Is There a Role for Growth and Differentiation Factor-15 in B-Cell Lymphoproliferative Neoplasms?

Growth and differentiation factor-15 (GDF-15) correlates with worse outcome of many tumours and any cause mortality. Data about its role in lymphoproliferative neoplasms (LPN) are scarce. Our research aimed to reveal the correlation between GDF-15 and standard laboratory parameters of LPN activity, and to get insight into the possible value of this cytokine assessment in lymphoma patients. Prospective research included 40 patients treated for aggressive or indolent LPN, and 31 with indolent LPN on "watch and wait" regimen. Analyses were performed before and after treatment in treated patients and on two separate occasions in the "watch and wait" group. ELISA technique with R&D assays according to the manufacturer manual, from stored sera at - 70 °C was used for GDF-15 level measurement. Statistical analyses were performed by IBM SPSS Statistics 22 using descriptive and inferential statistics. As appropriate, differences between groups were assessed by two tailed t-test, Mann-Whitney or x2 test. Spearman Rank Order Correlation was done to correlate GDF-15 with standard laboratory markers of disease activity. All tests are two-tailed with significance level p < 0. 05. GDF-15 (p = 0.028) and fibrinogen (p = 0.001) concentrations increased after treatment in indolent lymphoma patients while ß2 microglobulin decreased (p < 0.001). GDF-15 positively correlated with ß2microglobulin before (p < 0.001) and after (p = 0.031) therapy. There were no differences in any of the aforementioned parameters in the "watch and wait" group during observation. A positive correlation between GDF-15 and ß2 microglobulin in patients with indolent LPN who need treatment suggests potential value in risk assessment. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01695-6.

Rituximab in the therapy of stage III and IV follicular lymphoma: Results of the REFLECT 1 study of the Serbian Lymphoma Group.

PURPOSE: Follicular lymphoma (FL) is an indolent lymphoma that responds well to rituximab+chemotherapy. We evaluated the prognosis and efficacy of immunochemotherapy in patients with previously untreated, advanced FL. METHODS: REFLECT 1 is a multicentre, prospective study of 99 patients with previously untreated FL stage III-IV. All patients were treated with rituximab+chemotherapy x 6 cycles, plus 2 cycles of rituximab monotherapy. Clinical assessment was performed at baseline, after completion of the first 6 cycles of therapy and every 3 months from the end of immunochemotherapy to the end of the study period. RESULTS: Eighty-nine out of 99 patients with complete documentation were included. Complete remission (CR) was achieved in 61.6%, partial remission (PR) in 11.6% and progressive disease (PD) in 24.4% of the patients. Time to progression (TTP) and overall survival (OS) after the 1st, 2nd and 3rd year were 89.9, 72.7, 57.8%, and 94.2, 92,6 and 92.6%, respectively. The probability of achieving CR was significantly lower in the high risk group according to Follicular Lymphoma Prognostic Index (FLIPI) score. Expression of CD43 antigen had a significant impact on the probability of 2-year TTP and OS, and ECOG performance status had a significant impact on OS. CONCLUSIONS: Treatment with rituximab plus chemotherapy is effective in advanced stages of FL. Significant prognostic factors are FLIPI score for induction therapy outcome, CD43 antigen expression for OS and TTP and ECOG performance status for OS.

GLP-1 Receptor Agonists and Type 1 Diabetes - Where Do We Stand?

Type 1 diabetes (T1DM) is a disease characterized by autoimmune mediated destruction of the insulin producing beta cells of endocrine pancreas. Beside insulin deficiency, T1DM is also characterized by abnormal suppression of glucagon secretion in response to hyperglycemia. All these abnormalities are likely to leave patients dependent upon exogenous insulin administration for survival. GLP-1 is a hormone secreted by L-cells of distal small intestine and colon. GLP-1 exerts its effects through the interaction with GLP-1 receptor expressed in the pancreatic islets, lung, hypothalamus, stomach, heart and kidney. It belongs to the group of incretin peptides and it stimulates insulin and inhibits glucagon secretion. Actions of GLP-1 also include delaying of gastric emptying, reduction of appetite and induction of satiety. On the other hand, evidences mainly collected from animal models, have indicated the role of GLP-1 in increasing beta cell proliferation and differentiation and in decreasing the rate of beta cell apoptosis. GLP-1 receptor agonists are approved for the treatment of type 2 diabetes where they have established very important position. However, they are still not approved for use in T1DM, although they could have beneficial effects in both new onset and longstanding T1DM patients, mainly as an adjunctive therapy to insulin in order to improve glycemic control and body weight management in longstanding disease or to reduce insulin requirements or even to delay the absolute dependence upon insulin administration in new onset T1DM. Randomized, long-term, placebo controlled clinical trials are warranted before the official implementation of GLP-1 receptor agonists in the treatment of T1DM.

Distribution of killer cell immunoglobulin-like receptor genes in population of Vojvodina, Serbia.

BACKGROUND: Killer cell immunoglobulin-like receptors (KIRs) are glycoproteins regulating the response of natural killer (NK) cells and a few sub-sets of T-cells. The KIR gene frequencies and genotype content vary considerably among different ethnic groups. AIM: The aim of this study was to analyse KIR gene polymorphism in the population of Vojvodina and to compare it with selected worldwide populations. SUBJECTS AND METHODS: The studied sample consists of 134 healthy unrelated individuals, residents of different geographical regions of Vojvodina. DNA samples isolated from peripheral blood leukocytes by the silica-based extraction method were used in reverse PCR-SSO and PCR-SSP technique to detect the presence and absence of KIR genes. RESULTS: All 16 KIR genes, a total of 37 different KIR genotypes, were observed in the Vojvodina population with the presence of framework and pseudogenes in all individuals. The neighbour-joining phylogenetic tree shows that the Vojvodina population is in the same cluster with Croatians, Turkish, Russians, Czechs, Irish, Italians, French, Macedonians and Polish. The Vojvodina population shows polymorphism of the KIR gene family present in other European and European-derived populations studied previously. CONCLUSION: The present study may serve as a reference for comparisons in further anthropological and disease association studies and also provide more informative data valuable for donor search strategy in haematopoietic stem cell transplantation.

C-KIT signaling in cancer treatment.

Tumor progression is strongly associated with the activity of receptor tyrosine kinases (RTKs) and their intracellular signal transduction pathways, which regulate several cell functions including proliferation, apoptosis, motility, adhesion and angiogenesis. Detailed structural and functional studies of RTKs, including the stem cell factor receptor c-KIT, revealed the complexity of these receptor systems and contributed to development of targeted clinical approaches with relevance in both prognosis and therapy. C-KIT signaling network has been the subject of intense research and pharmaceutical strategies to identify novel target-based approaches for cancer treatment. Evidence that c-KIT signaling promotes cell proliferation and survival, along with the frequency in which this pathway is aberrantly activated in cancer, support the current efforts to identify approaches for its efficient inhibition. C-KIT mutations are associatied with several human malignancies, such as gastrointestinal stromal tumors, acute myeloid leukemia, mast cell leukemia, and melanoma. Novel therapies are developed that target some of the identified genetic defects. It is therefore anticipated that newly-identified genetic markers will acquire a predictive value, that is, the ability to predict differential efficacy of a therapy. This review describes the evolving understanding of c-KIT/SCF axis and their downstream signaling in cancer, and the strategies for c-KIT-directed targeted cancer therapy.

Angiogenesis and survival in patients with myelodysplastic syndrome.

Angiogenesis has been implicated in the pathogenesis and prognosis of myelodysplastic syndrome (MDS). In this study, we investigated the relationship between microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, common morphological and clinical factors, and survival in patients with MDS. We examined the MVD of paraffin-embedded bone marrow sections from 70 MDS patients and 31 controls. VEGF expression was determined in 50 patients and 20 controls. The median MVD in MDS patients was significantly higher than that in controls (p = 0.025), whereas there was no difference in VEGF expression between MDS patients and controls. In univariate analysis, increased MVD was associated with a shorter survival time (p = 0.023). However, in multivariate analysis, MVD was not an independent predictor of survival. The VEGF expression did not influence survival in univariate analysis. Survival was independently influenced by platelet count (p = 0.0073), cytogenetic risk category (p = 0.022), and transfusion dependence (p = 0.0073). Neither MVD nor VEGF expression were predictors for progression to acute myeloid leukemia in univariate analysis. Progression to acute myeloid leukemia was independently influenced only by the cytogenetic risk category (p = 0.022). This study confirmed increased MVD in MDS. It does not support an independent prognostic role of angiogenesis in MDS.

The hematopoietic cell transplantation comorbidity index is a predictor of early death and survival in adult acute myeloid leukemia patients.

The hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of early death and survival in elderly patients with acute myeloid leukemia (AML). The aim of this study was to determine the prognostic role of the HCT-CI for early death and survival in adult AML patients. In the single-center retrospective study, we analyzed the outcome of 233 adult AML patients. The results indicated that the HCT-CI score is an independent predictor of early death in entire cohort of adult patients with AML. In subgroup analysis, HCT-CI is an independent predictor for early death in elderly patients but not in patients younger than 60 years. A high HCT-CI score predicts shorter survival in adult patients with AML.

A nonlinear two compartmental fractional derivative model.

This study presents a new nonlinear two compartmental model and its application to the evaluation of valproic acid (VPA) pharmacokinetics in human volunteers after oral administration. We have used literature VPA concentrations. In the model, the integer order derivatives are replaced by derivatives of real order often called fractional order derivatives. Physically that means that the history (memory) of a biological process, realized as a transfer from one compartment to another, is taken into account with the mass balance conservation observed. Our contribution is the analysis of a specific nonlinear two compartmental model with the application in evaluation of VPA pharmacokinetics. The agreement of the values predicted by the proposed model with the values obtained through experiments is shown to be good. Thus, pharmacokinetics of VPA after oral application can be described well by a nonlinear two compartmental model with fractional derivatives of the same order proposed here. Parameters in the model are determined by the least-squares method and the particle swarm optimization (PSO) numerical procedure is used. The results show that the nonlinear fractional order two compartmental model for VPA pharmacokinetics is superior in comparison to the classical (integer order) linear two compartmental model and to the linear fractional order two compartmental model.

[Clinical efficacy of novel therapeutic combinations in the treatment of patients with relapsed or refractory myeloma].

Despite all advances in the treatment of patients with multiple myeloma, relapse is a constant event in this disease. Novel therapeutic agents like proteasome inhibitors, immunomodulatory drugs and their combinations have improved overall survival in patients with relapsed or refractory myeloma, with partial remission achieved in 50-70% and median duration of 6-14 months, as well as the quality of life of these patients. The novel therapeutic agents presented known and acceptable safety profile. The choice of the appropriate regimen is depending on components of initial therapy, degree of response and remission duration, patient's status like age, performance status, renal function impairment, pre-existing medical toxicity, cytogenetic abnormalities and, at the other side, aggressiveness of relapsed disease.

[General calculating model of the needs for allogenic stem cell transplantation for the patients with leukaemia and myelodysplastic syndrome in Vojvodina].

INTRODUCTION: Allogeneic stem cell transplantation (SCT) application represents a treatment of choice that enables the eradication of malignant clone and chance for remedy of the patients with hematological diseases. Only 30-40% of the potential patients for allogeneic SCT have an HLA identical sibling, due to the fact that families in most of the developed countries are relatively small. MATERIAL AND METHODS: This study gives a general model for calculating the needs for allogeneic SCT which, enables calculation of the needs for allogeneic SCT per 1 million inhabitants of Vojvodina on basis of number of potential patients who could be treated by allogeneic SCT The number of beds required for transplanted patients, and of days in hospital per year as well as the estimation of financial aspect of allogeneic SCT have been calculated by means of the cummulative risk method, considering the following parameters: the relative number of patients suffering from ANLL, ALL, CML, CLL and MDS, 45 and 55-year-old and younger, total incidence/ 100,000 inhabitants for each investigated disease and the average number of days in hospital of transplanted patients. RESULTS: Total annual needs for allogeneic SCT for the patients suffering from ANLL, ALL, CML, CLL and MDS together, in transplantation with stem cells from their related donors are 786 days, from the unrelated donors are 306 days, while for nonmyeloablative transplantation with stem cells from their related donors are 558 days and from the unrelated ones are 297 days. CONCLUSION: The general calculating model of the needs for allogeneic SCT could be used as a basis for planning a regional bone marrow donor registry and for creating a similar calculating model of the needs for allogeneic SCT in other diseases treatable by HSCT.

[Tyrosine kinases in etiopathogenesis and therapy of malignant diseases--C-kit activating mutations].

INTRODUCTION: In the last 15 years, the introduction of molecular biology methods and techniques for identifying mutations and measuring gene expression levels of mutated genes since recently, have enabled precise molecular diagnostics, classification and assessment of prognosis and therapeutic response of malignant disease to specific therapies. The increased knowledge of the cancer genome and the introduction of multiple new technologies in cancer research have significantly improved the drug discovery process, leading to key success in targeted cancer therapeutics, including tyrosine kinase inhibitors. Tyrosine kinase inhibitors are the molecular targeted neoadjuvant and adjuvant therapy of various malignancies. Many more results which are expected from ongoing trials are necessary to specify the appropriate dosages, stages at which to start the treatment, and which therapeutic combinations to apply.

[Clinical relevance of KIRs in hematopoietic stem cell transplantation].

INTRODUCTION: Natural Killer cells (NK cells) represent the subset of peripheral lymphocytes that play critical role in the innate immune response to virus-infected and tumor transformed cells. Lysis of NK sensitived target cells could be mediated independently of antigen stimulation, and unlike cytotoxic T-lymphocytes, they do not require peptide presentation by the major histocompatibility complex (MHC) molecules. NK cell cytotoxic activity is controlled by considerable number of cell surface Killer cell Immunoglobulin like Receptors (KIRs), which can exist in both inhibitory and activating isoforms. The inhibitory KIRs are mostly specific for HLA class I ligands and I HLA class like molecules, while the specificity of activating receptors is regarded to lectine-like superfamily. The role of NK cells in allogeneic haematopoietic stem cell transplantation (HSCT): NK cells are the first lymphocyte subset that reconstitute the peripheral blood following allogeneic HSCT By selecting donors mismatched for relevant HLA ligands in the context of recipients KIR genotype, multiple roles for alloreactive donor NK cells have been demonstrated, in diminishing Graft vs. Host Disease (GvHD) through selective killing of recipient dendritic cells, prevention of graft rejection by killing recipient T cells and participation in Graft vs. Leukaemia (GvL) effect through destruction of residual host tumor cells. CONCLUSION: Investigation of KIRs heterogenity play an important role in the field of HSCT, because it is useful for the early diagnosis of post transplant complications and can serve as a predictive risk factor for GvHD development.

[Natural killer cells--biology, functions and clinical relevance].

INTRODUCTION; Natural Killer cells (NK cells) represent the subset of peripheral lymphocytes that play critical role in the innate immune response to virus-infected and tumor transformed cells. Lysis of NK sensitive target cells could be mediated independently of antigen stimulation and without requirement of peptide presentation by the major histocompatibility complex (MHC) molecules. NK cell activity and functions are controlled by a considerable number of cell surface receptors, which exist in both inhibitory and activating isoforms. There are several groups of NK cell surface receptors: 1) killer immunoglobulin like receptors-KIR, 2) C-type lectin receptors, 3) natural citotoxicity receptors-NCR and 4) Toll-like receptors-TLR. FUNCTIONS OF NK RECEPTORS: Defining the biology of NK cell surface receptors has contributed to the concept of the manner how NK cells selectively recognize and lyse tumor and virally infected cells while sparing normal cells. Further, identification of NK receptor ligands and their expression on the normal and transformed cells has led to the development of clinical approaches to manipulating receptor/ligand interactions that showed clinical benefit. NK cells are the first lymphocyte subset that reconstitute the peripheral blood following allogeneic HSCT and multiple roles for alloreactive donor NK cells have been demonstrated, in diminishing Graft vs. Host Disease (GvHD) through selective killing recipient dendritic cells, prevention of graft rejection by killing recipient T cells and participation in Graft vs. Leukaemia (GvL) effect through destruction of residual host tumor cells. CONCLUSION: Besides their role in HSCT, NK cell receptors have an important clinical relevance that reflects from the fact that they play a crucial role in the development of some diseases as well as in possibilities of managing all NK receptors through selective expansion and usage of NK cells in cancer immunotherapy.

[Clinical and prognostic significance of CD34 expression in bone marrow biopsies in myelodysplastic syndrome].

INTRODUCTION: The expression of CD34 antigen is increased in a substantial portion of MDS patients, particularly in high risk patients, which was associated with unfavorable survival in some studies. The aim of this study was to determine the CD34 expression in bone marrow biopsies and its prognostic significance in MDS patients and to analyze it in the context of different clinical, laboratory and prognostic parameters. MATERIAL AND METHODS: The study was conducted in 53 MDS patients and 20 controls with normal bone marrow. The CD34 expression was determined by CD34 monoclonal antibody and labelled streptovidin biotin peroxidase method. The positivity was determined by counting the 500 cells and it was expressed as percentage. RESULTS: Among the 53 MDS patients there were 37 males and 16 females with average age of 62. The average CD34 expression in the MDS group was 1.37%, the range being 0-8.8%, and in the control group 0.78%, the range being 0-1.60%. The difference was statistically significant (p < 0.05). There was a statistically significant difference in the CD34 expression comparing RA and CMML group and high risk and low risk MDS (p < 0.02). The median survival in the patients with the CD34 expression with less than 2% was 22 months, while it was 6 months in the patients with the CD34 expression over 2% (p < 0.05). In a multivariate analysis the CD34 expression together with the karyotype and transfusion dependence had a statistical significance (p < 0.05). CONCLUSION: The CD34 expression in bone marrow biopsies is higher in the MDS patients comparing with the controls as well as in high risk comparing with low risk patients. The cutoff 2% seems to have a prognostic significance.

Syngeneic peripheral blood stem cell transplantation with immunosuppression for hepatitis-associated severe aplastic anemia.

Hepatitis-associated aplastic anemia occurs in up to 10% of all aplastic anemia cases. Syngeneic bone marrow transplantation is rare in patients with severe aplastic anemia and usually requires pre-transplant conditioning to provide engraftment. We report on a 29-year-old male patient with hepatitis-associated severe aplastic anemia who had a series of severe infectious conditions before transplantation, including tracheal inflammation. Life-threatening bleeding, which developed after bronchoscopy, was successfully treated with activated recombinant factor VII and platelet transfusions. Syngeneic peripheral blood stem cell transplantation using immunosuppressive treatment with antithymocyte globulin and cyclosporin A without high-dose pre-transplant conditioning was performed, followed by complete hematologic and hepatic recovery.

[Prognostic factors in patients with diffuse large B-cell lymphoma].

Diffuse large B-cell lymphoma is an aggressive type of lymphoma, potentially curable, with heterogeneous prognosis. The aim of this study was to determine prognostic significance of clinical, laboratory and immunohystochemical factors. The retrospective study was done in 50 patients with diffuse large B-cell lymphoma. The following parameters were investigated: demographic (age, sex), clinical (time to diagnosis, B symptoms, clinical stage), laboratory (erythrocyte sedimentarion rate, haemoglobin, lactate dehydrogenase, albumine), standard and revised international prognostic index, and immunohystochemical parameters, cluster designation 20, B-cell-2, and Ki67 expression. There were 20 females and 30 males, their average age being 54 (22-83) years. The majority of patients had advanced disease: B symptoms in 76%, III and IV stage in 78%, increased lactate dehydrogenase in 74%, high risk standard international prognostic index in 62% of patients. B-cell leukemia/lymphoma 2 expression was found in 57%, and high Ki67 in 62% of patients. Rituximab-Cyclophosphamnide, Hydroxydaunorubicin, Vincristine, Prednisolone and Rituximab-Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Etoposide, Prednisolone were conducted in 72% (36), and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone-like treatment in 28% (14) of patients. The complete remission rate was 74%, and the partial remission rate was 9%. A significant difference in survival was found between low intermediate and high intermediate S-IPI risk groups, good and bad risk R-IPI, and patients with complete remission and patients with other treatment responses. The other parameters, including Bcl-2 and Ki67 expression, and type of treatment did not show significant influence on survival. The expected five-year survival was 69%. Our results have shown that international prognostic index, and complete remission status have prognostic significance in diffuse large B-cell lymphomas.

Randomized, prospective trial comparing bridging therapy using low-molecular-weight heparin with maintenance of oral anticoagulation during extraction of teeth.

PURPOSE: To evaluate postoperative bleeding and thromboembolic complications during dental extractions in anticoagulated patients, using 2 different protocols. PATIENTS AND METHODS: In total, 214 anticoagulated patients in need of simple dental extractions were randomized into 2 groups. Group A consisted of 109 patients on continuous oral anticoagulation therapy (OAT), with a mean international normalized ratio (INR) of 2.45 +/- 0.54. Local hemostasis in these patients was achieved with resorbable collagen sponges, without wound suturing. Group B consisted of 105 patients on bridging therapy with low-molecular-weight heparin (nadroparin-calcium), with a mean INR of 1.26 +/- 0.11 on the day of the procedure. Neither local hemostatic agents nor suturing of the wound was used in these patients. RESULTS: Eight (7.34%) patients in group A and 5 (4.76%) patients in group B manifested postextractional bleeding, without statistical significance (chi(2), Yates' = 0.253, P > .05). All cases of hemorrhage were mild and easily controlled using local hemostatic measures. None of the participants in either group experienced thromboembolic complications. CONCLUSIONS: In patients receiving OAT with an INR

Translational research in complex etiopathogenesis and therapy of hematological malignancies: the specific role of tyrosine kinases signaling and inhibition.

During the recent genomics and proteomics era, high-resolution, genome-wide approaches have revealed numerous promising new drug targets and disease biomarkers, accelerating and emphasizing the need for targeted molecular therapy compounds. Significant progress has been made in understanding the pathogenesis of hematological malignancies there by, revealing new drug targets. Introduction of multiple new technologies in cancer research have significantly improved the drug discovery process, leading to key success in targeted cancer therapeutics, including tyrosine kinase inhibitors. The studies of receptor tyrosine kinases and their role in malignant transformation are already translated from the preclinical level (cell-based and animal models) to clinical studies, enabling the more complete understanding of tumor cell biology and improvement of tumor therapy.

[Peripiheral blood hematopoietic stem cells--biology, apheresis collection and cryopreservation].

INTRODUCTION: ilematopoiesis is a continuous, dynamic and highly complex process resulting in production of various mature blood cells from a small population of pluripotent stem and progenitor cells through diverse proliferative and differentiative events. Numerous studies have demonstrated that a complex network of interactive cytokines regulates the survival, maturation, and proliferation of hematopoietic stem and progenitor cells. APPLICATION OF CELL-MEDIATED THERAPY: Massive application of different cell-mediated therapeutic methods has resulted in an increased need for both specific IISPCs and operating procedures providing minimal cell damage during collection, processing and storage in a liquid or fiozen state. Therefore, the basic aim of cell harvesting, selection, as well as cryopreservation is to minimize cell damage during these procedures. HSPCs are cells which exhibit extensive self-renewal and proliferative capacity, associated with the capacity to differentiate into all blood cells and other cell lineages (plasticity of HSPC). Thanks to these properties, stem cells can provide complete and permanent restoration of hematopoiesis, which is the basis for clinical employment of HSPC transplantation. In addition, totipotent stem cells can be used for the so called "cell-therapy" in different clinical settings (e.g. myocardial regeneration after acute infarction). CONCLUSION: Despite the fact that HSPC transplantation is already in routine use, some questions related to the optimal blood progenitor/cell collection, selection, storage and clinical use are still unresolved. Therefore, this review only briefly discusses the therapeutic use of HSPCs in different clinical areas and focuses on the recommendations, as well as the specific transfusion policies related to HSPC collection, processing, and cryopreservation with an emphasis on quality control.