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Standard of care (SOC) anticoagulation for thromboembolism (TE) prevention in children with cardiac disease includes low molecular weight heparins or vitamin K antagonists. Limited data exists for alternate use of direct oral anticoagulants in children.The investigators aimed to obtain safety and efficacy data for edoxaban in children.We performed a phase 3, multinational, prospective, randomized, open-label, blinded-endpoint trial in patients 18 years of age with cardiac disease (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots (Thrombotic Events) in Children at Risk Because of Cardiac Disease] trial). Patients were randomized 2:1 to age- and weight-based oral edoxaban once daily vs SOC for 3 months (main study period), stratified by cardiac diagnosis. Both groups could continue in an open-label edoxaban extension arm through 1 year. The primary endpoint was adjudicated clinically relevant bleeding (CRB). The main secondary endpoint was symptomatic TE or asymptomatic intracardiac thrombosis.The modified intention-to-treat cohort included 167 children. One patient per group experienced a nonmajor CRB in the main period. Treatment-emergent adverse events occurred in 46.8% (51 of 109) with edoxaban and 41.4% (24 of 58) with SOC. One SOC patient experienced 2 TE events (DVT with PE). Among 147 children in the extension, 1 CRB event (0.7%) and 4 TEs occurred (2.8%; 2 strokes and 2 of 33 Kawasaki disease patients with coronary artery thromboses and/or myocardial infarctions).Edoxaban is a potential alternative mode of thromboprophylaxis in children with cardiac disease showing low rates of CRB and TEs with advantages of once daily dosing and infrequent monitoring requirement. (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots] (Thrombotic Events) in Children at Risk Because of Cardiac Disease trial; NCT03395639).

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous malignancy and consists of several genetic abnormalities. Some of these abnormalities are used in clinics for risk calculation and treatment decisions. Patients with ZNF384 rearrangements had a distinct expression profile regardless of their diagnosis, BCP-ALL or mixed phenotype acute leukemia (MPAL) and defined as a new subtype of ALL. In this study, we screened 42 MPAL and 91 BCP-ALL patients for the most common ZNF384 fusions; ZNF384::TCF3, ZNF384::EP300 and ZNF384::TAF15 by using PCR. We identified ZNF384 fusions in 9.5% of MPAL and 7.6% of BCP-ALL. A novel breakpoint was identified in ZNF384::TCF3 fusion in one BCP-ALL patient. T-myeloid MPAL patients showed significantly lower ZNF384 expression compared to lymphoid groups. Patients with ZNF384r had intermediate survival rates based on other subtypes. Prognostic and patient-specific treatment evaluation of ZNF384 fusions in both ALL and MPAL might help to improve risk characterization of patients. 35921545

Aim: The present study aims to identify the anticancer effect of novel 1H-indole-2,3-dione 3- thiosemicarbazone derivatives. These compounds could be promising anticancer agents in leukemia treatment. Background : Conventional chemotherapeutic agents accumulate in both normal and tumor cells due to nonspecificity. For effective cancer treatment, new drugs need to be developed to make chemotherapeutics selective for cancer cells. The ultimate goal of cancer treatment is to reduce systemic toxicity and improve the quality of life. Method: In this study, the anticancer effects of 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives (A-L) were investigated in chronic myelogenous leukemia K562, Burkitt’s lymphoma P3HR1, acute promyelocytic leukemia HL60 cells, and vincristine-resistant sublines of K562 and P3HR1 cells. Additionally, the compounds were tested on lymphoid-derived cells from ALL patients. In order to investigate the particular mechanism of death caused by the cytotoxic effects of the compounds, immunohistochemical caspase 3 staining was performed in P3HR1 cells, and the resulting apoptotic activities were demonstrated. Result: All tested compounds have been found to have cytotoxic effects against lymphoma cells at submicromolar concentrations (IC50= 0.89-1.80 μM). Most compounds show significant selectivity for the P3HR1 and P3HR1 Vin resistance. The most effective and selective compound is 4-bromophenyl substituted compound I (IC50=0.96 and 0.89 μM). Cyclohexyl and benzyl substituted compounds D and E have also been found to have cytotoxic effects against K562 cell lines (IC50=2.38 μM), while the allyl substituted compound C is effective on all cell lines (IC50=1.13-2.21 μM). 4-Fluorophenyl substituted F compound has been observed to be effective on all cells (IC50=1.00-2.41 μM) except K562 cell. Compound C is the only compound that shows inhibition of HL-60 cells (IC50= 1.13 μM). Additionally, all compounds exhibited cytotoxic effects on lymphoidderived cells at 1μM concentration. These results are in accordance with the results obtained in lymphoma cells. Conclusion: All compounds tested have submicromolar concentrations of cytotoxic effects on cells. These compounds hold potential for use in future treatments of leukemia.

The tumor suppressor protein 53 (TP53) gene is one of the most studied genes in cancer. Although TP53 variants are rare events in acute leukemia, recent observations showed that relapse samples might harbor TP53 variants. Here, we aimed to determine TP53 variants (hotspot region, exon 4–11) in childhood acute lymphoblastic leukemia (B and T-ALL) patients (n = 94) including diagnostic-relapse pairs (n = 15) by amplicon sequencing and evaluate the clinical impact of these variants. In total, nine different (E298*, R283C, R273H, L252F, C229F, I195T, E286G, c.955_956insC, and c.920-1G > C) variants were identified in 17 (18%) childhood ALL patients. c.(920-1G> C) splice site variant and c.(955_956insC) insertion were reported for the first time. In diagnose-relapse pair samples, we identified acquired and/or loss of TP53 variants in the samples at the time of relapse. TP53 variants were found to be more common in T-ALL (37%) than in B-ALL patients (9%). Pathogenic TP53 variants were associated with a shorter overall survival time (p = 0.001).TP53 variants were found to be associated with inferior outcomes in our cohort and can be an independent risk factor for poor prognosis in childhood acute leukemia patients. Identification of low-frequent variants with next-generation sequencing approaches enables better knowledge of the clonal dynamics of ALL.

Emapalumab, a fully human anti-IFNγ monoclonal antibody, has been approved in the US as second-line treatment of primary hemophagocytic lymphohistiocytosis (HLH) patients and has shown promise in patients with graft failure (GF) requiring a second allogeneic hematopoietic stem cell transplantation (HSCT). The blockade of IFNγ activity may increase the risk of severe infections, including fatal mycobacteriosis. We report a case of secondary HLH-related GF in the context of HLA-haploidentical HSCT successfully treated with emapalumab in the presence of concomitant life-threatening infections, including disseminated tuberculosis (TB). A 4 years old girl with Adenosine Deaminase-Severe Combined Immunodeficiency complicated by disseminated TB came to our attention for ex-vivo hematopoietic stem cell-gene therapy. After engraftment failure of gene corrected cells, she received two HLA-haploidentical T-cell depleted HSCT from the father, both failed due to GF related to concomitant multiple infections and secondary HLH. Emapalumab administration allowed to control HLH, as well as to prevent GF after a third haplo-HSCT from the mother. Remarkably, all infections improved with antimicrobial medications and disseminated TB did not show any reactivation. This seminal case supports emapalumab use for treatment of secondary HLH and prevention of GF in patients undergoing haplo-HSCT even in the presence of multiple infections, including TB.

To determine the possibility of further improving clinical stereotactic body radiotherapy (SBRT) plans using normal tissue complication probability (NTCP) objectives in order to minimize the risk for carotid blowout syndrome (CBOS).10 patients with inoperable locally recurrent head and neck cancer, who underwent SBRT using CyberKnife were analyzed. For each patient, three treatment plans were examined: (1) cone-based without delineation of the ipsilateral internal carotid (clinical plan used to treat the patients); (2) cone-based with the carotid retrospectively delineated and spared; and (3) Iris-based with carotid sparing. The dose-volume histograms of the target and primary organs at risk were calculated. The three sets of plans were compared based on dosimetric and TCP/NTCP (tumor control and normal tissue complication probabilities) metrics. For the NTCP values of carotid, the relative seriality model was used with the following parameters: DAcross the 10 patient plans, the average TCP did not significantly change when the plans were re-optimized to spare the carotid. The estimated risk of CBOS was significantly decreased in the re-optimized plans, by 14.9% ± 7.4% for the cone-based plans and 17.7% ± 7.1% for the iris-based plans (p = 0.002 for both). The iris-based plans had significant (p = 0.02) reduced CBOS risk and delivery time (20.1% ± 7.4% time reduction, p = 0.002) compared to the cone-based plans.A significant improvement in the quality of the clinical plans could be achieved through the delineation of the internal carotids and the use of more modern treatment delivery modalities. In this way, for the same target coverage, a significant reduction in the risk of CBOS could be achieved. The range of risk reduction varied depending on the proximity of carotid artery to the target.

Children with cancer have an increased risk for hepatitis B virus (HBV) infections due to chemotherapy-induced secondary immunodeficiency and frequent blood transfusions. The aim of this study is to evaluate the efficacy and safety of hepatitis B vaccination during the intensive induction chemotherapy in children with cancer found to be seronegative for hepatitis B on admission.Children newly diagnosed with cancer were evaluated for the presence of hepatitis B surface antigen (HBsAg) and antibody on admission. The children negative for both were included in the study. A super-accelerated vaccination scheme (3 booster doses at days 1-5, 8-12, and 28-33) was administered to these seronegative children concurrently with induction chemotherapy. Antibody response was checked 4-8 weeks after the last vaccination and 6 months after the end of the treatment.Eleven out of 122 children were seronegative for hepatitis B on admission (9%). Acute lymphoblastic leukemia, lymphoma, and solid tumors were diagnosed in 5, 4, and 2 children, respectively. Complete seroconversion was achieved in 4-8 weeks after the last vaccination with high titers of anti-HBs antibody, and all patients remained antibody-positive until 6 months after the completion of chemotherapy.The risk of transfusion-related infections increases with a number of transfused products and donor exposures, and it is more significant for immunosuppressed children with hematologic and oncologic malignancies. Hepatitis B vaccination could safely be applied with brisk and sustained responses in this vulnerable population, based on the local epidemiological data.

[No Abstract Available], Novartis Pharmaceuticals Corporation, This study was sponsored and funded by Novartis Pharmaceuticals Corporation.

Objective: HLA class I and II alleles are shown to be associated with certain diseases. A restricted numbers of alleles were found to be related to alloimmunisation in thalassemia population. The role of human leucocyte antigens in thalassemia is trend topic. In this study, the aim was to evaluate the differences in HLA frequencies of beta thalassemia patients comparing with healthy controls. Methodology: The data were collected of 100 patients who were diagnosed with beta thalassemia and 100 healthy controls were included in the study. The low resolution HLA-A, -B, -DRB1, tissue group data were performed Istanbul University, Faculty of Medicine, Medical Biology Department HLA typing laboratory. All data were analyzed retrospectively and their HLA allele frequencies were analyzed by SPSS (v22) program. Results: We found an increased frequency of HLA-B*14 (8% versus 2%) and HLA-B*52 (17% versus 2%) compared to the control group (p=0.05, OR=4.26; p

The phase 2, open-label study (DIALOG) of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) met its coprimary end points, showing sustained nilotinib efficacy in patients with newly diagnosed (ND) or imatinib/dasatinib resistant/intolerant (R/I) CML. This update assessed growth and safety profiles in patients who had completed ≥48, 28-day treatment cycles of nilotinib 230 mg/m2 twice daily, or previously discontinued the study. Height was assessed regularly and reported using standard deviation scores (SDSs) based on World Health Organization growth charts. All data were summarized descriptively (cutoff, 6 March 2019). Overall, 33 patients in the R/I cohort and 25 patients in the ND cohort received nilotinib. Each cohort showed a negative slope in height SDS over the course of the study, indicating attenuated growth rates during nilotinib treatment: overall median change from baseline in height SDS after 48 cycles was −0.54 SDS (range, − 1.6 to 0.4) and −0.91 SDS (−1.4 to −0.1) in R/I and ND cohorts, respectively. Patients in the R/I cohort were shorter at baseline than those in the ND cohort, and remained so throughout the study. The most common all-cause adverse events were increased blood bilirubin (53.4%), headache (46.6%), pyrexia (37.9%), and increased alanine transferase (36.2%). Apart from the impact on growth, the safety profile of nilotinib was generally consistent with previous reports. This study was registered on www.clinicaltrials.gov at #NCT01844765.

Iron deposition in various organs can cause endocrine complications in patients with transfusion-dependent beta-thalassemia. The aim was to investigate the relationship between endocrine complications and pancreatic iron overload using magnetic resonance imaging (MRI). Forty patients with transfusion-dependent thalassemia (TDT) were enrolled in the study. The magnetic resonance imagings of the patients were performed using a 1.5 Tesla Philips MRI scanner. Two out of three patients had at least one clinical endocrine complication. The rate of iron deposition was 62.5% in liver, and 45% in pancreas tissue, and was 12.5% in heart tissue. Pancreatic T2* and hepatic T2* values were significantly positively correlated (p = 0.006). Pancreatic T2* and ferritin were significantly negatively correlated (p = 0.03). Cardiac T2* values were negatively correlated with fasting blood glucose (p = 0.03). Patients with short stature had significantly higher cardiac iron burden (22.3 vs. 36.6 T2*ms; p00.01) and patients with hypothyroidism had higher liver iron concentrations (9.9 vs. 6.4 LIC mg/g; p = 0.05). The ferritin level of 841 ng/mL, and liver iron concentration (LIC) value of 8.7 mg/g were detected as the threshold level for severe pancreatic iron burden (AUC 70%, p:0.04, AUC 80%, p = 0.002, respectively). Moreover, males were found to have decreased pancreas T2* values compared with the values in females (T2* 19.3 vs. 29.9, p = 0.05). Patients with higher ferritin levels over than 840 ng/mL should be closely monitored for pancreatic iron deposition, and patients with endocrine complications should be assessed in terms of cardiac iron burden.

Coagulation factor XIII (FXIII) is a fibrin-stabilizing factor with additional roles in wound healing and interactions between the decidua and fetus. Congenital FXIII deficiency is rare bleeding disorder. Inhibitor development against FXIII in inherited FXIII deficency is also uncommon, but may cause severe, life-threatening bleeding. FXIII is the last step in the coagulation cascade with normal coagulation paramaters (PT, aPTT), the detection of inhibitor to FXIII is quite difficult. The treatment of inhibitor-positive congenital FXIII deficiency is challenging due to the lack of a role of by-pass agents such as FVII. The best known ways of treatment in these cases are the use of high-dose FXIII concentrates and immunosuppression. Herein, we report the management of postoperative bleeding diathesis in a patient with FXIII deficiency who developed inhibitors, and to follow the clinical course of the disease with FXIII concentrate and immunosuppression.

WOS:000614296900001 PMID: 33538100 Adults with cancer are reported to have a higher risk for coronavirus disease (COVID-19) infection and more severe disease and mortality than the general population.1,2 Although children seem to be at a lower risk for COVID-19 than adults,3–5 data specifically addressing children with cancer are limited

Introduction: The lymphoid enhancer factor 1 (LEF1) is a DNA-binding transcription factor that functions in the Wnt signaling pathway. Increased LEF1 activity is associated with progression of several types of cancer including leukemia. Here, we investigated LEF1 isoform expression and genomic variations in acute lymphoblastic leukemia (ALL). Methods: LEF1 isoform expression was evaluated by quantitative real-time PCR in 87 newly diagnosed childhood ALL patients and controls. Moreover, Western blot analysis was performed for detection of LEF1 expression and the hotspot region of LEF1 was screened by deep sequencing. Results: The LEF1 mRNA expression of B cell ALL patients was higher than the controls (LEF1-total P = .011, LEF1-long P = .026). Moreover, B-ALL samples showing higher total LEF1 expression had significantly shorter relapse-free survival (P = .008) and overall survival (P = .011). Although full-length LEF1 expression was similar to the controls in T-ALL, 50% (n = 15) of the ALL patients had increased full-length LEF1 protein expression. Imbalance between short- and full-length LEF1 isoforms may lead to cell survival in ALL. Beside the LEF1 activation, LEF1 gene variations were rarely observed in our cohort. Conclusion: The results indicate that the Wnt pathway may have a pathogenic function in a group of ALL patients and high LEF1-total expression might be a marker for shorter relapse-free survival time in B cell ALL. WOS:000639287900001 33844466 Q3

Objective: Iron burden resulting from ineffective erythropoiesisand multiple transfusions can cause oxidative stress in patientswith ß-thalassemia. Here we aimed to examine the total antioxidant and oxidant capacity (TAC and TOC) along with its relationto endogenous antioxidants (bilirubin and uric acid) in patientswith ß-thalassemia.Material and Method: Forty-five patients with transfusion-dependent (TDT) (n=30) and non-transfusion-dependent (NTDT)(n=15) ß-thalassemia and 20 healthy subjects were enrolled inthe study. Analyses were done using Total Antioxidant Status(TAS) and Total Oxidant Status (TOS) kits.Results: The TAC level of the patients was significantly increasedcompared to healthy subjects (2.75 vs. 2.10 mmol/L; p=0.01).The total bilirubin level was significantly elevated in NTDT patients compared to TDT patients (5.7±3.3 vs.1.9±1.4; p

Congenital factor VIII (FVIII) deficiency causes hemophilia A due to different types of defects in the FVIII gene. Although the chromogenic measurement is the reference method and shows less variability, a one-stage assay is the most commonly preferred method for measurement of FVIII. In this study, we aimed to evaluate the analytical performances of chromogenic and one-stage assays, and compare the results prior to introduction of newly developed extended half-life recombinant FVIII products.Sixty-six blood samples from residual material of Istanbul Faculty of Medicine, Central Laboratory workflow comprised the study group. Samples were classified; plasma FVIII40 IU and FVIII40 IU. FVIII activities were measured using one-stage clotting and chromogenic assays on a CS-2500 analyzer. Analytical performances were determined through precision, linearity, carryover, and comparability studies.The within-run CV% of the one-stage assay on the CS-2500 had 1.6%, 2.6%, the between day CV% were 8.5%, 4.9 % for low and high controls, respectively. The within-run CV% of chromogenic method had 1.2% and 0.9%. Both methods demonstrated good linearity (R20.998), and the comparisons of both assays exhibited good agreement with minor bias for FVIII activity40 IU. However, a significant bias was obtained for FVIII activity40 IU.We obtained higher results using the one-stage assay compared with the chromogenic assay, and a significant bias was found for the samples lower than 40 IU. The discrepancy can explained by the presence of a weak agreement for samples lower than 10 IU due to the lower detection limit of the chromogenic assay used in this study (1.5%).

Anticoagulant treatment of pediatric central venous catheter–related venous thromboembolism (CVC-VTE) has not been specifically evaluated. In EINSTEIN-Jr, 500 children with any VTE received rivaroxaban or standard anticoagulants. A predefined analysis of the CVC-VTE cohort was performed. Children with CVC-VTE (age, birth to 17 years) were administered rivaroxaban or standard anticoagulants during the 1-month (children

The endocrinological complications are a great concern in transfusion-dependent β-thalassemia (β-thal) patients. The pituitary iron deposition is regarded as the main cause of hormonal changes in thalassemic patients. In this study, our aim was to explore the association between endocrinological complications and pituitary iron overload by magnetic resonance imaging (MRI). Fifty transfusion-dependent thalassemia (TDT) patients were recruited for the study. Pituitary MRIs of patients were taken using a 1.5 Tesla Philips MRI machine. There was at least one clinical endocrine complication in two of three patients. The iron accumulation was moderate in the liver (60.0%) and was mild in hypophysis (16.0%) and in heart (8.0%). The hypogonadism and diabetes mellitus (DM) were not seen with a significantly increased pituitary iron burden. The hypogonadism was related to cardiac iron deposition (

A review of the literature on COVID-19 pandemic in patients with thalassemias is presented. Globally, the prevalence of COVID-19 among β-thalassemia patients seems to be lower than in general population; associated co-morbidities aggravated the severity of COVID- 19, leading to a poorer prognosis, irrespective of age. A multicenter registry will enhance the understanding of COVID-19 in these patients and will lead to more evidence-based management recommendations. (www.actabiomedica.it)

Objectives: This study aims to investigate, retrospectively, the epidemiological and clinical characteristics, laboratory results, radiologic findings and outcomes of novel coronavirus disease-19 (COVID-19) in patients with transfusion dependent β thalassemia (β-thalassemia major-TM), non-transfusion dependent β thalassemia (β-thalassemia intermedia -TI) and sickle cell disease (SCD). Design, setting: A total of 17 Centers, from 10 countries, following 9,499 patients with hemoglobinopathies participated in the survey. Main outcome measures: Clinical, laboratory and radiologic findings and outcomes of patients with COVID-19 were collected from medical records and summarized. Results: A total of 13 patients, 7 with TM, 3 with TI and 3 with SCD, with confirmed COVID-19, were identified from 6 Centers from different countries. The overall mean age of patients was 33.7±12.3 years (range:13-66); 9/13 (69.2%) patients were females. The commonest symptoms in the 10 symptomatic patients were: fever (80%), cough (70%), headache (60%), fatigue (60%), gastrointestinal symptoms (diarrhea /vomiting/abdominal pain; 50%), tachypnea/dyspnea (40%), and sore throat (40%). Six patients had pneumonia (unilateral, bilateral or multiple opacity) and 4 needed oxygen therapy. An oxygen saturation ≤ 93% was documented in 3 patients at diagnosis. 6/10 patients had an exacerbation of anemia (2 with SCD, associated with back and chest pain in 1 patient), and 3 (

Immune thrombocytopenia (ITP) is a rare autoimmune disease and hematologic disorder characterized by reduced platelet counts that can result in significant symptoms, such as bleeding, bruising, epistaxis, or petechiae. The thrombopoietin receptor agonist eltrombopag (EPAG) is a second-line agent used to treat chronic ITP purpura in adults and children.The present retrospective study evaluated the efficacy, safety, and side effects of EPAG treatment in pediatric patients with acute refractory and chronic immune thrombocytopenia, particularly focusing on iron-deficiency anemia.The diagnosis was chronic ITP in 89 patients and acute refractory ITP in 16 patients. The mean age of patients was 9.5±4.5 years (minimum-maximum: 1.2-18 years) at the beginning of EPAG treatment. The overall response rate was 74.3% (n=78). The mean time for platelet count of ≥50x109/L was 11.6±8 weeks (range: 1-34 weeks). The treatment was stopped for 27 patients (25.7%) at an average of 6.8±9 months (range: 1-38 months). The reason for discontinuation was lack of response in 18 patients, nonadherence in 4 patients, and hepatotoxicity in 2 patients. Response to treatment continued for an average of 4 months after cessation of EPAG in 3 patients.Results of the current study imply that EPAG is an effective therapeutic option in pediatric patients with acute refractory and chronic ITP. However, patients must be closely monitored for response and side effects during treatment, and especially for iron deficiency.İmmün trombositopeni (İTP) nadir otoimmün bir hastalık olup, platelet sayısındaki azalmaya bağlı olarak peteşi, ekimoz, epistaksis gibi kanama semptomları ile karakterizedir. Trombopoietin reseptör agonisti eltrombopag (EPAG), yetişkinlerde ve çocuklarda kronik immün trombositopeni tedavisinde kullanılan ikinci basamak bir ajandır.Bu retrospektif çalışma, akut refrakter ve kronik immün trombositopenili çocuk hastalarda EPAG tedavisinin etkinliğini, güvenilirliğini, yan etkilerini özellikle de demir eksikliği anemisi gelişimini değerlendirmiştir.Hastalarımızın 89’u kronik İTP, 16’sı ise akut refrakter İTP tanısı ile takip edilmekte idi. Tedavi başlangıcı sırasında hastalarımızın yaş ortalamaları 9,5±4,5 yıl (1,2-18 yıl) idi. Toplam yanıt oranımız %74,3 (n=78) idi. Platelet sayısının ≥50x109/L olması için geçen ortalama süre 11,6±8 hafta (1-34 hafta) idi. Tedavi 27 hastamızda (%25,7) ortalama 6,8±9 ayda (1-38 ay) kesildi. Tedavi kesim nedenlerimiz; 18 hastada yanıtsızlık, 4 hastada tedaviye uyumsuzluk, 2 hastamızda ise hepatotoksisite idi. Üç hastada ise EPAG tedavisi kesilmesinden sonra yanıt ortalama 4 ay devam etti.Çalışmamız, EPAG tedavisinin akut refrakter ve kronik İTP’li pediyatrik hastalarda etkili bir terapötik seçenek olduğunu göstermektedir. Bununla birlikte, hastalar EPAG tedavisi sırasında yanıt ve yan etkiler ve özellikle demir eksikliği açısından yakından izlenmelidir.

Infections, drugs, malignancies, immunodeficiency, and autoimmunity may cause neutropenia. In primary autoimmune neutropenia, anti-neutrophil antibodies (ANeuA) bind to membrane antigens of neutrophils, which give rise to peripheral destruction of neutrophils. However, it is not always easy to detect these antibodies. This study aims to investigate the etiology of neutropenia, and at the same time to evaluate the immune mechanisms by ANeuA testing using granulocyte indirect immunofluorescence test. In our study, 310 neutropenic patients who were between 3 months and 18 years of age were evaluated. ANeuA screening tests were performed in 108 neutropenic patients (group 1), and these patients were divided into 2 subgroups as persistent neutropenia (group 1P, n=12) and recovered neutropenia (group 1R, n=96). Besides, a control group in the same age range was formed, consisting of 39 non-neutropenic children (group 2). ANeuA serum levels were also checked in these groups, and no statistically significant difference could be found between groups 1 and 2, or between groups 1P and 1R, regarding ANeuA levels. As a conclusion, our study was the first comprehensive research in Turkey investigating the large-scale etiology of neutropenia. Moreover, while ANeuA screening tests did not provide sufficient insight for immune neutropenia, we argue that it is not necessary for routine use and that further research in the etiology of neutropenia is required.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy caused by a variety of genetic abnormalities and epigenetic dysregulation. The incidence of AML is strongly related to age, with the highest incidence rates being in older adults. The loss of function mutations in BCOR and BCORL1 genes have been identified in AML. BCL6 corepressor (BCOR) and BCL6 corepressor like 1 (BCORL1) are important epigenetic regu-lators as a member of Polycomb repressive complex 1 (PRC1.1), involved in histone modification processes.We analyzed the BCOR and BCORL1 mRNA expression in 74 adult and 22 pediatric patients with AML by Real-Time quantitative PCR in this study.Our results indicated that both BCOR and BCORL1 mRNA expressions decrease with age (p = 0.009 and p = 0.008, respectively) and there is a positive correlation between BCOR and BCORL1 mRNA expression (p0.001). BCOR and BCORL1 mRNA expressions were not significantly different in both adult and pediatric patients with AML compared to control (p0.05).Our findings indicate that expression of BCOR and BCORL1 mRNA are down-regulated with age. The increase in AML incidence with age suggests that age-associated BCOR and BCORL1 down-regulation might potentially contribute to age-related epigenetic alterations and form a predisposing condition for the development of elderly AML.

Objective: PTEN/AKT pathway deregulations have been reported to be associated with treatment response in acute leukemia. This study examined pediatric T-cell acute lymphoblastic leukemia (T-ALL) samples for PTEN and AKT1 gene variations and evaluated the clinical findings. Materials and Methods: Fifty diagnostic bone marrow samples of childhood T-ALL cases were investigated for the hotspot regions of the PTEN and AKT1 genes by targeted next-generation sequencing. Results: A total of five PTEN variations were found in three of the 50 T-ALL cases (6%). Three of the PTEN variations were first reported in this study. Furthermore, one patient clearly had two different mutant clones for PTEN. Two intronic single-nucleotide variations were found in AKT1 and none of the patients carried pathogenic AKT1 variations. Conclusion: Targeted deep sequencing allowed us to detect both lowlevel variations and clonal diversity. Low-level PTEN/AKT1 variation frequency makes it harder to investigate the clinical associations of the variants. on the other hand, characterization of the PTEN/ AKT signaling members is important for improving case-specific therapeutic strategies. Amaç: PTEN/AKT yolak düzensizliklerinin akut lösemide tedavi yanıtı ile ilişkili olduğu bildirilmiştir. Çalışmanın kapsamı, pediatrik T-ALL hastalarının PTEN ve AKT1 genlerinin sıcak bölge varyasyonları için incelenmesi ve klinik bulgularla değerlendirilmesidir. Gereç ve Yöntemler: Elli pediatrik T-ALL olgusunun tanı zamanı kemik iliği örnekleri, PTEN ve AKT1 genlerinin sıcak bölgeleri için hedefe yönelik yeni nesil dizileme ile dizilenmiştir. Bulgular: Elli T-ALL olgusunun %6’sında PTEN varyasyonu saptanmıştır. Tespit edilen varyasyonlardan üçü ilk defa bu çalışmada gösterilmiştir. Ayrıca bir hastanın PTEN açısından iki farklı mutant klon taşıdığı belirlenmiştir. AKT1 geninde iki intronik tek nükleotid polimorfizmi tespit edilirken hiçbir olguda patojenik AKT1 varyasyonu saptanmamıştır. Sonuç: Derin dizileme, hem düşük düzeydeki varyasyonların hem de klonal çeşitliliğin belirlenmesine olanak sağlamıştır. T-ALL hastalarındaki düşük düzey PTEN/AKT1 varyasyon sıklığı, varyantların klinikle ilişkisinin ortaya çıkarılmasını zorlaştırmaktadır. Diğer yandan, PTEN/AKT sinyal yolağının karakterizasyonu hasta spesifik terapötik stratejilerin uygulanabilirliği için önemlidir.

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children /=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >/=1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0.51-6.27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development. 01 januari 2020

This study aimed at assessing renal functions in patients with transfusion-dependent thalassemia (TDT). Fifty patients and 30 controls were enrolled in this prospective study. Serum levels of electrolytes and albumin were measured by a spectrophotometer. Serum levels of cystatin-C and urinary levels of β2-microglobulin were measured by nephelometric method. Thirty-eight patients were receiving deferasirox and 8 were on deferiprone. Serum electrolytes and albumin levels of the patients were found to be within normal ranges. Urinary β2-microglobulin and serum cystatin-C levels were significantly higher in patients than controls. They did not significantly differ between the subgroup of patients on deferiprone and the control group, whereas they were found to be higher in patients using deferasirox compared to controls. Urinary β2-microglobulin levels significantly increased in patients who were receiving high-dose deferasirox compared to those who were receiving a daily dose of 15-20 mg/kg or controls. Subclinical renal injury may be present in TDT patients.Bu çalışmada transfüzyona bağımlı talasemi (TBT) hastalarında böbrek fonksiyonlarının değerlendirilmesi amaçlanmıştır. Prospektif çalışmaya, 50 TBT ve 30 kontrol grubu dahil edildi. Serum elektrolitleri ve albumin düzeyleri spektrofotometre ile ölçüldü. Serum sistatin-C ve idrar β2-mikroglobülin düzeyleri nefelometrik yöntemle ölçüldü. Otuz sekiz hasta deferasiroks, 8 hasta deferipron alıyordu. Hastaların serum elektrolitleri ve albumin düzeyleri normal sınırlardaydı. İdrar β2-mikroglobulin ve serum sistatin-C düzeyleri hasta grubunda kontrol grubundakilere göre anlamlı derecede yüksekti. Serum Cys-C ve idrar β2-mikroglobulin düzeyleri, deferipron kullananlar ve kontrol grubu arasında anlamlı farklılık göstermezken, deferasiroks kullananlarda kontrol grubuna göre daha yüksek bulundu. İdrar β2 mikroglobulin düzeyleri, yüksek doz deferasiroks alan hastalarda, 15-20 mg/kg/gün deferasiroks alanlara veya kontrol grubuna göre anlamlı şekilde artmıştı. Transfüzyona bağımlı talasemi hastalarında subklinik olarak renal hasar mevcut olabilir.

WOS: 000426572200002, PubMed ID: 28404539, Objective: The Turkish Society of Pediatric Hematology set up a National Hemoglobinopathy Registry to demonstrate the demographic and disease characteristics of patients and assess the efficacy of a hemoglobinopathy control program (HCP) over 10 years in Turkey. Materials and Methods: A total of 2046 patients from 27 thalassemia centers were registered, of which 1988 were eligible for analysis. This cohort mainly comprised patients with beta-thalassemia major (n = 1658, 83.4%) and intermedia (n = 215, 10.8%). Results: The majority of patients were from the coastal areas of Turkey. The high number of patients in Southeastern Anatolia was due to that area having the highest rates of consanguineous marriage and fertility. The most common 11 mutations represented 90% of all beta-thalassemia alleles and 47% of those were IVS1-110(G->A) mutations. The probability of undergoing splenectomy within the first 10 years of life was 20%, a rate unchanged since the 1980s. Iron chelators were administered as monotherapy regimens in 95% of patients and deferasirox was prescribed in 81.3% of those cases. Deferasirox administration was the highest (93.6%) in patients aged, Ege Children's Foundation; Novartis Pharmaceuticals CorporationNovartis, The authors thank Caglar Serdar, Aylin Gokduman, and Tolga Turgay of Plexus Information Technologies for their website support. The current study and the work presented here are from an Investigator Initiated Trial, which was sponsored by the Ege Children's Foundation and funded by Novartis Pharmaceuticals Corporation.

Minimizing side effects by using response-adopted therapy strategies plays an important role in the management of pediatric Hodgkin lymphoma (HL); however, the criteria for the definition of adequate or inadequate response are controversial. The aim of this study is to compare different methods of interpretation of 18F-FDG-PET/CT (PET) in the prediction of disease outcome in order to determine the optimum method in this regard. Baseline, interim and post-treatment PET scans of 72 children were interpreted according to revised International Harmonization Project criteria (IHP) and Deauville criteria. Cut-off values for changes in interim and post-treatment FDG uptake (ΔSUVmax) in the prediction of progression-free survival (PFS) were measured using ROC analysis. Quantitative and visual data were compared with each other in the prediction of PFS. Mean interim and post-treatment ΔSUVmax of the primary lesions were 77.4 ± 19.5 and 68.8 ± 30.4% and respective cut-off values were 82 and 73%. However, only post-treatment ΔSUVmax yielded statistically significant results in the prediction of 3-year PFS (p = 0.043). Interim ΔSUVmax was further analyzed according to the values reported in the literature (66 and 77%) yet statistically significant results were not reached (p = 0.604 and 0.431). For interim evaluation, IHP criteria was correlated to Deauville criteria (p = 0.002 and p = 0.001) and ΔSUVmax (p = 0.03), whereas for post-treatment evaluation, significant correlation with ΔSUVmax (p = 0.04) but marginally significant (p = 0.055 and p = 0.058) correlation with Deauville criteria were achieved. Overall, 1, 3 and 5-year PFS were 95.7 ± 0.2, 89.6 ± 0.4 and 80.8 ± 0.7%, respectively. All methods demonstrated comparable performance in the prediction of 3-year PFS; however, interim PET using Deauville criteria and post-treatment PET using IHP criteria were statistically significant. All methods demonstrated high negative-predictive value but substantially low positive-predictive value. Deauville criteria are superior to other methods in the prediction of pediatric HL outcome using interim PET data. On the other hand, quantitative evaluation and visual evaluation by IHP can be used reliably at the end of the treatment. In this regard, we report the optimal cut-off value of SUVmax reduction as 73%.

In beta-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by beta-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle-promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-X(L). The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.

Objective: Our aim was to determine the prevalence of maternal and neonatal vitamin B12 (vit-B12) and folate deficiencies, a new cutoff value of serum vit-B12 in newborns using vit-B12-related metabolites and also cutoff values of homocysteine (Hcy), propionyl (C3) carnitine, and methyl malonic acid (MMA) in newborns using a vit-B12 cutoff value of 200 pg/mL. Methods: Healthy pregnant women (without iron deficiency) and 98 healthy, term, singleton babies were included. Blood samples were obtained from women 0-8 h before birth and from cord blood during birth for hemogram and to measure serum vit-B12, folate, and Hcy levels. Maternal and cord blood serum vit-B12 levels were classified as low < 200 pg/mL, marginal 200-300 pg/mL, and normal >= 300 pg/mL. Neonatal urine MMA levels were analyzed in mothers with a vit-B12 concentration < 300 pg/mL. C3 carnitine levels of newborns were acquired from extended newborn screening. Receiver operating characteristics curve (ROC) analysis was used for serum vit-B12, urine MMA, C3 carnitine, and Hcy. Results: Of total, 98 pregnant women (28.6 +/- 5.5-year-old) and 98 newborn were included. Vit-B12 level was lower than 300 pg/mL in 93% of the pregnant women and 61% of cord blood samples. Folate deficiency was not found in either group. There was statistically significant negative correlation between baby C3 carnitine, cord blood folate (r = -0.265, p = .008) and cord blood vit-B12 (r = -0.220, p = .029). In backward stepwise linear regression analysis, maternal vit-B12 level exerted the most marked effect on cord blood vit-B12 level (adjusted R-2 = 0.457). In ROC analysis, the Hcy cutoff value was 4.77 mu mol/L (68.4% sensitivity, 58.3% specificity, p = .012) for the detection of vit-B12 deficiency. Conclusion: Vit-B12 deficiency remains an important health issue for pregnant women and newborns. Our study revealed a cutoff value for Hcy for the detection of nutritional vit-B12 deficiency that could be used in practice for newborns. Scientific Research Projects Coordination Unit of Istanbul UniversityIstanbul University [4107] This work was supported by Scientific Research Projects Coordination Unit of Istanbul University [Project no: 4107]. WOS:000474100800001 31204544 Q3

Chronic myeloid leukemia (CML) is rare in children and accounts for £15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome–positive (Ph1) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph1 CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph1 CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph1 CML-CP were enrolled, and 58 were treated (R/I, n 5 33; newly diagnosed, n 5 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph1 CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765. (Blood. 2019;134(23):2036-2045).

Genomic profiles of leukemia patients lead to characterization of variations that provide the molecular classification of risk groups, prediction of clinical outcome and therapeutic decisions. In this study, we examined the diagnostic (n = 77) and relapsed (n = 31) pediatric B-cell acute lymphoblastic leukemia (B-ALL) samples for the most common leukemia-associated gene variations CRLF2, JAK2, PAX5 and IL7R using deep sequencing and copy number alterations (CNAs) (CDKN2A/2B, PAX5, RB1, BTG1, ETV6, CSF2RA, IL3RA and CRLF2) by multiplex ligation proximity assay (MLPA), and evaluated for the clonal changes through relapse. Single nucleotide variations SNVs were detected in 19% of diagnostic 15.3% of relapse samples. The CNAs were detected in 55% of diagnosed patients; most common affected genes were CDKN2A/2B, PAX5, and CRLF2. Relapse samples did not accumulate a greater number of CNAs or SNVs than the cohort of diagnostic samples, but the clonal dynamics showed the accumulation/disappearance of specific gene variations explained the course of relapse. The CDKN2A/2B were most frequently altered in relapse samples and 32% of relapse samples carried at least one CNA. Moreover, CDKN2A/2B alterations and/or JAK2 variations were associated with decreased relapse-free survival. On the other hand, CRLF2 copy number alterations predicted a better survival rate in B-ALL. These findings contribute to the knowledge of CDKN2A/2B and CRLF2 alterations and their prognostic value in B-ALL. The integration of genomic data in clinical practice will enable better stratification of ALL patients and allow deeper understanding of the nature of relapse. Scientific Research Projects Coordination Unit of Istanbul UniversityIstanbul University [48096, TDP-2016-20520] This work supported by the Scientific Research Projects Coordination Unit of Istanbul University (Project no. 48096 and TDP-2016-20520) and the authors would like to thank the Interlaboratory Robustness of Next-Generation Sequencing Phase II study group members. Khusan Khodzhaev assisted in figures preperation. We highly appreciate the efforts of Monica Özkan, MSN, RN in language editing of this paper. WOS:000474694900008 31228652 Q3