Distinguishing of primary mediastinal B-cell lymphoma and diffuse large B-cell lymphoma using real-time quantitative polymerase chain reaction.

Primary mediastinal B-cell lymphoma (PMBL) seems to be reliably distinguished from diffuse large B-cell lymphoma (DLBCL) with microarray technology. We measured expression of Fcer2, Pdl2 and Blk genes using real-time quantitative polymerase chain reaction (RTqPCR) on formalin fixed, paraffin embedded material (FFPE) and suggested a formula to discriminate PMBL from DLBCL. For 39/82 included patients the diagnosis of PMBL was expected clinico-pathologically. Diagnosis of 10/39 and 2/43 of clinically considered PMBLs and DLBCLs, respectively, was not genetically confirmed. Compared to confirmed PMBLs, unconfirmed ones showed clinical features similar to DLBCLs, e.g. spleen infiltration (p=0,028) and decreased invasiveness in pericardium (p=0,045). They tended to have more common infradiaphragmatic involvement, less often tumor sclerosis or fluidothorax. There were no immunohistochemical differences between genetically confirmed and unconfirmed PMBLs. New approach of distinguishing PMBL and DLBCL is presented. It is based on expression of three genes in routinely available FFPE material using RTqPCR.

Reduced-intensity conditioning for allogeneic stem cell transplantation in patients with chronic myeloid leukemia is associated with better overall survival but inferior disease-free survival when compared with myeloablative conditioning - a retrospective study of the Czech National Hematopoietic Stem Cell Transplantation Registry.

Allogeneic stem cell transplantation (AlloSCT) has been currently recommended in the treatment of patients with chronic myeloid leukemia (CML) as a second option after imatinib failure or in selected group of patients with high-risk CML and low risk for transplant-related mortality. The actual role of reduced-intensity conditioning (RIC) before AlloSCT in CML patients has not been yet conclusively established. The Czech National Hematopoietic Stem Cell Transplantation Registry has conducted a retrospective analysis of all patients (n=29) transplanted after RIC from the Registry database containing 295 patients with CML transplanted in the Czech Republic in years 1988-2005 and compared them with patients at comparable age (median age 48.3 and 50.6 years, respectively; p=0.587) transplanted during the same period of time using conventional myeloablative conditioning (n=26). Survival advantage of patients transplanted after RIC has been confirmed by log rank test (p=0.036) despite the fact that the relapse rate was significantly higher in RIC group (44.8% versus 0%). Both groups did not differ significantly in the use of voluntary unrelated donors, type of the grafts and in incidence of acute graft versus host disease (GVHD). However, there were trends for higher risk of CML and higher use of unrelated donors in the myeloablative group while peripheral stem cell grafts and chronic GVHD were observed more frequently in the RIC group. Transplant-related mortality was the leading cause of death in both groups of patients. Our results should be interpreted with caution because they may be influenced by small groups of subjects and also the impact of patients with high EBMT risk score on inferior survival in the myeloablative group cannot be fully eliminated. More retrospective and prospective studies are needed to elucidate the actual role of RIC before AlloSCT for CML.

[High dose therapy with autologous stem cell transplantation in patients with Hodgkin's lymphoma: long-term follow-up in patients treated in one center]. / Vysokodávkovaná terapie s autologní transplantací krvetvorných bunek u nemocných s Hodgkinovým lymfomem: dlouhodobé sledování nemocných lécených v jednom centru.

BACKGROUND: Majority of patients with Hodgkin's Lymphoma (HL) can be cured by first line therapy. The high dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the option which can be used in the situation when the conventional therapy failed. METHODS AND RESULTS. Beginning 1994 till 2005 84 pts with HL who did not respond the conventional chemotherapy underwent 105 HDT procedures with ASCT. The median age at the time of HDT was 30.5 years. The reason for salvage therapy followed by HDT with ASCT was the failure to achieve 1st complete remission-- CR (n 16) or the subsequent relapse or progression (n 68). The disease status at the time of HDT after conventional salvage chemotherapy was assessed as chemosensitive in 65 pts (77.4%) and chemoresistant in 19 pts (22.6%). The most frequent HDT regimen used was BEAM (82 HDT), 22 pts entered into the tandem HDT program. Bone marrow only was used as the source of progenitor cells in 4 ASCT, peripheral blood progenitor cells (PBPC) only were used in 85 ASCT and the combination of both in 16 ASCT. The disease status after the HDT with ASCT was assessed (77 pts were qualifiable) as CR in 39 pts (50.6%), PR in 31 (40.3%) and as stable disease or progression in 7 pts (9.1%). Treatment related mortality in HDT with PBPC was 3.9%. The median follow up is 5.3 years. The five year probability of event free survival (EFS) is 43.1% and overall survival 53.2%. The EFS and OS probability respectively for the chemosensitive patients was 48.6% and 62.9% respectively. The status at HDT and the results after it have prognostic significance. There were observed 39 deaths and 26 of them were caused by disease progression. Secondary tumor was observed in 5 pts and in all of them it caused the death. CONCLUSIONS: The HDT with ASCT allows the long-term survival without disease progression in about a half of the patients with reasonable toxicity.

[Allogeneic hematopoietic stem cell transplantation in patients with chronic myeloid leukemia in the Czech Republic--a retrospective analysis of results in years 1988-2005]. / Alogenní transplantace krvetvorných bunek u nemocných s chronickou myeloidni leukemií v Ceské republice: retrospektivní hodnocení výsledku z let 1988 az 2005.

Analyses of hematopoietic stem cell transplantation (SCT) results are of high importance for decision-making on treatment strategy for patients with SCT as a possible therapeutic alternative. In this paper the Czech National Registry of SCT and Transplantation Centre in Pilsen present their joint retrospective analysis of the results of allogeneic SCT in patients with chronic myeloid leukemia (CML) performed in the Czech Republic from 1988 to spring 2005. 295 patients (179 men and 116 women) ranging in age from 6.9 to 59.5 years (median 37.3) underwent transplants. In most cases the donor was an HLA-identical sibling (164; 55.6%) or a voluntary unrelated donor from the register (110; 37.3%), in a minority of cases another relative of the patient (21; 7.1%). Myeloablative conditioning was used in 90% of patients. The source of hematopoietic stem cells was bone marrow in 57%, peripheral blood in 41% and combination of both in 2% of cases. 83.4% of patients underwent transplant in the chronic phase of the illness while 7.8% in the acceleration phase and 6.1% in the blastic phase respectively. The median interval from the diagnosis to SCT was 316 days. Median follow-up after SCT was 2 years. SCT was complicated by acute graft versus host disease of grade II-IV in 33.7% of patients and by chronic graft versus host disease in 36.3% of patients. Median survival was not reached, 18 (6.1%) of patients died due to the relapse of CML and the cause of 101 (34.2%) deaths was transplant-related. Significant trends were observed during the study period: SCT were performed more frequently in older patients, less than one year from the diagnosis, reduced-intensity conditioning was used more often and the source of hematopoietic stem cells was peripheral blood in the majority of patients (p = 0.188 - < 0.0001). Also, transplantation activity changed - the annual rate of SCT increased steadily until 1999, while there was no such an increase between 2000 and 2005. The use of peripheral stem cells was associated with chronic graft versus host disease (p = 0.007). In Cox multivariate analysis the EBMT risk score and the interval from the diagnosis to SCT were identified as independent factors in patient survival. An "ideal" patient, aged under 30, undergoing transplant in the chronic phase of CML within one year since the diagnosis after 2000 had a survival probability of 88% for three years after SCT. It can be concluded that results of allogeneic SCT in CML in the Czech Republic reflect current global trends, are comparable with results achieved in other countries and show significant improvements.

[Cell clonality in myelodysplastic syndrome]. / Bunecná klonalita u myelodysplastického syndromu.

INTRODUCTION: Myelodysplastic syndromes (MDS) are classified as oncohematologic, clonal diseases. However, some MDS subtypes lack malignant clinical features. Literary data on the clonality of blood cells in MDS are controversial. Therefore we examined the clonality in the group of our own MDS patients. We were especially interested in the comparison of the clonality of myeloid and lymphoid cell line-ages. METHODS AND MATERIAL: Using X-chromosome inactivation methods based on polymorphism in human androgen receptor gene (HUMARA), iduronate sulphatase gene (IDS) and protein p55 gene, we assessed the clonality of granulocytes, monocytes and T-lymphocytes of 49 female patients with MDS and 12 control women of various ages. RESULTS: Though the results were heterogeneous, certain trends were observed: most frequently monoclonality of monocytes was found (51%), granulocytes were monoclonal in 33% of cases, monoclonal T lymphocytes only in 8% of cases. There was no case with monoclonal T lymphocytes and simultaneously polyclonal myeloid cell fractions. Results differ in relation to the subtypes of MDS. Among controls we observed monoclonality of myeloid cells in one case of an old lady. WE CONCLUDE: The results confirm the presence of malignant clone of myeloid cells in MDS, which can be of variable size. The examination of the clonality in MDS can be significant for the therapy decision. Monoclonal myeloid cells are found least frequently in refractory anemia, most frequently in RAEB-T. Monoclonality of cells in sideroblastic anemia is interesting. The prevailing polyclonality of T lymphocytes in MDS can be explained by the presence of a long-lived cell population originating from the period before the development of MDS. The role of the polyclonal memory T cells in the antitumor immunity in MDS is discussed.

[Pathogenesis and therapy of multiple sclerosis]. / Patogeneza a terapie mnohotné (roztrousené) sklerózy mozkomísní.

Multiple sclerosis (MS) is one of the most frequent serious neurologic diseases. Etiologically, MS involves genetic, viral and other factors. The key pathogenic mechanisms reside in the autoimmune reaction of activated CD4+ T lymphocytes crossing the haematoencephalic barrier and attacking different epitopes of the basic protein and proteolipid of myelin sheaths. The damaging reaction involving activated macrophages, destructive inflammatory cytokines and toxic radicals leads to the development of disseminated plaques. The passage of autoimmune T lymphocytes to the brain tissue is facilitated by overexpression of adhesion molecules on endothelial cells, neural cells and immunocytes. The diagnosis of MS is based on characteristic changes in the blood and liquor, and on the results of modern methods, especially (gadolinium enhanced) MRI. The "classical" treatment is based on glucorticosteroids, azathioprine, cyclophosphamide and other chemicals which are not fully satisfactory and are accompanied by serious side-effects. Therefore, attention will be paid to three prospective biological methods of treatment: 1) peroral application of bovine myelin, its fractions, and synthetic copolymer-1, aimed at the restoration of immune tolerance; 2) injections of natural and recombinant interferon-beta, interfering with the pathogenic IFN-gamma and other cytokines; 3) systemic enzyme therapy (residing in peroral application of combinations of animal and herbal hydrolytic enzymes), which modulates adhesion molecules and suppresses the activation of autoimmune T lymphocytes. The chief results of clinical studies with respect to the effectiveness and safety of these therapeutic methods, will be summarized. (Ref. 34.)

Midodrine, a new therapeutic agent: recent experience.

Midodrine, marketed as Gutron by Hafslund Nycomed, was given at a dose of 2.5 mg three times daily always half an hour after the main meal for a period of 84 days to 8 women in the age of 25.42 years--average 34.5 yrs--and BMI of 19.8. These women with a blood pressure value below 100/60 mmHg most of the time displayed signs of neuroticism but had no organic and neurologic lesion. Clinical internal examination, Jarmatz-de Marée test, ECG-supine, standing, Holter dynamic ECG, ergometry, arterial and venous plethysmography, Doppler distal pressures-supine, standing, clinical neurological examination, EEG, perfusion brain tomography-supine, standing, urine examination--chemically and microscopically--, blood count, Na, K, Cl, glucose, urea, creatinine, uric acid, bilirubin, gamma-GT, alk. phosphatase, LDH, ALT, AST, thrombocyte index and the count of desquamated endothelia in blood before and after the end of 84-days Gutron therapy were carried out. It was ascertained that: (1) Gutron had no side effects; the marked subjective improvement reported by all patients persisted for months after the end of therapy. (2) No changes in biochemical parameters, ECG, Holter ECG monitoring, pulse rate, Doppler index and EEG were found. (3) Gutron did not raise the tendency to platelet aggregation and had no toxic effect on the vascular endothelium as demonstrated by unchanged thrombocyte index and endothelaemia. (4) Gutron administration was associated with a significant rise in upright diastolic pressure, especially when standing for prolonged periods--Jarmatz-de Marée test.(ABSTRACT TRUNCATED AT 250 WORDS)

[Treatment of polyneuropathy using sabeluzole]. / Lécba polyneuropatií sabeluzolem.

Two groups of patients suffering from polyneuropathy were treated by sabeluzol. The first group--a double blind placebo controlled study consisting of 30 diabetics of type II did not prove either significant differences of their subjective complaints or changes of their objective findings (the dose of sabeluzole being 2 x 10 mg/d). The second group--open study--consisting of 26 patients suffering from polyneuropathy of various origin, treated by sabeluzole 3 x 10 mg/d. The therapeutic effect was significantly higher in comparison to the above mentioned lower doses of the medicament (manifesting statistical significance of 5 and 10%); the authors make a point of sabeluzol's therapeutic efficacy, especially in cases with acute polyneuropathy onset and point out the necessity of several months lasting treatment. Positive effect upon the pseudoneurasthenic syndrome in many patients indicates its usefulness also in other disorders than are these of polyneuropathy.

Pharmacokinetics of lamotrigine (Lamictal) in plasma and saliva.

The kinetics of lamotrigine (LTG) disposition in plasma and saliva was evaluated in patients undergoing long-term antiepileptic drug therapy. Blood and saliva samples were collected simultaneously at intervals during the study and the concentration of LTG was measured by HPLC. Concentrations of LTG in saliva were proportional to plasma LTG concentrations, with a significant (p) correlation of r = 0.95 + 0.18. The saliva concentration-time curves of LTG were parallel to those derived for plasma LTG. The kinetics of LTG absorption, elimination and mean residence time were identical in both saliva and plasma estimations. The saliva/plasma ratio, determined from the terminal phase of individual patient LTG concentration vs time curves, was used to predict plasma LTG concentrations from saliva determinations. The binding of LTG to plasma proteins remained constant in patients treated with sodium valproate and/or enzyme-inducing drugs. Thus, LTG determination in saliva represents a noninvasive alternative for therapeutic drug monitoring and may also be employed for studying LTG pharmacokinetics.

[The effect of muscle relaxants on the function of the vestibulo-ocular reflex arc]. / Vliv myorelaxancií na funkce vestibulokulárního reflexního okruhu.

Baclofen affects in experiments the reactivity of the vestibuloocular reflex by influencing the time constant of the vestibular nystagmus. The authors compare in three healthy volunteers the reactivity of the vestibular apparatus after administration of Baclofen and a new muscle-relaxant drug tizanidine. The authors evaluate basic parameters of the vestibular and optokinetic nystagmus (gain and time constant), discuss the problem of GABAergic (Baclofen) and monoaminergic (tizanide) receptors kin the area of the vestibular apparatus. As regards the effect on the reactivity of the vestibular system, tizanidine does not affect immediately the response of the vestibuloocular reflex but interferes with processes ensured by the central neuronal integrator.

Vestibular abnormalities in encephalopathia pugilistica.

Vestibulological examination of boxers revealed that 80% had vestibular abnormalities. These were obvious, but well compensated, so that they remained hidden in everyday life and appeared only on laboratory examination or under stress. Regarding the origin of vestibulo-ocular reflex, abnormalities in boxing contribute three etiopathogenetic factors: the first is the direct traumatization of the vestibular apparatus by a direct blow. The second is the diffuse damage of the brain-stem white matter and of vestibular nuclei. The third factor is the traumatization of the cervical spine via the traumatization of the proprioceptive systems, cervical sympathetic and the adjacent vascular mechanisms. One-third of the abnormalities are caused by direct labyrinthine traumatization. The findings of simultaneous EEG, OKN and ETT abnormalities in one-half of our subjects suggests that there are probably also supratentorial lesions caused by the above-mentioned mechanisms.

Terguride in parkinsonism. A multicenter trial.

Terguride is an ergoline derivative with mixed agonistic/antagonistic dopaminergic activity. This led to a paradoxical suggestion that it is effective in the treatment of both schizophrenia and parkinsonism. A total of 65 in- or outpatients with parkinsonism mostly of vascular or idiopathic etiology were included in a 4-week, open, multicenter trial. Terguride was administered under an increasing dose schedule which was leveled off according to the clinical response. Mostly because of nausea, vomiting, and lack of improvement 25% of inpatients and 61% of outpatients were removed from the study. The average daily dose at the end of the trial was 4.2 mg, ranging from 1.0 to 5.5 mg. The average Simpson and Angus scale total score and performance in the Spiral Drawing Task improved significantly during the trial by 20% and 38% respectively. The following adverse effects were noted most frequently throughout the study (including those who withdrew): constipation (occurred in 42% of all ratings performed during the trial) drowsiness and nausea (16% each). Adverse circulatory effects were negligible. Psychotic symptoms, including depression, confusion, hallucinations, and paranoid syndrome, each occurred in 1 patient, i.e., at a lower rate than with other dopaminergic drugs. Scotopic electroretinograms in a subsample of 7 patients showed a significant transitory decrease in the B-wave amplitude at the end of the 1st week and a subsequent return to pretreatment values.