Monoclonal gammopathy of clinical signifi cance with osteosclerotic lesions - a case report and a literature review.

INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8 g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.

[Acquired haemophilia A]. / Získaná hemofilie A.

Acquired haemophilia A is a rare auto-immune disease caused by an inhibitory antibody to factor VIII. Patients with this disorder are at high risk of severe bleeding until the inhibitor has been eradicated. Management of this disorder consists in rapid accurate diagnosis, control of bleeding and eradication of the inhibitor by immunosuppression. The cessation of bleeding is based mainly on recombinant factor VIIa and activated prothrombin complex concentrate which are approximately equally efficacious. Immunosuppression is still based on steroids alone or with combination with cyclopfosphamide which may result in a higher rate of remission. New drugs as rituximab or cyclosporine A are the second line option. In case of life-threatening bleeding immunoadsorption and high dose of fac-tor VIII could be advantageous.

[Prognostic significance of morphology in multiple myeloma]. / Prognostický význam morfologického hodnocení u mnohocetného myelomu.

BACKGROUNDS: Multiple myeloma is the second most common hematological disease caused by clonal proliferation of B cells. Evaluation of number of plasmocytes in the bone marrow is still one of the basic diagnostic criteria. The aim of this study was to verify if this evaluation has prognostic value even in the era of new drugs. MATERIAL AND METHODS: Two groups of MM patients were enrolled in this study. The group T - 45 newly diagnosed MM patients who underwent treatment with thalidomide. Group B - 86 patients in first relapse of MM without autologous transplantation of bone marrow that were treated with thalidomide and bortezomib in various combinations. Percentage of subtypes of plasmocytes in the bone marrow was evaluated based on progressive analysis of nucleus, chromatin and nucleo-cellular ratio (N/C). RESULTS: Mature plasma cells were found in 53.3% (group T) and 53.5% (group B) of patients; proplasmocytes I were found in 22.2% (group T) and 24.4% (group B) of patients; proplasmocytes II were found in 22.2% (group T) and 22.1% (group B) of patients and plasmablasts in 1% (group T) and 0% (group B). Patients who reached treatment response after first treatment had statistically significant number of proplasmocytes II when compared to group without treatment response (median 37% vs. 11%, p = 0.033). Group B patients with mature plasmocytes below 10% had significantly shorter overall survival than other patients when comparison of quartiles was performed. Group B patients with higher infiltration of proplasmocytes I than median of 15% had lower overall survival (median 50.3 months vs. 74.9 months, p = 0,024); the same was true for evaluation of proplasmocytes II (median OS 41.3 months vs. 74.9 months, p = 0,011). CONCLUSION: Numerical evaluations of plasma cells in the bone marrow remain basic diagnostic criteria of MM even in the era of new genomics analyses. More precise morphological evaluation of 8 subtypes of plasma cells brings important prognostic information that is necessary for new protocols for immunomodulatory drugs and proteasome inhibitors.

Prognostic significance of morphological assessment of plasma cells in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy caused by clonal proliferation of malignant plasma cells (PC). The aim of the work is to determine prognostic significance of morphological subtypes of PC in relation to overall treatment response, long-term survival and other conventional prognostic parameters. One hundred and thirty-nine newly diagnosed MM patients who underwent autologous transplantation in clinical trials conducted in one center were included. Percentual representation of subtypes of plasma cells in bone marrow was measured based on progressive analysis of nucleolus, nuclear chromatin and ratio of nuclei to the volume of cytoplasm (N/C ratio) creating 8 subtypes P000-P111 and four subclassifications of cells. Mature plasma cells (P000, P001) were found in 42.4% of patients; proplasmocytes I (P010, P011, P100) in 38.1% of patients, and proplasmocytes II (P101, P110) in 19.4% of patients. Patients who reached treatment response after autologous transplantation had statistically significant lower frequency of mature plasma cells than patients with no treatment response (median 24.0% vs. 36.0 %; p=0.032). Patients with mature plasma cells of subtype P000 an patients with value P000 ≥ 37% (median 46.8 months vs. 77.8 months; p = 0.020). Patients with proplasmocytes II subtype P110 rings valuable prognostic information and correlation with other prognostic factors as well as total treatment response and survival in MM patients who underwent autologous transplantation.

[Thrombohaemorrhagic syndrome in patients with a myeloproliferative disease with thrombocythemia]. / Trombohemoragický syndrom u nemocných s myeloproliferativním onemocnenim s trombocytemií.

Thrombohaemorrhagic syndrome is a clinical syndrome manifesting with concurrent bleeding and thrombosis. It is associated with a range of pathological states, typically with myeloproliferative diseases, paraproteinaemia, liver disease as well as disseminated intravascular coagulation and similar syndromes (so called DIC-like syndrome). Thrombohaemorrhagic syndrome might be a symptom of chronic myeloproliferations, particularly if these are associated with thrombocythemia. It is most frequently linked to essential thrombocythemia. However, in this disease, it seems that the clinical symptoms of bleeding and thrombosis might not be directly determined by the number of platelets, as it would suggest itself, but that this can be consequent to other changes. These may include predisposition to thrombophilia, cardiovascular risk, leukocytosis etc. as well as, for example, platelet dysfunction. The present study focuses on platelet dysfunction in conjunction with clinical symptoms of bleeding and thrombosis.

[Essential thrombocythaemia and other myeloproliferative disorders with thrombocythaemia treated with Thromboreductin. A report from the database of register for the 1st quarter of 2010]. / Esenciální trombocytemie a jiné myeloproliferate s trombocytemií lécené Thromboreductinem. Výstupy z databáze Registru k 1. ctvrtletí roku 2010.

In the Czech Republic, anagrelid is used according to the recommendations of the Czech Working Group on Myeloproliferative Disorders for treatment ofthrombocythaemias associated with chronic myeloproliferative disorders--mainly essential thrombocythaemia and, regularly, reports are being presented from the Register of Patients Treated with Thromboreductin, most recently last year (Vnitr Lék 2009; 55: I-XII). The Register commenced in 2005 and from then it aims to determine detailed clinical and laboratory profiles of the patients. The structure of the Register has changed significantly in the course of its existence, reflecting the reports from each of the analyses conducted so far. Also, the data entry in the database improves every year and it reaches 97% on some of the items. The longest evaluation period in some of the patients is 108 months. By April 2010, the Register database contained data on 717 patients. Of these, 672 patients with the diagnosis of a Ph-negative chronic myeloproliferative disorder were evaluated. This year's analysis included the patients with essential thrombocythaemia, polycythaemia vera and primary myelofibrosis only. The analysis included 418 women and 254 men with median age of50 years. Unlike the first years, 2/3 of the current sample are non pretreated patients, meaning that the patients reach the specialized centres early in their treatment. Also, patients, and the older patients in particular, are more frequently treated with combined regimens including Thromboreductin. We increasingly observe hypertension as one of the monitored risk factors preceding the disease and laboratory parameters showJAK2 mutation in more than a half of patients while some form ofthrombotic diathesis is found in the anamnesis of 7-10% of patients. Some bleeding is observed in 1-5% of the registered patients. In comparison to the previous years, this is a decrease in the prevalence of clinical symptoms prior to the disease onset; this is very likely associated with an earlier patient diagnosis within the asymptomatic phase of the disease. Therapeutically, we achieve a fast treatment response but there still are 16.3% of sufficient afterone year of treatment. Thromboreductin dose is increasing but even in this group it does not exceeds the mean of 2.38 mg per 24 hours. Complications are observed in 6.2% of patients in the first year of therapy, and ofthese, thrombotic events in about 2.5% and (small) bleeding complications in 4% of patients. The data suggest that we still do not reach treatment response in a certain proportion of patients after a year of their therapy. Even though the care results from the analysed data improve every year, the Register helps to uncover some issues that still remain, such as treatment intensification and other treatment modifications.

FEIBA in treatment of acute bleeding episodes in patients with haemophilia A and factor VIII inhibitors: a retrospective survey in regional haemophilia centre.

FEIBA (factor eight inhibitor by-passing activity) is used to achieve haemostasis in haemophiliacs with inhibitor. The aim of this study was to evaluate efficacy and consumption of the product in treatment of haemorrhages in haemophiliacs with factor VIII inhibitor, and determine factors that can influence the results of treatment. We used data from our haemophilia centre from years 2000-2008. Six haemophiliacs with factor VIII inhibitor were treated on demand with FEIBA for 61 bleeding episodes (45 haemarthroses, six muscle bleeds, six other sites bleeds and four multiple sites bleeds). The median cumulative dose of FEIBA per bleeding episode was 205 U kg(-1). Bleeding was stopped in 96.7% (59 of 61) of events but re-bleeding occurred in 3 events (4.9%) within 48 h after cessation of bleeding. In home treatment (20 of 61) bleeding stopped in 90% (18 of 20) without recurrence and the median consumption per event was reduced to 153 U kg(-1). Without the use of home treatment the median consumption was 250 U kg(-1) per event and bleeding ceased definitely in 92.7% (38 of 41) of cases. The cumulative dose of FEIBA was lower for three episodes with re-bleeding: median 96 U kg(-1) but not in the two cases of ineffective treatment: 361 U kg(-1). FEIBA in management of bleeding episodes completely resolved the haemorrhage in 91.8% of events and in a further 4.9% if treatment was restarted. Using home treatment saved expenditure due to the lower cumulative dose needed for treatment of haemorrhage.

[Antiphospholipid syndrome in the year 2009]. / Antifosfolipidový syndrom v roce 2009.

Antiphospholipid syndrome is a prothrombotic disorder characterized by vascular occlusions and/or pregnancy morbidity in the presence of antiphospholipid antibodies. These autoantibodies represent a large and heterogenous family of circulating immunoglobulins usually identified as anticardiolipin antibodies and antibodies directed against beta2-glykoprotein I or as lupus anticoagulant. A number of criteria for diagnosis of antiphospholipid syndrome have been proposed. In this review, we focused on long-term process of diagnostic procedures development and future directions in scientific research in this field.

[Treatment of haemorrhage with transfusion preparations and blood derivatives]. / Lécba krvácení transfuzními prípravky a krevními deriváty.

Appropriate use of blood components and blood products improved both patients care and use of health care resources. In bleeding and/or risk bleeding situations use of these products is often indicated. The authors summarise different guidelines, experiences, indications and problems in hemotherapy concerning bleeding complications.

[Preparation of patients with haemostatic disorder for invasive medical interventions]. / Príprava pacientu s poruchou hemostázy k invazivním lékarským zákrokum.

The current trend in medicine is to sustain the possibility for necessary procedures to be performed in patients who suffer from haemostatic disorders which complicate eventual surgery. Among such disorders are congenital blood coagulation disorders, haemostatic disorders concomitant with other diseases and also therapies which affect haemostasis either on purpose or as part of adverse effects. Among coagulation disorders are congenital haemorrhagic or thrombotic conditions, acquired blood coagulation disorders--combined in the vast majority of cases-- and associated with pregnancy, severe internal diseases and surgery related diseases, severe injuries, wounds, burns, malignancies, systemic connective tissue diseases, inflammatory bowel disease, and a number of other diseases. A separate issue is that ofanticoagulation therapy--both antiplatelet, used in the treatment or prevention of venous thrombosis, and anticoagulation, predominantly used to manage venous thromboembolism. Also considered should be any therapy which may have a negative impact on coagulation due to its adverse effects.

[Preparation of patients with haemostasis disorder for dental surgery]. / Príprava nemocných s poruchou hemostázy ke stomatochirurgickým výkonum.

The most of patients need dental care during their time of life. It can be situation to detect bleeding disorder in patients who have been suggested apparently healthy to this time. In patients with known bleeding tendency it can be situation in which good interdisciplinary coordination is necessary. In the most cases patients with anticoagulation treatment are involved between those with haemostasis problems. Nevertheless, they do not need therapy interruption in the most of cases, only the knowing actual therapeutic level of INR and appropriate stomatologist's erudition. Another situation is in patients with severe haemostatic bleeding disorder. They don't need only special procedure in dental extractions but also lifelong dental care. One can establish patients, in whom it is not possible only outpatient treatment but in whom a few days hospitalization is necessary. Above all they are patients with haemophilia and inhibitor, those with multiple or surgery extractions and persons with multiple haemostasis impairment.

[The preparation of a patient with long-term anticoagulant cumarin treatment for invasive surgery]. / Príprava nemocných na dlouhodobé antikoagulacní lécbe kumariny k invazivním zákrokum.

Coumarins belong to drugs widely used and the spectrum of their use is going to grow. From this point of view and/or because the coumarins are adminstrated in patients who are treated for the other diseases--medical or surgical--at the same time, it is necessary to modify, interrupt or replace peroral anticoagulant treatment in the dependence on various aspects. It requires to compound different algorithms for given situations solution. It is always to decide, if the situation is imperative from the view of solution planed, what risk brings proposed treatment and what is the risk of anticoagulant treatment modification.

[Complications of heparin administration]. / Komplikace podávání heparinu.

Heparin as an indirect anticoagulant is used in the clinical practice for more than 60 years. It is an effective drug, but it has limitations. To the side effects belong the heparin resistance, risk of bleeding (haemorrhage), hypersensitivity reactions and heparin-induced osteoporosis. The low-molecular-weight heparins exhibit fewer side effects, but it is still necessary to know about them.

[Anticoagulant treatment failure]. / Selhání antikoagulacní lécby.

Anticoagulant therapy includes unfractionated heparin and vitamin K antagonists' administration. In both of these two types of drugs a treatment failure could occur. Currently available anticoagulants have a numerous disadvantages which could be involved in causes of their malfunctioning. During every new event of the re-thrombosis it is necessary to analyse all circumstances which influence this unfavourable outcome. Firstly, cases during adequate and non-adequate therapy should be distinguished. Secondly, it is important to identify the reasons of the treatment failure. Cancer and/or antiphospholipid antibodies are the main causes of re-thrombosis during adequate therapy. The conditions, which could steer for to non-adequate anticoagulation are various, and their identification could be difficult. The most important thing in this process is the objective documentation of the re-thrombosis. More efficacious, safer, and easier to use anticoagulants are under development. Some of them could bring a problem solution for these patients who underwent anticoagulant treatment failure.

[Incidence of selected antiphospholipid antibodies in a group of patients with systemic lupus erythematosus]. / Výskyt vybraných antifosfolipidových protilátek u skupiny nemocných se systémovým lupus erythematodes.

Antiphospholipid antibodies (APLA) present very heterogeneous groups of antibodies which can significantly and in various ways influence processes on different levels of coagulation cascade. Their presence can be accompanied with repetitive venous and arterial thromboses, recurrent loses of foetus, and thrombocytopenia. Incidence of these thrombotic disorders was monitored in a group of 46 patients with systemic lupus erythematodes (SLE). Positive lupus anticoagulant (LA), antiphospholipid antibodies complex, and thrombocyte counts were assessed. Thrombotic disorders were assessed in a retrospective analysis. In the LA+ group 62% of patients had history of venous thromboses, 31% had history of arterial thromboses, and 18% had history of spontaneous abortions. In a group without positive LA 18% of venous thromboses (p = 0.0006) and 6% of arterial thromboses (p = 0.03) were indicated. In the assessment of spontaneous abortions no statistically significant difference was found. An average value of thrombocytes in LA+ group was 152 +/- 66 x 10(5)/l, in LA- group 223 +/- 86 x 10(5)/l, which is statistically significant difference (p < 0.05). In the assessment of thrombotic disorders in a group with combination LA+ and APA+ statistical significance was indicated only in venous thromboses (p = 0.004). We can state from the results that in thrombotic disorders which can be seen in the framework of systemic tissue disorders positive LA and APA and a range of other factors such as activity of a basic disease, associated diseases, and treatment which can aggravate thrombotic disorders of individual patients can participate.

Generation of dendritic cells using cell culture bags--description of a method and review of literature.

Anticancer immunotherapy using dendritic cell-based vaccines is a strategy aimed at the induction and maintenance of immune responses against cancer cells. Clinical applications of dendritic cells (DCs) require stringent adherence to Good Manufacturing Practice (GMP) methods and rigorous standardization of DC-based vaccine preparation. Recently, closed systems for DC culture have been developed with a goal to minimize the risk of contamination. Here, we compare the yield, immunophenotype, and functional properties of DCs generated in Lifecell X-Fold culture bags and in plastic wells, both from adherence-selected monocytes, and review the current literature on closed systems for DC generation. We found that both the overall yield and the yield of CD83+ cells in cell culture bags was lower than in the standard culture method. No statistically significant differences were observed in the expression of DC immunophenotypic markers. The capability of DCs cultured in bags and in wells to induce the proliferation of allogeneic mononuclear cells were equivalent. The performance of DCs in mixed lymphocyte reaction correlated significantly (p = 0.005) with the CD83 expression but not with the CD80, CD86, HLA-DR, CD1a, and CD1c expression. We conclude that the immunophenotype and stimulatory properties of DCs cultured in closed cell culture bags are similar to those generated by conventional method using cell culture wells.

[Hereditary thrombocytopenia. Differential diagnosis of a case]. / Dedicné trombocytopenie. Diferenciální diagnostika jednoho prípadu.

Hereditary thrombocytopenias are a heterogeneous group of extremely rare diseases characterized by a reduced number of blood platelets and by bleeding tendency of variable severity. Some of these diseases are exclusive to platelets, while in others the pathology extends to other cell types. Although rare, hereditary thrombocytopenias should be considered in the diagnosis. Hereditary thrombocytopenias have been classified into three groups depending on platelet volume. Hereditary thrombocytopenias with giant platelets form one of these groups. About fourteen clinical entities of inherited giant platelet disorders have been described. Bernard-Soulier syndrome, grey platelet syndrome and May-Hegglin anomaly are the most common giant platelet thrombocytopenias. May-Hegglin anomaly is condition characterized by the triad of thrombocytopenia, giant platelets, and pale-blue inclusions in leukocytes. May-Hegglin anomaly has an autosomal-dominant mode of inheritance. We described clinical and laboratory features of three adult women from one family with recently diagnosed May-Hegglin anomaly. Described cases are probably the first observed cases of May-Hegglin anomaly in the Czech lands.

[Hemophagocytic syndrome (case report and literature review)]. / Hemofagocytární syndrom (Kazuistika a review literatury).

The haemophagocytic syndrome (HPS) is clinically characterized by fever, pancytopenia and hepatosplenomegaly. Usually it takes an acute course with a high mortality. The pathogenetic basis is inadequate activation of the immune system--in particular Th1-lymphocytes with subsequent overproduction of cytokines and extreme activation of macrophages with haemophagocytosis. The activated cells infiltrate organs, cause tissue damage and clinical manifestations of the syndrome. From the etiological aspect two forms exist: primary (familial) with autosomal recessive inheritance and the secondary form which forms a heterogeneous sub-group, caused as a rule by infection and/or a tumour. The prognosis seems somewhat more favourable in secondary forms. In treatment which is essentially the same for both forms, chemotherapy combined with immunosuppression proves useful, in more aggressive forms chemotherapy as used in the treatment of non-Hodgkin lymphomas. The only curative method is transplantation of haematopoietic stem cells which is also the treatment of first choice in the familial form of haemophagocytosis. In the submitted paper the authors present a review of contemporary knowledge on this treacherous and relatively rare entity. The haemopgagocytic syndrome should be always taken into account in the differential diagnosis of fever with an obscure etiology. The authors assume that the haemophagocytic syndrome is rarely considered in practice and therefore is usually inadequately diagnosed and thus not treated in time. In the conclusion the authors describe the case-records of a 26-year-old female patient with haemophagocytic syndrome which developed during pregnancy.

Detection of 13q abnormalities in multiple myeloma using immunomagnetically selected plasma cells.

Accurate prognostic evaluation of patients with multiple myeloma (MM) is required for their stratification for more adequate therapy. Chromosomal G-banding and interphase fluorescence in situ hybridization (FISH) on cell-nonspecific samples and on myeloma cells selected by magnetic-activated cell separation (MACS) were used to study 13 samples from 12 multiple myeloma (MM) patients. Bone marrow (BM) samples were analysed using three approaches. Standard mitotic samples were prepared and analysed after G-banding. Interphase FISH was performed to detect the 13q14 deletion in unselected BM cells. In parallel, myeloma cells were selected from the BM using the CD138-specific antibody. The high-purity myeloma cell suspension was then analysed by interphase FISH for the 13q14 deletion. Magnetic separation yielded enriched myeloma cell suspensions with the mean viability of 98.0% (range: 97.0%-99.0%), and the purity of 97.6% (range: 87.2%-99.2%) as detected morphologically, and 85.2% (range: 44.8%-98.4%) as detected by immunophenotyping for CD138+ cells. Interphase FISH revealed the 13q14.3 deletion in 5 of 13 (38.5%) of cell-nonspecific samples and in 9 of 13 (69.2%) of enriched myeloma cell suspensions. In conclusion, interphase FISH on immunomagnetically selected MM cells increases the detection of the 13q14 deletion in BM samples from the patients with MM.

[The factor V Leiden mutation in users of hormonal contraceptives]. / Leidenská mutace faktoru V u uzivatelek hormonální antikoncepce.

OBJECTIVE: To assess the frequency of factor V Leiden in oral contraceptive users and to define possible anamnestic data that could predict the presence of factor V Leiden. METHODS: Between 1997 and 1998, 583 users of oral estrogen-progestin contraceptives with no history of thrombotic disease were examined. Factor V Leiden was assessed by PCR after isolating DNA from a peripheral venous blood sample. Among other factors, such things as a family history of thromboembolic disease, myocardial infarction and/or stroke in a first-degree relative were monitored. In 448 users cardiovascular complications were evaluated during six months of oral contraceptive use. The data were analyzed using a MS Excel program. P-values were assessed by pair-tests and chi-square tests. SETTING: 1st Department of Obstetrics and Gynecology of Medical Faculty, Masaryk University, Brno. RESULTS: Factor V Leiden frequency was 6.5% in the study group. There were no differences between carriers and others in age, body weight, body mass index and blood pressure. Carriers had significantly more frequently positive family histories of thromboembolic disease or myocardial infarction or stroke. There were no cardiovascular complications observed in a group of 448 users. The positive family histories of any of the above-mentioned conditions have high specificity (97-99%) and a negative predictive value (0.94) with a low sensitivity (2.6-15.8%) in predicting factor V Leiden presence. CONCLUSION: We found a relatively high incidence of Factor V Leiden among oral contraceptive users without a history of thrombotic disease. Through a positive family history of thromboembolic disease or myocardial infarction or stroke, we can predict a Factor V Leiden presence with high specificity but low sensitivity.