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Background: The comprehensive management of patients with Hodgkin’s lymphoma (HL) is a success story in contemporary oncology. Over the past decades, the survival rate of patients with HL has significantly improved. The objective of this analysis is to evaluate and document the progress in the management of Hodgkin’s lymphoma in patients in our country, reflected in their vital statistics, over time periods defined by the respective standard of treatment. Material and methods: The present study is designed as a retrospective-prospective study. We analyzed different modalities of treatment and compared 5 and 10-year overall survival rates in a total of 588 Hodgkin’s lymphoma patients treated at the University Clinic for Hematology in Skopje during two consecutive time periods, before 2000 and after 2000. The entire observation period is from 1980 to 2020. All patients are above the age of 14, with a documented histopathological diagnosis of Hodgkin’s lymphoma and with evaluable medical documentation, including clinical and laboratory data on their initial condition, the administered therapy, as well as the clinical follow-up of the patients. Results: The basic clinical features of the analyzed population across the two periods correlate with those reported in the relevant medical literature, with only slight deviations. Ten-year overall survival rates improved by 31.7% through the two calendar periods. During the last two decades of the previous century (1980-2000) the initial treatment options were COPP and COPP-like regimens for the vast majority of patients (94.7%), leading to disease remission in 80% of them. After 2000, 95.8% of de novo diagnosed patients have been treated with ABVD chemotherapy as a frontline choice and the complete response rate is 88.4%. We confirmed the superiority of ABVD in terms of efficacy, improved tumor and disease control, as well as its long-term clinical outcome. While in the past we had very limited options for relapsed/refractory HL patients, the analysis of the results of HL patients treated with various therapeutic approaches in the latter period, defines BEACOPP as the preferred choice. High-dose chemotherapy, followed by autologous hematopoietic stem cell graft, as a strategy for our R/R patients in the timeframe after 2000, ensures a 5-year overall survival for 51% of them, whereas 45% of the patients survive more than 10 years. Conclusion: This analysis from our Hodgkin’s lymphoma database illustrates that there has been tremendous improvement in the long-term survival rates since the turn of this century. At our institution we strive to implement positive trends in practice, as suggested by relevant guidelines, regarding the evolution and progress in the diagnostic workup, treatment, and the overall management of patients with Hodgkin’s disease. The objective would be to secure favorable vital statistics for our patient population, now reaching 83.5% at 10 years, which closely correlates with the data of more developed countries and centers. In future clinical trials we will also evaluate the efficacy of brentuximab-vedotin and new PD-1 blocking antibodies.

Background: Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL) (formerly termed enteropathy-associated T cell lymphoma, type II) is an extremely rare peripheral T-cell lymphoma that involves the malignant proliferation of a T- lymphocyte in the gastrointestinal tract. Over time, these T cells commonly spread throughout the mucosal lining of a portion of the GI tract (particularly the jejunum and ileum of the small intestine), lead to GI tract nodules and ulcerations, and cause symptoms such as abdominal pain, weight loss, diarrhea, obstruction, bleeding, and/or perforation. Its clinical, morphologic, and immunophenotypic features distinguishing it from the more common Enteropathy Associated T-Lymphoma (previously EATL type I) made it a separate entity. Case report: We present a case of a rare extremely aggressive T cell lymphoma that originates from the gastrointestinal tract, spreads to surrounding organs and is refractory to surgery and chemotherapy. We describe а case report of 79 years old patient with clinical features of acute abdomen, ileus, treated with surgery two times. During the first surgery partial resection of jejunum was performed. Pathohistology and immunоhistochemistry findings of MEITL. PET/CT scan revealed infiltration of intestinum, uterus, ovarium. During the second operation partial resection of ileum and hysterectomy with adnexectomy was performed. The patient is treated with antracycline-based regimen CHOP21 (4 cycles). Re-evaluation with second PET/CT scan revealed residual tumor on the intestinum and bladder. The patient deteriorate with acute renal failure and multi-organ failure. Despite aggressive treatment with extensive surgery and aggressive anthracycline-based chemotherapy, in a short time the tumor spread to surrounding organs (sigma, bladder). The patient survived 11 months from the initial definitive diagnosis. Conclusion: MEITL is a challenging primary intestinal T cell lymphoma to treat as the outcome is frequently poor despite surgery and chemotherapy. Most patients are elderly with co-morbidities and they usually present late rendering any therapy ineffective. Young age, early Ann-Arbor/Lugano disease stage, good performance scale status, patients receiving autologous stem cell transplantation and less bulky disease are associated with an improved survival outcome. Further research is needed to incorporate new therapeutic modalities based on molecular research for successful treatment of this aggressive lymphoma.

The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the interplay of treatment modalities used in the current clinical practice and TME. Bortezomib-based triplets are the standard for MM first-line treatment. Bortezomib is a proteasome inhibitor (PI) which inhibits the nuclear factor kappa B (NF-κB) pathway. However, bortezomib is decreasing the expression of chemokine receptor CXCR4 as well, possibly leading to the escape of extramedullary disease. Immunomodulatory drugs (IMiDs), lenalidomide, and pomalidomide downregulate regulatory T cells (Tregs). Daratumumab, anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody (MoAb), downregulates Tregs CD38+. Bisphosphonates inhibit osteoclasts and angiogenesis. Sustained suppression of bone resorption characterises the activity of MoAb denosumab. The plerixafor, used in the process of stem cell mobilisation and harvesting, block the interaction of chemokine receptors CXCR4-CXCL12, leading to disruption of MM cells’ interaction with the TME, and mobilisation into the circulation. The introduction of several T-cell-based immunotherapeutic modalities, such as chimeric-antigen-receptor-transduced T cells (CAR T cells) and bispecific antibodies, represents a new perspective in MM treatment affecting TME immune evasion. The optimal treatment approach to MM patients should be adjusted to all aspects of the individual profile including the TME niche.

Introduction. Autoimmune diseases are a family of more than 100 heterogeneous conditions that affect 5 to 8% of the world’s population. The etiology is still un-known but the disregulation of the regulatory T-lymphocytes play a central role inthe autoimmunity and the success of the long-term remission. Although conventional immunosuppression and new biological agents can provide disease control in severely affected patients, such treatments are rarely curative and alternative strategies are needed. Indeed, severe forms of systemic autoimmune diseases, such as multiple sclerosis (MS), systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), hematologic immune cytopenia (HIC) and Crohn’s disease are difficult to be treated. High-dose immunosuppressive therapy followed by autologous stem cells transplantation is reliable option for a successive treatment of this group of patients. Aim. To determine the safety of the procedure of autologous stem cell transplantation in patients with autoimmune diseases and concomitant malignant hematological disorders. Methods. During a period of 15 years (from September 2000 to September 2015) at the University Clinic of Hematology in Skopje we have treated 6 patients with autoimmune disease and concomitant hematological neoplasm. None of the patients was treated for primary autoimmune diseases. Two men and 4 women, with median age of 47 years were treated. Sjogren syndrome and multiple myeloma were found in 2 patients, polyartheritis nodosa and multiple myeloma in 1 patient, rheumatoid arthritis and acute myeloblastic leukemia in 1, systemic lupus erythematosus and non-Hodgkin lymphoma in 1; severe psoriasis and acute myeloblastic leukemia in 1 patient. Results. All treated patients are alive after trans-planted procedure, with transplant related mortality day +100: 0. Conclusion. Autologous stem cell transplantation is safe and recommended option for treatment ofpatients with autoimmune disease and hematologic neoplasm.

Previous molecular analyses of α-thalassemia (α-thal) in the Republic of Macedonia have identified the following genetic defects: –α3.7 (rightward), –(α)20.5 and – –MED I deletions and Hb Icaria [α...

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia due to platelet autoantibodies, causing an accelerated clearance of opsonized platelets by phagocytes. The etiology of ITP remains unclear, both genetic and environmental factors may have a role in the disease development. The aim of our study was to investigate a possible association of three single nucleotide polymorphisms (SNP) in the genes for interleukin beta (IL1B-511C/T), tumor necrosis factor beta (TNF+252G/A) and tumor necrosis factor alpha (TNFA-308G/A) with ITP. We have analyzed 125 adult patients with ITP and 120 healthy matched controls. Genotyping was performed by using PCR- RFLP methods. Our results demonstrated significantly different genotype distributions and allele frequencies for TNFB+252G/A in patients with ITP, p = 0.005 and p = 0.009 with Yates correction. We did not find any significant differences in the genotype distribution or allele frequencies for the other two genes. We have found significantly different genotype distribution and allele frequencies for TNFA- 308G/A between patients with unresponsive and responsive ITP patients, p = 0.016 and p = 0.009. There were no significant differences in genotype distribution and allele frequencies for ILB-511C/T and TNFB+252G/A polymorphisms between those two groups of patients. We did not find any significant differences in genotype distribution and allele frequencies for all three polymorphisms between splenectomized and unsplenectomized ITP patients. The obtained data indicate that the A allele of TNFB+252G/A is more frequent in these patients than in the controls and that this polymorphism may play a significant role in disease susceptibility. The A allele of TNFA-308G/A was more frequent in patients with unresponsive ITP, indicating that this gene polymorphisms may contribute to therapy resistance.

Background: Bone lytic lesion in Multiple myeloma are the most commonly presented symptoms which require treatment with bisphosphonates (BPs). BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. Osteonecrosis of the jaw (ONJ) has been associated recently with the use of BPs. Aim: The aim of these study is to evaluate the incidence of ONJ in patients with MM treated with mixed biphosphonates. Patients and methods: We analyzed total 296 myeloma patients (150 male and 146 female). Mostly effected age group with 58,1% is age more than 60 years up to 88 years, diagnosed in our institution in the period 2005-2015. We used intravenous or oral forms of biphosphonates such as pamidronate, ibandronate, clodronate and zolendronic acid. The patients were evaluated for ONJ. Results: The incidence of ONJ in our group of patients treated with Bps was 4,6% from our group of 260 patients 87,8% received BPs therapy and patients which haven’t received BPs 12,2%. From this group, 95,4% (248) didn’t show ONJ, and 4,6% (12) showed ONJ. The period of this treatment with BPs is an important risk factor for development of ONJ, average duration of BPs therapy in patients which show adverse effects is 26.8±13.7 months, from the total number of 12 patients that developed ONJ adverse effects, we have 8 patients which received treatment with Zolendronic acid and the remaining 4 patients which were treated with other BPs combinations without Zolendronic acid. Conclusions: All patients treated for MM must continue with the therapy with Zolendronic acid and Pamidronate, each patient must be individually treated according to his response of the treatment (dose, frequency and duration of therapy).

Background. Peripheral blood stem cells (PBSC) have largely replaced conventional, unprimed bone marrow (BM) as source for autologous transplantation. Aim. To present the mobilizing strategies in patients with lymphoproliferative diseases taking in consideration demographic and treatment related variables that have influence as prognostic factors. Material and Methods. The study was accomplished with patients treated with autologous transplantation at University Hematology Hospital, Skopje, and Republic of Macedonia during 5 year period. A total of 70 patients with lymphoproliferative diseases were included in this study. Results. Patients transplanted with PBSC, compared with patients transplanted with BM showed p

Association Between Sharp's Radiographic Index and Acute Phase Reactants in Rheumatoid ArthritisThe aim of this study was to evaluate the activity of rheumatoid arthritis (RA) by hand radiography (Sharp's radiographic index), and assessment of acute phase reactants - erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and rheumatoid factor (RF), and to determine their value as prognostic markers for disease outcome in patients with early RA treated with disease modifying antirheumatic drugs (DMARDs)-Methotrexate (MTH); to register and quantify clinical, radiographic and laboratorial differences in certain time intervals in a group of patients treated with immunomodulation therapy with MTH; to determine which of the acute phase reactants would be the most useful marker for evaluation of disease activity in long-term follow-up in RA patients; to select high-risk groups with aggressive course of disease, in order to emphasize the necessity of early and aggressive treatment. Thirty patients with early RA (disease evolution up to 1 year) were evaluated in several time intervals. The score of the Sharp's index showed greater radiographic progression of the joint damage of hands in time intervals between 0-time and 12 months (p=0.0167) and between 0-time and 18 months (p=0.0089). Statistical analysis showed differences in values of CRP in four time intervals (p=0.00002). Considering CRP, there were statistically significant differences among mean values in four time intervals (p=0.0428) (standard deviations showed greater variations). There were no statistically significant differences among mean values of RF in four time intervals (p=0.573). At 0-time in 3 (10%) patients progression of the Sharp's index was found, after 6 months in 13 (39%) patients, while after 12 and 18 months progression of the Sharp's index was found in an identical number of patients, 15 (50%). In most patients high values of CRP and RF were found. Progression of the radiographic damage is especially expressed in patients with high values of ESR, CRP, RF and existence of previous erosions of hands, which are predictors for aggressive course of disease. CRP is the most useful marker for the evaluation of RA activity in the long-term followup of RA patients.

A high-quality hemoglobinopathy diagnosis is based on the results of a number of tests including assays for molecular identification of causative mutations. We describe the current diagnostic strategy for the identification of b-thalassemias and hemoglobin (Hb) variants at the International Reference Laboratory for Haemoglobinopathies, Research Centre for Genetic Engineering and Biotechnology (RCGEB) “Georgi D. Efremov,” Skopje, Republic of Macedonia. Our overall approach and most of the methods we use for detection of mutations are designed for the specific target population. We discuss new technical improvements that have allowed us to substantially reduce the average time necessary for reaching a conclusive diagnosis.