Izražaj cirkulirajućih mikronaRNA (miR-125a, miR-125b, miR-126, miR-99b, miR-let7a) u bolesnika s mijelodisplastičnim sindromom [Expression of circulating microRNA (miR-125a, miR-125b, miR-126, miR-99b, miR-let7a) in myelodysplastic syndrome patients]

Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematologic disorders of hematopoietic stem cells, followed by ineffective hematopoiesis of one or more cell lines with the onset of consequent cytopenia with an increased risk of progression to acute myeloid leukemia. According to the World Health Organization classification, the diagnosis of MDS is based on morphological, clinical, cytogenetic, immunophenotypic and biological criteria. In everyday clinical practice, the diagnosis of MDS is based on invasive cytomorphological analysis of peripheral blood and bone marrow cells, determination of blast percent, type and degree of dysplasia, presence of ring sideroblasts, and cytogenetic analysis of bone marrow cells. Micro Messenger Ribonucleic Acids (miRNAs) are short, non-coding molecules of 18 to 25 nucleotides in length that play an important role in regulating cell development and metabolism, their differentiation and proliferation, regulation of the cell cycle and cell death. Tumor cells release miRNAs into the circulation (plasma, serum) where they remain relatively stable. Although their discovery allowed linking of disease and miRNA gene expression, a precondition for their clinical application was the determination of gene expression by real-time quantitative polymerase chain reaction with satisfactory efficacy and specificity. In the literature, gene expression of miRNAs has been linked to the diagnosis, classification and progression of various diseases. Many studies have been conducted so far about the molecular mechanisms and epigenetic pathways in MDS and their prognostic and therapeutic significance, but few studies have analyzed the importance of miRNAs in MDS. The aim of this study was to examine the level of change of gene expression of specific mRNAs (miR-125a, miR-99b, miR-126, miR-125b, miR-let-7a) in plasma of healthy volunteers and subjects diagnosed with MDS. Gene expression of these specific mRNAs was determined in plasma samples from healthy volunteers (18) and subjects with MDS (41). This paper describes for the first time the expression of a selected miRNA cluster (125a, 125b, 99b, let-7a) in the plasma of untreated MDS patients. A significant difference was found between the study group and healthy control in miR-99b level, where at normalized values relative to miR-126, an increased level in subjects compared to control was observed 4,521 times (P = 0.004). Diagnostic and prognostic significance of miR-125a was observed and correlated negatively with erythrocyte count and hemoglobin level in the diagnosis of MDS.The results of the study suggest that gene expression of miRNA (125a, 125b, 99b, let7a) could be regulated by the same mechanism and may be clinically relevant in subjects with MDS

WOUNDS IN HEMATOLOGY PATIENTS

Kod hematološkog bolesnika rane mogu biti dio kliničke slike u trenutku postavljanja dijagnoze, posljedica infekcije, nuspojave terapije ili napredovanja tumorske bolesti s kožnim infiltratima. liječenje rana kod hematoloških bolesnika zahtijeva multidisciplinaran pristup hematologa, kirurga, dermatologa, mikrobiologa i ostalog medicinskog osoblja koje je uključeno u svakodnevnu brigu o bolesniku. Kako se radi o onkološkim imunosuprimiranim bolesnicima, iznimno je važno pridržavati se mjera asepse te spriječiti infekcije rana zbog kojih bi se zakomplicirao ionako dugotrajan oporavak i zaliječenje. Važno je na vrijeme prepoznati ranu s malignom infiltracijom jer je pravodobna kemoterapija u takvom slučaju kurativna mjera.Hematology patients can have wounds as part of the initial presentation of the disease, as a result of infection or therapy. Wound therapy is very important and requires multidisciplinary approach of the hematologist, surgeon, dermatologist, and all other medical staff involved in the patient’s care. It is very important to provide aseptic care and prevent infections that could complicate the patient’s recovery and cure. It is very important to recognize the wound with malignant infiltration because an appropriate chemotherapy can be curative

LIJEČENJE ANEMIJE KRONIČNE BUBREŽNE BOLESTI U PREDIJALIZNOJ FAZI

Erythropoiesis-stimulating agents (ESAs) administered either subcutaneously (sc.) or intravenously (iv.), along with iv. or oral iron therapy, are currently the cornerstones for treating anemia in patients with chronic kidney disease (CKD). Multiple factors are involved in the pathogenesis of anemia in CKD: iron deficiency, inadequate production of erythropoietin (Epo), hepcidin and hypoxia-inducible factors (HIFs). Patients with CKD are prone to iron deficiency (absolute and functional). In this study, we compared the efficacy and safety profile of oral and intravenous iron with erythropoietin beta (subcutaneously in a dose of 4000-6000 IU every week) for the treatment of iron deficiency anemia in 43 non dialysis patients (ND-CKD) with the confirmed diagnosis of iron deficiency anemia (A) at Merkur University Hospital. Exclusion criteria were patients on dialysis or transplantation, with heart failure, secondary hyperparathyroidism, malignancy, thromboembolism, gastrointestinal bleeding, hsCRP >5 mg/L, patients taking medicines that suppress Epo production, and uncontrolled resistant hypertension. Patients were divided into groups on intravenous iron in doses of 1000 mg every month and oral daily intake of iron (ferrous fumarate 350 mg). Iron supplementation was administrated in order to achieve serum ferritin 200-500 mg/L. Hemoglobin (Hb) was checked at the beginning and after 12 months in both groups. Paired sample t-test was applied for comparison of results. The mean level of iron at the beginning in M/F was 9.7/7.9±0.28/0.31 and after 12 months 10.7/8.94±0.27/0.43 μmol/L. In the treatment groups, the mean Hb level was 9.19±0.84 g/dL (A) and 9.72±0.95 g/ dL (B). The mean increase in Hb was 10.65±0.97 g/dL (A) and 10.42±1.22 g/dL (B) at 12 months (p20%. Srednja razina vrijednosti željeza na početku iznosila je u M/F 9,7/7,9±0,28/0,31, dok je na kraju studije bila 10,7/8,94±0,27/0,43 μmol/L. Razina hemoglobina (Hb) je na početku iznosila 9,19±0,84 g/dL (skupina A) i 9,72±0,95 g/dL (skupina B). Na kraju praćenja došlo je u obje skupine do porasta razine Hb u odnosu na početne vrijednosti: 10,65±0,97 g/dL (skupina A) i 10,42±1,22 g/ dL (skupina B) (p<0,001), no između skupina A i B nije utvrđena statistički značajna razlika. Rezultati studije pokazuju da je liječenje anemije KBB postojećim dostupnim lijekovima učinkovito u slučaju isključenja čimbenika koji mogu doprinijeti rezistenciji na liječenje. Kako najveći broj bolesnika s KBB ima postojeće čimbenike koji doprinose rezistenciji liječenja anemije KBB-a, u budućnosti najviše obećava primjena stabilizatora HIF-a

Patient with myelodysplastic syndrome in emergency department

Mijelodisplastični sindrom (MDS) grupa je klonskih mijeloidnih poremećaja s heterogenom kliničkom slikom, a najveći broj komplikacija posljedica je citopenija koje su karakteristično obilježje. Etiologija nije dovoljno poznata. Internacionalni bodovni sustav (engl. The International Prognostic Scoring System – IPSS) služi kao prognostički čimbenik za neliječene bolesnike s MDS-om. Nedjelotvorna hematopoeza, pa tako i eritropoeza, dovode do anemije, što je najčešći uzrok dolaska bolesnika s MDS-om u hitnu službu. Vrlo često bolesnici imaju brojna pridružena stanja poput kronične bubrežne bolesti i hipertenzije, a mogu imati i kliničku sliku akutnoga koronarnog sindroma. Prikazujemo 83-godišnju bolesnicu s MDS-om dijagnosticiranim 2014. godine i koja dosad nije liječena specifičnom hematološkom terapijom. Zbrinjavanje starijih hematoloških bolesnika u hitnoj službi nalaže sveobuhvatni pristup zbog često prisutnih pridruženih stanja koja se dodatno mogu pogoršati uz MDS.Myelodysplastic syndromes (MDS) are a group of clonal disorders arising from hematopoietic stem cells and are generally characterized by inefficient hematopoiesis and dysplasia. The International Prognostic Scoring Sytem (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). Ineffective hematopoiesis leading to anemia is the most common cause of the arrival of patients with MDS in the emergency room . Patients with MDS have a number of associated conditions such as chronic kidney disease and hypertension, and may be present as acute coronary syndrome. We report a case of a 83-year-old female with MDS that was diagnosed in 2014 and had no specific treatment. She presented to the emergency department at the beginning of 2016 because of epigastric and chest pain that began in the morning. Diagnosis of subacute STEMI with a scar formed on front wall and elevated high-sensitivity troponin (hsTnI) which amounted to 1,369 ng / L (reference value < 15.6 ng / L) was made , and the patient was hospitalized in the Coronary Care Unit . The care for this population of patients, mainly elderly, in the emergency department requires a comprehensive approach due to the presence of associated conditions such as hypertension, chronic kidney disease and ischemic heart disease. Cardiovascular diseases (CVD) are the leading cause of death in all countries worldwide

Dasatinib-induced nephrotic syndrome: a case of phenoconversion?

We present the case of a 33-year-old chronic myeloid leukemia (CML) female patient, in whom the occurrence of nephrotic syndrome, during the treatment with tyrosine kinase activity inhibitors (TKIs), was potentially influenced by transient phenoconversion. Seven years after the CML diagnosis in 2004 and complete response, the patient experienced pain in the mandible and extremities. After this, imatinib was replaced by nilotinib, but generalized maculopapular rash was presented and successfully treated with antihistamines. The therapy was then discontinued due to planned pregnancy, and the patient experienced a relapse of CML with BCR-ABL/ABL1 transcripts of 18.9%. Dasatinib was introduced, and CML was in remission. Two years later, urine protein levels (6.19 g/L) and erythrocyte sedimentation rate were elevated (ESR = 90 mm/3.6 ks). The patient was diagnosed with nephrotic syndrome. With dasatinib dose reduction, urine protein level returned to the reference range. In order to determine the best genotype-guided therapy, the patient underwent pharmacogenomic testing, showing a homozygous CYP3A4 genotype *1/*1, associated with extensive metabolizer (EM) enzyme phenotype, typical for normal rates of drug metabolism for TKIs. However, this was inconsistent with nephrotic syndrome occurrence. A possible explanation would be CYP3A4 EM genotype coding a poor metabolizer enzyme phenotype, leading to the drug accumulation in the patient’s blood. This transient phenoconversion can be explained by inflammation with elevated ESR during nephrotic syndrome. This case shows that a broader approach that recognizes genetic, clinical, and epigenomic factors is required for a quality decision on the personalized therapy regimen

ARE WE ENTERING CHEMO-FREE ERA IN CHRONIC LYMPHOCYTIC LEUKEMIA? THE ROLE OF IBRUTINIB AND VENETOCLAX AND LESSONS LEARNT FROM IDELALISIB

Glavni cilj ovog preglednog rada je predstaviti novu klasu lijekova u kroničnoj limfocitnoj leukemiji (KLL), najčešćoj leukemiji odrasle dobi, inhibitore staničnog signaliziranja B receptora (BCR). KLL se klasično liječila imunokemoterapijom, no pojedini bolesnici (poodmakla životna dob, nepovoljni biološki faktori) imali su lošu prognozu. S boljim razumijevanjem patogeneze unutarstaničnih putova pojavila se mogućnost selektivne inhibicije i ciljane terapije u KLL. Prvi lijek u svojoj klasi ibrutinib, inhibitor bruton kinaze, pokazao se superiornim u fazama III kliničkih pokusa te je eliminirao negativne prognostičke faktore u liječenju KLL, pogotovo del (17p), s adekvatnim profi lom toksičnosti što su prepoznale regulatorne agencije. Drugi BCR inhibitori idelalisib i venetoklaks su iznimno aktivni u relapsnom okruženju, no idelalisib se pokazao neprihvatljivo toksičnim u prvoj liniji liječenja što nam može poslužiti kao lekcija u dizajnu kliničkih pokusa s ovim lijekovima. Usprkos učinkovitosti, potreban je dodatni napredak u ovom području koji se nalazi u kombinacijama s imunoterapijom ili imunokemoterapijom, te mogućoj međusobnoj kombinaciji kako bismo dodatno poboljšali ishode. No, najveća zapreka BCR inhibitorima da uđu u široku praksu je njihova cijena i utjecaj na zdravstveni sustav što nažalost ograničuje našu mogućnost da liječimo bolesnike s KLL u eri bez kemoterapije.The main aim of this review is to present a novel class of agents, the inhibitors of B cell receptor (BCR) signaling pathway, used in the treatment of chronic lymphocytic leukemia (CLL) as the most common leukemia in the Western world. Traditionally, CLL was treated with immunochemotherapy, but certain subpupulations (elderly, biological prognostic factors) had poor outcome. With advances in our understanding the pathogenesis of intracellular pathways, the possibility of selective inhibition and targeted therapy in CLL has arisen. The fi rst agent in the class of BCR inhibitors, ibrutinib, a Bruton kinase inhibitor, has been shown superior in phase III clinical trials eliminating negative prognostic factors such as del(17p), with adequate toxicity profi le, which was recognized by the respective regulatory agencies. Other BCR inhibitors idelalisib and venetoclax are extremely active in relapsed setting, but unfortunately, idelalisib combinations in fi rst line clinical trials resulted in unacceptable toxicity, which is a cautionary tale on designing trials. Despite their effi cacy, we are only at the beginning to improve them by combination with monoclonal antibodies, immunochemotherapy, or between each other to improve outcomes of CLL treatment even further. However, the main obstacle to chemo-free era in CLL is their price resulting in limited access to these agents and inequity in the modern treatment of CLL

ARE WE ENTERING CHEMO-FREE ERA IN CHRONIC LYMPHOCYTIC LEUKEMIA? THE ROLE OF IBRUTINIB AND VENETOCLAX AND LESSONS LEARNT FROM IDELALISIB

Glavni cilj ovog preglednog rada je predstaviti novu klasu lijekova u kroničnoj limfocitnoj leukemiji (KLL), najčešćoj leukemiji odrasle dobi, inhibitore staničnog signaliziranja B receptora (BCR). KLL se klasično liječila imunokemoterapijom, no pojedini bolesnici (poodmakla životna dob, nepovoljni biološki faktori) imali su lošu prognozu. S boljim razumijevanjem patogeneze unutarstaničnih putova pojavila se mogućnost selektivne inhibicije i ciljane terapije u KLL. Prvi lijek u svojoj klasi ibrutinib, inhibitor bruton kinaze, pokazao se superiornim u fazama III kliničkih pokusa te je eliminirao negativne prognostičke faktore u liječenju KLL, pogotovo del (17p), s adekvatnim profi lom toksičnosti što su prepoznale regulatorne agencije. Drugi BCR inhibitori idelalisib i venetoklaks su iznimno aktivni u relapsnom okruženju, no idelalisib se pokazao neprihvatljivo toksičnim u prvoj liniji liječenja što nam može poslužiti kao lekcija u dizajnu kliničkih pokusa s ovim lijekovima. Usprkos učinkovitosti, potreban je dodatni napredak u ovom području koji se nalazi u kombinacijama s imunoterapijom ili imunokemoterapijom, te mogućoj međusobnoj kombinaciji kako bismo dodatno poboljšali ishode. No, najveća zapreka BCR inhibitorima da uđu u široku praksu je njihova cijena i utjecaj na zdravstveni sustav što nažalost ograničuje našu mogućnost da liječimo bolesnike s KLL u eri bez kemoterapije.The main aim of this review is to present a novel class of agents, the inhibitors of B cell receptor (BCR) signaling pathway, used in the treatment of chronic lymphocytic leukemia (CLL) as the most common leukemia in the Western world. Traditionally, CLL was treated with immunochemotherapy, but certain subpupulations (elderly, biological prognostic factors) had poor outcome. With advances in our understanding the pathogenesis of intracellular pathways, the possibility of selective inhibition and targeted therapy in CLL has arisen. The fi rst agent in the class of BCR inhibitors, ibrutinib, a Bruton kinase inhibitor, has been shown superior in phase III clinical trials eliminating negative prognostic factors such as del(17p), with adequate toxicity profi le, which was recognized by the respective regulatory agencies. Other BCR inhibitors idelalisib and venetoclax are extremely active in relapsed setting, but unfortunately, idelalisib combinations in fi rst line clinical trials resulted in unacceptable toxicity, which is a cautionary tale on designing trials. Despite their effi cacy, we are only at the beginning to improve them by combination with monoclonal antibodies, immunochemotherapy, or between each other to improve outcomes of CLL treatment even further. However, the main obstacle to chemo-free era in CLL is their price resulting in limited access to these agents and inequity in the modern treatment of CLL

Suvremeni pristup ne-Hodgkinovu limfomu plaštene zone: pregled literature [Current approach to non-Hodgkin mantle cell lymphoma: literature review]

Mantle cell lymphoma (MCL) represents the fourth most common type of non-Hodgkin lymphomas. It is characterized by aggressive course and frequent relapses. The main aim of this review is to evaluate current treatment approach towards this type of lymphoma. In younger patients the chemotherapy including high doses of cytarabine is the gold standard. In case of complete or partial remission, the consolidation with autologous stem cell transplantation is indicated as consolidation approach. In older patients CHOP-R regimen is not the treatment of choice. These patients should be treated with bendamustine in combination with rituximab. In case of complete or partial remission, further therapy with rituximab maintenance as consolidation represents an option. The vast majority of patients with MCL will ultimately relapse which poses a challenge in treatment approach. The approach in relapsed MCL can be divided in two types: chemotherapy or biologic therapy. In young fit patients chemotherapy based on bendamustine and cytarabine is a reasonable option. In patients with comorbidities or poor performance status biologic agents are reasonable options. Ibrutinib, Bruton kinase inhibitor, is characterized by highest overall response rate and the longest duration of response and should be offered to these patients. With the development of novel potent inhibitor of B cell receptor signaling pathway, these agents may become the gold standard in future and introduce the treatment of MCL in „chemo-free“era

SKIN SIDE - EFFECTS OF HYDROXYUREA THERAPY

Kod hematološkog bolesnika, kožne promjene mogu biti dio kliničke slike u trenutku postavljanja dijagnoze ili napredovanja bolesti koji se oćituju kožnim iniltratima, posljedica infekcije ili nuspojave terapije. hidroksiureja je peroralni citostatik uz kojeg se mogu pojavljivati dermatološke nuspojave čak i i nekoliko godina od početka liječenja. Prikazujemo bolesnicu s ulkusima potkoljenica nastalima u tijeku terapije hidroksiurejom. Važno je na vrijeme prepoznati kožne promjene vezane uz hidroksiureju jer je ukidanje navedenog citostatika u takvom slučaju kurativno.Hematology patients can have wounds as part of the initial presentation of the disease, as a result of infection, side effects of therapy, or disease progression with skin iniltration. hydroxyurea is an oral cytotoxic drug with known cutaneous side effects that can appear years after treatment initiation. here we present a case of a female patient who developed crural ulcerations during hydroxyurea treatment. It is very important to recognize the wound related to hydroxyurea treatment because drug discontinuation is usually curative