Incidence and Mortality Patterns of Acute Myeloid Leukemia in Belgrade, Serbia (1999⁻2013).

Introduction: To assess incidence and mortality trends of acute myeloid leukemia (AML) in Belgrade (Serbia) in a 15-year period (from 1999 to 2013). Material and Methods: Data were obtained from the Cancer Registry of Serbia, Institute of Public Health of Serbia. Standardized incidence and mortality rates per 100,000 inhabitants were calculated by direct standardization method using World Standard Population. Analysis of raw data indicated single-digit numbers per year and per 5-year age cohorts. Therefore, we merged years of diagnosis to three-year intervals, creating so-called "moving averages". We also merged study population to 10-year age cohorts. Results: Both incidence and mortality rates increased with age, i.e., the lowest rates were observed in the youngest age groups and the highest rates were observed in oldest age groups. In all age groups, except the youngest (15⁻24 years), AML incidence was statistically significantly higher in men compared with women. Average age-adjusted incidence was 2.73/100,000 (95% confidence interval (CI) 2.28⁻3.71). Average age-adjusted mortality was 1.81/100,000 (95% CI 1.30⁻2.26). Overall, there were no significant changes in incidence trend. Age-adjusted incidence rates had increasing tendency among men aged 65⁻74 years (B = 0.80, standard error (SE) = 0.11; p = 0.005) and in total population aged 65⁻74 years (B = 0.41, SE = 0.09; p = 0.023). Increasing tendency in incidence of AML among women was observed in age group >75 years (B = 0.63, SE = 0.14; p = 0.019). No changes of mortality trend were observed. Conclusion: There was no significant change in trends of AML from 1999 to 2013 in the population of Belgrade.

Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease.

The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.

Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype.

BACKGROUND: Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK). The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up. PATIENTS AND METHODS: In our study samples from 110 adult de novo AML-NK were studied for the presence of IDH1 and IDH2 mutations, their associations with other prognostic markers and disease outcome. We also analyzed the stability of these mutations during the course of the disease in complete remission (CR) and relapse. RESULTS: IDH mutations were found in 25 (23%) patients. IDH+ patients tend to have lower CR rate compared to IDH-patients (44% vs 62.2%, p = 0.152), and had slightly lower disease free survival (12 months vs 17 months; p = 0.091). On the other hand, the presence of IDH mutations had significant impact on overall survival (2 vs 7 months; p = 0.039). The stability of IDH mutations were studied sequentially in 19 IDH+ patients. All of them lost the mutation in CR, and the same IDH mutations were detected in relapsed samples. CONCLUSIONS: Our study shows that the presence of IDH mutations confer an adverse effect in AML-NK patients, which in combination with other molecular markers can lead to an improved risk stratification and better treatment. Also, IDH mutations are very stable during the course of the disease and can be potentially used as markers for minimal residual disease detection.

Comparison of two laboratory assays in monitoring the efficacy of different prophylaxis regimens for severe haemophilia.

BACKGROUND: The goal of this study was to compare the validity of two laboratory assays, rotation thromboelastometry (ROTEM) and endogenous thrombin potential (ETP), in monitoring and evaluating different prophylactic treatment regimens in patients with severe haemophilia. METHODS: Twenty adult patients with severe haemophilia were divided into three groups according to treatment regimen with concentrate of factor (F) VIII/IX: full-dose prophylaxis (5 patients), intermediate-dose prophylaxis (5 patients), and on demand treatment (10 patients). RESULTS: The ROTEM for the group treated with full-dose prophylaxis was significantly lower than ROTEM for the group treated with intermediate-dose prophylaxis (p = 0.025). Among the patients given full-dose prophylaxis, 40% (2 patients) had prolonged ROTEM after 3 months of treatment, while among those given intermediate-dose prophylaxis all patients (100%, 5 patients) had prolonged ROTEM (p = 0.038). The ETP was significantly improved after 3 months of full-dose in comparison with intermediate-dose prophylaxis (p = 0.042). CONCLUSIONS: ROTEM and ETP are useful laboratory assays for monitoring efficacy of different prophylaxis regimens with concentrate of FVIII/IX in patients with severe haemophilia, helping in making decisions regarding optimal dose-regimen prophylaxis.

The effect of paraprotein on platelet aggregation.

BACKGROUND: Some patients with paraproteinemia have platelet aggregation disorders and the aim of this study was to examine disturbance of platelet aggregation in healthy blood donors by isolated paraprotein in vitro. METHODS: Using Rivanol, paraprotein was separated from the serum of ten patients with paraproteinemia, who had decreased platelet aggregation with several inducers. Platelet aggregation in ten healthy donors was measured with and without addition of the isolated induced paraprotein. The test was repeated with added human immunoglobulins for intravenous use. RESULTS: Average of maximal levels of platelet aggregation has been significantly decreased in plasma rich in platelets (PRP) of healthy donors after addition of paraprotein when inducers are used: adenosine diphosphate (ADP) (P = 0.007), collagen (COL) (P = 0.008), ristocetin (RIS) (P = 0.001), and epinephrine (EPI) (P = 0.002). Average of latent time of platelet aggregation was significantly prolonged in healthy donors after addition of paraprotein with inducers: COL (P = 0.008), RIS (P = 0.008) and EPI (P = 0.006) while addition of human immunoglobulins caused no change in platelet aggregation. In comparison, when human immunoglobulins were added, maximal platelet aggregation and latent time did not change significantly. Paraprotein isolated from patients with paraproteinamia, who had decrease platelet aggregation, had significantly decreased platelet aggregation when added to PRP of healthy donors, in vitro. CONCLUSION: Platelet aggregation was not significantly changed was confirmed with addition of human immunoglobulins.

Induction chemotherapy versus palliative treatment for acute myeloid leukemia in a consecutive cohort of elderly patients.

A retrospective survey of 210 consecutive patients aged ≥ 65 years (median age 69 years, range 65-88 years) with acute myeloid leukemia (AML) diagnosed at a single center over a 6-year period (January 2001 to December 2006) is presented. De novo AML was diagnosed in 179 (85.2 %) patients and 31 (14.7 %) patients had a secondary AML. Twenty-three patients had M0 (11 %), 36 M1 (17.15 %), 57 M2 (27.1 %), eight M3 (3.8 %), 45 M4 (21.4 %), 31 M5 (14.8 %), one M6 (0.5 %), one M7 (0.5 %), and eight patients had unclassified myeloid leukemia (3.8 %) according to French-American-British (FAB) Study Group Classification. Eight patients with M3 (acute promyelocytic leukemia) were excluded from the study. Cytogenetic analysis was performed in 172/202 (85 %) patients. The normal karyotype was found in 81/172 (47 %), high risk aberrations in 32/172 (18.6 %), and favorable karyotype in 13/172 (7.5 %) patients. Supportive and palliative therapies were applied in 115 (56.9 %) patients, a no induction chemotherapy (NIC) group, and 87 (43.1 %) patients received induction chemotherapy (IC group). Complete remission (CR) was achieved in 45/87 (51.7 %) in the IC group and in 5/115 (4.3 %) in the NIC group of patients. After a median follow up of 4 years, 194 (96 %) patients died. The variables significantly associated with a longer overall survival (OS) by univariate analysis were an age of <75 years, a better ECOG performance status (PS) (p = 0.000, CI 95.0 %, 1.358-2.049), a serum LDH activity <600 U/l (p = 0.000, CI 95.0 %, 1.465-2.946), lower white blood cell (WBC) count at diagnosis (p = 0.011, CI 95.0 %, 1.102-2.100), lower comorbidity HCT-CI index (p = 0.000, CI 95 % 2.209-3.458), absence of splenomegaly (p = 0.015, CI 95.0 %, 1.082-2.102) and hepatomegaly (p = 0.008, CI 95.0 %, 1.125-2.171), and no preceding nonhematological malignancy. Multivariate analysis showed that significant factors affecting OS in the IC group were achievement of CR (p = 0.000), the ECOG PS (p = 0.045) and the ECOG PS (p = 0.000), and HCT-CI (p = 0.000) in the NIC group of elderly patients. The present study suggests that a subgroup of elderly patients with both ECOG PS and HCT-CI ≤ 2 at presentation may be eligible for intensive induction chemotherapy.

Clinical significance of genetic aberrations in secondary acute myeloid leukemia.

The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% ± 9.4% vs. 35.4% ± 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.33-5.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms.

Prognostic impact of NPM1 mutations in Serbian adult patients with acute myeloid leukemia.

Based on current findings, the presence of NPM1 mutations in acute myeloid leukemia (AML) patients is associated with an increased probability of complete remission (CR) and better overall survival (OS). We determined the incidence and prognostic relevance of NPM1 mutations, their association with FLT3 and IDH mutations, and other clinical characteristics in Serbian adult AML patients. Samples from 111 adult de novo AML patients, including 73 AML cases with a normal karyotype (NK-AML), were studied. NPM1, FLT3, and IDH mutations were detected by PCR and direct sequencing. NPM1 mutations were detected in 22.5% of patients. The presence of NPM1 mutations predicted a low CR rate and shorter OS. NPM1 mutations showed an association with both FLT3 and IDH mutations. Survival analysis based on NPM1/FLT3 mutational status revealed a lower OS for NPM1(+)/FLT3(-) compared to the NPM1(-)/FLT3(-) group in NK-AML patients. The lack of impact or unfavorable prognostic effect of NPM1 mutations found in this study can be assigned to a small cohort of analyzed AML patients, as can the presence of FLT3 and IDH mutations or other genetic lesions that cooperate with NPM1 mutations influencing prognosis.

Application of targeted next generation sequencing for the mutational profiling of patients with acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common cancer in children, whereas it is less common in adults. Identification of cytogenetic aberrations and a small number of molecular abnormalities are still the most important risk and therapy stratification methods in clinical practice today. Next generation sequencing (NGS) technology provides a large amount of data contributing to elucidation of mutational landscape of childhood (cALL) and adult ALL (aALL). METHODS: We analyzed DNA samples from 34 cALL and aALL patients, using NGS targeted sequencing TruSeq Amplicon - Cancer Panel (TSACP) which targets mutational hotspots in 48 cancer related genes. RESULTS: We identified a total of 330 variants in the coding regions, out of which only 95 were potentially protein-changing. Observed in individual patients, detected mutations predominantly disrupted Ras/RTK pathway (STK11, KIT, MET, NRAS, KRAS, PTEN). Additionally, we identified 5 patients with the same mutation in HNF1A gene, disrupting both Wnt and Notch signaling pathway. In two patients we detected variants in NOTCH1 gene. HNF1A and NOTCH1 variants were mutually exclusive, while genes involved in Ras/RTK pathway exhibit a tendency of mutation accumulation. CONCLUSIONS: Our results showed that ALL contains low number of mutations, without significant differences between cALL and aALL (median per patient 2 and 3, respectively). Detected mutations affect few key signaling pathways, primarily Ras/RTK cascade. This study contributes to knowledge of ALL mutational landscape, leading to better understanding of molecular basis of this disease.

Serbian lymphoma study group (SLG): the prognosis of AIDS-related non-Hodgkin's lymphoma.

BACKGROUND: The majority of patients with AIDS-related non-Hodgkin's lymphoma (ARL) present with advanced disease, aggressive histological type, B-symptoms, and often with an extranodal localization. The prognosis is generally poor. The use of highly active antiretroviral therapy (HAART), in combination with chemotherapy, has improved the outcome of ARL. AIMS: The aims of this study were to detect prognostic factors for patients with ARL and estimate efficacy of concomitant chemotherapy and HAART on overall survival (OS) of these patients. Also, two different chemotherapy regimens have been tested: low dose (ld) mBACOD and CHOP. METHODS: The study series involved 28 patients with ARL treated at the Clinical Center of Serbia in Belgrade during the period 1996-2006. Twenty-six patients had an aggressive type of lymphoma while 2 had an indolent type. Nineteen patients were treated with chemotherapy, 10 with ld mBACOD and 9 with CHOP. Concomitant HAART and chemotherapy were used in 14 patients. RESULTS: This study demonstrated that significant factors for OS in patients with ARL were the high International Prognostic Index (P=0.019), previous AIDS event (P=0.04), aggressive histological type of NHL (P=0.007) and extranodal disease (P=0.04). The usage of concomitant HAART and chemotherapy had significant effect on median survival (90 months), compared with chemotherapy alone (10 months) (P=0.0002). The patients treated with CHOP had a better response than patients treated with ld mBACOD, but this difference was not significant. CONCLUSIONS: Our data suggest that aggressive presentation of ARL implicates the need not only for more intensive chemotherapy regimens, but the concomitant usage of HAART, which should result in higher rates of OS in ARL patients.

Outcomes of primary thyroid non-Hodgkin's lymphoma: a series of nine consecutive cases.

Primary non-Hodgkin's lymphoma (NHL) of the thyroid gland is a rare disease with an incidence of 0.5 per 100,000 population. Stages IE and IIE thyroid NHL have been traditionally treated by surgical resection; however, modern treatment consists of chemotherapy and local radiotherapy, and surgery is often reserved for tissue diagnosis and relief of airway compression. We retrospectively reviewed the management and outcomes of nine consecutive patients with thyroid NHL, eight females and one male (median age 63 yr, range 34-71 yr) treated between 1994 and 1999. Five patients had disease stage IE and 4 stage IIE. Median follow-up was 72 mo. Pathohistology and immunohistochemistry identified two patients with mucosa-associated lymphoid tissue (MALT), three follicular center cell lymphoma (FCC), two patients large B-cell lymphoma (BLCL), one a marginal zone lymphoma (MZL), and one patient a peripheral T-cell lymphoma (PTCL). Total thyroidectomy was performed in three patients and subtotal thyroidectomy in four. One (MALT) patient underwent surgery alone; three patients surgery, radiotherapy, and chemotherapy (two FCC, one PTCL); three patients surgery and chemotherapy (one MALT, one FCC, one LBCL); and two chemotherapy alone (one LBCL, one MZL). Median survival was 79 mo (range 13-124 mo). The PTCL patient, a 34-yr-old man, died from disseminated disease at 13 mo despite secondary chemotherapy, and one LBCL patient with extensively invasive local disease died from stroke 17 mo after diagnosis. The remaining seven patients remain in remission with no local or systemic relapse at a mean of 86 mo. With appropriate therapy primary thyroid NHL has a favorable course; however, prognosis depends on the histology, local spread, and the stage of the disease at presentation, as well as the patient's performance status. Surgery in combination with chemotherapy and/or radiotherapy is still warranted for intermediate and high-grade thyroid NHLs, with over 77% of patients achieving long-term remission. Peripheral T-cell lymphoma carries a poor prognosis.

Use of Wilms Tumor 1 Gene Expression as a Reliable Marker for Prognosis and Minimal Residual Disease Monitoring in Acute Myeloid Leukemia With Normal Karyotype Patients.

BACKGROUND: Acute myeloid leukemia with normal karyotype (AML-NK) represents the largest group of AML patients classified with an intermediate prognosis. A constant need exists to introduce new molecular markers for more precise risk stratification and for minimal residual disease (MRD) monitoring. PATIENTS AND METHODS: Quantitative assessment of Wilms tumor 1 (WT1) gene transcripts was performed using real-time polymerase chain reaction. The bone marrow samples were collected at the diagnosis from 104 AML-NK patients and from 34 of these patients during follow-up or disease relapse. RESULTS: We found that overexpression of the WT1 gene (WT1high status), present in 25.5% of patients, was an independent unfavorable factor for achieving complete remission. WT1high status was also associated with resistance to therapy and shorter disease-free survival and overall survival. Assessment of the log reduction value of WT1 expression, measured in paired diagnosis/complete remission samples, revealed that patients with a log reduction of < 2 had a tendency toward shorter disease-free survival and overall survival and a greater incidence of disease relapse. Combining WT1 gene expression status with NPM1 and FLT3-ITD mutational status, we found that the tumor behavior of intermediate patients (FLT3-ITD-/NPM1- double negative) with WT1high status is almost the same as the tumor behavior of the adverse risk group. CONCLUSION: WT1 expression status represents a good molecular marker of prognosis, response to treatment, and MRD monitoring. Above all, the usage of the WT1 expression level as an additional marker for more precise risk stratification of AML-NK patients could lead to more adapted, personalized treatment protocols.

Hypercalcemia with multiple osteolytic lesions and increased circulating tumor necrosis factor in an adult patient with B-cell acute lymphoblastic leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is very rarely presented with diffuse osteolytic lesions and hypercalcemia. CASE OUTLINE: We report a 28-year-old male with the B-cell ALL who presented with extensive osteolytic lesions, bone pain, hepatosplenomegaly, and pancytopenia without circulating blasts in peripheral blood. An increased serum level of tumor necrosis factor (TNF-α) was registered while the levels of IL-1α and IL-1ß were normal. The patient failed to achieve remission on two induction regimens but achieved one after the successful allogeneic stem cell transplantation, which lasted for six months, after which he developed a relapse and died. CONCLUSION: The presented case may serve as a clinical demonstration of possible involvement of TNF-α as a pathogenic factor in the evolution of osteolytic lesions that are occasionally observed in patients with ALL. This might have relevance in the management of such patients as chemotherapy alone may not represent the beneficial option in this clinical context.

Peripartum cardiomyopathy in a patient treated for acute myeloid leukemia.

INTRODUCTION: Peripartum cardiomyopathy usually presents with systolic heart failure during the last months of pregnancy and up to five months postpartum. The disease is rare and can be fatal. CASE OUTLINE: We report a 30-year-old female who was diagnosed with acute myeloid leukemia, with maturation and cytogenetic finding of t(8;21)(q22;q22),del(9)(q22) in January 2004. She was treated with chemotherapy and achieved complete remission that lasts to date. She became pregnant and delivered a healthy newborn with caesarean section in 2009. Seven months later, she again became pregnant and delivered the second child with caesarean section in January 2011. Seven days after delivery she developed symptoms and signs of heart failure. Electrocardiogram showed sinus rhythm, low voltage and negative T-waves in inferior and lateral leads. Echocardiography revealed global left ventricular dysfunction with ejection fraction of 15%, with mobile thrombotic mass of 12 mm attached to the left ventricle wall. She was treated with both unfractionated and low-molecular heparin, diuretics, cardiotonics, and beta-blockers. Within six following weeks left ventricle systolic function improved up to 25-30%. The full clinical recovery was achieved in September 2013, resulting in absence of heart failure and left ventricular ejection fraction of 54%. CONCLUSION: Peripartum cardiomyopathy is a rare condition. The cause of cardiomyopathy is unknown, but it is believed that it could be triggered by various conditions and risk factors. Although the patient was treated with cardiotoxic drugs (doxorubicin and mitoxantrone) in permitted doses, they could have been contributory factors of myocardial damage. Close monitoring of cardiac function in the peripartal period might be beneficial in patients treated with cardiotoxic drugs.

Mucormycosis of the paranasal sinuses in a patient with acute myeloid leukemia.

Introduction: Invasive fungal infection is among the leading causes of morbidity, mortality, and economic burden for patients with acute leukemia after induction of chemotherapy. In the past few decades, the incidence of invasive fungal infection has increased dramatically. Its management has been further complicated by the increasing frequency of infection by non-Aspergillus molds (e.g. Mucorales). Neutropenic patients are at a high risk of developing an invasive mucormycosis with fulminant course and high mortality rate (35­100%). Case Outline: We are presenting the case of a 72-year-old male with an acute monoblastic leukemia. The patient was treated during five days with hydroxycarbamide 2 × 500 mg/day, followed by cytarabine 2 × 20 mg/sc over the next 10 days. He developed febrile neutropenia, headache, and edema of the right orbital region of the face. Computed tomography of the sinuses revealed shadow in sinuses with thickening of mucosa of the right paranasal sinuses. Lavage and aspirate from the sinuses revealed Rhizopus oryzae. Mucormycosis was successfully treated with amphotericin B (5 mg/kg/day) followed by ketoconazole (400 mg/day). Two months later the patient died from primary disease. Conclusion: In patients with acute leukemia who developed aplasia, febrile neutropenia, and pain in paranasal sinuses, fungal infection should be taken into consideration. New and non-invasive methods for taking samples from sinuses should be standardized in order to establish an early and accurate diagnosis of mucormycosis with the source in paranasal sinuses, and to start early treatment by a proper antifungal drug. Clear communication between physician and mycologist is critical to ensure proper and timely sampling of lavage and aspirate from sinuses and correct specimen processing when mucormycosis is suspected clinically.

Acute Myocardial Infarction during Induction Chemotherapy for Acute MLL t(4;11) Leukemia with Lineage Switch and Extreme Leukocytosis.

INTRODUCTION: In patients with acute leukemias hemorrhage is the most frequent problem. Vein thrombotic events may appear rarely but arterial thromboses are exceptionally rare. We present a patient with acute leukemia and bilateral deep leg vein thrombosis who developed an acute myocardial infarction (AMI) during induction chemotherapy. The etiology and treatment of AMI in patients with acute leukemia, which is a rare occurrence, is discussed. CASE OUTLINE: In April of 2012 a 37-year-old male presented with bilateral deep leg vein thrombosis and malaise. Laboratory data were as follows: Hb 118 g/L, WBC 354 x 10(9)/L (with 91% blasts in differential leukocyte count), platelets 60x109/L. Bone marrow aspirate and immunophenotype revealed the presence of acute lymphoblastic leukemia. Cytogenetic analysis was as follows: 46,XY,t(4;11)(q21:q23) [2]/62-82,XYt(4;11)[18]. Molecular analysis showed MLL-AF4 rearrangement. The patient was on low molecular weight heparin and combined chemotherapy according to protocol HyperCVAD. On day 10 after chemotherapy he got chest pain. Three days later AMI was diagnosed (creatine kinase 66 U/L, CK-MB 13U/L, troponin 1.19 µg/L). Electrocardiogram showed the ST elevation in leads D1, D2, aVL, V5 and V6 and "micro q" in D1. On echocardiography, hypokinesia of the left ventricle and ejection fraction of 39% was found. After recovering from AMI and restoring left ventricle ejection fraction to 59%, second course of HyperCVAD was given. The control bone marrow aspirate showed 88% of blasts but with monoblastic appearance. Flow cytometry confirmed a lineage switch from lymphoblasts to monoblasts. In further course of the disease he was treated with a variety of chemotherapeutic combinations without achieving remission. Eventually, palliative chemotherapy was administered to reduce the bulk of blasts. He died five months after the initial diagnosis. CONCLUSION: AMI in young adults with acute leukemia is a very rare complication which may occur in patients with very high white blood cell count in addition with presence of a CD56 adhesion molecule and other concomitant thrombophilic factors. The treatment of AMI in patients with acute leukemias should include antiplatelet and anticoagulant therapy, even with more aggressive methods depending on patient's age and clinical risk assessment.

[Favorable Outcome of Hepatosplenic Candidiasis in a Patient with Acute Leukemia].

INTRODUCTION: Acute leukemias treatment requires strong chemotherapy. Patients that develop bone marrow aplasia become immunocompromised, thus becoming liable to bacterial and fungal infections. Fungal infections caused by Candida are frequent. Hepatosplenic candidiasis (HSC) is a frequent consequence of invasive candidiasis which is clinically presented with prolonged febrility unresponsive to antibiotics. CASE OUTLINE: A 53-year-old patient with acute myeloid leukemia was submitted to standard chemotherapy "3+7" regimen (daunoblastine 80 mg i.v. on days 1 to 3, cytarabine 2 x 170 mg i.v. during 7 days) and achieved complete remission. However, during remission he developed febrility unresponsive to antibiotics. Computerised tomography (CT) of the abdomen showed multiple hypodense lesions within the liver and spleen. Haemocultures on fungi were negative. However, seroconversion of biomarkers for invasive fungal infection (FI) (Candida and Aspergillus antigen/Ag and antibody/Ab) indicated possible HSC. Only high positivity of anti-Candida IgG antibodies, positivity of mannan and CT finding we regarded sufficient for the diagnosis and antimycotic therapy.Three months of treatment with different antimycotics were necessary for complete disappearance of both clinical symptoms and CT findings. CONCLUSION: In patients with prolonged febrile neutropenia IFI has to be strongly suspected. If imaging techniques show multiple hypodense lesions within liver and spleen, HSC has to be taken seriously into consideration. We believe that, along with CT finding, positive laboratory Candida biomarkers (mannan and IgG antibodies) should be considered sufficient for"probable HSC" and commencement of antifungal therapy, which must be long enough, i.e. until complete disappearance of clinical symptoms and CT findings are achieved.

Thrombotic events in acute promyelocytic leukemia.

INTRODUCTION: Thrombotic events (TE) appear to be more common in acute promyelocytic leukemia (APL) than in other acute leukemias, with reported prevalence ranging from 2 to 10-15%. MATERIALS AND METHODS: We retrospectively analyzed the data on TE appearance in 63 APL patients. RESULTS: TE occured in 13 (20.6%) cases, four arterial (6.3%) and nine venous (14.3%). TE were more frequently diagnosed after initiation of weekly D-dimer monitoring (7 TE during 20 months vs 6 during 76 months, P=0.032). Patients with and without venous thrombosis were significantly different regarding female/male ratio (P=0.046), PT (P=0.022), aPTT (P=0.044), ISTH DIC score (P=0.001), bcr3 (P=0.02) and FLT3-ITD (P=0.028) mutation. The most significant risk factor for venous TE occurrence in multivariate analysis was FLT3-ITD mutation (P=0.034). PAI-1 4G/4G polymorphism was five times more frequent in patients with venous TE than without it (P=0.05). Regarding risk factors for arterial TE we failed to identify any. CONCLUSIONS: We have demonstrated that APL-related TE rate is higher than previously reported and that weekly D-dimer monitoring might help to identify patients with silent thrombosis. Moreover, our study suggests a possible relationship between venous TE occurrence and several laboratory findings (PT, aPTT, ISTH DIC score, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G). Prophylactic use of heparin might be considered in patients with ISTH DIC score<5, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G.

A novel t(2;17) in transformation of essential thrombocythemia to acute myelocytic leukemia.

A transformation of essential thrombocythemia to acute myelocytic leukemia (AML), myelodysplastic syndrome, or agnogenic myelocytic metaplasia is a relatively rare event. It occurs in 1%-4.5% of all patients with either treated or untreated essential thrombocythemia. Cytogenetic changes in the transformation to AML are common. We report the case of a patient treated for essential thrombocythemia with hydroxyurea for 49 months. He developed AML with a t(2;17), which to our knowledge has not been described in the literature.