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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new human disease. December 31, 2019 marked the day the World Health Organization (WHO) first became aware of an infectious outbreak in the Hubei province in China. Until January 2021, more than two million people died from COVID-19. The use of convalescent plasma (CP) has been widely used in different outbreaks as the first therapeutic option given the lack of effective medications or vaccines, and often as a last chance or experimental treatment. CP is a strategy of passive immunisation. Possible mechanisms of CP-COVID-19 action are antiviral and immunomodulatory. The established protocol for CP-COVID-19 collection defines activities and criteria related to recruiting and informing potential CP donors, clinical and laboratory examination, plasma collection, labelling and storage. Plasma is collected by apheresis/plasmapheresis. Administration of plasma is performed at the request of clinicians, according to the strict indications based on the severity of clinical picture, expressed by precisely determined "scoring" of symptoms. The risks transfusion recipients are likely to be exposed to do not differ from those of standard plasma recipients. At the Blood Transfusion Institute of Serbia, the first plasmapheresis from the recovered patient-donor was performed on 11 April 2020 and so far, collection and distribution of CP-COVID-19 have been performed continuously. During the observation period, preliminary results of the effect of CP transfusion, along with other applied therapy, indicate its favourable effect, both worldwide and in Serbia. CP-COVID-19 should be used as early as possible in the course of infection in order to achieve the best outcomes.

Background/Aim. The treatment of chronic myeloid leukemia (CML) has changed dramatically with the advent of targeted therapies. This study aimed to assess the efficacy of generic imatinib in CML patients treated in our center. Methods. The study was retrospective. It included 101 patients diagnosed with CML ? chronic phase (CP). The patients were divided into two groups. Group 1 included 55 patients initially treated with branded imatinib and then switched to generic imatinib. Group 2 consisted of 46 newly diagnosed patients who received only generic imatinib from the beginning of therapy. Results. The patients were treated with branded imatinib for the mean of 42 months (range 6?132 months) before switching to generic imatinib. Treatment with generic imatinib lasted for 25 months on average (range 3?66 months). A quarter of the patients from the group 1 lost their cytogenetic reponse after being switched to generic imatinib, but with-out signs of transformation to acute leukemia. The patients treated with branded imatinib had a significantly longer event-free survival (EFS) and failure-free survival (FFS) (log-rank p = 0.01 and p = 0.03, respectively). These results could have been influenced by frequent changes of the brand and dosage formulation of generic imatinib. Conclusions. Our study showed a significantly longer EFS and FFS in the patients who were initially treated with branded imatinib, compared to those treated with generic imatinib only. These results provide useful information, but have to be interpreted within the context of the crossover study.

Background/Aim. Despite the introduction of new oral anticoagulants (dabigatran, rivoroxaban, apixaban), vitamin K antagonists (VKA), such as warfarin and acenocoumarol are still the most widely used oral anticoagulants for the treatment of non-valvular atrial fibrillation (NVAF). Time in therapeutic range (TTR) represents a measure of the quality of the anticoagulant effect of these drugs, and it is considered that the lower value of TTR is associated with the adverse effects of therapy. The study aim was to evaluate of the effectiveness of VKA therapy in patients with NVAF and to identify factors affecting the anticoagulation efficacy. Methods. A retrospective study was conducted on a population of 725 outpatients with NVAF, treated with VKA and followed in Blood Transfusion Institute of Nis from January to December 2017. Laboratory control of the INR was done from capillary blood of patients on Thrombotrack Solo (Axis Shield, Norway) and Thrombostat (Behnk Elektronik, Germany). Targeted therapeutic INR was between 2.0 and 3.0. For each patient we evaluated all available INR values to calculate the individual TTR according to the Rosendaal method. Results. The study included a total of 725 patients with NVAF which had 6105 INR measurements, what is 8.13±2.47 INR measurements per patient. The mean value of TTR and was 60.15±17.52%, but 49.72% of patients had a TTR less than 60%. Patients were at high risk of thrombosis in 6.15% of time (INR 4.5). The most significant independent factors affecting the quality of VKA therapy are gender, arterial hypertension, diabetes mellitus and the use of amiodarone and antiplatelet drugs (aspirin, clopidogrel). Conclusion. The TTR is undoubtedly useful indicator of the effectiveness of VKA treatment. The most important predictors of poorer efficacy of VKA therapy are arterial hypertension, diabetes mellitus, patints' gender and the use of amiodarone and antiplatelet (aspirin, clopidogrel) drugs. To improve the quality of VKA therapy, education of patient and better collaboration with them, as well as a successful teamwork with clinicians are also imperative.

Using intraoperative salvage of blood/erythrocytes (ISB/E) in the practice, rationalized application of allogeneic blood products and hemostatic-active drugs - based on "point-of-care" (POC) monitoring findings - it is possible to improve diagnosis and evaluate of transfusion hazards and increase efficacy of therapy of patients with excessive bleedings, with reduction of perioperative morbidity and mortality in cardiac surgery. This study was performed as a prospective analysis of platelet function using "multiple platelet function analyzer" (MEA; by Multiplate) system and examination of hemostasis by rotational thromboelastometry (ROTEM) during and immediately following myocardial revascularization and surgical treatment of valves in the Institute of Cardiovascular Diseases "Dedinje" for six years period for therapy of 1021 random selected patients. The study aim was to evaluate the influence of ISB/E and hemostatic drugs - indicated based on the results of platelet count and function (Multiplate) and hemostasis monitoring (ROTEM) in compared to allogeneic transfusions - on the incidence of bleedings, treatment efficiency and overall clinical outcome. In the perioperative period, a total of 617 (60.4%) patients were treated with ISB/E reinfusion only. Other patients (404; 39.6%) received allogeneic blood components too. Total 391 of them (38.3%) were treated (together by ISB/E) with transfusion of one to three units of allogeneic red blood cells (RBCs). There were only 13 (1.3%) polytransfunded (typically 10 - 15 units) patients. The rate of cardio-surgical reinterventions due to bleeding was only 2.5%. In conclusion, the application of the ISB/E strategy represents an effective and safe (reduced immune-mediated complications and risk of disease transmission) therapeutic approach. By monitoring MEA/ROTEM and implementation the algorithm of current transfusion therapy, it is possible to reduce significantly of allogeneic blood component therapy. The use of allogeneic RBCs is justified only when the possibilities of autologous transfusion and pharmacological hemostatic therapy have been exhausted.

There are four stem cell (SC) transplant centers in Serbia that carry out their activities within the European Group for Blood and Marrow Transplantation (EBMT). They are positioned in the Clinical Center of Serbia, Military Medical Academy, Institute for Mother and Child Healthcare "Dr. Vukan Čupić" and in the Clinical Center of Vojvodina. The aim of this paper is to analyze the basic approaches and aspects, as well as main parameters and guidelines - related to the optimization of the functioning of SC transplantation centers. The existence of a competent and motivated professional employees of the transplant center, as well as an adequate operational locality/area and up to date equipments are imperative for the successful performance of this specific and complex procedure. The current tendency - and in the near future an obligation or requirement - is for each transplant center within the EBMT to be fully staffed and structurally equipped and ready to be included in the accreditation process by the Joint Accreditation Committee International. Begining the accreditation process implies, in addition to the implementation of education and training of employees, the establishment and implementation of specific quality control standards (ISO 9001: 2015, ISO 13485, ISO 13485: 2016, ISO 15189: 2007, ISO 17025, ISO / IEC 7025: 2005). The activity indicators of every transplant center have to be transparent and presented by: the number of treated patients, the rate of transplant mortality, the duration and quality of patient's lives. Also important parameters are various methods of economic analyses - different specific cost-benefit analyses. In conclusion, in order to achieve consistent/comparable therapeutic effects and outcomes for patients globally - it is imperative that transplant centers and related organizations work together on the quality system assurance, using a continuous and adequate "educational and organizational-structural models".

The spread of the COVID-19 virus has a strong influence on blood collection, maintaining a stable supply of all blood components and the safety of the transfusion itself. SARS-CoV-2 has a long incubation period (1-14 days, on average 5-6 days, longest reported 24 days) and causes asymptomatic infection in a large number of patients, which is a great challenge in a recruitment of blood donors and achieving a safe transfusion. Precise recommendations and precautions have been adopted regarding the criteria for temporary refusal of blood donors during the COVID-19 pandemic, organization of mobile teams and collection sites, disposal of medical waste, examination of potential donors and mandatory body temperature measurement. Although transmission of COVID-19 via blood and blood components has not been demonstrated, some countries have also introduced mandatory NAT testing for SARS-CoV-2 as a part of blood screening testing. Also, proactive measures have been taken, such as temporary storage of blood in quarantine for 14 days after collection, while special attention is paid to efficient management of blood component stocks and development of a collection plan, in order to avoid shortage of certain blood components or their expiration. The first step in this regard is to revise the measures which have the aim for improving the usability of blood components, ie reducing waste of stocks, which primarily refers to the temporary extension of the shelf life of blood components. Extending the shelf life of erythrocytes (longer than 35 to 49 days, which is defined at the national level) should be considered as early as possible, because once a shortage of erythrocytes occurs, they will be issued long before the expiration date. Previous studies have not shown significant side effects of erythrocyte transfusion with extended shelf life, so it is possible to consider the flexibility of blood processing and erythrocyte storage conditions with mandatory internal process validation and component quality control. The shelf life of platelet concentrate should be extended from 5 days to 7 or even 8 days, with mandatory bacteriological testing or pathogen inactivation. Another option to increase the platelet supply for prophylactic purposes is to reduce the platelet dose by dividing the existing components. Frozen fresh plasma has the longest shelf life (up to 3 years), so maintaining stable reserves is much safer than for cellular components. Liquid plasma (never previously frozen) has a shelf life of 7-40 days, and can be used in conditions of reduced freezer capacity, shortage of staff working on blood processing or for the production of convalescent plasma. Pathogen inactivation of plasma and platelets allows 3-6 log reduction of SARS-CoV-2 and MERS-CoV. The decision to introduce some of the methods of pathogen inactivation should be made taking into account the costs and resources required for implementation. For countries that do not have pathogenic inactivation already in routine practice, its rapid introduction is a big task. For now, the risk of SARS-CoV-2 transmission through the blood appears to be very low, although our understanding of the virus and behavior during a pandemic will improve over time. In this regard, pathogen inactivation of convalescent plasma should also be considered.

Hematopoietic stem cells (SCs) are responsible for the production and replacement (proliferation) of an extensive quantity of functionally competent blood cells (differentiation) during the entire life, while simultaneously maintaining the ability to reproduce themselves (self-renewal). A complex network of interactive substances and factors organize and protect the survival, maturation and multiplication of SCs. Hemobiological events in the bone marrow (BM) are synchronized and balanced by the extracellular matrix and microenvironment provided by stromal cells. These cells-including macrophages, fibroblasts, dendritic, endothelial and other cells-stimulate SCs by producing specific hematopoietic growth factors. Other cytokines secreted by stromal cells regulate the adhesion molecules positioned on SCs, allowing them to remain in the BM or migrate to an area where the respective cell type is needed. Thus, hematopoietic SCs could be defined as cells with high proliferative capacity and extensive potential to differentiate into all blood cells or some somatic cell types (SC plasticity)-such as cardiomyocytes, myocytes, osteocytes, chondrocytes, hepatocytes, and even endothelial cells. Recent increasing clinical use of cell-mediated therapeutic approaches has resulted in increased needs for SCs, but in superior operating procedures during their ex vivo manipulations. The aim of cell harvestings is to obtain a higher SC yield and improved viability or clonogenicity. The goal of optimized cryoinvestigation protocols is to get a minimized cell damages (cryoinjury). Despite the fact that different SC collection protocols and cell freezing practice are already in routine use, a lot of questions related to the optimal SC ex vivo manipulations are still unresolved. This review summarizes fundamental knowledge and methodological approaches, and recapitulates data enabling progress on constantly evolving research frontiers in the SC area. The studies (including also our investigations) that evaluated the efficiency and safety of SC-treatment (transplants and regenerative medicine) will be also concisely presented.

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The patient was admitted for urgent coronary angiography following an acute anterior ST segment elevation myocardial reinfarction (STEMI) caused by acute stent thrombosis. A stent had been implanted 10 days prior to the reinfarction for an acute anterior STEMI. However, the patient had stopped taking ticagrelor post-discharge. Primary percutaneous coronary intervention of the left anterior descending artery was performed. Subsequently, due to a high C-reactive protein (CRP) level, 3 CRP apheresis sessions were performed, with the first session starting 12 h after the onset of symptoms. A significant drop in CRP was noted after each apheresis. The post-procedural course was uneventful.

Background/Aim. Intravenous drug users (IDUs) are still a high risk-group for cross-reacting blood-borne infections, for vertical pathogen transmission as well as for potentially blood/plasma donation (especially as ?paid? donors). The aim of our study was to establish the profile of opiate addict and prevalence of blood-borne pathogens ? Hepatitis B virus (HBV), Hepatitis C virus (HCV) and Human Immunodeficiency Virus (HIV) among 99 patients on substitution therapy with methadone and buprenorphine from Sumadia District. Methods. The Treatment Demand Indicator (TDI) of Pompidou-questionnaire was used to assess the history of drug abuse and risk behavior. All blood samples were tested for HBV surface antigen (HBsAg), anti-HCV antibody (anti-HCV) and HIV antigen/antibody (HIVAg/ Ab) by Enzyme-Linked ImmunoSorbent Assay (ELISA) or Chemiluminescent Immuno-Assay (CIA). Investigations were also performed for HBV, HCV and HIV by molecular testing ? Polymerase Chain Reaction (PCR) method. Results. The majority of patients were males (81.8%), median age 32 (19?57) years, lived in a city (99%), unemployed (58.6%), with finished secondary school (67.7%), unsafe injecting practices (34.3%) and never previously tested for HBV (39.4%), HCV (36.4%) nor HIV (28.3%); only 4% of them previously got HBV-vaccine. The complementary testing resulted with following results: HBV ELISA/CIA and PCR negativity for 66 patients and positive results (by ELISA/CIA and PCR) for 19 patients. However, a difference was observed in the ELISA/CIAnegative/ PCR-positive result for 12 and ELISA/CIApositive/ PCR-negative for two patients respectively. Further, the negative results for HCV (ELISA/CIA and PCR testing) were found in 15 IDUs and positive results (using both methods) were found in 58 patients. Different results for ELISA/CIA-negative / PCR-positive results were found in 11 IDUs and ELISA/CIA-positive/PCR ? negative results were found in 15 patients. All investigated IDUs were negative for HIV (ELISA/CIA and PCR testing) and for pathogens of opportunistic infection (Cryptococcus neoformans; Pneumocystis carinii; PCR testing), as well as for West Nile Virus (PCR testing). Just one IDU was positive for syphilis (ELISA and confirmatory testing). Conclusion. Our study demonstrated that the positivity for HBV and HCV is still very high (33.4% and 84.8%, respectively) in IDUs. Thus, we suggest that drug users have to be periodically screened using a complementary serological/molecular testing ? concerning differences/discrepancies in the results obtained using these methods.

Introduction. Risk stratification is an important aspect of COVID-19 management, especially in patients admitted to ICU as it can provide more useful consumption of health resources, as well as prioritize critical care services in situations of overwhelming number of patients. Materials and Methods. A multivariable predictive model for mortality was developed using data solely from a derivation cohort of 160 COVID-19 patients with moderate to severe ARDS admitted to ICU. The regression coefficients from the final multivariate model of the derivation study were used to assign points for the risk model, consisted of all significant variables from the multivariate analysis and age as a known risk factor for COVID-19 patient mortality. The newly developed AIDA score was arrived at by assigning 5 points for serum albumin and 1 point for IL-6, D dimer, and age. The score was further validated on a cohort of 304 patients admitted to ICU due to the severe form of COVID-19. Results. The study population included 160 COVID-19 patients admitted to ICU in the derivation and 304 in the validation cohort. The mean patient age was 66.7 years (range, 20–93 years), with 68.1% men and 31.9% women. Most patients (76.8%) had comorbidities with hypertension (67.7%), diabetes (31.7), and coronary artery disease (19.3) as the most frequent. A total of 316 patients (68.3%) were treated with mechanical ventilation. Ninety-six (60.0%) in the derivation cohort and 221 (72.7%) patients in the validation cohort had a lethal outcome. The population was divided into the following risk categories for mortality based on the risk model score: low risk (score 0–1) and at-risk ( score > 1 ). In addition, patients were considered at high risk with a risk score > 2 . By applying the risk model to the validation cohort ( n = 304 ), the positive predictive value was 78.8% (95% CI 75.5% to 81.8%); the negative predictive value was 46.6% (95% CI 37.3% to 56.2%); the sensitivity was 82.4% (95% CI 76.7% to 87.1%), and the specificity was 41.0% (95% CI 30.3% to 52.3%). The C statistic was 0.863 (95% CI 0.805-0.921) and 0.665 (95% CI 0.598-0.732) in the derivation and validation cohorts, respectively, indicating a high discriminative value of the proposed score. Conclusion. In the present study, AIDA score showed a valuable significance in estimating the mortality risk in patients with the severe form of COVID-19 disease at admission to ICU. Further external validation on a larger group of patients is needed to provide more insights into the utility of this score in everyday practice.

Introduction. Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality. Methods. We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients. Results. The mean patient age was 65.6 years (range, 29–92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25th to 75th percentile: 6–18), while the median total number of hospital stay was 18 (25th to 75th percentile: 12–28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis. Conclusion. In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality.

The objective of this chapter is to provide a systematic overview of current knowledge regarding therapeutic apheresis—primarily therapeutic plateletapheresis (TP)—and to summarize evidence-based practical approaches related to cytapheresis treatment of “hyperthrombocytosis” or “extreme thrombocytosis” (ETC). Our results of platelet (Plt) quantitative/qualitative analyses and evaluation of efficacy of apheresis systems/devices—on the basis of Plt removal and in vivo Plt depletion—will be presented. Our preclinical researches confirmed that in Plt concentrates, the initial ratio of discoid shapes was 70%, spherical 20%, and less valuable (dendritic/balloonized) shapes 10%—with morphological score of platelets (MSP = 300–400). After storage, the ratio of discoid and spherical shapes was decreased, while the less valuable ones progressively increased (MSP = 200). Electron microscopy has shown discoid shapes with typical ultrastructural properties. Spherical shapes with reduced electron density and peripheral location of granules/organelles were detected. Also, dendritic shapes with cytoskeletal “rearrangement,” membrane system integrity damages, and pseudopodia formations were documented. Our clinical study demonstrated that TP was useful in ETC treatment and should help prevention of “thrombo-hemorrhagic” events—until chemotherapy, antiplatelet drugs, and other medication take effect. During TP treatment, Plt count and morphology/ultrastructure were examined. Plt functions by multiplate analyzer were evaluated. We concluded that intensive TP was an effective, safe, and rapid cytoreductive treatment for ET.

Background/Aim. Autologous stem cell transplants (ASCTs) improve the rate of overall survival (OS) in patients with hematological malignancies such as multiple myeloma (MM) after induction chemotherapy, aggressive non-Hodgkin's lymphomas (NHL), and relapsed, chemotherapy- sensitive Hodgkin's lymphoma (HL). The study aim was to evaluate influence of applied CD34+ cell quantity on clinical outcome, as well as early post-transplant and overall survival (OS) of HL and MM patients following ASCT. Methods. This study included a total of 210 patients (90 HL/120 MM) who underwent ASCT. Stem cell (SC) mobilization was accomplished by granulocyte-colony stimulating factor (G-CSF) 10–16 μg/kg body mass (bm) following chemotherapy. For proven poor mobilizers, mobilization with G-CSF (16 μg/kgbm) and Plerixafor (24 or 48 mg) was performed. To our best knowledge, it was the first usage of the Plerixafor in our country in the ASCT-setting. Harvesting was initiated merely at "cut-off-value" of CD34+ cells ≥ 20 × 106/L in peripheral blood with "target-dose" of CD34+ cells ≥ 5 × 106/kgbm in harvest. The CD34+ cell count and viability was determined using flow cytometry. Results. The majority of HL patients (76.7%) were infused with > 5.0 × 106/kgbm CD34+ cells, while 68.3% of MM patients were treated by approximately 4.0–5.4 × 106/kgbm CD34+ dose, respectively. Beneficial response (complete/ partial remission) was achieved in 83.3% (HL) and 94.2% (MM) patients. Among parameters that influenced survival of HL patients with positive response to the therapy, multivariate analysis (pre-ASCT performance status, CD34+ cell quantity applied, rapid hematopoietic, i.e. lymphocyte and platelet recovery) indicated that higher CD34+ cell dose used, along with pre-ASCT performance status correlated with superior event-free survival (EFS) and OS following ASCT. In MM patients, multivariate analysis (renal impairment, infused CD34+ cell quantity, early platelet recovery) indicated that the number of CD34+ cells infused was the most important parameter that influenced both EFS and OS after ASCT. Conclusion. Data obtained in this study undoubtedly confirmed that CD34+ cell dose applied is an independent factor that may contribute to superior clinical outcome and OS of HL and MM patients following ASCT. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 41004 and Grant no. III 41030]

Introduction. Bence-Jones myeloma multiplex is a progressive disease characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of incomplete immunoglobulins, containing only the light chain portion of the immunoglobulins. This type of myeloma occurs 15-20%. The median overall survival is approximately 4 years. Aim of this study was to define prognostic factors affecting overall survival in Bence-Jones multiple myeloma patients. Material and Methods. From 1995 to 2015, we treated 75 patients (49 men and 26 female), average age 55.9 years (range 31-85). Results. Conventional chemotherapy introductory clinical response was achieved in 54 patients (72%), while in 21 patients (28%) the established disease was resistant. Transplantation was done in 45 patients (60%), while 30 patients (40%) were treated with conventional chemotherapy. In the group of patients with transplantation done, tandem was carried out in 11 patients and secondary stem cell transplantation was done in 5 relapsed patients. With 1 patient with tandem stem cell transplantation allogenic (singen) stem cell transplantation was done. Transplant related mortality is 1.5%. The transplanted patients had significantly longer PFS (mediana 13 months vs 7 months, p

Introduction. Autologous stem cell transplantation combined with high dose chemotherapy is an effective and safe approach in the treatment of different hematological malignancies. Nowadays, autologous stem cell transplantation represents a standard therapeutic option in the treatment of multiple myeloma, lymphomas and other hematological malignancies. Aim is to analyze the available medical data of patients with multiple myeloma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma acute myeloid and lymphoblastic leukemia, who underwent autologous stem cell transplantation, and to compare the results with published data from other similar studies. Material and Methods. A retrospective study included 90 patients with multiple myeloma, acute myeloid and lymphoblastic leukemia, non-Hodgkin’s and Hodgkin’s lymphoma who underwent autologous stem cell transplantation in the period from 2004 to August 2017. Results. In relation to the underlying disease, the distribution of the respondents was as follows: 39 patients had multiple myeloma, 25 non-Hodgkin’s lymphoma, 20 Hodgkin’s lymphoma and 6 had acute leukemia. 75 patients (89.3%) had the large volume apheresis procedure, while 9 patients (10.7%) had the conventional two-day apheresis procedure. The average number of the mononuclear cells in the apheresis product was 7,8x108/kg, and the number of the CD34 + cells was about 12,11x106 kg. After applying the conditioning regimen, depending on the underlying disease, neutrophils engraftment mainly occurred on the 11th while the platelet engraftment occurred on the 14th post-transplant day. Transplant-related mortality was low, and the mortality rate was 3.57%. Conclusion. Autologous stem cell transplantation is an efficient method of treatment for patients with he­matological malignancies. It is associated with a low rate of complications as well as low rate of transplant-related mortality.

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Autologous stem cell transplant with high-dose chemotherapy is considered to be an effective treatment strategy for outcome improvement in lymphoma patients, especially those with refractory and relapsed disease. Despite the feasibility and efficacy of autologous stem cell transplant, patients with lymphoma still face the risk for relapse, mostly patients who have adverse prognostic features. Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant is recognized as the most effective strategy for relapsed or refractory Hodgkin lymphoma or aggressive non-Hodgkin lymphoma improving their response rate. First line therapy is ABVD (Hodgkin lymphoma patients), R-CHOP or R-CHOP-like regimens while salvage regimens such as DHAP, ESHAP, ICE represent the standard of care for relapsed/refractory lymphoma patients. Before autologous stem cell transplant, standard condition regimens are BEAM or CBV.

Background: In patients with ST-elevation myocardial infarction (STEMI), C-reactive protein (CRP) levels are associated with larger infarct size, transmural extent, and poor function of left ventricle and independently predict 30-day mortality. CRP-apheresis following STEMI showed to be feasible, safe, and has significant beneficial effect both on myocardial infarction size and wall motion. To the best of our knowledge, this is only the second published clinical evaluation of the efficacy and safety of selective CRP-apheresis in the STEMI treatment using Spectra-Optia and Pentrasorb CRP-adsorber systems. Case Report: A 53-year-old female was referred with anterior STEMI. After percutaneous coronary intervention, patient received standard post-STEMI therapy according to current guidelines. Selective therapeutic plasma exchange (TPE) was performed using Spectra-Optia (Terumo BCT; USA) and Pentrasorb CRP-adsorber (Pentracor GmbH; Germany) systems. Antecubital veins were used for vascular access and acid-citrate-dextrose solution (ACD formula A; total volume = 1,026 mL) was utilized as anticoagulant. The volume of processed blood was 15,600 mL. The removed “natural” plasma (total volume = 8,329 mL) was replaced with CRP-depleted autologous plasma (total volume = 8,085 mL). This intensive TPE-treatment was well tolerated, without adverse effects, or complications. The CRP plasma levels were: initial = 4.2 mg/L 6 h after acute myocardial infarction (AMI), pre-apheresis = 16.4 mg/L, and post-apheresis = 4.59 mg/L (CRP-depletion = 72%). There were neither significant changes observed in biochemistry nor any alterations in plasma hemostatic activity investigated before and after CRP-adsorption performed. Conclusion: Early performed CRP-apheresis is a promising innovative therapeutic approach for STEMI treatment that could provide a reduced size of infarction zone – with inferior occurrence of heart failure after AMI. However, precise and complete evaluation of the efficacy and safety of this treatment requires further multicenter randomized and larger clinical studies.

Prognostic significance of immune microenvironment has been emphasized using the most advanced analysis, with consecutive attempts to reveal prognostic impact of this findings. The aim of this study was to compare and define prognostic significance of clinical parameters, microvessel density (MVD) in tumour tissue and expression of CD44s as adhesive molecule on tumour cells in diffuse large B cell lymphoma-DLBCL, primary central nervous system DLBCL-CNS DLBCL and follicular lymphoma-FL. A total of 202 histopathological samples (115 DLBCL/65 FL/22 CNS DLBCL) were evaluated. Overall response (complete/partial remission) was achieved in 81.3 % DLBCL patients, 81.8 % primary CNS DLBCL and 92.3 % FL. Absolute lymphocyte count-ALC/Absolute monocyte count-AMC2.6 in DLBCL and ALC/AMC ≥ 4.7 in FL were associated with better event-free survival (EFS) and overall survival (OS) (p 0.05). In DLBCL, MVD 42 blood vessels/0.36 mm(2) correlated with primary resistant disease (p 0.0001), poorer EFS and OS (p = 0.014). High CD44s expression in FL correlated with inferior EFS and OS (p 0.01). In DLBCL, multivariate Cox regression analysis showed that ALC/AMC was independent parameter that affected OS (HR 3.27, 95 % CI 1.51-7.09, p = 0.003) along with the NCCN-IPI (HR 1.39, 95 % CI 1.08-1.79, p = 0.01). Furthermore, in FL, ALC/AMC mostly influenced OS (HR 5.21, 95 % CI 1.17-23.21, p = 0.03), followed with the FLIPI (HR 3.98, 95 % CI 1.06-14.95, p = 0.041). In DLBCL and FL, ALC/AMC is simple and robust tool that is, with current prognostic scores, able to define long-term survival and identify patients with inferior outcome. The introduction of immunochemotherapy might altered the prognostic significance of microenvionmental biomarkers (MVD and CD44s).

Introduction. Multiple sclerosis (MS) is an immunemediated disease of the central nervous system that affects young individuals and leads to severe disability. High dose immunoablation followed by autologous hemopoietic stem cell transplantation (AHSCT) has been considered in the last 15 years as potentialy effective therapeutic approach for agressive MS. The most recent long-time follow-up results suggest that AHSCT is not only effective for highly aggressive MS, but for relapsing-remitting MS as well, providing long-term remission, or maybe even cure. We presented a 10- year follow-up of the first MS patient being treated by immunoablation therapy and AHSCT. Case report. A 27-year-old male experienced the first symptoms - intermitent numbness and paresthesia of arms and legs of what was treated for two years by psychiatrist as anxiety disorder. After he developed severe paraparesis he was admitted to the Neurology Clinic and diagnosed with MS. Our patient developed aggressive MS with frequent relapses, rapid disability progression and transition to secondary progressive form 6 years after MS onset [the Expanded Disability Status Scale (EDSS) 7.0 Ambulation Index (AI) 7]. AHSCT was performed, cyclophosphamide was used for hemopoietic stem cell mobilization and the BEAM protocol was used as conditionig regimen. No major adverse events followed the AHSCT. Neurological impairment improved, EDSS 6.5, AI 6 and during a 10-year followup remained unchanged. Brain MRI follow-up showed the absence of gadolinium enhancing lesions and a mild progression of brain atrophy. Conclusion. The patient with rapidly evolving, aggressive, noninflammatory MS initialy improved and remained stable, without disability progression for 10 years, after AHSCT. This kind of treatment should be considered in aggressive MS, or in disease modifying treatment nonresponsive MS patients, since appropriately timed AHSCT treatment may not only prevent disability progression but reduce the achieved level of disability, as well.

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Background/Aim. Intramyocardial bone marrow mononuclear cells (BMMNC) implantation concomitant to coronary artery bypass grafting (CABG) surgery as an option for regenerative therapy in chronic ischemic heart failure was tested in a very few number of studies, with not consistent conclusions regarding improvement in left ventricular function, and with a follow-up period between 6 months and 1 year. This study was focused on testing of the hypothesis that intramyocardial BMMNC implantation, concomitant to CABG surgery in ischemic cardiomyopathy patients, leads to better postoperative long-term results regarding the primary endpoint of conditional status-functional capacity and the secondary endpoint of mortality than CABG surgery alone in a median follow-up period of 5 years. Methods. A total of 30 patients with ischemic cardiomyopathy and the median left ventricular ejection fraction (LVEF) of 35.9 ± 4.7% were prospectively and randomly enrolled in a single center interventional, open labeled clinical trial as two groups: group I of 15 patients designated as the study group to receive CABG surgery and intramyocardial implantation of BMMNC and group II of 15 patients as the control group to receive only the CABG procedure. All the patients in both groups received the average of 3.4 ± 0.7 implanted coronary grafts, and all of them received the left internal mammary artery (LIMA) to the left anterior descending (LAD) and autovenous to other coronaries. Results. The group with BMMNC and CABG had the average of 17.5 ± 3.8 injections of BMMNC suspension with the average number of injected bone marrow mononuclear cells of 70.7 ± 32.4 × 106 in the total average volume of 5.7 ± 1.5 mL. In this volume the average count of CD34+ and CD133+ cells was 3.96 ± 2.77 × 106 and 2.65 ± 1.71 × 106, respectively. All the patients were followed up in 2.5 to 7.5 years (median, 5 years). At the end of the follow-up period, significantly more patients from the group that received BMMNC were in the functional class I compared to the CABG only group (14/15 vs 5/15; p = 0.002). After 6 months the results on 6-minute walk test (6-MWT) were significantly different between the groups (435 m in the BMMNC and CABG group and 315 m in the CABG only group; p = 0.001), and continued to be preserved and improved on the final follow-up (520 m in the BMMNC and CABG group vs 343 m in the CABG only group; p < 0.001). Cardiovascular mortality was also significantly reduced in the BMMNC and CABG group (p = 0.049). Conclusion. Implanatation of BMMNC concomitant to CABG is a safe and feasible procedure that demonstates not only the improved functional capacity but also a reduced cardiac mortality in a 5-year follow-up in patients with ischemic cardiomyopathy scheduled for CABG surgery.

Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings into perspective these experiences with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11–46). Two were found to haveHIF2Asomatic mosaicism. No relatives were affected. All patients were diagnosed with polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8–38) and SOMs at 29 years (range 22–38). PGLs were multiple, recurrent and metastatic in 100, 100 and 29% of all cases, and SOMs in 40, 40 and 60%, respectively. All PGLs were primarily norepinephrine-producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel–Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA). Therefore, [18F]-FDOPA PET/CT, not [68Ga]-(DOTA)-[Tyr3]-octreotate ([68Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges.

Background/Aim. Introducing tyrosine kinase inhibitors (TKIs) has essentially changed curative approach, to be precise, clearly improved treatment efficacy for chronic myeloid leukemia (CML). Thus, the place and usage of allogeneic stem cell transplant (SCT) in CML treatment - as a former "nearly monopolistic" therapeutic manner - is nowadays controversial. The objective of this retrospective study was to evaluate the results obtained in the treatment of CML patients, with a particular attempt to define parameters critical for clinical benefit and superior overall outcome following allogeneic SCT. Methods. A total of 32 CML patients (27 in chronic phase and 5 with advanced disease), with female/male ratio 11/21, aged from 9 to 54 (32 in average) years, underwent allogeneic SCTs (1993 to 2009). The initial treatment for 25 patients was interferon alpha (IFN-α) with or without ARA-C, and additional 7 patients with no response to imatinib mesylat (IM). The time from diagnosis to SCT was approximately 12 (range 3- 37) months. The patient were categorized according to the risk for the disease, transplant-related mortality (TRM) scoring system, and stem cell (SC) source. The basic conditioning regimen was a combination of busulphan and cyclophosphamide (BuCy-2). Graft-versus-host disease (GvHD) was typically prevented with cyclosporine-A (CsA) and methotrexate (MTX). Results. Engraftment was observed in 26 (84.4%) patients, with polymorphonuclear (PMNs) and platelet (Plt) recovery on the 15th (range 10-22) and 19th (range 11-29) posttranspalnt days, respectively. Acute GvHD (aGvHD) had 13/26 (50%), and chronic GvHD (cGvHD) 10/21 (47.1%) patients. The incidence of overall TRM was 46.8% (15/32), while early death was noticed in 4 (12.5%) patients. A cause of death in 9 (28.1%) patients was cGvHD, in 2 (6.25%) patients infection, and in 3 (9.35%) cases disease-relapse was occurred. Fourteen (43.7%) of the patients are still alive, 9 from the low-risk group for TRM, with long-term survival from 1 to 16 years. Patients who received SCs from peripheral blood (PB) vs bone marrow (BM) had significantly faster engraftment (p < 0.05), lower oropharingeal mucositis rate (25% vs 70%; p < 0.05), but more frequent cGvHD (83.3% vs 30.3%; p < 0.05). A significantly improved (log-rank = 2.39; p < 0.01) overall survival (OS) was obtained in BM-setting. Conclusion. The results obtained in this study are in accordance with data from analogous clinical trials. Exactly, in the era of the new target therapy (TKI application), allogeneic SCT can be still a convenient therapeutic approach for well-selected CMLpatients, especially for those with initial high-risk disease and lower probability of TRM.

The aim of this study was to evaluate the prognostic significance of international prognostic index (IPI), mantle cell lymphoma IPI (MIPI), simplified MIPI (sMIPI), and MIPI biological (MIPIb), as well as their correlation with immunophenotype, clinical characteristics, and overall survival (OS), in a selected group of 54 patients with advanced-stage mantle cell lymphoma (MCL), treated uniformly with CHOP. Seventeen patients had IV clinical stage (CS), while other 37 had leukemic phase at presentation. Diffuse type of marrow infiltration was verified in 68.5% and nodular in remainder patients. Extranodal localization (25.9%) included bowel (20.4%), pleural effusion, sinus, and palpebral infiltration. All of analyzed patients expressed typical MCL immunophenotypic profile: CD19(+)CD20(+)CD22(+)CD5(+)Cyclin-D1(+)FMC7(+)CD79b(+)smIg(+)CD38(+/-)CD23(-)CD10(-). Median OS of the whole group was 23 months, without significant differences between IV CS and leukemic phase patients. Thirty-two patients (59.3%) responded to initial treatment, 9 (16.7%) with complete and 23 (42.6%) with partial remission. Negative prognostic influence on OS had high IPI (P0.01), high sMIPI (P0.001), MIPI (P0.01), MIPIb (P0.01), extranodal localization (P0.01), and diffuse marrow infiltration (P0.01). Testing between randomly selected groups showed that patients with lower proportion of CD5(+) cells (80%) correlated with cytological blastoid variant and had shorter survival comparing with the group with higher proportion of CD5(+) cells (80%) (P0.01). Using univariate Cox regression, we proved that IPI, sMIPI, MIPI, and MIPIb had an independent predictive importance (P0.01) for OS in uniformly treated advanced MCL patients, although sMIPI prognostic significance was the highest (P0.001).

Background/Aim. Peripheral blood (PB) is used more frequently as a source of stem cells (SCs) for allogeneic transplantation. However, the influence of cell source on the clinical outcome of SC transplantation is not yet well established. The aim of this study was to compare the results of PBSC transplantation (PBSCT) with bone marrow transplantation (BMT) on the basis of engraftment, frequency and severity of immediate (mucositis, acute Graft versus Host Disease - aGvHD) and delayed (chronic GvHD - cGvHD) complications, as well as transplant-related mortality (TRM), transfusion needs, relapses and overall survival (OS). Methods. We analyzed 158 patients, women/men ratio 64/94 median age 29 (range 9-57), who underwent allogeneic SC transplantation between 1989 and 2009. All included patients had diseases as follows: acute myeloid leukemia (AML) - 39, acute lymphoblastic leukemia (ALL) - 47, chronic myeloid leukemia (CML) - 32, myelodysplastic syndrome (MDS) - 10, Hodgkin?s lymphoma (HL) - 2, multiple myeloma (MM) - 3, granulocytic sarcoma (GrSa) - 3, severe aplastic anemia (sAA) - 22. The patients underwent transplantations were divided into two groups: BMT group (74 patients) and PBSCT group (84 patients). Each recipient had HLA identical sibling donor. SCs from bone marrow were collected by multiple aspirations of iliac bone and from PB by one ?Large Volume Leukapheresis? (after recombinant human granulocyte colony stimulating factor, rHuG-CSF) application (5-12 ?g/kgbm, 5 days). Conditioning regimens were applied according to primary disease, GvHD prophylaxis consisted of combination of a cyclosporine A and methotrexate. Results. Engraftment, according to the count of polymorphonuclear and platelets, were significantly (p < 0.001) faster in the PBSCT vs BMT group. The needs for transfusion support were significantly (p < 0.01) higher in the BMT group. Those patients had more frequently oropharingeal mucositis grade 3/4 (33.3% vs 10.0%, p < 0.05). There were no significant differences in the incidence of aGvHD and cGvHD between the two groups. The patients who underwent PBSCT had more frequently extensive cGvHD in comparison with the BMT group (29.1% vs 11.29%, p < 0.05). SC source (SCS) had no significant influence on the TRM (21.62% vs 23.8%, p = 0.64) and the incidence of relapses (21.6% vs 29.7%, p = 0.32). Finally, the patients treated by BMT had a significantly better OS (logrank 2.33, p < 0.05). Conclusion. SCs harvesting from PB resulted in improved cell yield, faster engraftment, as well as in a decrease of immediate transplantation related complications with a reduced treatment cost. Allogeneic PBSCT were associated with more frequent extensive cGvHD, while the influence of SCS in TRM and relapses was not observed. Finally, the longterm OS was better in the patients treated by BMT. To verify impact of SC source on transplantation (PBSCT vs BMT) overall efficacy, more larger randomized clinical studies are needed.

Therapeutical concept for myeloma mulitplex (MM) patients has been significantly improved over the previous years. As in other haematological malignancies, in MM also, induction treatment goal is to achieve complete remission (CR) of the disease. The importance of CR on overall survival (OS) in MM was first estimated in the high dose chemotherapy (CT) with autologous stem cell transplantation (ASCT). Induction treatment with 3-6 cycles of combined CT based on Dexamethason (VAD) following with one or two courses of high doses of Melphalan with ASCT leads to 20-40% CR and 40-55% CR/VGPR with median survival of 4-5 years. These are significantly better results compared to previous conventional therapy, and considering such findings, ASCT became the treatment of choice for MM patients aged below 65 years. The introduction of novel agents, such as immunomodulatory drugs (Thalidomid, Lenalidomid) and proteasome inhibitors (Bortezomib) into induction therapy have improved treatment of MM patients even more. The combination of Dexamethason with Thalidomid, Bortezomib or Lenalidomid, on the average in 3-4 cycles, arises the level of CR/ VGPR (very good partial response) even to 60-75%. Bortezomib based regimens are recommended in the treatment of ?high risk? group of patients with MM. Recommended conditioning regimen is 200 mg/m2 of Melphalan. If either CR or VGPR is not achieved, recommendation is to perform the second ASCT as a part of ?tandem?concept. Thalidomid applied as a ?maintenance therapy? after ASCT may prolong OS. Until now, allogeneic ASCT, as the first line treatment for MM patients aged below 65 years, has been applied only in clinical trials.

Background. In countries without a national organization for retrieval and distribution of organs of the deceased donors, problem of organ shortage is still not resolved. In order to increase the number of kidney transplantations we started with the program of living unrelated - spousal donors. The aim of this study was to compare treatment outcome and renal graft function in patients receiving the graft from spousal and those receiving ghe graft from living related donors. Method. We retrospectively identified 14 patients who received renal allograft from spousal donors between 1996 and 2009 (group I). The control group consisted of 14 patients who got graft from related donor retrieved from the database and matched than with respect to sex, age, kidney disease, immunological and viral pretransplant status, the initial method of the end stage renal disease treatment and ABO compatibility. In the follow-up period of 41 ± 38 months we recorded immunosuppressive therapy, surgical complications, episodes of acute rejection, CMV infection and graft function, assessed by serum creatinine levels at the beginning and in the end of the follow-up period. All patients had pretransplant negative cross-match. In ABO incompatible patients pretransplant isoagglutinine titer was zero. Results. The patients with a spousal donor had worse HLA matching. There were no significant differences between the groups in surgical, infective, immunological complications and graft function. Two patients from the group I returned to hemodialysis after 82 and 22 months due to serious comorbidities. Conclusion. In spite of the worse HLA matching, graft survival and function of renal grafts from spousal donors were as good as those retrieved from related donors.

Background/Aim. High-dose chemotherapy with autologous stem cell transplantacion (ASCT) has shown to produce long-term disease-free survival in patients with chemotherapysensitive Hodgkin disease. The aim of the study was to evaluate efficacy of ASCT in the treatment of Hodgkin's disease. Methods. Between May 1997 and September 2008, 34 patients with Hodgkin's disease in median age of 25 (range 16-60) years, underwent ASCT. Autologous SCT were performed as consolidation therapy in one poor-risk patients with complete response (CR) and in 10 patients in partial remission (PR) after induction chemotherapy (32.5%), for chemosensitive relapse (CSR 1 and CSR 2) in 47% patients and in 20.5% patients with chemoresistant disease (CRD). All except one patient were in stage III/IV, extranodal site of disease had 24 patients and bulky disease had l0 patients. All the patients received a uniform preparatory regimen (BEAM). Results. An overall response was achieved in 30 of 32 evaluated patients, with 62.5% in CR and 31.25% in PR. After applying radiotherapy, two patients with PR after ASCT reached CR. Median follow-up was 15.5 months (range 3-133 months). The probability of overall survival (OS) and progression-free survival (PFS) at a 3-year period for all patients was 51.9 % and 48.9%, respectively. For 22 patients in CR after ASCT, a 3-year DFS was 66.5%. Estimates of 2.5-year survival were 14.3%, 61.9% and 100% for CRD, CSR and for patients with CR/PR, respectively (p < 0.01). However, when patients undergoing consolidation were analyzed separately from those in CSR, no significant difference in OS and PFS was observed according to the disease status at ASCT. In univariate analysis for OS, PFS i DFS, extranodal site of disease and disease bulk had no predictive value. Twelve patients died. The main cause of death was Hodgkin's disease. Transplant-related mortality was 3.1%. One patient with CRD developed secondary acute myeloid leukemia and died 28 months after the transplantation. Conclusion. Autologous SCT is efficient as consolidation therapy in high-risk patients and in chemosensitive relapse, but it has no benefit in patients with chemoresistant disease.

Background/Aim. Due to improved methods for removal of ABO isoagglutinins and novel immunosuppressive protocols, short and long term outcome in blood group incompatible is similar to blood group compatible kidney transplantation. The aim of this study was to determine the efficacy of our original method for removal of ABO isoagglutinins from the blood in ABO-incompatible kidney allograft recipients. Method. Between 2006 and 2008 twelve patients were transplanted from ABO incompatible living donors. Titers of ABO isoagglutinins were 4-128 (IgG). Immunosuppressive therapy started 14 days before kidney transplantation with rituximab, followed by a triple therapy (prednisone + tacrolimus + mycophenolate mofetil) and the first plasma exchange (PE) procedure, in which one plasma volume was substituted with albumin and saline on day 7 before transplantation. For selective extracorporeal immunoadsorption, the removed plasma was mixed with donor blood type filtered red blood cells, centrifuged and the supernatant separated and preserved. In the next PE procedure, the removed plasma was replaced with immunoadsorbed plasma, and so on. Titers of ABO agglutinins, renal allograft function and survival were followed-up. Results. The pre-transplant treatment consisting of 1-5 PE procedures and immunosuppressive therapy resulted in target ABO agglutinins titers below 4. During a 10-24 month follow-up three patients had an early acute rejection, one patient acute rejection and hemolytic anemia, two patients surgical complications and one of them lost his graft. In the post-transplant period, the titers of ABO antibodies remained below 4. All the patients had stable kidney allograft function with mean serum creatinine ?SD of 129 ? 45 ?mol/l at the end of the study. Conclusion. Our method for removal of ABO antibodies was effective in a limited series of patients and short-term follow-up.

Buducnost celijske terapije u lecenju neuroloskih bolesti je pocela. Ostaju vazna pitanja na koja odgovor mogu dati samo dobro osmisljene medjunarodne studije, a ticu se vrste celija, nacina njihovog umnozavanja i aplikacije, kao i optimalnog vremenskog okvira za ovakvu vrstu lecenja.

Paragangliomas are tumors arising from the extra-adrenal paragangliar neural crest cells. The sympathoadrenal neuroendocrine system consists of extra-adrenal paragangliar cellular layer along the paravertebral and para-aortic axis, and the adrenal medullae. Paraganglioma should be included in the differential diagnosis of secondary erythrocytosis due to its possible ectopic erythropoietin (EPO) secretion. Thus, in this report we present a 24-year-old female patient with onset of unregulated ectopic EPO secretion, and consecutive erythrocytosis followed by hypertension, secondary to paraganglioma of multifocal retroperitoneal localization. Clinical, laboratory, and radiological investigations confirmed both an elevated EPO level and the presence of multiple paraganglioma. This paraneoplastic-mediated medical condition with high risk of cellular hyperviscosity syndrome (CHVS) requires prompt diagnosis and rapid therapeutic interventions. Initially, simple phlebotomy procedures were used; following that, tumors were surgically removed. In the course of the disease, this tumor relapsed, and urgent apheresis, as a treatment of life-threatening state, was used. The therapy performed resulted in a rapid blood viscosity depletion and a significant (P < 0.01) serum EPO reduction, as well as the general clinical benefit. Therefore, we conclude that the use of our own “multi-manner” apheresis (erythrocythapheresis plus plasma exchange), for long-time interval (until further causative therapy), effectively cross-bridged the possible hazards of EPO-dependent CHVS.

The aim of the study was to evaluate retrospectively clinical course of 27 patients with primary central nervous system lymphoma (PCNSL) diagnosed and treated by different surgical approaches. Initial therapy-diagnostic approach included surgery with total tumour reduction (TTR) performed in 12 patients (44.4%), while partial reduction and biopsy were performed in 8 (29.7%) and 7 (25.9%) patients, respectively. All patients were treated with chemotherapy based on high-dose methotrexate (HD-MTX) with/without whole-brain radiotherapy (WBRT).The median overall survival (OS) and event-free survival were 37 and 31 months, respectively, with overall response rate of 74%. The patients who underwent an open surgery with TTR had significantly longer OS (median not reached), comparing with partial tumour reduction or biopsy only (Log-Rank χ(2) 6.08, p = 0.014) when median OS was 23 months. In patients with performance status according to Eastern Cooperative Oncology Group (ECOG PS) ≥ 3, OS was 23 months, contrary to ECOG PS 1-2 when median was not reached. The International Extranodal Lymphoma Study Group score (low, intermediate and high) also influenced OS between three risk groups (Log-Rank χ(2) 12.5, p = 0.002).The treatment of PCNSL still remains doubtful, however possible benefit from the TTR followed with HD-MTX with/without WBRT should be reconsidered.

The concept of cancer stem cells has been a compelling but controversial idea for many years. It suggests that at the root of any cancer there is a small subset of cancer cells that are solely responsible for driving the growth and evolution of a patient’s cancer. These cancer stem cells replenish themselves and produce the other types of cancer cells, as normal stem cells produce other normal tissues. The concept is important, because it suggests that only by developing treatments that get rid of the cancer stem cells will you be able to eradicate the cancer. Likewise, if you could selectively eliminate these cancer stem cells, the other remaining cancer cells would not be able to sustain the cancer. This chapter will summarize the novelties in cancer treatment that would be able to target specifically cancer stem cells.

Through the identification of various research outcomes, it has become clear that two primary objectives lie ahead for the promulgation of the role of cancer stem cells in future treatment modalities: (1) identification of protein surface markers/biomarkers on the surface or inside of these cells that uniquely identify them against normal cells in human tissue that thereby allow the development of therapeutic interventions based on selective targeting of cancer stem cells, and (2) characterization of cancer stem cells in their ability to adapt to current forms of treatment so as to limit the proliferation of more resistant and dangerous forms of previous cancers through the identification of mutational “hot spots” in the aforementioned cancer stem-cell markers. Through analysis of multiple research articles in the field over a range of several years, we assess the current understanding of the cancer stem-cell concept due to controversies and doubts linked to cancer stem-cell entities in order to research and develop areas of opportunity for novel and creative targeted cancer therapy, including those new treatment options already in place in the clinical setting.

The review on classical antitumor therapy including the anticancer stem cell therapy novelties is presented with disadvantages and advantages. The concept of targeted tumor therapy has evolved during last years into the concept of targeted stem cell therapy. The difference between the two is that in the first case we are targeting the pool of tumor cells as well as normal cells while in the second case we should target just cancer stem cells (CSCs). The new theories on CSCs are comprehended in the light of new conceptual approaches. CSC markers are envisioned as a new category of biomarkers which would be guides toward precise distinction between tumor cells and CSCs. CSCs have the highest tumorigenic potential in the entire pool of tumor cells and due to that should be essential and primary target of the therapy. Thus, targeting of other less cancerogenic and normal cells would be omitted. CSCs due to that reside in tissues either as minimal residual disease or simply as a very low number of cloned cells. When reaching critical size or count, they cause tumor relapse.

This report presents our experience with cytaphereses performed in treatment of 476 patients. Leukapheresis was used in management of 68 patients with hyperleukocytosis leukostasis (WBCor = 150 x 10(9)L(-1)). Average decrease in cell count after treatment was 73.3%. Plateletapheresis for 32 patients (plateletsor = 1500 x 10(9)L(-1)) was applied in order to prevent the thrombotic-hemorrhagic syndrome and resulted in a moderate platelet count reduction (84.3%). Erythrocytaphereses performed in treatment of 376 patients by manual or automated technique resulted in a rapid blood viscosity drop (42.4+/-7.1%). Patients with red blood cell exchanges (severe malaria and autoimmune hemolytic crisis) were in life-threatening situations and resulted in a prompt reduction of parasitized or antibody-coated RBCs and anemia correction. This study indicates that "conventional" TCs resulted in considerable cytoreduction only in patients with especially high cell count. This effect was not associated with bone marrow remission. The best clinical effect and long-term benefits were obtained using RBCX and antimalarial drugs in malaria patients who have had high-level parasitized-RBCs with multiorgan dysfunction.

In our country, the first apheresis was performed in the late 1960s (by manual technique), and the first cell separator was used in 1979. The number of blood component collections performed from 1994 to 2004 was: 11,170 (total), i.e., 8540 (NBTI), 1180 (IT-MMA), 1050 (BTI of Novi Sad) and 400 (BTI Nis). The number of PBSC harvests during 1996-2004 was 386 for treatment of 272 patients. For treatment of myocardial infarction, "cell-therapy" by autologous stem cells was introduced in 2004 at the MMA. The results of PE treatments performed (7632 sessions) by our group for various immune-mediated and other disorders were generally beneficial, but the effect is not associated with bone marrow remission. TC procedures (total number=1279) resulted in a significant fall in the blood cell counts and hemorheological improvement, as well as the removal and replacement of abnormal red blood cells. Greater standardization of different apheresis protocols is required.

Background. It has been established that many patients with chronic hepatitis C have elevated serum iron, feritin levels and iron deposits in the liver. Therefore, the liver damage due to hepatitis C virus may be aggravated with iron overload. In many studies higher levels of iron in the blood and the liver were connected with the decreased response to interferon-alfa therapy for chronic viral hepatitis C. Recent introduction of pegylated interferons plus ribavirin has improved the therapeutic response, so it is now possible to cure more than 50% of the patients. Case report. Three patients with chronic hepatitis C and iron overload were presented. Iron reduction therapy using phlebotomy or eritrocytapheresis with plasmapheresis was done at different times in regard to specific antiviral therapy or as a sole therapy. Conclusion. It has been shown that iron reduction, sole or combined with antiviral therapy, led to the deacreased aminotransferase serum activity and might have slow down the evolution of chronic hepatitis C viral infection.

BACKGROUND: Whole-blood (WB) leukoreduction filters in current use retain the majority of PLTs. A new whole-blood filter, which retains significantly fewer of the PLTs (or saves PLTs [WB-SP]), has been developed. The performance characteristics of the WB-SP filter have been evaluated in a multicenter study. STUDY DESIGN AND METHODS: A total of 617 units of WB was collected into quadruple bag sets with an integrated WB-SP filter, leukoreduced, and processed into leukoreduced RBCs (LR-RBC), plasma (LR-PL), and buffy coats (LR-BC) from which, pooled, leukoreduced, PLT concentrates (LR-PCs) were produced. Recovery, yield, and residual WBCs were assessed in prepared blood components. RESULTS: The median residual WBC number in the LR-RBCs was 0.05 × 106 (range

Studije na zivotinjama i prva klinicka iskustva na ljudima pokazuju da nakon primene progenitornih celija mioblasta ili poreklom iz kostne srzi dolazi do poboljsanja srcane funkcije. Pomenute metode jos nose sa sobom veoma veliki broj pitanja. Da li je zaista moguce regenerisati miokard ?nekim? novim mioblastima, za koje se ocekuje da se diferenciraju u patoloskim uslovima u plemenito visoko diferentovano, funkcionalno tkivo miokarda? Kada je u pitanju ishemijska bolest srca ne treba zaboraviti osnovni problem - koronarnu insuficijenciju, koja se samom kardiomioplastikom ne resava. Kombinacija revaskularizacionih procedura sa celijskom kardiomioplastikom je sine qua non za prezivljavanje i transplantovanih celija. Da li je veca debljina oziljka na miokardu i njegova elasticnost dovoljna korist da bi se ove celije transplantovale kod bolesnika sa teskim oziljnim promenama na srcu? Koji su bolesnici pravi kandidati za ovaj vid terapije, koji je optimalan broj mioblasta koji treba transplantovati i koji je najbolji nacin za transplantaciju? Ovo su samo neka od ozbiljnih pitanja na koje je sada tesko dati odgovor. Sa druge strane, transplantacija progenitornih celija iz kostne srzi ili njihova mobilizacija faktorima rasta u perifernu krv su metode za pospesivanje arteriogeneze i angiogeneze, koja moze biti veoma brza i efikasna u smislu spasavanja ugrozenog miokarda u akutnim koronarnim sindromima, a dovoljna u sprecavanju ishemije kod teskih hronicnih koronarnih bolesnika. Visednevna primena faktora rasta omogucava dugotrajnu mobilizaciju velikog broja progenitora mezenhimskih celija iz kostne srzi, tj. pospesuje proces koji se i inace dogadja pod uticajem ishemije i nekrozom potaknutane imunske reakcije. Medjutim, koje faktore rasta, kada i u kojoj dozi, treba dati za mobilizaciju endotelnih i mioblastnih progenitora? Da li neki od njih mogu da pospese reperfuziono ostecenje miokarda? Koliko dugo treba primenjivati takvu terapiju? Da li je treba dati samo bolesnicima sa no reflow fenomenom? Dakle, brojna su pitanja koja se namecu i kada je u pitanju ovaj vid celijske terapije. U svakom slucaju dosadasnja istrazivanja otvaraju nove puteve i potrebne su vece, dobro kontrolisane randomizovane studije koje ce lagano da odgovaraju na jedno po jedno od pomenutih pitanja! Kardiologija se spusta na novi nivo, nivo osnovnih bioloskih procesa, diferencijacije, regeneracije, gensku terapiju, terapiju koja je usmerena na razvijanje mikrocirkulacije. Kao i u svemu ranije, bice potrebno puno godina da osetimo korist od istine za kojom tragamo.

Serum concentrations of proinflammatory cytokine interleukin-8 (IL-8) in 15 patients with surgically revascularized myocardium by triple venous cardiopulmonary bypass (CPB x 3) and in 10 patients with implanted artificial aortic valves (AV) were measured. Average IL-8 concentrations in ?CPB x 3? patients and in those with artficial aortic valve were 7,3 +/- 11,6 pg/mL 24 hours before surgery, i.e. 3,3 +/- 3,4 pg/mL; six hours after surgical procedure 32,7 +/- 71,4 pg/mL, i.e. 8,9 +/- 9,9 pg/mL; and 24 hours after surgery 10,9+/-9,7pg/mL, i.e. 8,3 +/- 4,6 pg/mL. Extracorporeal circulation (ECC) caused significant increase of IL-8 serum concentration in both investigated groups six hours after surgery. Comparing preoperative values of the both groups, as well as those of 6 and 24 hours after surgery, no significant values of IL-8 were found. Various types of open heart surgical procedures had no influence on the extent of the production and secretion of proinflammatory IL-8 cytokine measured in patients during 24 hours after surgery.