[Bone changes in multiple myeloma--current etiopathogenic, diagnostic and therapeutic aspects]. / Kostné zmeny pri mnohopocetnom myelóme--súcasné etiopatogenetické, diagnostické a liecebné aspekty.

Myelomatous bone disease affects about 90% patients with multiple myeloma and solitary myeloma as well. In initial stage it is manifested as osteopenia with osteoporosis or osteolytic foci, pathologic fractures followed by neurologic complications. Ethiopathogenitically a role is played by cytokine interactions with local chemokines produced by myeloma cells and activated stromal and hemopoietic cells (osteoblasts, monocytes, macrophages) resp. From the TNF-alpha family glycoprotein complexes are liberated (RANK-L), which support activation and proliferation or are inhibitory (osteoprotegerins). Similarly in the family TGF-beta several izotypes of antiinflammatory cytokines are known (the most important is TGF-beta 1 and the morphogenetic protein-2), which have a fibrotizing effect in bones, because the produced osteoid is insufficiently mineralized. The effect is a pathologic remodelation of the skeleton. In the diagnosis of multiple myeloma the immunological knowledge is used in the initial diagnosis (immunophenotypization, follow up of TNF-alpha, TGF-beta 1, IL-1, IL-6 etc). Important are also biochemistry values of increased osteoresorption (changes of calcium, parathormone, excretion of collagen fission products, osteocalcin, the bone alkaline phosphatase). In the following part the authors inform about favourable results of long-term treatment with bisphosphonates (Bonefos, Ibandronate) in combination with anti-tumor chemotherapy in 364 patients. During a 15 years observation period median survival of 94 months with a 35% probability of 10 year survival was achieved with a significant decrease of bone complications in 58% compared to 14% in the placebo group.

[Richter's syndrome (bimorphologic malignant lymphoma)]. / Richterov syndróm (bimorfný malígny lymfóm).

Two distinct morphological types of malignant lymphoma in the same patient occur mostly due to transformation of a low grade lymphoma (CLL) into a large--cell non-Hodgkin lymphoma (high-grade lymphoma). Later reports have brough evidence of a clonal relationship between CLL and supervening NHL. The Richter's syndrome was found to be more frequent in patients with CLL displaying either multiple chromosomal aberrations or monoclonal gammapaties. In the last two decades reports have evidenced the existence of two types of the Richter's syndrome: one, the "classical" as a terminal event in a long evolving CLL, the other "variant" as the first clinical manifestation of a previously unrecognized subclinical CLL. Aggressive chemotherapy of CLL play a role in transformation of CLL to Richter's syndrome.

Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.

PURPOSE: To evaluate the impact of an additive therapy with an oral enzyme (OE) preparation given for more than 6 months additionally to standard combination chemotherapy (vincristine/melphalan/cyclophosphamide/prednisone (VMCP)- or methylprednisolone/ vincristine/CCNU/cyclophosphamide/melphalan (MOCCA)-regimen) in the primary treatment of patients with multiple myeloma stages I-III. METHODS: A cohort of 265 patients with multiple myeloma stages I-III was consecutively treated at our institution in two parallel groups (control group (n = 99): chemotherapy +/-OE for less than 6 months; OE-group (n = 166): chemotherapy + OE for more than 6 months). The median follow-up time in the stages I, II, and III for the OE-group was 61, 37, and 46.5 months, respectively; for the control group the respective values were 33, 51.5, and 31.5 months. The primary endpoint of the study was disease-specific survival. Secondary endpoints were response to therapy, duration of first response and side effects. The chosen method for evaluation was the technique of a retrolective cohort analysis with a concurrent control group. Survival analysis was performed by the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model. RESULTS: Significantly higher overall response rates and longer duration of remissions were observed in the OE-group. Primary responders showed a longer mean survival time than non-responders. Additive therapy with OE given for more than 6 months decreased the hazard of death for patients at all stages of disease by approximately 60%. Observation time was not long enough to estimate the median survival for patients at stages I and II; for stage III patients it was 47 months in the control group versus 83 months for the patients treated with OE (P = 0.0014) which means a 3-year gain of survival time. Significant prognostic factors for survival, in the Cox regression analysis, were stage of disease and therapy with OE. The OE-therapy was generally well tolerated (3.6% of patients with mild to moderate gastrointestinal symptoms). CONCLUSION: OEs represent a promising new additive therapy in multiple myeloma which will be further evaluated in a randomized phase III trial in the USA.

[Selection of donor-recipient pairs in families for allogenic bone marrow transplantation]. / Výber párov darca-príjemca v rodinách pre alogénnu transplantáciu kostnej drene.

In the years 1985-1999 452 were families investigated with the aim to find up an HLA-identical sibling for a patient suffering from a disease, the treatment of which requires bone marrow transplantation. Total number of investigated siblings (including patients) was 1334. HLA typing was done by serological methods, mixed lymphocyte culture test (MLC), and in the last three years also by DNA-typing (PCR-SSP). 188 HLA identical donor-recipient sib-pairs were found. At the same time the number shows that a potential donor could be found in 41.5% of investigated families.

[Frequency of HLA-A, HLA-B and HLA-Cw antigens in the Slovak population]. / Frekvencia antigénov HLA-A, -B, -Cw v Slovenskej populácii.

Results on HLA-A, -B and -Cw antigen frequencies in the Slovak population are presented. HLA-A, -B, -Cw antigens were determined in 654 healthy unrelated individuals. The highest frequency was observed for the antigens HLA-A2, -A1; HLA-B12, -B35, and HLA-Cw8. The least frequent antigens were HLA-A34, -A36, HLA-B58, -B67, -B70, -B77, and HLA-Cw8. The results were compared with those of the previous study and with those of Czech, Austrian and Hungarian populations. No statistically significant differences were observed. (Tab. 5, Fig. 2, Ref. 9.)

[Induction of autoimmune phenomena in lymphoproliferative diseases]. / Indukcia autoimúnnych fenoménov lymfoproliferatívnym ochorením.

The association of lymphoma with the positivity of antinuclear antibodies is unclear. The predisposition to neoplasma in the group of patients with systemic autoimmune diseases is known. Our case report contains steps of the differential diagnostic procedure leading from the diagnosis of systemic lupus erythematosus to the final assessment of non-Hodgkin lymphoma. (Ref. 11.)

[Systemic amyloidosis as a cause of so-called atherosclerotic hemorrhagic complications]. / Systémová amyloidóza ako prícina tzv. aterosklerotických krvácavých komplikácií.

BACKGROUND: A survey of the pathogenesis, diagnostics and treatment of amyloidosis is presented, illustrated by long-term clinical experience with the treatment of 28 patients with primary amyloidosis, 4 patients with familial and 7 patients with secondary amyloidosis. METHODS AND RESULTS: To all patients combined treatment of glucocorticosteroids and cytostatics was administered. For primary amyloidosis methylprednisolone, vincristine (oncovine), cyclosphosphamide, alkeran, chlorethylnitrosourea (MOCCA), and in secondary amyloidosis cyclophosphamide, vincristine, prednisone (CVP). In all patients, this treatment was combined with dimethylsulphoxide treatment (DMSO) administered in intravenous infusion (5 g/100 ml saline) for 3-5 days before the start of cytostatic therapy. In primary amyloidosis the median of survival was 48 months, in secondary amyloidosis the median survival was 72 months. CONCLUSIONS: The authors emphasise the need of an early diagnosis and start of comprehensive therapy completed in recent years successfully with immunomodulatory therapy using hydrolytic enzymes (WOBE MUGOS).

[Autologous stem cell transplantation in a patient with juvenile chronic arthritis]. / Autológna transplantácia krvotvorných buniek u chorého s juvenilnou chronickou artritídou.

In the submitted case-history the authors describe autologous haematopoietic stem cell transplantation (ASCT) in a patient suffering from juvenile chronic arthritis (JCA). ASCT was indicated by rheumatologists and haematologists for refractory polyarticular JCA. Mobilization with cyclophosphamide and granulocyte-colony stimulating factor was effective in terms of CD34+ cell shift to peripheral blood and the good quality autograft reliably led to haematopoetic recovery after megachemotherapy. The peritransplant period was not complicated with life threatening events. Immunosuppressive effect of autotransplant has reduced signs of rheumatoid disease activity and enabled conventional drug dose reduction. Autotransplant of haematopoietic stem cells has a potential to reduce activity of juvenile chronic arthritis.

[New beta0-thalassaemic insertion mutation (CD 7/8, +G) in a Slovak family, associated with the Mediterranean haplotype IX]. / Nová beta0-talasemická posunová mutace (CD 7/8, +G) ve slovenské rodine asociovaná s mediteránním haplotypem IX.

The authors describe a newly identified beta0-thalassaemic mutation found in two subjects from two generations of a Slovak family. The beta0-thalassaemic allele developed by insertion of one nucleotide (+G, CD 7/8) into the first exon of the beta-globin gene. The mutation causes a shift of the open globin reading frame which leads to the development of a terminal codon in codon 22. The thalassaemic allele is associated with the mediterranean haplotype IX. The mutation has in both heterozygotes the phenotype of beta0-thalassaemia minor with a slightly elevated level of HbF.

Pharmacokinetics of factor VIII in hemophilia A patients assessed by frequency response method.

The frequency response method, having its mathematical underpinnings in the theory of linear dynamic systems, was utilized to model pharmacokinetic systems describing the fate of factor VIII (F VIII) administered to hemophilia A patients before surgery. The pharmacokinetic system was defined on the basis of the patient's data in such a way that the injection of F VIII during 5-15 min was considered the input, and the corresponding plasma F VIII concentration profile consisting of both the injection and post-injection part the output of this system. The approach is an alternative to routine procedures based only on evaluation of the post-injection part of the F VIII concentration profile. With respect to the common sampling schedule of F VIII, simple second-order models were found acceptable for all the patients involved in the study. However, in the patients whose plasma F VIII concentration profiles did not decrease monotonously after the injection, these models failed to approximate secondary peaks indicating the presence of time delays in F VIII kinetics. The results obtained were discussed with respect to applications of pharmacokinetic models for the adjusted dose continuous infusion of F VIII in hemophilia A patients during and after surgical interventions.

Allogeneic BMT for haematological disorders: single centre experience of University Hospital Bratislava.

Data on 65 sibling bone marrow transplantations (BMT) for various hematological disorders are reported. 51 patients had leukemia, 8 severe aplastic anemia, 4 myelodysplastic syndrome, one suffered from non-Hodgkin lymphoma and one from myeloid metaplasia. All but two patients have engrafted. Overall, 43 (66%) of 65 patients were alive 0,03-7,2 years (median not reached) as of June 23, 1997. Median time of observation was 13 months. Outcome of standard risk patients was significantly better than that of high risk patients (p=0,006). Our data confirm, that sibling BMT is an effective treatment modality with acceptable toxicity for younger patients with an early stage of serious hematological disorders.

[Osteoporosis in multiple myeloma]. / Problém osteoporózy pri mnohopocetnom myelóme.

The problem of osteoporosis is world-wide in people above 50 years of age. As this period is also a risk period for the development of multiple myeloma or other malignant processes, comprehensive differential diagnosis of malignant and benign osteoporosis is essential. By retrospective analysis of a 12-year group of 270 patients treated by chemotherapy on account of multiple myeloma the authors selected a group of 151 patients treated in addition to chemotherapy and immunomodulating drugs (mixture of proteolytic enzymes-Wobe Mugos) for 2-3 years, also with biphosphonates. At the time ofdiagnosis osteoporosis was in 24.5% patients the only finding on bones. When biphosphonates (Bonefos, Ibandronate) and chemotherapy were administered during a three-year observation period the bone process was stable in 61.59%, osseous changes disappeared in 11.26% and progression of osteolysis was recorded in 27.15%. The objective of the work was to emphasize the importance of a correct diagnosis of osseous changes which can progress even in clinically asymptomatic myelomas.

[Unstable Santa Ana hemoglobin or alpha 2 beta 2 88 (F4) Leu-Pro detected in a Slovak girl]. / Nestabilní hemoglobin Santa Ana nebo alpha 2 beta 2 88 (F4) Leu-Pro identifikovaný u slovenské dívky.

The unstable haemoglobin variant Ana (alpha 2 beta 2 88 (F4) Leu-Pro) was identified to cause haemolysis in a 10-year-old Slovak girl. She was followed for haemolytic anaemia symptoms since two years of age. Clinical signs are hepatosplenomegaly and moderate haemolytic anaemia not requiring blood transfusions. It is the first case of an unstable haemoglobinopathy found in Slovak Republic as far as we know. Hypothesis of 'de novo' origin of the mutation in the propositus is supported by the parents' and brother's laboratory findings.

[Density of adhesive proteins after oral administration of proteolytic enzymes in multiple myeloma]. / Sledovanie denzity adhezívnych proteínov po perorálnom podaní proteolytických enzýmov pri mnohopocetnom myelóme.

The authors present information on the presence of adhesive proteins on membranes of myeloma and precursor cells isolated from bone marrow and blood from a group of 33 patients examined by fluorescent flow cytometry. They also compare the density of integrins (CD29, CD49e, CD41, CD51 and CD61) and adhesive proteins from the group of "homing" receptors (CD44) and IgG "superfamily" (LFA-1, LFA-3, ICAM-1, N-CAM) and their changes after a single oral dose of a mixture of proteolytic enzymes (Wobe Mugos, Wobenzym, MUCOS Pharma, FRG). The authors observed a significant drop of CD29, CD54 (ICAM-1), CD58 (LFA-3) after Wobe Mugos, CD49, CD51, CD58 after Wobenzyme. The insignificant decline of density of CD44 on cells, as well as of the soluble receptor of CD44 after oral administration of proteolytic enzymes in serum, incl. the mentioned changes of integrins and other adhesive proteins, indicate the importance of enzyme preparations in the supporting treatment of malignant processes.

Amphotericin B lipid complex to treat invasive fungal infections in cancer patients: report of efficacy and safety in 20 patients.

20 patients with proven or suspected fungal infections were treated with the amphotericin B lipid complex (ABLC) with a daily dose of 5 mg/kg for 1-25 days. 6 patients died during the therapy due to fungal infection (3) or underlying disease (3). One patient was not evaluable. 13 patients were cured and improved. ABLC was administered in patients with renal disease avoiding the use of conventional amphotericin B (AmB) because of nephrotoxicity or after failure with AmB. Except for hypokalemia persisting after AmB in 5 patients, no systemic adverse reaction appeared. ABLC is a promising, well-tolerated and effective drug for the therapy of fungal infections after the failure of a previous antifungal therapy or after toxic reactions due to AmB.

[Comparison of the effectiveness and tolerance of Aktiferrin, a ferrous sulfate capsule preparation and Tardyferon pills in patients with uncomplicated sideropenic anemia]. / Porovnanie úcinnosti a tolerancie ferosulfátových prípravkov Aktiferrin kapsle a Tardyferon drazé u pacientov s nekomplikovanou sideropenickou anémiou.

BACKGROUND: The most frequent complications of oral administration of medicinal iron are gastrointestinal complaints the incidence of which correlates with the iron content of the preparation. The objective of the present work was to compare the effectiveness and tolerance of two ferrous sulphate preparations, Aktiferrin capsules and Tardyferon dragées which differ as to the elemental iron content. METHODS AND RESULTS: To two groups of patients with sideropenic anaemia selected at random (39 women and 1 men, age 14-61 years, median 28 years) Aktiferrin or Tardyferon was administered. Administration of the preparations which have a more than double different elemental iron content had a comparable effect on the investigated haematological parameters. In the group treated with Akiferrin no GIT intolerance was observed, in the group with Tardyferon it was observed in four patients. CONCLUSIONS: Aktiferrin has a comparable therapeutic effect although it contains 2.5 times less elemental iron, as compared with Tardyferon.

Mutations in the pyruvate kinase L gene in patients with hereditary hemolytic anemia.

We have completely sequenced the introns of the human L-type pyruvate kinase (PK) gene using the published cDNA sequence. Subsequently, DNA from 12 unrelated PK deficiency (PKD) patients of Central European origin was investigated for mutations in this gene by solid-phase sequencing. We detected 10 different mutations, 9 of which result in single amino acid alterations, whereas the tenth destroys a splice site. Eight of the 10 mutations have not been described before. We found 7 missense mutations: G994-->A (Gly-332-->Ser), G1006-->T (Ala-336-->Ser), A1081-->G (Asn-361-->Asp), G1174-->A (Ala-392-->Thr), G1493-->A (Arg-498-->His), G1529-->A (Arg-510-->Gln), C1594-->T (Arg-532-->Trp), one in-frame triplet deletion (del) as well as one insertion (ins): del AAG1060-62 (del Lys-354), ins AGC after C1203 (ins Ser after Cys-401), and one splice-site mutation at the border of intron A to exon 3: g/G283-->a/G. Although the enzymatic properties are substantially changed in all PK mutations, only two affected amino acid positions are in or close to the active site. Mutations C1594-->T, G994-->A, del AAG1060-62 and the splice-site mutation g/G283-->a/G have been detected in two different patients each. Mutation G1529-->A was found in five different alleles. Haplotype analysis with the A/C polymorphism at position 1705 gave evidence for a single origin of this most frequent mutation in PKD as suggested by Baronciani and Beutler (Proc Natl Acad Sci USA 90:4324, 1993). Carrier detection and prenatal diagnosis are now feasible for the affected families.

[Dominant beta-thalassemia alleles in the Czech and Slovak population (beta-thalassemia mutations in 112(T-A) and 121(G-T) codons and the unstable Hradec Králové hemoglobin or alpha 2 beta 2 115 (G17) Ala-Asp)]. / Dominantní beta-talasemické alely v ceské a slovenské populaci [beta-talasemické mutace v kodonech 112 (T-A) a 121 (G-T) a nestabilní hemoglobinová varianta Hradec Králové nebo alpha 2 beta 2 115 (G 17) Ala-Asp].

In four unrelated families of Czech and Slovak origin two nonsense dominant beta-thalassaemic alleles (CD 121 (G-T); CD 112 (T-A)) and in one family simple substitution in codon 115 (GCC-GAC) or alpha 2 beta 2 115 (G17) Ala-Asp HB-Hradec Králové were identified. Mutations in codons 112 and 115 were described for the first time. Phenotypic manifestation of beta-thal. intermedia was revealed in three families with CD 121 (G-T) and in a family with a mutation in CD 112, but the phenotypic manifestations differed markedly in individual subjects. Heinz bodies were detected in erythrocytes of the peripheral blood in two families. An exact explanation of phenotypic deviations in patients with the same mutation even within the same family were not obtained even in studies of alpha genes and the promoter area of the beta gene. The unstable variant of Hb-Hradec Králové is manifested in the mother and daughter by haemolytic anaemia with some traits of beta-thal. The authors discuss contemporary findings from the pathophysiology of recessive and dominant beta-thal. mutations and explain some of the phenotypic consequences. A relatively high incidence of dominant beta-thal. mutations in the Czech and Slovak Republic (4 of 12 families known world wide with a nonsense beta-thal. mutation in the 3rd exon) is explained by the absence of selective preference of these mutations in malaria infested areas as a result of serious clinical manifestations in heterozygotes. The haplotype in one of the families suggests a de novo origin of the mutation in CD 121.

[Long-term survival in multiple myeloma]. / Dlhodobé prezitie pri mnohopocetnom myelóme.

The authors present the results of 23-year protocol studies of survival with multiple myeloma, focused on problems of perspective long-term survival. Of 535 diagnosed patients between 1970 and 1990 the authors checked regularly and treated 475. In addition to 60 latent forms where treatment was administered only when clinical symptoms developed or after progression of laboratory signs, to all patients treatment was administered according to protocols (monotherapy-cyclophosphamide prednisone in 1970-1975 only to 30 patients, the remainder had combined treatment--COPP, VMCP, MOCCA); in the third stage of the disease MOCCA treatment is better. The median of survival of patients after VMCP treatment (in stage II) MOCCA (in stage III) is more than 90 months, 15% survive for more than 10 years. The authors emphasize the importance of combined intensive treatment of patients for the prognosis of survival. Long-term experience revealed that patients achieve an objective response in 85%, while the risk of leukaemic and cancerogenic complications is low (1.1%). The therapeutic effect and survival period are favourably affected by immunomodulation treatment (Interferon, proteolytic enzymes, thymus factor).

Prognostic value of plasma-cell immunophenotype in patients with multiple myeloma.

A review is given of the prognostic significance of immunophenotyping of blood lymphoplasmocytic cells. From a group of 250 patients followed from 1981 through 1991 a subgroup of 70 patients (followed 1986 through 1991) were phenotyped at 6-month intervals by immunofluorescence tests with monoclonal antibodies for cytoplasmic immunoglobulin, kappa-lambda index, CD71, CD10, CD20, CD38, and HLA-DR receptors. In course of a longitudinal study it was found that prognostic significance for shortened survival can be derived from the presence of circulating CD10, CD71, and CD20 positive undifferentiated cells in peripheral blood. There was a correlation between increase of CALLA positive and CD71 positive cells. Further, an increase of undifferentiated clone occurred during transition of the disease to an aggressive phase. The median survival of the total group of 250 patients treated by the VMCP/MOCCA protocol, according to statistical analysis, was 90 months, the median survival of the aggressive stage with plasmoblastic and lymphoplasmocytic cell type, respectively, was only 12 months. The significance of phenotypization in the prognostic evaluation of variant heterogenous myeloma types is stressed.