AIMS: The aim of this study was to compare the expression profile of selected DNA methyltransferases and global DNA methylation status in patients with different phases of multiple myeloma (MM) . For the analysis, different cellular populations including unsorted myeloma cells and a set of plasma cells purified by relevant antibodies were used. Consequently, laboratory data were compared to patients' clinical data. PATIENTS AND METHODS: For the analysis, unsorted bone marrow cell population of 44 MM patients (30 newly diagnosed, 9 relapsed and 5 patients in remission) and a set of 8 patients' samples of sorted plasma cells were used. We used commercially available RNA isolated from BM of 3 healthy individuals as control samples. Expression analysis of three DNA methyltransferases - DNMT1, DNMT3A, and DNMT3B was performed by quantitative RT-PCR and the patient global DNA methylation profiles were detected by colorimetric assay. RESULTS: Unchanged DNMT1 expression was detected in the selected cohort of patients. Normalized DNMT3A gene expression was globally higher in comparison with controls in unsorted and sorted cell populations. Low (0.08-1.81%) global DNA methylation status in unsorted samples of multiple myeloma patients did not correlate either with expression profiles of monitored DNA methyltransferases or with the stages of MM based on Durie-Salmon and International Staging System. CONCLUSION: This is the first comparative study between DNA methyltransferases expression profiles and global DNA methylation status in different phases of multiple myeloma patients. No significant correlation between the level of global methylation and the clinical stage of the unsorted cell population of patients with multiple myeloma was registered. Overexpression of the DNMT3A gene occurred in both sorted and unsorted cell populations of patients with multiple myeloma. This fact highlights the DNMT3A as a potential marker of multiple myeloma tumor progression. Moreover, we demonstrated comparable results in the expression of DNA methyltransferases in both sorted and unsorted cell populations. This is a promising result from the methodical point of view because when compared to samples of unsorted multiple myeloma cells, samples of sorted cells bring reduction of the number of possible analyses performed.

• Klíčová slova
• DNA methylation, DNA methyltransferases, multiple myeloma,
• MeSH
• DNA methyltransferasa 3A MeSH
• DNA MeSH
• lidé MeSH
• metylace DNA * MeSH
• mnohočetný myelom * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA methyltransferasa 3A MeSH
• DNA MeSH

Smouldering multiple myeloma (SMM) presents without MM defining symptoms. We aimed to identify patients with SMM with an 80% risk of progression within 2 years using only serum parameters. In total, 527 patients with SMM were included and divided into a training group (287 patients from the Czech Myeloma Group [CMG]) and an independent validation group (240 patients from Heidelberg). The median follow-up was 2·4 and 2·5 years, respectively. Progression to MM occurred in 51·9% of the CMG and 38·8% of the Heidelberg patients, respectively. The median risk of progression was 11·0% (CMG) and 9·7% (Heidelberg) per year, during the 5 years after diagnosis. A serum involved/uninvolved free light-chain ratio of >30, immunoparesis, and serum monoclonal (M) protein of ≥2·3 g/dl emerged as powerful predictors of 2-year progression rate with a hazard ratio (HR) of 2·49 (95% confidence interval [CI] 1·49-4·17), HR of 2·01 (95% CI 1·36-2·96) and HR of 2·00 (95% CI 1·44-2·79) (P < 0·001) in univariate Cox regression analysis, respectively. Based on this, the CMG model identified patients with SMM with a 2-year risk of progression of 78·7% (95% CI 53·1-95·7; HR 6·8; P < 0·001, CMG) and 81·3% (95% CI 47·1-98·8; HR 38·63; P < 0·001, Heidelberg). Serum parameters in the CMG model allow identification of patients with SMM with an 80% risk of progression to symptomatic MM within 2 years.

• Klíčová slova
• multiple myeloma, overall survival, prognostic marker, progression-free survival, risk factors,
• MeSH
• dospělí MeSH
• doutnající mnohočetný myelom diagnóza   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• progrese nemoci MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

INTRODUCTION: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition with a risk of malignant conversion. PATIENTS AND METHODS: With the aim to estimate the cumulative risk MGUS progression to hematologic malignancies, we analyzed a nationwide population-based cohort of 1887 MGUS patients from the Czech Registry of Monoclonal Gammopathies (RMG) between 2007 and 2013. RESULTS: During the follow-up period (median 4 years; range 0.6-34.8), progression to hematologic malignancies was observed in 8.6% (162 of 1887) of patients. Factors associated with progression were as follows: M-protein concentration ≥1.5 g/dL, pathological sFLC (<0.26 or >1.65) ratio, bone marrow plasma cells (BMPCs) in cytology >5%, immunoparesis, age ≥69 years, and the level of serum hemoglobin at baseline <12.0 g/dL. Combining these factors, we propose a new risk model (CMG model). The risk of progression at 10 years was 1.6%, 16.9%, 22.9%, 39.4%, and 52.3%, respectively, if 0 (reference group), one, two, three, or four to five risk factors are present (P<.001) with HR 63 times higher compared to the reference MGUS group. CONCLUSION: The new CMG model was established with an advantage for better identification of MGUS patients at low risk.

• Klíčová slova
• monoclonal gammopathy, multiple myeloma, progression, risk factors,
• MeSH
• biologické markery MeSH
• hodnocení rizik MeSH
• hybridizace in situ fluorescenční MeSH
• Kaplanův-Meierův odhad MeSH
• kostní dřeň patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• monoklonální gamapatie nejasného významu diagnóza   epidemiologie   metabolismus   MeSH
• myelomové proteiny metabolismus   MeSH
• nádorová transformace buněk MeSH
• plazmatické buňky metabolismus   patologie   MeSH
• progrese nemoci MeSH
• proporcionální rizikové modely MeSH
• registrace MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• surveillance populace MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• biologické markery MeSH
• multiple myeloma M-proteins MeSH Prohlížeč
• myelomové proteiny MeSH

Amyloidosis is a heterogeneous group of diseases characterized by the deposition of amyloid. It is caused by extracellular deposition of insoluble fibrils with beta-pleated sheet configuration. The protein misfolding abnormalities result in amyloid fibrils and may manifest as primary, secondary, or familial amyloidosis. Amyloid deposition can occur in multiple organs (eg, heart, liver, kidney, skin, eyes, lungs, nervous system) resulting in a variety of clinical manifestations. Cardiac involvement can occur as part of a systemic disease or as a localized phenomenon. Cardiac involvement in all types of amyloidosis represents a major negative prognostic factor. Early diagnosis, multi-disciplinary cooperation and proper therapy are key aspects of care for patients with amyloid cardiomyopathy. Early diagnosis is crucial, especially in AL amyloidosis, as patients with advanced heart disease are unsuitable candidates for modern, effective hematological treatment including autologous stem cell transplantation. Despite signal development in diagnostics and therapy, the prognosis for patients with advanced cardiac involvement remains poor. This article is an overview of amyloidosis, providing information about the characteristics of cardiac amyloidosis, and present a structured approach to diagnosis, treatment and prognosis of this condition.

• Klíčová slova
• amyloid cardiomyopathy, amyloidosis, heart diseases, heart failure, restrictive cardiomyopathy,
• MeSH
• amyloidóza komplikace   diagnóza   patofyziologie   terapie   MeSH
• časná diagnóza MeSH
• kardiomyopatie diagnóza   etiologie   patofyziologie   terapie   MeSH
• lidé MeSH
• prognóza MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens. METHODS: In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234. FINDINGS: Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]). INTERPRETATION: Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases. FUNDING: Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.

• MeSH
• bendamustin hydrochlorid aplikace a dávkování   MeSH
• chronická lymfatická leukemie farmakoterapie   patologie   patofyziologie   MeSH
• cyklofosfamid aplikace a dávkování   MeSH
• dospělí MeSH
• imunoterapie * MeSH
• indukce remise MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   terapeutické užití   MeSH
• rituximab aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• vidarabin aplikace a dávkování   analogy a deriváty   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• bendamustin hydrochlorid MeSH
• cyklofosfamid MeSH
• fludarabine MeSH Prohlížeč
• rituximab MeSH
• vidarabin MeSH

• MeSH
• fatální výsledek MeSH
• inzerční mutageneze * MeSH
• lidé MeSH
• lidské chromozomy, pár 11 MeSH
• lidské chromozomy, pár 12 MeSH
• lidské chromozomy, pár 19 MeSH
• lidské chromozomy, pár 6 MeSH
• myelodysplastické syndromy komplikace   diagnóza   genetika   MeSH
• myeloidní leukemie etiologie   MeSH
• protein ETS, translokační varianta 6 MeSH
• protoonkogenní proteiny c-ets genetika   MeSH
• refrakterní anemie s nadbytkem blastů genetika   MeSH
• represorové proteiny genetika   MeSH
• senioři MeSH
• translokace genetická * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH
• Názvy látek
• protoonkogenní proteiny c-ets MeSH
• represorové proteiny MeSH

AIMS: We assessed the long-term outcome of consecutive patients in the chronic phase of chronic myeloid leukemia (CML) treated with interferon-alpha (INF-α) in Central and Northern Moravia between 1989 and 2006. METHODS: A retrospective study focused on the response, prognostic factors and side-effects of INF-α. RESULTS: 118 patients (67 males and 51 females, median age 50 years; range 18-71) were analyzed. The median follow-up was 82.6 months (12.4-212.6). Thirty-six patients (30.5%) achieved major cytogenetic response (CyR) in median of 18.3 months (3.7-47.3) and maintained it for a median of 64.0 months (7.0-176.0). Sixty-one patients treated with INF-α for more than 12 months had an overall survival (OS) of 137.0 months (95% CI 117.6-156.4). Eighteen (29.5%) achieved complete CyR (CCyR). 109 patients discontinued the treatment with INF-α because of hematologic or cytogenetic resistance in 53 (48.7%), progression of CML in 31 (28.4%) and intolerance to INF-α in 17 (15.6%) patients. The percentage of peripheral blasts, leukocyte count (>50x10(9)/L), splenomegaly, anemia (Hgb≤110 g/L) and Sokal score had statistical impact on the OS in univariate assessment but only the Sokal score remained significant in multivariate analysis. Additional cytogenetic abnormalities at diagnosis were associated with poor prognosis. CONCLUSIONS: In most patients, treatment with INF-α had to be stopped because of a failure to induce response, progression of CML or side-effects but nearly one third of patients treated at least for one year had a long-term benefit from INF-α. The best prognosis was associated with achievement of CCyR and negativity of BCR-ABL in nested RT-PCR.

• MeSH
• aplikace orální MeSH
• bcr-abl fúzní proteiny metabolismus   MeSH
• chronická fáze myeloidní leukemie farmakoterapie   mortalita   MeSH
• dospělí MeSH
• interferon alfa aplikace a dávkování   škodlivé účinky   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   MeSH
• retrospektivní studie MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bcr-abl fúzní proteiny MeSH
• interferon alfa MeSH
• protinádorové látky MeSH

AIM: The aim of this study was to assess coagulation markers of endothelial damage and examine new markers of endothelial activation such as matrix metalloproteinases (MMPs) in a group of healthy pregnant women. Matrix metalloproteinase (MMP)-2, in particular, plays a major role in the degradation of the extracellular matrix confirming its essential function in both the survival (angiogenesis) and death of endothelial cells. Detection of specific coagulation factors, mainly released from the vascular endothelium such as vWF, sTM (soluble thrombomodulin) and ePCR (endothelial protein C receptor) and factors dependent on endothelial activation such as t-PA and PAI-1, could provide information on possible endothelial dysfunction and help differentiate pregnant patients with an altered thrombotic state. METHODS: Healthy pregnant women underwent complete assessment for endothelial damage (as vWF, vWF activity, sTM, ePCR, EMP, MMP-2, MMP-9 and TIMP-2) using the ELISA and other methods. RESULTS AND CONCLUSIONS: The results show that endothelial activation during pregnancy is different from that in other pathological conditions involving endothelial damage and typically characterized by higher levels of both coagulation endothelial markers and MMPs. In pregnancy, changes in extracellular matrix composition and matrix metalloproteinase activity also occur and promote vascular remodeling but, only in the uterus. Predisposing risk factors for epithelial dysfunction, and vascular mediators associated with vascular remodeling must be assessed from concentrations in whole blood. The levels of MMPs are not increased in the circulation and the local situation in the uterus cannot be monitored this way. However, MMP-2 processes and modulates the functions of many other vasoactive and pro-inflammatory molecules including adrenomedullin, big endothelin-1, calcitonin gene-related peptide, CCL7/MCP-3, CXCL12/SDF-1, galectin-3, IGFBP-3, IL-1 Beta, S100A8, and S100A9. These molecules represent new potential molecular markers of endothelial damage during pregnancy.

• MeSH
• biologické markery analýza   MeSH
• cévní endotel fyziologie   patofyziologie   MeSH
• extracelulární matrix metabolismus   MeSH
• koagulační faktory metabolismus   MeSH
• komplikace těhotenství patofyziologie   MeSH
• lidé MeSH
• matrixové metaloproteinasy metabolismus   MeSH
• těhotenství fyziologie   MeSH
• tkáňové inhibitory metaloproteinas metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství fyziologie   MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• koagulační faktory MeSH
• matrixové metaloproteinasy MeSH
• tkáňové inhibitory metaloproteinas MeSH

BACKGROUND: Most results on the treatment of chronic myeloid leukaemia (CML) with imatinib were obtained from clinical trials that may differ from the routine practice. We report the results of treatment of consecutive patients with CML at ten major centres during 2000-2008. PATIENTS AND METHODS: Data reporting was retrospective in 2000-2004 and prospective from 2005 on. A total of 661 patients [301 women and 360 men; median age 51 (range, 15-83)] with Ph+CML were registered. The median follow-up was 46.1 months (0-122.2). RESULTS: Most patients were treated with first- (379; 57.3%) or second-line (193; 29.2%) imatinib; some of the patients underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (83; 12.6%), but 6.1% were treated with other modalities [40 patients; median age 66 (range, 32-83)]. The probability of overall survival (OS) at 5 years, according to Kaplan and Meier, was 88.9%, 77.5% and 68.7% for chronic-phase patients treated with first-line imatinib, second-line imatinib and first-line AHSCT, respectively, but only 25.2% for patients receiving other modalities. The OS was dependent on the disease phase and Sokal, Hasford and European group for blood and marrow transplantation (EBMT) risk scores (P<0.001; each). Only 46.2% of deaths in patients treated with other modalities were attributable to CML. Elderly patients over 65 years achieved similar response rates and progression-free survival to the younger ones. There was a trend for inferior results of AHSCT performed after the failure of imatinib (P=0.075), probably as a result of differences in EBMT risk scores (P<0.001). CONCLUSIONS: The ability to achieve results comparable to those of previous clinical studies in our CML cohort was influenced by centralised care. Decisions not to initiate imatinib or to delay AHSCT may have a negative impact on OS, but comorbidities may limit the treatment potential of imatinib in the elderly.

• MeSH
• benzamidy MeSH
• chronická myeloidní leukemie mortalita   terapie   MeSH
• dospělí MeSH
• homologní transplantace MeSH
• imatinib mesylát MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• piperaziny terapeutické užití   MeSH
• přežití bez známek nemoci MeSH
• prospektivní studie MeSH
• protinádorové látky terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• registrace MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transplantace hematopoetických kmenových buněk MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Slovenská republika epidemiologie   MeSH
• Názvy látek
• benzamidy MeSH
• imatinib mesylát MeSH
• piperaziny MeSH
• protinádorové látky MeSH
• pyrimidiny MeSH

BACKGROUND: Follicular lymphoma accounts for about 20-30% of non-Hodgkin's lymphomas. Clinical behaviour and overall prognosis are highly variable, ranging from indolent forms with occasional spontaneous remissions to rapidly progressive disease. METHODS AND RESULTS: Modern treatment strategies have shifted from a primarily "palliative" approach to more intensive risk-adapted therapy with the intention of achieving complete long-term remission. New targeted treatment with monoclonal antibodies (MoAb) and radioimmunoconjugates (RIT) has resulted in unprecedented improvements in treatment outcome. At the same time, a large amount of information is now available on lymphomagenesis, the role of the microenvironment of lymphomatous follicles and cytogenetic abnormalities. We can better understand the role of the patient's innate anti-lymphoma immunity. Although no standard front-line therapy has been established, increasingly more data show that risk-adapted treatment strategy have survival benefits for high-risk patients. For this reason, accurate prognostic indices are urgently needed to find optimal therapies for particular lymphoma patients. Whereas the currently used FLIPI index was established in the pre-rituximab era, the newly designed FLIPI 2 index still needs to be confirmed in prospective trials. CONCLUSION: New therapeutic approaches with MoAb, RIT and other biological agents allow the population to be divided into increasing numbers of groups with different outcomes. All in all, in the near future, we will probably not use only one basic prognostic index for all populations of FL patients. New prognostic schemes should analyze patients separately and include both disease- and patient/host-related parameters.

• MeSH
• folikulární lymfom farmakoterapie   imunologie   mortalita   patologie   MeSH
• hodnocení rizik MeSH
• lidé MeSH
• míra přežití MeSH
• myší monoklonální protilátky terapeutické užití   MeSH
• přežití bez známek nemoci MeSH
• prognóza MeSH
• protinádorové látky terapeutické užití   MeSH
• rituximab MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• myší monoklonální protilátky MeSH
• protinádorové látky MeSH
• rituximab MeSH