Severity of clinical manifestation, and prognosis of patients with myelofibrosis

Introduction: Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by bone marrow fibrosis and ineffective extramedullary hematopoiesis, which presents with anemia, constitutional symptoms, and excessive splenomegaly. A number of factors are involved in the pathogenesis of the anemia in PMF, including impaired iron metabolism regulation. It was found that higher levels of the key regulator of iron metabolism - the peptide hormone hepcidin in patients with PMF, are associated with the severity of the anemia, blood transfusion dependence and decreased overall survival.Aim: The aim of the study was to analyze the serum levels of hepcidin in patients with PMF and its impact on the clinical course, prognosis, and outcome of the disease.Materials and Methods: A total of 68 patients with PMF and 12 healthy controls were analyzed. Serum hepcidin levels were measured by ELISA.  The results were statistically analyzed by dispersion, comparison, and correlation methods.Results: Then mean hepcidin levels in patients with PMF were statistically significantly higher compared to healthy controls. (99.05 ng/mL; 20.57 ng/mL; F = 7.95; p = 0.006). High levels of hepcidin correlated with high risk according to DIPSS (p = 0.046), carrier of JakV617F mutation (p = 0.022), fibrotic phase according to WHO 2016 (p = 0.062), and the number of blood transfusions per month (p = 0.005). Higher hepcidin levels were not relevant to overall survival.Conclusion: Hepcidin is a biological marker the monitoring of which in the course of MF would help for a more accurate clinical and prognostic assessment of the disease

Outcome after azacitidine treatment in patients with high-risk myelodysplastic syndrome and acute myeloid leukemia in the Clinic of Hematology at St. Marina University Hospital, Varna

Introduction: Hypomethylating agents have become a standard therapy for high-risk myelodysplastic syndromes (MDS) and elderly patients with acute myeloid leukemia (AML).Aim: The aim of the study was to assess the efficacy of azacitidine treatment in patients with MDS and AML followed for 18 months.Materials and Methods: Twenty-seven patients with MDS and AML treated in the Clinic of Hematology at St. Marina University Hospital, Varna were included in the study. Azacitidine was administered subcutaneously in at a dose of 75 mg/m2 for 7 days. Disease assessment was performed on  the 3rd month, 6th month, and at progression.Results: Twenty-seven patients were analyzed. Their median age was 71.5 years. Nine had refractory anemia with excess of blasts II (RAEB II), 5 had chronic myelomonocytic leukemia II (CMML II), 1 was with unclassifiable MDS (MDS-U), and 12 with AML. The median number of administered cycles was 6 (1-19). Eleven patients completed 6 cycles of azacitidine. Partial response was achieved in 9 patients (33%) (7 MDS and 2 AML), stable disease in 8 (29%) (5 MDS and 3 AML). Progressive disease was observed in 10 patients (37%). The response correlated with the type of the disease (p=0.03), cytogenetic risk (p=0.01), and survival (p=0.000). At 18 months, 60% of MDS patients were alive compared to 41.7% in the AML group. The median time to death in the AML patient group was 2.5 months. The mean overall survival was 10.4 months (12.6 months for MDS patients and 5.4 months for AML patients).Conclusion: The therapy with azacitidine is an option for elderly patients with high-risk MDS.  In patients with AML a rapid progression is observed during the first two cycles with mortality rate of 58.3%

Use of medicinal plants in cardiovascular diseases

Сърдечно-съдовите заболявания са група болести, засягащи сърцето и кръвоносните съдове (артерии и вени). Причините за сърдечно-съдовите заболявания са различни, но най-честите са атеросклерозата и артериалната хипертония. Те са най-значимата причина за смъртността в световен мащаб. Над 17,6 милиона души в света умират всяка година в резултат на сърдечно-съдови заболявания.Проблемът е особено актуален за нашата страна, като данните сочат, че в България на всеки 3 човека 2 умират от сърдечно-съдови заболявания. Разходите за здравеопазването в България за 2013 са 3,3 млрд. лв. Около 18% от бюджета на НЗОК отива за лечение на сърдечно-съдови заболявания.Днес антихипертензивното лечение най-общо може да се раздели на лечение с класически медикаменти и лекарства от нови генерации. Трябва да бъдем наясно, че невинаги монотерапията ще постигне желания ефект, средният брой лекарства, необходими за достигане и трайно поддържане на желаните нива на артериалното налягане, е около и над 3. Следователно много често се използва комбинираната терапия за избор на медикаменти с изявена органна протекция, при която да се достигнат прицелните нива на артериалното налягане. Оптималният контрол на налягането спомага за намаляване на сърдечно-съдовата болест и смъртност.Поддържането на здравословно и балансирано хранене, както и здравословен начин на живот може да помогне да се избегне рискът от високо кръвно налягане.Главното действие на билките, които прила гаме при сърдечно-съдовите заболявания, е да подобрят кръвоснабдяването на сърдечния мускул и крайниците, както и да заздравят стените на кръвоносните съдове.На билколечение и профилактика подлежат неусложнените случаи с коронарна недостатъчност и с ритъмни и проводни нарушения. За целта се използват дроги, чиито съставки разширяват коронарните съдове и имат диуретично действие. Такъв ефект имат цвета от глог - Fl.Crataegi ; стръкове от горицвет - Hb.Adonidis vernalis; чесънът - Allium sativum; момина сълза - Convallaria majalis f.Liliaceae.Cardiovascular diseases are a group of conditions affecting the heart and the blood vessels (arteries and veins). The reasons for the cardiovascular diseases are different, but the most frequent ones are atherosclerosis and arterial hypertonia. They are the most significant reasons for mortality on an international scale. Over 17.6 million of people in the world die each year as a result of cardiovascular diseases. The problem is especially pressing in our country, where the data shows that in Bulgaria of every 3 persons, 2 die from cardiovascular illnesses. The health care costs in Bulgaria for 2013 are 3.3 billion BGN. Around 18% of the budget of the National Fund for Health Insurance go for treatment of cardiovascular diseases.Today the treatment for hypertension in general can be divided into treatment with classical medications and such with new generation medications. We must be aware that monotherapy will not always achieve the desired effect. The average number of medications, required for achieving and sustaining longterm levels of arterial pressure is around and above 3. Therefore, combined therapy is used very often for choosing medications with obvious organ protection, which reach the target levels of arterial pressure. The optimal control of pressure helps decrease the amount cardiovascular diseases and their mortality. Maintaining a healthy and balanced diet, as well as healthy lifestyle can help avoid the risk of high blood pressure.The main effect of herbs, which we use in cardiovascular diseases, is improving the blood supply to the hearth muscle and limbs, as well as strengthening of the blodd vessel walls.Subject to herb treatment and prevention are non-complicated cases of coronary insufficiency and rhythm and conduction disorders. For that purpose we use drugs, whose ingredients widen the coronary vessels and act as diuretics. Such effect have the flower of hawthorn - Fl.Crataegi; sprigs of pheasant‘s eye - Hb.Adonidisvernalis; garlic - Alliumsativum; lily-ofthe- valley - Convallariamajalis f.Liliaceae

BIOLOGICAL ACTIVITY OF BULGARIAN FOLIA BETULAE DRY EXTRACT

Objective: The aim of this study was to investigate the biological activity of dry Folia Betulae (FB) extract.Methods: Extracts from birch leaves were obtained by different technological methods–maceration and percolation, extraction with different concentrations of ethanol, changes in temperature regimen. The influence of the technological factors on the content of the biologically active substances (BAS) was examined. A phytochemical characterization of the extracts and their standardization were made, according to important groups of BAS–flavonoids (rutin, quercetin) and terpenes (betulin and betulinic acid), by means of HPLC methods for detection and quantitative determination. A model extract, with optimal content of BAS was chosen for subsequent in vitro investigation of its biological activity. Antimicrobial activity was studied via in vitro tests using bacterial isolates–Staphylococcus aureus, Escherichia coli and Candida albicans. The physiological activity was investigated by using in vitro test with smooth muscle strips. The antiproliferative activity of FB extract on eukaryotic cells was examined on cell cultures in vitro. Two cell cultures were used: the mouse lymphoma cell line L5178Y and the serum-free McCoy-Plovdiv cells.Results: The dry extract from FB has a dose–dependent antibacterial effect. The bactericidal effect on Staphylococcus aureus is stronger than the one on Escherichia coli. Results prove that adding the extract leads to stimulating effect on muscle contractility. It demonstrates biological activity, expressed as changes in cell morphology, proliferation and vitality as well as initiation of apoptosis.Conclusion: The results obtained largely overlap with literature data and explain some of the applications of this plant in traditional medicine.Â

Metabolite Profile and Antioxidant Activity of Some Species of Genus Scutellaria Growing in Bulgaria

Until now, the interest to plants from genus Scutellaria in Bulgaria has been focused mainly on the terpenes in them. The purpose of this study is to enrich the information on the composition of the Bulgarian Scutellaria species in terms of both polyphenolic content as well as primary metabolites such as mono-, oligosaccharides and organic acids. An aerial part of three Scutellaria species growing in four low mountain regions of Southern Bulgaria was used. The flavonoids scutellarin, baicalin, baicalein, wogonin, wogonoside, luteolin, chrysin and a caffeoyl phenylethanoid glycoside-verbascoside have been identified via HPLC in different extracts from Scutellaria altissima, Scutellaria albida and Scutellaria galericulata. The antioxidant activity of the extracts has been evaluated. The Scutellaria altissima from Mezek and Scutellaria galericulata from Parvenets we studied, which are the richest in flavonoids (represented mainly by baicalin, scutellarin and wogonoside), show the highest Oxygen Radical Absorption Capacity. Hydroxyl Radical Averting Capacity of Scutellaria albida from Mezek and Scutellaria altissima from Bachkovo is the most pronounced, probably due to the content of scutellarin and luteolin and chrysin, respectively. Antioxidant activity of aqueous, methanolic and 70% and 96% ethanol extracts were also determined by the electrochemical method

Metabolite Profile and Antioxidant Activity of Some Species of Genus Scutellaria Growing in Bulgaria

Until now, the interest to plants from genus Scutellaria in Bulgaria has been focused mainly on the terpenes in them. The purpose of this study is to enrich the information on the composition of the Bulgarian Scutellaria species in terms of both polyphenolic content as well as primary metabolites such as mono-, oligosaccharides and organic acids. An aerial part of three Scutellaria species growing in four low mountain regions of Southern Bulgaria was used. The flavonoids scutellarin, baicalin, baicalein, wogonin, wogonoside, luteolin, chrysin and a caffeoyl phenylethanoid glycoside-verbascoside have been identified via HPLC in different extracts from Scutellaria altissima, Scutellaria albida and Scutellaria galericulata. The antioxidant activity of the extracts has been evaluated. The Scutellaria altissima from Mezek and Scutellaria galericulata from Parvenets we studied, which are the richest in flavonoids (represented mainly by baicalin, scutellarin and wogonoside), show the highest Oxygen Radical Absorption Capacity. Hydroxyl Radical Averting Capacity of Scutellaria albida from Mezek and Scutellaria altissima from Bachkovo is the most pronounced, probably due to the content of scutellarin and luteolin and chrysin, respectively. Antioxidant activity of aqueous, methanolic and 70% and 96% ethanol extracts were also determined by the electrochemical method

Therapeutic approach in the treatment of newly diagnosed elderly patients with secondary acute myeloid leukemia—a clinical case and review of the literature

Acute myeloid leukemia (AML) is a therapeutic challenge in elderly patients because of the biology of the leukemia and the poor functional status of the patient. Acute myeloid leukemia following previous treatment (t-AML) is defined as a separate subtype of AML, which is associated with the late effects of previous chemotherapy or radiotherapy. The therapeutic results of patients with t-AML are limited and optimal treatment in these patients is an even greater challenge.Our patient is a 68-year-old woman who was hospitalized due to isolated anemia. The patient was diagnosed with breast cancer in 1996 and ovarian cancer in 2014, which were in remission at the time of the present hospitalization. Diagnostic procedures revealed therapy-related myelodysplastic syndrome (t-MDS) with a complex karyotype. The patient was stratified as high risk according to the revised IPSS. The patient received the best supportive care. Two months later, she was re-hospitalized due to fever, progressive weakness and fatigue, stomach discomfort, loss of appetite. Laboratory tests showed pancytopenia with 25% of myeloblasts in peripheral blood. The reassessment of the disease revealed evolution to t-AML with MDS-associated changes. Treatment with a hypomethylating agent was initiated. Unfortunately, the patient died with the symptoms of sudden cardiac death.The therapeutic decision in elderly patients with t-AML is difficult and multifactorial. Combinations of already approved agents and new molecules will improve and diversify the therapeutic choices in elderly patients with high-risk AML

Primary Myelofibrosis, Post-Erythremia Vera and Post- Essential Thrombocythemia Myelofibrosis - Impact of Inflammatory Cytokines (Interleukin 6, Interleukin 8) and Regulators of Iron Metabolism (Hepcidin) in The Pathogenesis of Anemic Syndrome // Първична, пост-еритремична, пост-тромбоцитемична миелофиброза - участието на инфламаторни цитокини (interleukin 6, interleukin 8) и регулаторите на железния метаболизъм (хепсидин) в патогенезата на анемичния синдром

Myelofibrosis (MF) is a clonal haematological neoplasm with heterogeneous clinical manifestation, fibrotic tissue replacement of the haematopoiesis, bone marrow failure, extramedullary haematopoiesis, excessive splenomegaly and presence of severe anaemia. Impaired regulation of iron metabolism by dysregulation of hepcidin secretion is a suspected factor in the development of anaemia. These mechanisms are involved in the pathogenesis of anaemia in solid tumours, chronic inflammatory diseases, ageing, haematological neoplasms. A higher level of hepcidin has been demonstrated in patients with MF compared to healthy controls, which determines the severity of anaemia, blood transfusions dependence and is a sign of shortened survival. Cytokine dysregulation is also involved in the pathogenesis of anaemia in MF. Significantly increased levels of IL-8 and IL-6 were revealed. They are independent prognostic factors for survival. Patients with MF have significantly higher levels of hepcidin, IL-6 and IL-8 compared to a healthy population. They are independent prognostic factors for the development of anaemia. The risk model, including the combination of above-threshold values of the studied parameters and their relation with patient and disease characteristics, proves that at-risk patients are predominantly male, develop anaemia and thrombocytopenia; exhibit constitutional symptoms and are blood transfusion-dependent; have a disease duration > 1 year and are Jak2 V617F positive, with grade 3 fibrosis and ferritin values > 500 µg /l. Hepcidin, IL-6 and IL-8 have a potential indirect role in developing and exacerbating anaemia in MF. The three parameters may be additional risk factors for the evolution and outcome of the disease.Миелофиброзата (МФ) е клонална хематологична неоплазия с хетерогенна клинична изява, прояви на фибротично заместване на кръвотворенето, костно-мозъчна недостатъчност, екстрамедуларна хемопоеза, ексцесивна спленомегалия и наличие на тежък анемичен синдром. Подозиран фактор в развитието на анемия при МФ е нарушена регулация на желязната обмяна чрез повлияване секрецията на хепсидин. Тези механизми участват в патогенезата на анемия при солидни тумори, хронични възпалителни процеси, стареене, хематологични неоплазии. Доказва се по-високо ниво на хепсидин при пациенти с МФ в сравнение със здрави контроли, което определя тежестта на анемичния синдром, хемотрансфузиите и е белег за скъсена преживяемост. Цитокиновата дисрегулация също участва в патогенезата на анемичния синдром при МФ. Установени са сигнификантно увеличени нива на IL-8 и IL-6. Те са независим прогностичен фактор за преживяемост. Пациентите с МФ имат значимо по-високи нива на хепсидин, IL-6 и IL-8 в сравнение със здравата популация. Те са независим прогностичен фактор за развитието на анемия. Разработен рисков модел, включващ комбинацията от надпрагови стойности на изследваните параметри и връзката им с характеристики на пациента и заболяването, доказва, че рисковите пациенти са от мъжки пол, развиват анемия и тромбоцитопения; проявяват конституционални симптоми и са трансфузионно зависими; имат продължителност на заболяването > 1 година и са Jak2 V617F позитивни, с фиброза степен 3 и стойности на феритин > 500 µg/l. Хепсидин, IL-6 и IL-8 имат вероятна косвена роля във възникването и задълбочаването на анемичния синдром при МФ. Трите показателя могат да са допълнителни рискови фактори по отношение на еволюцията и изхода на заболяването

IMPACT OF THE IMPAIRED IRON HOMEOSTASIS ON THE PATHOGENESIS OF ANEMIA IN PRIMARY MYELOFIBROSIS

Anemia is a well established prognostic factor in primary myelofibrosis (PMF). Recent data suggests that markers of abnormal iron homeostasis, which are known to be affected by both iron overload and inflammation, may be involved in the pathogenesis of anemia in PMF. Aim: To evaluate the relation between anemia, bone marrow fibrosis, prognostic score, survival and parameters of iron metabolism. Materials and methods: We studied 72 patients with PMF. The following parameters were analyzed: degree of bone marrow fibrosis, hemoglobin level, MCV, components of iron homeostasis (total iron binding capacity (TIBC), ferritin, serum iron). The prognostic score was determined according to IPSS and DIPSS. Statistical analysis was performed by SPSS version 19. Results: We found significant correlation between the level of hemoglobin and degree of bone marrow fibrosis and prognostic score. The MCV was analyzed in 56 of the patients and was found low in 9,5 % of them. However, there was no significant correlation between degree of fibrosis and the lower MCV. We found significant straight correlation between degree of fibrosis, serum ferritin level (p=0.006) and TIBC (p=0.018). In univariate analysis, significant feedback correlation was established between hemoglobin and serum ferritin level. Conclusion: Our results reveal the possible role of the impaired iron metabolism in the pathogenesis of anemia in PMF. Further studies are needed in order to elucidate the precise mechanisms of this process

Efficacy of Inotuzumab Ozogamicin plus Ponatinib Followed by Allogeneic Stem Cell Transplantation in a Patient with Relapsed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive disease with poor outcomes. Despite the incorporation of tyrosine kinase inhibitors (TKIs) in the therapeutic strategies, patients who relapse after chemotherapy plus TKI have poor overall survival (OS) and less chance to proceed to hematopoietic stem cell transplantation (HSCT) which remains the only curative approach. Therefore, new drugs, such as antibody-targeted therapies alone or in combination with TKIs, offer new therapeutic options for those patients. However, the combination of inotuzumab plus ponatinib has limited application. We present a case of a patient affected by Ph + ALL with T315I mutation successfully treated after early relapse with inotuzumab plus ponatinib, followed by allogeneic HSCT and ponatinib maintenance