Repeated administration of carcinogen in critical developmental periods increases susceptibility of female Wistar: han rats to mammary carcinogenesis induction.

Analysis and knowledge of individual strain susceptibility of experimental animals to induction of carcinogenesis is important especially in regard to possibility of transfer of these facts to human pathology, first of all to chemopreventive projects. Our group (AHLERS et al. [1]) reported very low sensitivity of female Wistar:Han rats to induction of mammary carcinogenesis by 7,12-dimethylbenz(a)anthracene (DMBA) and by N-methyl-N-nitrosourea (NMU). The aim of this paper was to increase the sensitivity of females of this strain to mammary carcinogenesis induction by repeated administration of NMU in a dose 50 mg/kg of b.w. in critical periods: on 3-4 postnatal days, on 21 day (critical period for development of ductal parts of mammary gland) and between 50-55 days (maximal proliferation of whole gland). In comparison with 38% incidence of mammary tumors after the single dose and 65% incidence after 3 subsequent doses between 50-60 days, the combination of administration (only) on 21 day and between 50-55 postanatal days resulted in 88% incidence the sensitivity of animals reached the level of highly susceptible rat strains. The latency period was significantly increased in groups with NMU given on 3-4, 21 days and between 45-55 days respectively, on 21 day and between 45-55 days in comparison with control group (one dose of NMU). The tumor frequency per group and per animal in all groups with repeated NMU administration was significantly higher than that of control group. The volume of tumors was not influenced either by repeated carcinogen application or by time of its administration. These results expand the possibilities of analysis of carcinogen effects in individual periods of rat postnatal development.

[A homozygous quantitative defect of alpha 2-antiplasmin in a family from central Slovakia]. / Homozygotný kvantitatívny defekt alfa2-antiplazmínu v rodine zo stredného Slovenska.

Alpha2-antiplasmin is the main inhibitor of plasma fibrinolytic system. An inborn defect of alpha2-antiplasmin was first described by Koie et al. in 1978 in connection with severe haemorrhage syndrome. The authors present a case report of 45 years old woman living in middle Slovakia with severe haemorrhagic syndrome started in childhood (epistaxis, skin and muscle hematomas, appendectomy with 6 weeks recovery, hardly manageable haemorrhage after teeth extractions, menorrhage, metrorrhage). Laboratory tests were negative for platelet function defects and coagulation system defects. Low level of alpha2-antiplasmin activity (10%) was detected with use of synthetic chromogenic substrate method and low amount (2%) with ELISA method. In asymptomatic daughter was decreased level of alpha2-antiplasmin (activity 51%, quantity 32%) detected. On the basis of patient history, laboratory investigations and comparison with published cases the haemorrhagic syndrome is considered to be an inborn homozygous quantitative defect of alpha2-antiplasmin. Detection of the defect in further haemorrhagic and risk situations (including laparotomy, multiple teeth extractions, obstetric surgery) led to following therapeutic measures: careful local care [by procedures], tranexamic acid in sufficient dose [4 g/day in continual i.v. infusion, or 4 x 1 g in 1/hour infusions, 4 x 1 g perorally], in sufficient duration [14 days by procedures]. Therapeutic approach after detection of the defect is efficient. (Tab. 2, Ref. 13.)

Melatonin and retinyl acetate as chemopreventives in DMBA-induced mammary carcinogenesis in female Sprague-Dawley rats.

One goal of experimental oncology is to find and test effective chemopreventive substances which can suppress malignant transformation of the cells, their accumulation and invasion. Mammary gland tumours were induced by DMBA applied intragastrically (10 mg/rat, three times) every three days between postnatal days 50 and 60 in female Sprague-Dawley rats. One day after the last dose we started chemoprevention with Mel, RA and combination of both drugs, which lasted 25 weeks. Mel was drunk continuously as a solution in tap water (100 micrograms/ml). RA was applied daily in the dose of 8.2 mg/rat at the base of the tongue. There were four experimental groups: 1. control--no chemoprevention, 2. Mel treatment, 3. RA treatment, 4. application RA + Mel. At the end of the experiment the incidence, frequency, latency and average volume of tumours were evaluated. In the group treated with Mel tumour incidence, latency and volume did not differ from controls; the frequency of tumours was decreased. Treatment with RA and with combination RA + Mel decreased mammary tumour incidence to 38% (RA) and 48% (RA + Mel); it also decreased frequency and prolonged latency. Thus chemoprotective effects of RA and combination of RA with Mel were proved in mammary carcinogenesis induced by DMBA. The oncostatic effect of Mel alone was not confirmed. In our recent paper (Bojková et al., 2000) drinking of lower doses of Mel during the late afternoon and night prolonged the latency period and in combination with RA showed an oncostatic effect on mammary carcinogenesis induced by NMU. Further studies are needed to elucidate the conditions of successful chemoprevention with Mel.

Effects of retinyl acetate and melatonin on N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. A preliminary report.

The aim of this project was to evaluate the effect of retinyl acetate (RA), melatonin (Mel) and their combination on N-methyl-N-nitrosourea (NMU)-induced rat mammary carcinogenesis. Female Sprague-Dawley rats were given two intraperitoneal doses of NMU, each of 50 mg/kg of b.w. between 43rd to 57th postnatal day. The administration of RA started 11 days and the administration of Mel 12 days before the first dose of NMU. RA was given daily in a dose of 8.2 mg per animal and day at the base of the tongue. Mel was given as a solution (20 micrograms/ml of tap water) between 3 p.m. and 8 a.m., from 8 a.m. to 3 p.m. the animals were drinking tap water only. The experiment was finished 22 weeks after the first administration of the carcinogen. The tumour incidence in the control group was 88%, in the group treated with RA 80% and in the group treated with Mel 61%. A substantial decrease in tumour incidence to 37% was noted in the group treated with RA plus Mel. Significant differences in incidence were noted in the group treated with the combination of RA and Mel as compared to the control group and the group treated with RA. Chemoprevention lengthened the latency significantly in the group treated with Mel and with the combination of RA and Mel. The decrease in tumour frequency per group was confirmed in the group treated with the combination of RA and Mel; differences between groups in the frequency per tumour-bearing animal were not observed. The volume of mammary tumours in the groups treated with chemopreventive agents was not changed.

Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow.

We report 17 cytopenic patients with myelodysplastic syndrome (MDS) of refractory anaemia (RA) subtype with hyper-, normo- or hypo-cellular bone marrow (BM), who were treated with cyclosporin A (CyA). Substantial haematological response was observed in 14 patients (82%): their anaemia improved and all transfusion-dependent patients achieved transfusion independence. Complete trilineage recovery was observed in four patients (23%). The CyA therapy has not yet failed in any of the 14 successfully treated patients during follow-up times ranging from 5 to 30 months. CyA was well tolerated in 14 patients; serious side-effects required termination of the therapy in three patients in whom the blood count rapidly deteriorated to former levels upon cessation of therapy. Two patients benefited from a combination therapy of CyA and erythropoietin. Six patients experienced various autoimmune phenomena. CyA could thus offer an alternative treatment for certain MDS patients with RA regardless of hyper-, normo- or hypo-cellularity of bone marrow (BM). The mechanism of the beneficial effect of CyA is discussed and remains the subject of an ongoing study.

[Primary hepatosplenic (gamma delta) T-cell lymphoma: clinico-pathologic analysis of 3 cases]. / Primárny hepatosplenický (gamma delta) lymfóm T-pôvodu: klinicko-patologický rozbor troch prípadov.

The authors analyze three cases of hepatosplenic (gamma-delta) T-cell lymphoma which is a newly defined unit in the spectrum of primary splenic lymphomas. The first two were diagnosed in sequential biopsies of bone marrow, splenectomic material and the liver of female patients aged 38 and 67 years. In the clinical picture dominated symptoms of progressing splenomegaly, hepatomegaly, haemolytic anaemia and different manifestations of leuco- and thrombocytopenia with expulsion of tumour cells into the peripheral blood. The first patient died after complete remission with signs of heart failure, the second one is surviving for 11 months in partial remission. The third case, a 66-year-old male patient, died suddenly during a 16-day hospitalization on account of diagnosis of hepatopathy and anaemic syndrome, as a result of cardiorespiratory failure. The diagnosis was established only post mortem. In none of the patients signs of affected lymph nodes were present. The authors analyze problems of bioptic diagnosis of the mentioned lymphoma, in particular biopsy of bone marrow in the stage of its initial infiltration. The key to diagnosis is in addition to knowledge of clinical manifestations the typical morphology and intrasinusoid propagation of tumour cells and immunohistochemical evidence of their T-phenotype. The predominance of initial manifestations of haemolytic anaemia calls for differential diagnosis of haemolytic conditions and confirmation of their secondary character.

[Mixed myelodysplastic and myeloproliferative syndromes]. / Smísené myelodysplastické a myeloproliferativní syndromy.

BACKGROUND: An injury to the hemopoietic stem cell may lead to the aplasia of hemopoiesis, myelodysplasia and to an unregulated myeloproliferation. There is not a strict demarcation of them, so that mixed syndromes can develop as are hypoplastic syndromes on one side and mixed myelodysplastic and myeloproliferative syndromes (MDS-MPS) on the other side. METHODS AND RESULTS: Among our 616 pts with MDS we looked for those cases, who had beside myelodysplasia signs of myeloproliferation with increased number of blood cells. They were examined in detail including bone-marrow histology, bone marrow cultivation, cytogenetics and bcr-abl gen. Signs of MDS-MPS were found in 22 patients at the first contact with the patient (13 patients had thrombocytemia and 9 patients had leukocytosis). Further 7 patients were diagnosed as MDS, proliferative syndrome developed after several months (MDS-MPS in evolution). The level of thrombocytemia was relatively stable, the number of leukocytes was progressive. All subtypes of MDS were found. All subjects had variable degree of anemia. Ring-sideroblasts and myelofibrosis were frequent finding in MDS-MPS. Men prevailed in patients with leukocytosis. Cytogenetic and cultivation findings were similar to MDS cases, deletion of long arm of chromosome 20 was present in 3 patients. Five patients transformed to acute myeloid leukemia. CONCLUSIONS: Sings of myelodysplasia and myeloproliferation were found in 4% of our MDS patients, designated as mixed myelodysplastic and myeloproliferative syndrome (MDS-MPS). In this syndrome beside evident signs of myelodysplasia thrombocythemia or leukocytosis with the release of bone marrow precursors are present. In only one case polycythemia was encountered.

Mixed myelodysplastic and myeloproliferative syndromes.

Aplastic anemia, myelodysplastic syndromes (MDS) and chronic myeloproliferative diseases (MPD) are stem cell disorders. There is no clear-cut demarcation of them. Hypoplastic MDS displays features of aplastic anemia and MDS, on the other side mixed myelodysplastic and myeloproliferative syndromes (MDS-MPS) develop. In our collection of 566 MDS patients, features of myelodysplasia as well as myeloproliferation, MDS-MPS, were present in 25 patients (4.4%). Twelve patients had at the time of diagnosis megakaryocytic proliferation and thrombocythemia beside signs of MDS, and seven had myelodysplasia with granulocytic proliferation and leukocytosis. In another six patients, MDS was the first diagnosis and the proliferative phase developed later during the course of the disease. These patients can be characterized as MDS-MPS in evolution. All subjects had a variable degree of anemia. While the level of thrombocythemia has been relatively stable, the number of leukocytes has been progressive, but rarely extended beyond 100 x 10(9)/l. Ring-sideroblasts and myelofibrosis were frequent findings. Two more homogeneous MDS-MPS groups emerged in our analysis: sideroblastic anemia with thrombocythemia and a group fulfilling the criteria of Philadelphia chromosome negative and bcr-abl negative "atypical chronic myeloid leukemia (aCML)'. One patient with thrombocythemia and three with leukocytosis (23%) transformed to acute myeloid leukemia (AML). Men prevailed (12/13) in patients with leukocytosis and MDS-MPS in evolution. Of the 46% MDS-MPS patients with chromosomal aberrations, del(20)(q) is of interest.

[Immunophenotyping with flow cytometry in patients with acute leukemia]. / Imunofenotypizácia prietokovým cytometrom u pacientov s akútnou leukémiou.

The authors evaluate their own results of examinations using a flow cytometer in 72 patients (22 children and 50 adults) with acute leukaemia, incl. 34 acute lymphatic leukaemias and 38 acute myeloid leukaemias during the period between January 1994 and October 1995. At the same time the authors draw attention to the clinical importance in the diagnosis, treatment and prognosis as well as to different findings in children and adults.

[Complications of central venous catheterization in hematologic patients--prospective study of 193 catheterizations]. / Komplikácie centrálnej zilnej kanylácie u hematologických chorých--prospektívna stúdia 193 kanylácií.

A Prospective Study of 193 Catheterizations 193 central venous catheters introduced in 142 patients with haematological diseases were studied prospectively for complications in 1984-1992. 165 polyethylene, 14 Hickman and 14 polyurethane catheters were inserted into subclavian vein via infraclavicular access using Seldinger technique exclusively. Except bleeding, that was not serious, immediate complications occurred in 4%. Cumulative duration of catheterizations was 6370 days with median duration of one cannulation of 15 days, range 1 to 489 days. In polyethylene catheters duration of catheterization was influenced significantly by tunnelization. More than half of cannulations were accompanied by technical complications. Incidence of clinical thrombosis was 6.7%. Infectious complications were the most serious with the incidence of proven and suspected catheter-related sepsis of 25.8%, local inflammation of 41.4% and tunnel inflammation of 12.8%. They were caused in 82% of cases by gram-positive bacteria. Catheter-related sepsis was significantly associated with local inflammation, duration of cannulation and leukopenia and application of parenteral nutrition. Hickman catheters had the best "complication to catheterization duration" ratio, that give reasons for using these catheters in this group of patients.

[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.

[Comparison of Tarivid and Biseptol in the prevention of bacterial infections in patients with acute leukemia]. / Porovnanie Tarividu a Biseptolu v prevencii bakteriálnej infekcie u chorých s akútnou leukémiou.

In 42 patients with induction treatment of acute myeloblastic and lymphoblastic leukaemia the authors compared efficacy of selective decontamination of the gastrointestinal tract in prevention of infections during neutropenia less than 0.5.10(9)/l in two comparable groups. Twenty-two patients were treated with Ofloxacin (Tarivid, Hoechst Co.), 20 patients with Trimetroprim-Sulfamethoxazol (Biseptol, Polfa Co.). Both groups had concurrently also Ketoconazol in prevention of mycotic infection. The investigation revealed that Tarivid is a suitable alternative drug for selective decontamination, because it delays the onset of acquired infection, as compared with Biseptol, it reduced more efficiently the frequency of Gram-negative colonization and life-threatening Gram-negative sepsis, caused by resistent strains; its tolerance is significantly better. There was no significant difference in the occurrence of febrile days, febrile episodes, the duration of antibiotic treatment, the number of sepsis in two groups. The effect of Tarivid and Biseptol on the Gram-positive microbial flora is inadequate. Subclavian catheter increases in particularly the risk of Gram-positive sepsis in both groups.

Comparison of two non-cross-resistant combinations (ABVP/LOPP) with COPP plus bleomycin in the treatment of advanced Hodgkin's disease.

Eighty patients with advanced Hodgkin's disease were randomized either to treatment with combination of doxorubicin, bleomycin, vinblastine, and prednisone (ABVP), alternating with lomustine, vincristine, procarbazine, and prednisone (LOPP)--Group A, or to combination of cyclophosphamide, vincristine, procarbazine, prednisone, and low dose of bleomycin (COPP-Bleo)--Group B. Thirty-nine out of 41 patients (95%) in Group A achieved complete remission (CR) as compared to 25 CR in 39 patients (64%) in Group B. Patients with systemic symptoms, bulky disease, and nodular sclerosis achieved significantly more CR after treatment with ABVP/LOPP regimen than with COPP-Bleo regimen. Ninety percent of patients are alive in Group A (median observation time 97+ months) as compared to 58% in Group B (median observation time 97+ months). Ninety-two percent of complete responders are in CR in Group A as compared to 53% of complete responders in Group B. These differences between both groups are significant. More serious (WHO grade III and IV) myelosuppression as well as stomatitis and alopecia were observed in Group A. Gastrointestinal toxicity and neurotoxicity was more frequent in Group A. No patient died due to toxicity in Group A as compared to one patient in Group B. Non-cross-resistant alternating regimen ABVP/LOPP was more effective in the treatment of advanced Hodgkin's disease than the COPP-Bleo regimen, especially for patients with advanced Stage IVB Hodgkin's disease.

[Results of treatment of acute lymphoblastic leukemia over a 12-year period]. / Výsledky liecby akutnej lymfoblastickej leukémie za 12-rocné obdobie.

In the course of a 12-year period the authors treated at the Paediatric Department of the Regional Institute of National Health in Banská Bystrica 72 children with acute lymphoblastic leukaemia according to four protocols. Complete remission was achieved by 67 children, i.e. 93%. None of the children died from complications of treatment during complete remission. A relapse during treatment or soon after its termination occurred in 23 children, i.e. 31.9%. A second complete remission was achieved in 15 children, i.e. 65.2%. During the second complete remission seven children survive for 0.5-91.5 months. Twenty children died, i.e. 27.8%. All children had at the time of death signs of malignant disease. Fifty-two children survive at present for 1-132 months. The cumulative ratio of surviving children in the 12th year since the diagnosis is 0.57, the cumulative ratio of children in initial complete remission in the 12th year is 0.51.

[Clinical evaluation of granulocyte concentrates in the treatment of malignant disorders of hematopoiesis]. / Klinické zhodnotenie granulocytovýgh koncentrátov pri liecbe malígnych ochorení krvotvovby.

The authors evaluate in a retrospective, non-randomized two-year study the action of 57 granulocyte concentrates from a Fenwal CS 3000 separator in 12 patients used for induction therapy of acute leukaemia, malignant lymphoma and agranulocytosis, as compared with a control group of 18 patients without concentrates. The indication for selection was granulocytopenia of less than 0.5.10(9)/l, temperatures resistant to antibiotics for more than 48 hours, mainly gram-negative sepsis and a severe localized infection. A significant reduction of febrile days was achieved, to 6.08 as compared with 12.44 (p less than 0.001) along with cure of the infection. Survival, evaluated on the 21st day of the investigation in the treated group 66.6%, as compared with 61.1%, and the percentage of complete remissions 58% as compared with 55.56%, were not statistically significant (p greater than 0.05). The mean one-hour rise of granulocytes by 0.37 x 10(9)/l in the recipients had no clinical impact. With the exception of one patient a relationship was observed between the favourable action of transfusions and the trend of recovery of the patient's granulopoiesis and the onset of remission of the disease. Minor pyretic and allergic reactions occurred in three patients (5.2%).