Multiple Thromboembolic Events in Young Patient with Homozygous T-786C Mutation in the Endothelial Nitric Oxide Synthase Gene (ENOS).

Thromboembolic events are a common cause of morbidity and mortality with significant socioeconomic impact especially when young patients are affected. They are a rare medical event in young people and their clinical presentation can be mild or asymptomatic. The manifestation of symptoms and thrombotic events depends on both: the genetic mutations and the external risk factors that will induce the process. We present a case of a 34-year old young female, with three consecutive cerebrovascular insults in a period of ten years, and an acute myocardial infarction. There is a combination of gene mutations and polymorphism, with a predisposition to thromboembolic events. We emphasized the role of e-NOS (Endothelial nitric oxide synthase 786 T>C mutation) and the connection with smoking. The dual effect of the prolonged smoking and dysfunctional nitric oxide synthase in our young patient led to several thrombotic events. We discussed the various diagnostic tests and possible therapeutic and prophylactic strategies.

Milestones in Hematology and Oncology: From Fatal to Curable Disease.

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.

Reproductive Issues in Long-Term Surviving Patients following Therapy for Hodgkin's Disease in the Republic of North Macedonia: Risks of Infertility According to First-Line Treatment Regimens.

Infertility as a consequence of therapy presents a high psychosocial burden for HL patients. In the cohort of our analyzed patients, within the post-ABVD surviving patients, alterations of the spermogram were documented in a total of 6.1% of the male patients and 5.4% of the female patients developed amenorrhea. On the other hand, within the subgroup of surviving patients following BEACOPP chemotherapy, 60% of the male patients manifested defects in their spermogram, and as high as 28.6% of the female survivors reported loss of their monthly cycle. It has been reported on several occasions that even prior to treatment, the sperm of HL patients manifests poorer quality characteristics when analyzed against control specimens from healthy male donors. The analyzed results in ABVD-treated male HL patients confirm ABVD to be a safe regimen for males of all age categories, as well as for female patients under the age of thirty. In women above the age of 30, the infertility risk rate is relatively low (14%), which leaves the decision of preserving fertility to themselves. For all BEACOPP-treated female, as well as male patients, a consult with a reproductive medicine specialist is warranted prior to therapy, due to the high infertility risk, and the final decision should be made on an individual basis.

Bone Marrow Microenvironment Interplay and Current Clinical Practice in Multiple Myeloma: A Review of the Balkan Myeloma Study Group.

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.

FC gamma receptor polymorphisms in patients with immune thrombocytopenia.

INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune blood disease of unknown etiology. The aim of our study was to investigate a possible role of FCGR2A and FCGR3A polymorphisms in the development of primary ITP. METHODS: We analyzed 125 adult patients with ITP and 120 healthy controls. Genotyping was performed by using PCR-RFLP methods. RESULTS: Our results showed significantly higher frequency of high-affinity FCGR3A-158V allele in patients with ITP compared with control subjects (47.2% versus 37.5%; p = 0.037). We did not find significant differences in the genotype distribution or allele frequencies for FCGR2A-131H/R between patients and controls, p = 0.652 and p = 0.478. In the groups of patients with unresponsive and responsive ITP we found significantly different genotype distribution and allele frequencies for FCGR3A, p = 0.036 and p = 0.008 respectively. There was no significant difference in genotype and allele frequencies for FCGR2A between these two groups of patients. Our results confirmed that the combination of high-affinity FCGR2A-131H and FCGR3A-158V allele was more common in patients with ITP than in controls (55% versus 40%; p = 0.024). CONCLUSION: Our results suggest possible role of FCGR3A polymorphism in the etiology, development and clinical outcome of ITP, but larger prospective studies are needed to confirm these results.

First Cases of Hb Agrinio Described in Patients from the Republic of Macedonia.

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 [α142, Term→Lys (α2), HBA2: c.427T>A] and polyadenylation signal (polyA) [AATAAA>AATGAA (α2), HBA2: c.*92A>G] point mutations. Here, we report two unrelated patients from the Romani population in the Republic of Macedonia, homozygotes for the α2-globin gene variant Hb Agrinio [α29(B10)Leu→Pro; HBA2: c.89T>C]. To date, Hb Agrinio has been described only in individuals of Greek, Cypriot and Spanish origin. Both of our patients had early presentation of the disease (3.5 years and 2 months, respectively) with frequent blood transfusions from early infancy. They have a severe intermediate phenotype of thalassemia (Hb H disease) with hemoglobin (Hb) levels of 7.8 and 7.7 g/dL, respectively. Although the HBA2: c.89T>C mutation results in an α+ allele, the severe phenotype of the homozygotes is due to the production of hyperunstable α chains that undergo post translational precipitation. This leads to a greater degree of red cell damage and hemolytic anemia. The detection of Hb Agrinio in two unrelated families of Romani ethnic origin, may suggest it is a founder mutation in this population living in the Republic of Macedonia. Considering the severity of the clinical presentation of the homozygotes or compound heterozygotes for this rare Hb variant, a targeted molecular screening for Hb Agrinio mutation carriers should be considered in all patients of Romani ethnic origin with manifested microcytosis.

Osteonecrosis of the Jaw After Bisphosphonates Treatment in Patients with Multiple Myeloma.

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).