Cardiovascular complications among hematopoietic cell transplantation survivors - the role of cardiomarkers.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for numerous malignant and nonmalignant diseases. The number of survivors and length of follow-up after successful HSCT is continually increasing. HSCT can induce damage of various organs and tissues - from minimal potentially progressive subclinical changes to life-threatening conditions. The aim of this thesis was to assess the prognostic value of high sensitive cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing and early identification of patients at high risk of a cardiac event after allogeneic HSCT. PATIENTS AND METHODS: Sixty-three patients with the median age of 37 years at the time of allogeneic HSCT for hematologic diseases were studied. Cardiac bio-markers were serially measured before conditioning regimen and at days 1, 14 and 30 after HSCT. Cardiac systolic and diastolic functions were assessed before the conditioning regimen and 1 month after HSCT by echocardiography. RESULTS: The differences in plasma NT-proBNP and hs-cTnT concentrations during the 30 days following HSCT were statistically significant (P < 0.001 vs. P = 0.02). Seven of 63 patients (11.1 %) developed a cardiac event defined as cardiovascular dys-rhythmias, pericarditis with cardiac tamponade and heart failure. By multivariate analysis, the strongest prognostic factor of cardiac event was an increased level of hs-cTnT and NT-proBNP persisted for a period of 14 days after HSCT (P < 0.0001). The area under the curve from hs-cTnT testing plus NT-proBNP testing together (AUC = 0.95) was superior to each dia-gnostic modality alone. CONCLUSION: Measurements of plasma NT-proBNP and hs-cTnT concentrations might be a useful tool for identification of high-risk patients requiring further cardiological follow up. Measurement of hs-cTnT plus NT-proBNP together was superior to hs-cTnT and NT-proBNP measurements alone.

Metabolic syndrome in long-term survivors after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for numerous malignant and non-malignant diseases. The number of survivors and length of follow-up after successful HSCT is continually increasing. Hematopoietic stem cell transplantation can induce damage of various organs and tissues - from minimal potentially progressive subclinical changes to life-threatening conditions. The aim of this thesis was the evaluation of the prevalence of metabolic syndrome (MS) among survivors of allogeneic HSCT. PATIENTS AND METHODS: We analyzed 74 patients with a median age at transplant of 35 years, who had been followed for a median of 5 years (2-23 years) after allogeneic HSCT. MS was defined according to the National Cholesterol Education Programs Adult Treatment Panel III (NCEP ATP III) criteria and by the International Diabetes Federation (IDF) definition. RESULTS: The prevalence of MS among HSCT recipients was 40.5% applying the NCEP ATP III definition and 39.2% the IDF, a 2.02-fold increase compared to the general Slovak population. MS was more common in men. The most common MS features were abdominal obesity, hypertriglyceridemia and hypertension. The lowest prevalence of MS was in the age group of 20-29 years; and the highest prevalence in the age group of 60-69 years. The 10-year cumulative incidence of MS was 32.5%. The most significant risk factor for MS was total body irradiation, positive family history and age > 40 years at HSCT. Seven patients (9.45%) developed cardiovascular complications. The median 10-year general cardiovascular risk scores for males and females were found to be 13.3% and 6.68%, respectively. CONCLUSIONS: Detected increased prevalence of metabolic syndrome after allogeneic HSCT in patients surviving more than 2 years after this procedure may provide next stimulus to promote longer follow-up studies and to design of interventions to prevent late effects among survivors of serious hematologic diseases.

Humoral immune responses against facultative pathogen Candida utilis in atopic patients with vulvovaginal candidiasis. Candida utilis glucomannan - New serologic biomarker.

Vulvovaginal candidiasis is one of the most commonly reported female genital tract infections, affecting approximately 70-75% of childbearing age women at least once during their lifetime. Approximately 50% of patients have refractory episodes and in 5-10% of cases the disease has a chronic course. The fungal cell wall represents the important host-invader interface. Cell-wall polysaccharides represent biological response modifiers and the pathogen-associated molecular patterns and virulence factors. Glycans are sensed by germ-line encoded pattern recognition receptors and reactively participate in immune system cell signaling. The most dominant cell-wall antigenic structures of Candida species as ß-glucan, α- and ß-mannans, glucomannan and other immunogenic polysaccharides are of particular relevancy for specific in vitro diagnosis and long-term follow-up of the Candida infection. In this study we assessed the immunobiological activity of facultative pathogen Candida utilis cell glucomannan and its effectivity as in vitro serological marker for antibody testing. The novel serologic assay has been developed and optimized for C. utilis serodiagnosis. The comparison assays were performed to establish relationship between antibodies against C. utilis, C. albicans and S. cerevisiae main cell-wall antigens in patient sera. The study evaluates applicability of glucomannan as serodiagnostic antigen and as a trigger of antigenspecific IgG, IgM and IgA antibody isotypes in the cohort of 35 atopic female subjects with recurrent vulvovaginal candidiasis. Statistically significant sera values of specific anti-glycan IgM and IgA class antibodies were revealed. The results are suggestive for efficient serological application of C.utilis glucomannan as in vitro disease marker and prospectively for follow-up of the specific long-term antimycotic therapy.

Autologous hematopoietic stem cell transplantation for acute myeloid leukemia - single center experience.

We aimed to determine the effect of autologous hematopoietic stem cell transplantation (auto-HSCT) on acute myeloid leukemia (AML) patients as a valid alternative therapeutic option for patients without HLA-compatible donor. This retrospective single center study included 79 patients with AML older than 18 years. In this report, we describe the patient characteristics, engraftment, toxicity of treatment, complications, overall survival, and relapse incidence of 79 patients treated chemotherapy and followed by auto-HSCT. The descriptive statistics was used, and the method of Kaplan and Meier was applied to calculate the actuarial rate of overall survival. The patients achieved an absolute neutrophile count (ANC) of ≥ 0.5 x109/l in between 10 to 40 days; median was 14 days after auto-HSCT. The patients achieved platelet count ≥ 20 x109/l in between 10 to 209 days; median was 19 days after auto-HSCT. Hundred-day mortality after autologous transplant was 6.57% (5/76). The relapse rate was 39.5% (32 patients) and 7 patients (8.6%) were lost from follow-up. On the date of evaluation (April 30, 2016), 48 patients (60.8%) were alive, including 7 (8.6%) patients who are lost from follow-up (not responding to check-up request). The 5-year overall survival (OS) was 60.8%; median overall survival was not reached. The present clinical study has demonstrated safety and efficacy of myeloablative chemotherapy followed by auto-HSCT in the treatment of AML in first remission.

Allergen immunotherapy in polysensitized patient.

Specific allergen immunotherapy (AIT) is the only therapeutic method with positive impact on natural course of allergic disease - affecting clinical development (including the progression of rhinitis to asthma) and new sensitisations. The actual problem is the increasing number of patients manifesting poly-sensitivity in allergy skin tests and / or in specific IgE tests. Usually, AIT is not recommended in such individuals. The objective we are facing is that in many patients tested as poly-reactive, we have to distinguish in which cases it is a true polysensitization, and when it is due to cross-reactivity of specific IgE antibodies induced by panallergens. This may really determine when AIT may be an appropriate course of action. The article focuses on this problem in more detail, applying the long time Czech and Slovak experience with allergy testing and allergen immunotherapy.

Is there still a role for autologous stem cell transplantation in acute myeloid leukemia?

BACKGROUND: the role of autologous stem cell transplantation (ASCT) in treatment of acute myeloid leukemia (AML) remains unsettled. AIMS: retrospective analysis to evaluate the role of ASCT in patients with AML without HLA-matched donor. METHODS: between December 19, 1994 and August 1, 2012, a total of 63 patients with AML without HLA-matched donor in the department of Hematology and Transfusion Medicine, University Hospital, Bratislava, received an ASCT. Median age was 41 years (20-61 years). There were 35 (56%) males and 28 (44%) females. At the time of ASCT, 50 (79%) patients were in first complete remission (CR), 11 (18%) patients were in second CR and 2 (3%) patients were in relapse. RESULTS: with a median follow-up of 115 months (34-214 months), the 10 year overall survival (OS) and disease free survival (DFS) of all patients was 55% and 51%, respectively. Transplant-related mortality was 6%. The relapse rate was 38% and 9 years probability of relapse was 44%. CONCLUSION: ASCT is still an effective post-remission treatment in AML patients without HLA-matched donor; with the possibility of long-term survival or even cure in remarkable proportion of patients with AML, particularly in patients with favorable and intermediate cytogenetic risk. .

Immunity profile in breast cancer patients.

OBJECTIVES: Despite the multifactorial pathogenesis of malignant transformation, it is assumed that deficiency in some immune mechanisms plays a considerable role in its development. BACKGROUND: Chronically activated immune cells exert tumour-promoting effects directly by influencing the proliferation and survival of neoplastic cells, as well as by indirect modulation of neoplastic microenvironments in favour of tumour progression. PATIENTS AND METHODS: We refer to results of two separate investigations that aim to monitor the immune functions in patients with breast cancer. In the first investigation, we compare the picture of basic cellular immunity profile of patients in early stage of breast cancer with those suffering from advanced disease; in the second one, we compare the production of Th1-cytokines in patients in different stages of breast cancer and atopic healthy controls. RESULTS: We recognized that the totals of T-lymphocytes and T-helpers were lower and the expression of HLADR on T-lymphocytes were higher in patients with advanced disease; the expression of IL-2 and LFN-gamma by T-lymphocytes was decreased in metastatic breast cancer patients, however IL-2 production was increased in patients in early stage of disease. CONCLUSION: We conclude that the role of immune system in cancer development is ambivalent as it may be not only protective, but also harmful (Tab. 1, Fig. 3, Ref. 22). Full Text (Free, PDF) www.bmj.sk.

Isolated extra-medullary relapse of acute leukemia following allogeneic bone marrow transplantation.

Isolated extramedullary relapse (IEMR) of acute leukemia (AL) after allogeneic bone marrow transplantation (BMT) is a rare occurrence. It is seen more commonly after BMT than after conventional chemotherapy (CHT) alone. We describe the natural history and response to treatment in four patients with IEMR following allogeneic BMT. The results indicate a stronger graft-versus-leukemia (GVL) effect in the marrow than in the peripheral tissues (Fig. 4, Ref. 13). Full Text (Free, PDF) www.bmj.sk.

Allogeneic peripheral blood stem cell transplantations in children--a single center experience.

We analyzed 30 peripheral blood stem cell transplantations (PBSCT) from 25 human leukocyte antigen (HLA) matched sibling donors (MSD) and 4 HLA-matched unrelated donors (MUD) in 29 patients, done between November 1996 and March 2003. Patients aged 3 to 17 years underwent allogeneic PBSCT for malignant (16 patients) and non-malignant (13 patients) diseases. Sibling donors aged 3 to 23 years were given granulocyte colony-stimulating factor (G-CSF) 5-10 microg/kg/day for 4 to 5 days. All but one of the 29 donors underwent one single leukapheresis for stem cell collection. The patients received a median of 4.2 x 10(6) CD34+ cells/kg of body weight, they all engrafted after a median of 13.5 days (range 10-25 days). Acute graft-versus-host disease (GVHD) grade II to IV developed in 11 of 26 MSD transplants and in all 4 patients after MUD PBSCT. Eleven of 27 evaluable patients experienced chronic GVHD. After a median follow-up of 662 days, 20 out of 29 patients (69%) are alive, three of them need systemic immunosuppression for chronic GVHD. Six patients experienced relapse of their underlying malignant disease, one of them still alive in complete remission. Two patients died of grade IV acute GVHD and two others due to an opportunistic infection. Based upon our experience, PBSCT is a feasible and safe method for both pediatric donors and patients. It is associated with rapid engraftment, no greater incidence of acute but a higher incidence of chronic GVHD as compared to bone marrow transplantation (BMT) and therefore suitable mainly for children suffering from malignant diseases.

[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.

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.

[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.

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.

Drug-resistance associated alterations of cell surface antigen expression in a human anthracycline-resistant ovarian carcinoma cell line.

The anthracycline uptake and cell surface expression of plasma membrane antigens (HLA class I, c-erbB-2, protectin-CD59, integrin beta 1-chain-CD29, etc.) were compared on a parental anthracycline sensitive and an anthracycline-resistant subline of the human ovarian carcinoma cell line A2780. The anthracycline-resistant (A2780/ADR) subline incubated for 30 min in the presence of daunomycin displayed two subpopulations with different anthracycline cell content as determined by flow cytometry. The subpopulation with lower daunomycin cell content was absent in the parental anthracycline sensitive cell line. The most predominant antigenic changes on the resistant subline as compared with the sensitive one were as follow: Loss of HLA class I and a twofold increase in the expression of CD59 antigen and a slight decrease of integrin beta 1-chain on the cell surface of the resistant subline.

The role of metallothionein, glutathione, glutathione S-transferases and DNA repair in resistance to platinum drugs in a series of L1210 cell lines made resistant to anticancer platinum agents.

The glutathione contents, glutathione S-transferase activities and metallothionein contents have been measured in a series of L1210 cell lines which show decreased sensitivities to platinum drugs. Resistance to cisplatinum cisDDP, cis-diamminedichloroplatinum (II)] and chip [ioproplatin, cisdichloro-bis-isopropylamine-trans dihydroxy platinum IV] was found to correlate with glutathione levels but not metallothionein. Conversely, resistance to tetraplatin was found to be correlated with metallothionein but not glutathione levels. However, depletion of glutathione by buthionine 1-sulphoximine sensitizes all cell lines to the effects of cisDDP, chip and tetraplatin [d,1-trans-tetrachloro-1,2-diamino-cyclohexanplatinum (IV)]. Inhibition of DNA repair by aphidicholin or caffeine also partially restored sensitivity to these platinum drugs. These results indicate the complexity of the changes occurring upon the development of drug resistance.

[Results of detection of hepatitis C virus antibodies (anti-HCV) in blood donors and selected patients]. / Výsledky vysetrenia protilátok proti virusu hepatidy C (anti-HCV) u dárcov krvi a vybraných chorých.

The authors examined 509 donors for potential carriership of the virus of hepatitis C (HCV), using kits for the detection of anti-HCV. Concurrently they examined also 110 hameatological patients who had a major transfusion of blood, plasma and its derivatives. They found that in the so-called healthy population anti-HCV is present in 0.39%. In haematological patients, i.e. patients with frequent haemotherapy they detected 29 positive cases, i.e. 26.36%. The largest number of anti-HCV positive patients was in the group of haemocoagulopathies. The investigation confirmed the close association between haemotherapy and the transmission of HCV. The authors draw attention to the need to introduce anti-HCV examinations in the transfusion service as an important preventive provision.

Suitability of cisplatin solutions for 14-day continuous infusion by ambulatory pump.

The stability of cisplatin (DDP) solutions (1 and 1.6 mg/ml in saline-mannitol) in plastic infusion bags was studied for up to 14 days at 25 degrees C, 37 degrees C and 60 degrees C. Small changes in the solution were observed, but no evidence of any decomposition product was seen. Some precipitation of DDP was seen in the 1.6-mg/ml solution at the lower temperatures. Fluid loss from the bags was significant at the higher temperatures.

[Side-effects of continuous and discontinuous cytapheresis]. / Vedl'ajsie úcinky kontinuálnej a diskontinuálnej cytaferézy.

The authors evaluate the incidence of complications in 767 cytapreheses made on two types of blood cell separators. Complications, incl. technical problems before cytapheresis proper, were encountered more frequently during work with the discontinuous blood cell separators Haemonetics model 30 (27.%) than during work with the continuous automatic blood cell separator Fenwal CS 3000 (13.2%). Most frequently collapse and symptoms of hypocalcaemia were involved. Serious reactions account only for 7.6 and 4.4% of all reactions. The authors discuss the causes and possible prevention of complications during cytapheresis. With regard to the assessed results cytaprehesis by means of a separator can be considered a safe method in blood donors.