Safety and efficacy of deferasirox in patients with transfusion-dependent thalassemia: A 4-year single-center experience.

This study was organized to determine the efficacy and safety of deferasirox (DFX) in reducing the SF of patients with transfusion-dependent thalassemia (TDT). This is a retrospective, descriptive study of 101 transfusion- dependent patients with thalassemia major who were followed for 48 months. Twenty-nine patients who used an alternative chelator either alone or combined, who were not compliant to the treatment, changed the drug due to adverse reactions, and had multiple transfusions and did not complete 4 years of DFX use were excluded. A total 72 out of 101 patients completed the study. SF decreases were noted for the 6-12 and >18-year age groups, from a median of 1532 ng/mL to 1190 ng/mL, and from 1386 ng/mL to 1165 ng/mL, respectively (p > 0.05). The proportion of patients with SF concentrations >2000 ng/mL is decreased (29% at baseline decreased to 15% at the end of the study) during the 48 months. The median SF of those who used <30 mg/kg/day (n = 38) increased from 767 ng/mL to 1006 ng/mL, whereas the >30 mg/kg/day (n = 34) group's SF concentrations decreased from a median of 1575 ng/mL to 1209 ng/mL (p = 0.029). The decrease of median SF values for Syrian patients was statistically significant (p = 0.043). Most common adverse events were gastric irritation symptoms (19.4%). The total DFX discontinuation ratio was calculated as 9.7%. Although dosages between 25-30 mg/kg/day are adequate to stabilize SF concentrations higher dosages are needed to achieve a statistically significant decrease.

Deferasirox in children with transfusion-dependent thalassemia or sickle cell anemia: A large cohort real-life experience from Turkey (REACH-THEM).

OBJECTIVES: To evaluate the long-term efficacy and safety of deferasirox therapy in a large observational cohort of children with transfusion-dependent thalassemia (TDT) and sickle cell anemia (SCA) in Turkey. METHODS: This was a multicenter, prospective cohort study including TDT and SCA patients aged 2-18 years with iron overload (≥100 mL/kg of pRBC or a serum ferritin [SF] level >1000 µg/L) receiving deferasirox. Patients were followed for up to 3 years according to standard practice. RESULTS: A total of 439 patients were evaluated (415 [94.5%] TDT, 143 [32.6%] between 2 and 6 years). Serum ferritin levels consistently and significantly decreased across 3 years of deferasirox therapy from a median of 1775.5 to 1250.5 µg/L (P < 0.001). Serum ferritin decreases were noted in TDT (1804.9 to 1241 µg/L), SCA (1655.5 to 1260 µg/L), and across age groups of 2-6 years (1971.5 to 1499 µg/L), 7-12 years (1688.5 to 1159.8 µg/L), and 13-18 years (1496.5 to 1107 µg/L). Serum ferritin decreases were also noted for all deferasirox dose groups but only significant in patients with doses ≥30 mg/kg/d (n = 120, -579.6 median reduction, P < 0.001). Only 9 (2%) patients had adverse events suspected to be related to deferasirox. Serum creatinine slightly increased but remained within the normal range. CONCLUSIONS: Deferasirox has long-term efficacy and safety in children with TDT and SCA, although higher doses (≥30 mg/kg/d) may be required to achieve iron balance.

Causes of Hypochromic Microcytic Anemia in Children and Evaluation of Laboratory Parameters in the Differentiation.

Most common causes of microcytic anemia in children are iron deficiency anemia (IDA) and thalassemia. Differentiation of these and detection of coexistence is essential for genetic counseling and to set a treatment plan. Aim is to characterize the frequency of IDA and thalassemia trait (TT) in children presenting with hypochromic, microcytic anemia and to define the significance of blood count parameters in differential diagnosis. Of the 200 enrolled, 107 were male (53.5%). In total 154 had IDA (77%), 27 had ß-TT (13.5%), and in 11 (5.5%) both conditions coexisted. Eight patients had α-thalassemia gene mutations, 3 of these also had IDA. RBC, MCV, Mentzer index, serum iron, TIBC, ferritin were significantly different between IDA and ß-TT patients (P<0.001); however, RDW was not different between the 2 groups (P>0.05). Sensitivity and specificity of Mentzer index for the detection of ß-TT were 100% and 69.4%, respectively. The positive and negative predictive values of Mentzer index in diagnosing ß-TT were 36.6% and 100%, respectively. Differential diagnosis of microcytic anemia is important in children, especially in regions where IDA and thalassemia are both prevalent. We found that 7% of children referred to our clinic for hypochromic, microcytic anemia had both TT and IDA. Our data showed that serum iron, ferritin, TIBC, MCV, and Mentzer index were all valuable markers in diagnosing IDA and were significantly different compared with ß-TT patients; RDW was not different between the 2 groups.

Adrenomedullin--A New Marker in Febrile Neutropenia: Comparison With CRP and Procalcitonin.

In this study, we aimed to determine serum adrenomedullin levels and compare them with levels of C-reactive protein (CRP) and procalcitonin (PCT). Cancer patients aged 0-18 years who experienced febrile neutropenia attacks were included in the study. Adrenomedullin, CRP, and PCT were analyzed at admission, day 3, and days 7-10 later. Fifty episodes of febrile neutropenia that developed in 37 patients were analyzed in this study. The mean age of the patients was 7.5 ± 4.7 (1-18) years. The patients had leukemia (73%), solid tumors (19%), and lymphoma (8%). The percentages of the patients in the clinically documented infection (CDI), fever of unknown origin (FUO), sepsis, and microbiological documented infection (MDI) categories were 34%, 34%, 20%, and 12%, respectively. During the study period, four patients were lost. In the MDI group, adrenomedullin levels on day 3 were significantly higher than those in the CDI and FUO groups. PCT levels were significantly higher in the sepsis group than those in the CDI group at admission, day 3, and days 7-10. In the sepsis group, PCT levels on days 7-10 days were significantly higher than those in the sepsis group. PCT values from the deceased patients on days 7-10 were significantly higher than those from patients who survived. CRP levels did not differ significantly among the febrile neutropenia groups. First, in our study, adrenomedullin was used as a biomarker in the febrile neutropenia episodes of children with cancer. Among adrenomedullin, CRP, and PCT, procalcitonin demonstrates the highest correlation with the severity of infection.

Assessment of cardiac parameters in evaluation of cardiac functions in patients with thalassemia major.

The aim of the study was to evaluate cardiac function and early cardiac dysfunction of patients followed as thalassemia major. In this study, the authors compared 100 patients, diagnosed as thalassemia major with mean age 11.84 ± 4.35, with 60 healthy control subjects at the same age between 2008 and 2011. Early diagnosis of iron overload that may occur after repeated transfusions is important in this patient group. To detect early iron accumulation, the authors compared ferritin with the echo findings, the 24-hour Holter, and cardiac magnetic resonance imaging (MRI) T2* values in the patients of same age and sex, treated with chelators, without heart failure, nonsplenectomized, and do not differ in the presence of hepatitis C. Ferritin levels, left ventricular systolic functions (ejection fraction [EF], shortening fraction [SF]), left ventricular measurements, left ventricular diastolic functions, T2* image on cardiac magnetic resonance, heart rate variables in 24 hours, and Holter rhythm were evaluated to show the early failure of cardiac functions. In this study the authors confirmed that iron-related cardiac toxicity damages electrical activity earlier than myocardial contractility. Left ventricular diastolic diameter (LVDd), left ventricular mass (LVM), and LV systolic diameter (LVDs) levels were significantly higher in the patient group with ectopia. Patients with ectopia are the ones in whom LVM and LVDd are increased. In thalassemia major patients with ectopia, LF/HF ratio was markedly increased, QTc dispersion was clearly found higher in patients with ectopia rather than nonectopic patients. The standard deviation all normal RR interval series (SDNN) was found clearly lower in thalassemia major group with ectopia than control group because it is assumed that increase in cardiac sympathetic neuronal activity is related to exposure to chronic diastolic and systolic failure.

Mucoepidermoid carcinoma of the parotid gland in childhood survivor of acute lymphoblastic leukemia with need of radiotherapy for treatment and review of the literature.

Diagnosis of secondary malignancies began with the increasing survival in childhood cancer. Children treated for acute lymphoblastic leukemia (ALL) have an increased risk for developing mucoepidermoid carcinoma (MEC) of the parotid gland. The latent period ranges from 5 to 16 years. A 2 6/12-year-old girl was treated for pro-B ALL. Treatment included multidrug chemotherapy, prophylactic intrathecal methotrexate, and cranial radiotherapy. MEC of the left parotid gland was diagnosed at the age of 8 years, 3 years after completing treatment. She was treated with multiple surgery and radiotherapy. The authors aimed to emphasize the need for concern about second cancers of the parotid gland in children treated for ALL.

The value of echocardiography versus cardiac troponin I levels in the early detection of anthracycline cardiotoxicity in childhood acute leukemia: prospective evaluation of a 7-year-long clinical follow-up.

The present study was designed to evaluate the significance of echocardiography versus cardiac troponin I levels in early detection of anthracycline dependent cardiotoxicity in acute lymphoblastic leukemia (ALL) patients. A total of 276 pediatric ALL patients were included in the study prospectively along 3 phases of data collection lasted from 2002 to 2009; including phase I (March 2002 to February 2003; n = 25; 53.3% females), phase II (September 2003 to April 2004; n = 35; 57.1% females), and phase III (January 2005 to June 2009; n = 216; 52.7% females) with respect to cumulative anthracycline doses applied. Anthracycline was administered in accordance with berlin-Franfurt-Munich (BFM)-2000 protocol in doses of 30 to 350 mg/m(2) (in the first phase) and 30 to 240 mg/m(2) (in the following phases). Evaluation of cardiotoxicity was performed via echocardiography and measurement of cardiac troponin I levels. Patients in each phase were homogenous in terms of gender and age. Diastolic dysfunction determined via reduction E/A ratio below the cutoff value was demonstrated to deteriorate earlier than systolic functions and alteration in cardiac enzymes. Being similar between dose groups, cTnI levels were shown to rise in the presence of congestive heart failure. In conclusion, anthracycline cardiotoxicity appears to be detected in an earlier stage by using diastolic parameters compared to systolic parameters and cardiac enzymes.

Factor 8 Gene Mutation Spectrum of 270 Patients with Hemophilia A: Identification of 36 Novel Mutations

Objective: Hemophilia A (HA) is the most severe X-linked inherited bleeding disorder caused by hemizygous mutations in the factor 8 (F8) gene. The aim of this study is to determine the mutation spectrum of the F8 gene in a large HA cohort from Turkey, and then to establish a phenotype-genotype correlation. Materials and Methods: All HA cases (270 patients) analyzed molecularly in the Ege University Pediatric Genetics Molecular Laboratory between March 2017 and March 2018 were included in this study. To identify intron 22 inversion (Inv22), intron 1 inversion (Inv1), small deletion/insertions, and point mutations, molecular analyses of F8 were performed using a sequential application of molecular techniques. Results: The mutation detection success rate was 95.2%. Positive Inv22 was found in 106 patients (39.3%), Inv1 was found in 4 patients (1.5%), and 106 different disease-causing sequence variants were identified in 137 patients (50.6%). In 10 patients (3.7%), amplification failures involving one or more exonic regions, considered to be large intragenic deletions, were identified. Of 106 different F8 mutations, 36 were novel. The relationship between F8 genotype and inhibitor development was considered significant. Conclusion: A high mutation detection rate was achieved via the broad molecular techniques applied in this study, including 36 novel mutations. With regard to mutation types, mutation distribution and their impact on clinical severity and inhibitor development were found to be similar to those previously reported in other hemophilia population studies.

A novel mutation in the SLC19A2 gene in a Turkish male with thiamine-responsive megaloblastic anemia syndrome.

Odaman-Al I, Gezdirici A, Yildiz M, Ersoy G, Aydogan G, Salcioglu Z, Tahtakesen TN, Önal H, Küçükemre-Aydin B. A novel mutation in the SLC19A2 gene in a Turkish male with thiamine-responsive megaloblastic anemia syndrome. Turk J Pediatr 2019; 61: 257-260. Thiamine-responsive megaloblastic anemia (TRMA) is a very rare syndrome characterized by the triad of early onset megaloblastic anemia, sensorineural deafness and diabetes mellitus. Here we report, a 5-year-old boy who presented with transfusion dependent anemia and diabetes mellitus and was diagnosed with TRMA. Besides reporting a novel mutation of the causative gene SLC19A2, we wanted to emphasize this syndrome in the aspect of coexistence of insulin dependent diabetes, transfusion dependent anemia and thrombocytopenia.

A novel mutation in the SLC19A2 gene in a Turkish male with thiamine-responsive megaloblastic anemia syndrome.

Odaman-Al I, Gezdirici A, Yildiz M, Ersoy G, Aydogan G, Salcioglu Z, Tahtakesen TN, Önal H, Küçükemre-Aydin B. A novel mutation in the SLC19A2 gene in a Turkish male with thiamine-responsive megaloblastic anemia syndrome. Turk J Pediatr 2019; 61: 257-260. Thiamine-responsive megaloblastic anemia (TRMA) is a very rare syndrome characterized by the triad of early onset megaloblastic anemia, sensorineural deafness and diabetes mellitus. Here we report, a 5-year-old boy who presented with transfusion dependent anemia and diabetes mellitus and was diagnosed with TRMA. Besides reporting a novel mutation of the causative gene SLC19A2, we wanted to emphasize this syndrome in the aspect of coexistence of insulin dependent diabetes, transfusion dependent anemia and thrombocytopenia.

Clinical management, psychosocial characteristics, and quality of life in patients with homozygous familial hypercholesterolemia undergoing LDL-apheresis in Turkey: Results of a nationwide survey (A-HIT1 registry).

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening inherited disease leading to early-onset atherosclerosis and associated morbidity. Because of its rarity, longitudinal data on the management of HoFH in the real world are lacking, particularly on the impact the condition has on quality of life (QoL), including the impact of the extracorporeal lipid removal procedure apheresis (LA). METHODS: The A-HIT1 study included 88 patients with HoFH aged ≥12 years receiving regular LA in 19 centers in Turkey. Demographic and disease characteristics data were obtained. For patients aged ≥18 years, additional data on psychosocial status were obtained via the SF-36 score, the Hospital Anxiety and Depression Scale, and a HoFH-specific questionnaire. RESULTS: There was no standardized approach to therapy between centers. Mean (±SD) frequency of LA sessions was every 19.9 (±14) days, with only 11.6% receiving LA weekly, and 85% of patients were not willing to increase LA frequency. The most common concerns of patients were disease prognosis (31%), and physical, aesthetic, and psychological problems (27.5%, 15.9%, and 11.6%, respectively). Lower age at diagnosis was associated with better QoL, lower anxiety, improved functioning, and greater emotional well-being compared to later diagnosis. CONCLUSIONS: These findings demonstrate that adult patients with HoFH undergoing LA, experience significant impairment of QoL with an increased risk of depression. From patients' point of view, LA is time-consuming, uncomfortable, and difficult to cope with. The speed of diagnosis and referral has a considerable impact on patient well-being.

Congenital Factor Deficiencies in Children: A Report of a Single-Center Experience.

Congenital factor deficiencies (CFDs) refer to inherited deficiency of coagulation factors in the blood. A total of 481 patients with CFDs, who were diagnosed and followed at our Pediatric Hematology and Oncology Clinic between 1990 and 2015, were retrospectively evaluated. Of the 481 cases, 134 (27.8%) were hemophilia A, 38 (7.9%) were hemophilia B, 57 (11.8%) were von Willebrand disease (vWD), and 252 (52.3%) were rare bleeding disorders (RBDs). The median age of the patients at the time of diagnosis and at the time of the study was 4.1 years (range: 2 months to 20.4 years) and 13.4 years (range: 7 months to 31.3 years), respectively. The median duration of the follow-up time was 6.8 years (range: 2.5 months to 24.8 years). One hundred nineteen (47.2%) of 252 patients with RBDs were asymptomatic, 49 (41.1%) of whom diagnosed by family histories, 65 (54.6%) through preoperative laboratory studies, and 5 (4.2%) after prolonged bleeding during surgeries. Consanguinity rate for the RBDs was 47.2%. Prophylactic treatment was initiated in 80 patients, 58 of whom were hemophilia A, 7 were hemophilia B, 13 were RBDs, and 2 were vWD. Significant advances have been achieved during the past 2 decades in the treatment of patients with CFDs, particularly in patients with hemophilias. The rarity and clinical heterogeneity of RBDs lead to significant diagnostic challenges and improper management. In this regard, multinational collaborative efforts are needed with the hope that can improve the management of patients with RBDs.

A nation-wide survey of patients with homozygous familial hypercholesterolemia phenotype undergoing LDL-apheresis in Turkey (A-HIT 1 registry).

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is a genetic condition characterized by lethally high levels of low-density lipoprotein cholesterol (LDL-C) from birth, and requires rapid and aggressive intervention to prevent death due to coronary heart disease and/or atherosclerosis. Where available, lipoprotein apheresis (LA) is the mainstay of treatment to promote survival. METHODS: A-HIT1 registry was conducted with the aim of providing insight to the real-life management of HoFH patients undergoing LA in Turkey, where LA procedures are fully reimbursed and widely available. Participating centers provided patient information, including family history, treatment patterns and relevant laboratory values, via a standard questionnaire. RESULTS: The study evaluated 88 patients (mean age: 27 ±â€¯11 years, 41 women) in 19 centers. All patients were receiving regular LA with a clinical diagnosis of HoFH. Mean age at first symptom disease was 10 ±â€¯10 years, and at diagnosis it was 12 ±â€¯11 years; 74.7% were diagnosed before age 15 years; and only 31% before the age of 7. First referral of most patients was to pediatricians. Early onset coronary artery disease was present in 57.8% of patients. Mean age at first LA was 21 ±â€¯12 years. Only 11 (12.5%) patients were undergoing LA weekly. Mean frequency of apheresis sessions was 19 ±â€¯13 days. For the last four LA sessions, LDL-C levels reached the target in only in 5.7% of patients. CONCLUSIONS: Diagnosis of HoFH is delayed, and LDL targets are not reached. LA frequencies are not optimal. Urgent attention is needed to support the survival of patients with HoFH.

What have we learned from Turkish familial hypercholesterolemia registries (A-HIT1 and A-HIT2)?

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common genetic disease of high-level cholesterol leading to premature atherosclerosis. One of the key aspects to overcome FH burden is the generation of large-scale reliable data in terms of registries. This manuscript underlines the important results of nation-wide Turkish FH registries (A-HIT1 and A-HIT2). METHODS: A-HIT1 is a survey of homozygous FH patients undergoing low density lipoprotein (LDL) apheresis (LA). A-HIT2 is a registry of adult FH patients (homozygous and heterozygous) admitted to outpatient clinics. Both registries used clinical diagnosis of FH. RESULTS: A-HIT1 evaluated 88 patients (27 ±â€¯11 years, 41 women) in 19 centers. All patients were receiving regular LA. There was a 7.37 ±â€¯7.1-year delay between diagnosis and initiation of LA. LDL-cholesterol levels reached the target only in 5 cases. Mean frequency of apheresis sessions was 19 ±â€¯13 days. None of the centers had a standardized approach for LA. Mean frequency of apheresis sessions was every 19 ±â€¯13 (7-90) days. Only 2 centers were aware of the target LDL levels. A-HIT2 enrolled 1071 FH patients (53 ±â€¯8 years, 606 women) from 31 outpatients clinics specialized in cardiology (27), internal medicine (1), and endocrinology (3); 96.4% were heterozygous. 459 patients were on statin treatment. LDL targets were attained in 23 patients (2.1% of the whole population, 5% receiving statin) on treatment. However, 66% of statin-receiving patients were on intense doses of statins. Awareness of FH was 9.5% in the whole patient population. CONCLUSIONS: The first nationwide FH registries revealed that FH is still undertreated even in specialized centers in Turkey. Additional effective treatment regiments are urgently needed.

How do we encounter rare factor deficiencies in children? Single-centre results from Turkey.

BACKGROUND: Rare factor deficiencies (RFDs) are autosomal recessively inherited coagulation factor deficiencies encountered at a frequency of between one in 500, 000 and one in two million. MATERIALS AND METHODS: One hundred and ninety-two patients, diagnosed as having RFD, followed and treated in our clinic between 1990 and 2013 were retrospectively evaluated in this study. RESULTS: From the 192 patients, 142 had FVII, 15 had FX, 14 had FXI, 10 had fibrinogen, six had FV, two had FXIII, two had FV + FVIII and one had FII deficiency. One hundred and thirty of the cases were boys and 62 were girls. The age range was 2 weeks to 24 years and the ages at the admission were between 2 weeks and 16 years. The rate of consanguinity was 49.4%. Eighty-eight of our patients were asymptomatic (45.8%) and 104 were symptomatic (54.2%). Asymptomatic patients were diagnosed by family histories (39.8%), preoperative laboratory studies (54.6%) and operational bleeding (5.6%). Sixty-eight of our symptomatic patients displayed grade II (65.4%) and 36 displayed grade III bleeding symptoms (34.6%). First bleeding regions were skin (33%), nose (28%), central nervous system (CNS) (15.5%), oral cavity (10.5%), soft tissue (6%), joint (3%), urinary system (2%) and gastrointestinal system (GIS) (2%), respectively. The bleeding prevalence rates of our symptomatic patients are listed as epistaxis 62.5%, skin bleedings 53%, oral cavity bleeding 28.8%, haematomas 18.3%, CNS bleedings 17.3%, haemarthrosis 14.4%, GIS bleedings 3.8%, menorrhagia 2.9%, haematuria 1.9%, bleeding because of operations 1.9% and iliopsoas bleedings 1.9%. CNS bleedings (41%) take the first place among the serious bleedings of our cases, followed by haemarthrosis (36.4%), GIS bleedings (18.1%) and iliopsoas bleedings (4.5%). Prophylaxy was applied to nine patients (five patients with FVII, two patients with fibrinogen and one each with FV and FX deficiency). CONCLUSIONS: The characteristics of clinical presentations, first bleeding attacks, bleeding prevalence and severe bleedings as well as prophylactic approaches are discussed in this article.

Successful treatment of multiresistant Achromobacter xylosoxidans bacteremia in a child with acute myeloid leukemia.

Achromobacter xylosoxidans is an aerobic gram-negative bacillus and important cause of bacteremia in immunocompromised patients. We describe a leukemia pediatric patient with severe neutropenia who developed bacteremia with A xylosoxidans resistant to multiple antibiotics, and treated the patient with tigecycline and piperacillin-tazobactam in addition to supportive medications.

Real-Time PCR analysis of af4 and dek genes expression in acute promyelocytic leukemia t (15;17) patients.

Among several newly identified oncogenes, dek and af4 are attractive targets for researchers interested with leukemia. In this study quantitative Real-Time RT-PCR technique was used to define alterations in expression of dek and af4 genes associated with acute promyelocytic leukaemia (APL) t (15; 17). RNA samples obtained from bone marrow aspirates of fourteen APL patients, cDNA portions were labelled with Syber Green 1 dye and LightCycler analysis have been performed. Expression changes in patients were found not significant in comparison to healthy donors for af4 (P = 0.192) and dek (P = 0.0895). We suggest that af4 gene may have a role in leukomogenesis restricted to lymphoblastic lineage; also further studies must carry on with a larger series of patients in order to understand the relationship between the dek gene and APL. Our study was the first attempt for analysing dek and af4 genes in APL t (15; 17) patients by quantitative Real-Time RT-PCR. This rapid and sensitive method could be used to screen these genes in different types of leukaemia.