymorphism of VDR gene coding for the steroid receptor for vitamin Dmay be associated with higher disease incidence and also be of negative prognostic significance in breast cancer. This review presents an overall summary of the current knowledge and publications on vitamin D and breast cancer. Key words: vitamin D - 25- hydroxyvitamin D - vitamin D receptor - breast cancer This work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) and by MH CZ - DRO (MMCI, 00209805) and BBMRI_CZ (LM2010004). 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 "uniform requirements" for biomedical papers.Submitted: 29. 1. 2014Accepted: 5. 5. 2014.
    Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2014; 27(Supplementum):143-149.
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    ABSTRACT: With the recent addition of anti-angiogenic agents to cancer treatment, the angiogenesis regulators in platelets are gaining importance. Platelet factor 4 (PF-4/CXCL4) and Connective tissue activating peptide III (CTAP-III) are two platelet-associated chemokines that modulate tumor angiogenesis, inflammation within the tumor microenvironment, and in turn tumor growth. Here, we review the role of PF-4 and CTAP-III in the regulation of tumor angiogenesis; the results of clinical trial using recombinant PF-4 (rPF-4); and the use of PF-4 and CTAP-III as cancer biomarkers.
    Journal of Hematology & Oncology 06/2013; 6(1):42. · 4.46 Impact Factor
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    ABSTRACT: Vitamin D is an endogenous product of mammalian organisms from which an active agent of a steroid hormone nature is synthesized. These hormones participate in a variety of key metabolic processes in every nuclear cell, whether on endocrine, paracrine and autocrine or subcellular level. Vitamin D represents a very interesting molecule which participates in a great deal of body processes. This review summarizes the findings about the metabolism of vitamin D focusing on pathophysiology of malignant diseases. Keywords: vitamin D - malignant diseases - metabolism of vitamin D - anticancer effects of vitamin D.
    Casopís lékar̆ů c̆eských 01/2013; 152(1):20-30.
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    ABSTRACT: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3-69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile.
    Oncology 04/2012; 82(5):249-60. · 2.17 Impact Factor
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    ABSTRACT: Phase I trials in oncology usually enrolling patients with advanced disease who have failed standard treatment options. The primary endpoint of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid unnecessary exposure of patients to sub-therapeutic doses of an agent. The mission of phase I clinical trials is to accelerate the development of new anticancer drugs with the purpose of improving quality of life and survival for patients with cancer.
    Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2012; 25 Suppl 2:2S98-101.
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    ABSTRACT: CD3+ CD56+ NKT-like cells have been shown to produce substantial amounts of pro-inflammatory cytokines and to mediate lysis of malignant cells. Using flow cytometry, we evaluated the absolute NKT-like cell count in peripheral blood from individuals in a reference population and the median number was 0.085 x 10(9)/l. The average number of NKT-like cells in patients with disseminated cancer was 2.65 fold higher than in the reference population. The number of CD3+ CD56+ cells in solid tumour patients who achieved complete remission was comparable to the reference population. In breast cancer patients with initially (prior to therapy) increased number of NKT-like cells, we observed a trend toward longer disease-free survival. Thus we conclude that CD3+ CD56+ NKT-like cells have potential to suppress tumour evasion and are expanded in peripheral blood of some epithelial tumour patients.
    Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2012; 25 Suppl 2:2S21-5.
  • R Demlová
    Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2011; 24(1):54-5.
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    ABSTRACT: Targeted therapy has become an integral part of treatment procedures of malignant tumors. Colorectal carcinomas are frequently targeted with monoclonal anti-EGFR antibodies (cetuximab and panitumumab). Activating somatic mutations in codons 12 and 13 of the exon 2 of KRAS gene are considered negative predictive factors of response to anti-EGFR therapy in patients with metastatic colorectal cancer. In the Czech Republic, evaluation of mutational status of KRAS gene is performed in several referral laboratories. In 2009, these laboratories performed 2580 tests of the KRAS mutational status--out of these, 60.2% cases reported non-mutated, wild-type KRAS. In one of the referral laboratories, we demonstrate the logistics of KRAS testing procedure. Stratification of patients with metastatic colorectal tumors based on their KRAS mutational status has evolved to a standard procedure. Laboratories performing these methods shall therefore adhere to the recommendations of the professional and accredited societies.
    Casopís lékar̆ů c̆eských 01/2011; 150(6):321-6.
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    ABSTRACT: VOD Zhoubné onemocnění tlustého střeva (dg. C18), rektosig-moideálního spojení (C19) a konečníku (C20) je jednou z nej-častějších malignit v České republice. Nejčastější léčebnou modalitou u kolorektálního karcinomu je kurativní resekce ná-doru. Pacientům s karcinomem tlustého střeva klinického sta- Karlova v Praze, Lékafiská fakulta Hradec Králové, Ústav klinické biochemie a diagnostiky FN 3 P & R LAB a.s., Nov˘ Jiãín 4 CGB laboratofi a.s., Ostrava 5 Univerzila Palackého v Olomouci, Ústav molekulární a translaãní medicíny LF 6 Fakultní Thomayerova nemocnice s poliklinikou v Praze, Oddûlení patologie a molekulární medicíny 7 Bioptická laboratofi s.r.o., PlzeÀ 8 Univerzita Karlova v Praze, 1. lékafiská fakulta, Ústav patologie VFN 9 Univerzita Karlova v Praze, Lékafiská fakulta Hradec Králové, FingerlandÛv ústav patologie FN SOUHRN
    01/2011;
  • B Ondrácková, R Demlová, J Komínek
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    ABSTRACT: Targeted biologic therapy has been proven to be effective compared to the current therapy of metastatic renal cell carcinoma (mRCC) in clinical studies as well as in actual clinical practice, but its high cost is a potentially limiting factor. Since the local cost-effectiveness analysis is missing, we assessed the cost of sunitinib and sorafenib in the treatment of mRCC in a comprehensive cancer centre. A total of 31 patients were treated with sunitinib and/or sorafenib between 06/2006 and 09/2009 and then followed for at least 12 months. Clinical (disease progression, adverse events, dose reduction) and cost data (medication, examination, hospitalization) were assessed in the comprehensive cancer centre (1 Euro = 25.78 CZK). The multikinase inhibitors were the second line treatment for most patients after INF-alpha therapy failure (86.7%). The mean cost per month to progression (PD) was 94,141.8 CZK/3651.7 Euro (sunitinib: 11 months to PD, cost to PD 1,267,648.5 CZK/49,171.8 Euro; sorafenib: 8 months to PD, cost to PD 896,670.1 CZK / 34,781.6 Euro). The incremental cost-effectiveness ratio was 123,659.5 CZK / 4796.7 Euro per progression-free month in sunitinib vs sorafenib patients. The mean cost per month after PD was 45,767.0 CZK/1775.3 Euro with sequential therapy (sorafenib after sunitinib failure and vice-versa in more than half of patients) or best supportive care. 16 patients died during the study period with mean cost of 1,180,795.4CZK/45,802.8 Euro per 12 months (median between treatment initiation with sunitinib or sorafenib and death). 8 patients (26%) did not achieve progression (median progression-free survival to 09/2009: sunitinib 18 months, sorafenib 14 months). The cost of medication made up more than 95% of total costs to PD and more than 90% after PD. The cost per progression-free month was 123,659.5 CZK/4796.7 Euro in mRCC patients treated with sunitinib vs sorafenib.
    Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 01/2010; 23(6):439-45.
  • B Ondrackova, R Demlova
    Value in Health 01/2010; 13(7). · 2.19 Impact Factor
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    ABSTRACT: The construction and launch of the cyclotron & PET centre at the Masaryk Memorial Cancer Institute, which is run in cooperation with the Nuclear Research Institute Praha-Rez, allows the Masaryk Memorial Cancer Institute to engage in the research, development and application of new radiopharmaceuticals including compounds labelled by short-living positron emitters (especially 11C). For the immediate future, new projects are planned, e.g. using the proliferation marker 18F-fluoro-L-thymidine, or neuro-oncological studies using the proteosynthesis and amino acid transport marker 11C-methionine, and eventually also other compounds applicable outside of oncology. The existence of the PET centre at the Masaryk Memorial Cancer Institute therefore offers a wide range of possibilities to both patients and physicians in the Brno region and beyond.
    Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti 02/2009; 22(3):94-7.
  • R Demlova, B Ondrackova, J Kominek
    Value in Health 01/2009; 12(7). · 2.19 Impact Factor
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    ABSTRACT: To evaluate the influence of pretreatment plasma folate concentrations on methotrexate exposure in children with acute lymphoblastic leukemia/non-Hodgkin lymphoma treated with high-dose methotrexate, we assessed time profiles of plasma homocysteine, folate, and vitamin B(12) concentrations in children treated with high-dose methotrexate with leucovorin rescue. We analyzed 98 treatment courses. The study endpoints were to determine how methotrexate exposure is related to homocysteine accumulation and whether it is influenced by pretreatment plasma folate. Peak concentrations of homocysteine increased from the start of the intravenous infusion through cessation of methotrexate therapy up to time point t(42), when this trend was reversed by administration of folinic acid. The area under the curve (AUC) for plasma homocysteine showed decreasing course-to-course tendencies with a statistically significant decrease only between courses 1 and 2 (P <or=0.05), indicating decreased whole-body homocysteine accumulation in response to administration of consecutive methotrexate courses. Therapeutic courses with low initial folate concentrations (<or=10 nmol/L) gave significantly higher responses in homocysteine accumulation expressed both as (hcys)AUC(0-66 h) and the peak t(42) homocysteine concentrations than did courses with initial folate >10 nmol/L. Correspondingly, in the courses with low initial folate, peak plasma concentrations of methotrexate were significantly higher than in courses with high precourse concentrations of plasma folate. Endogenous pretreatment plasma folate modulates the magnitude of the methotrexate effect, providing support for a "folate overrescue" concept.
    Clinical Chemistry 04/2006; 52(4):692-700. · 7.15 Impact Factor
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    ABSTRACT: Vacuum biopsy device (mammotome) was primary developed for invasive diagnosis of the mammary gland. In Radiological department of Masaryk Memorial Cancer Institute we use the mammotome not only for breast tissue sampling. The device is used also for extraction of tumor specimens in advanced epithelial, mesenchymal or the other histological type of tumors for further chemoresistance testing.
    Casopís lékar̆ů c̆eských 02/2006; 145(5):399-402; discussion 402-3.
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    ABSTRACT: The primary endpoint of this study was to evaluate the efficacy (objective response rate; ORR) of combined chemotherapy with raltitrexed plus oxaliplatin as second-line treatment in patients with metastatic colorectal cancer (CRC). Secondary endpoints were overall survival (OS), time to progression (TTP) and toxicity (NCI-CTC criteria). The target population were patients with metastatic colorectal adenocarcinoma who progressed after first-line chemotherapy. Treatment consisted of raltitrexed 3 mg/m2 as a 15-minute intravenous (IV) infusion followed 45 minutes later by oxaliplatin 130 mg/m(2) IV as a 2-h infusion on Day 1, repeated every 3 weeks until further disease progression (PD), unacceptable toxicity or the decision of the patient. A total of 51 patients, all with WHO performance status 0-2 received a median of 6 treatment cycles (range 1-11). After 3 cycles, 8 of the 47 evaluable patients (17%) had experienced an ORR, 28 patients (59.6%) had experienced stable disease (SD) and 11 patients (23.4%) had PD. After 6 cycles, 1 of the 29 evaluable patients (3.5%) had an ORR, 13 patients (44.8%) had SD and 15 patients (51.7%) had PD. After a median follow-up of 48.9 weeks, median TTP was 18 weeks and median overall survival was 54.4 weeks. Treatment was well tolerated; grade 3 toxicities occurred in only 5/51 patients (9.8%). The most common toxicities were paraesthesia (62.7%), diarrhoea (23.5%), nausea (41.2%), vomiting (33.3%), hepatotoxicity (25.5%), and hematological toxicity (41.2%). In conclusion, the combination of oxaliplatin plus raltitrexed appears to be effective and well tolerated as second-line therapy in patients with disseminated CRC.
    Neoplasma 02/2006; 53(2):119-27. · 1.57 Impact Factor
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    ABSTRACT: Plasma homocysteine has recently been associated with the occurrence of methotrexate-related neurotoxicity. We observed extreme elevations of homocysteine in a 9-year-old boy presenting with leukemia treated with the ALL-BFM 95 protocol. Coma occurred at about the 71st hour from the first methotrexate administration, and lasted for 30 h but MRI and CT studies showed no intracranial pathology. The second course of high-dose methotrexate was administered with no complications. Homocysteine areas under the curve (AUC) were calculated as the sum of areas of rectangles during the 6-hour intervals from T(0) to T(72) hours (AUC(0--72)) and methotrexate AUCs were evaluated using MW/PHARM 3.3 software. The AUC of homocysteine during the first, toxic course was 5.2 times higher than AUC during the second administration, whereas AUC of methotrexate also differed by a factor of 5. Plasma concentrations of folate prior to the first and the second courses, respectively, were 4.4 versus 45 micromol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C 677 T mutation in the MTHFR gene. We suggest that plasma homocysteine, pretreatment plasma folate and possibly the presence of MTHFR mutations may be biomarkers of methotrexate toxicity and possibly its antifolate effect targeted towards the tumor as well.
    Oncology 02/2005; 69(3):269-72. · 2.17 Impact Factor
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    ABSTRACT: The majority of patients with breast carcinoma receive chemotherapy as a component of multimodality treatment. Over the past decade, it has become increasingly more common to deliver chemotherapy first, but this has raised new questions within all disciplines of cancer management. However, the effect of cytotoxic treatment cannot be predicted on individually specific basis, then identification of tumor characteristics associated with tumor therapeutic response and outcome is then of great clinical interest. We studied 141 patients at Masaryk Memorial Cancer Institute, who received neoadjuvant chemotherapy and/or chemotherapy + radiotherapy (CHT/CHT+RT) between 1994-2002. Tumor samples were taken prior to and after neoadjuvant therapy. We quantified the response to therapy pathologically and determined histological and molecular tumor characteristics (steroid receptors, CEA, Ca 15-3). In addition to therapeutic response as immediate outcome, event free survival (EFS) was examined as more complex primary end-point of the study. Complete remission (CR) has been achieved in 6.5%, partial remission (PR) in 49.6%, stable disease (SD) in 26.2% and progression disease (PD) in 17.7% patients. Patients were divided into two groups according to the result of neoadjuvant therapy--responders (CR+PR+SD, who successfully underwent surgery), and risk group (patients with SD or PD, who could not undergo surgery). Responders to neoadjuvant CHT/CHT+RT regimens reached statistically significant better EFS than non-responders, low tumor size (T2) and stage (II) categories were confirmed as additional predictive factors not only for EFS but for therapeutic response as well. The study primarily examined predictive power of tumor markers as CEA, Ca 15-3, and steroid receptors (ER/PR) and searched for their role in the prospective evaluation of neoadjuvant therapy. We evaluated these factors as potential predictors of EFS, independent in predictive power on therapeutic response to neoadjuvant therapy. Diagnostically valuable cut off points were proposed in ROC analysis for all these markers. Responders to the neoadjuvant therapy with Ca 15-3 <23.0 kU/l, CEA <5.0 mg/l, estrogen receptors (ER) >5.0 fmol/mg or both estrogen /progesterone receptors (ER/PR) positive had statistically significantly better EFS in comparison to patients with Ca 15-3 >23.0 kU/l, CEA >5.0 mg/l, ER <5.0 fmol/mg, or other cases than patients double positive in ER/PR. Marker Ca 15-3 revealed significant predictive power even within the group of non- responders, these patients with Ca 15-3 <23.0 kU/l had better EFS as compared to patients with Ca 15-3 >23.0 kU/l. Tumor size and low stage proved predictive value for immediate response to neoadjuvant therapy. Risk parameters for neoadjuvant therapy were T4, stage III, namely if RT was necessary. Therapeutic response to neoadjuvant therapy was independent on investigated molecular parameters, but there was strong predictive association of Ca 15-3, CEA and ER/PR receptors with event free survival development. Diagnostically valuable cut-off points were proposed and validated for sensitivity and specificity in ROC analysis.
    Neoplasma 01/2004; 51(6):471-80. · 1.57 Impact Factor