Pyruvate kinase deficiency in 29 Turkish patients with two novel intronic variants.

Pyruvate kinase (PK) is a key enzyme of anaerobic glycolysis. The genetic heterogeneity of PK deficiency (PKD) is high, and over 400 unique variants have been identified. Twenty-nine patients who had been diagnosed as PKD genetically in seven distinct paediatric haematology departments were evaluated. Fifteen of 23 patients (65.2%) had low PK levels. The PK:hexokinase ratio had 100% sensitivity for PKD diagnosis, superior to PK enzyme assay. Two novel intronic variants (c.695-1G>A and c.694+43C>T) have been described. PKD should be suspected in patients with chronic non-spherocytic haemolytic anaemia, even if enzyme levels are falsely normal. Total PKLR gene sequencing is necessary for the characterization of patients with PKD and for genetic counselling.

Prognosis of Second Primary Malignancies in Pediatric Acute Lymphoblastic Leukemia Survivors: A Multicenter Study by the Turkish Pediatric Hematology Society.

The improved survival rates of childhood cancers raise the long-term risk of second primary malignancy (SPM) in childhood and adolescent cancer survivors. The intensity of the treatment protocol used, the use of some groups of chemotherapeutics, and radiotherapy were found to be risk factors for the development of second primary malignancies (SPMs). Forty-one patients who developed acute myelocytic leukemia or any solid organ cancer within 25 years of follow-up, after completion of pediatric acute lymphoblastic leukemia (ALL) treatment, were included in the study. The mean duration of initial ALL diagnosis to SPM was 9.3 ± 6.1 years. The 3 most common SPMs were acute myelocytic leukemia, glial tumors, and thyroid cancer. Thirteen (81%) of 16 patients exposed to cranial irradiation had cancer related to the radiation field. In total 13/41 (32%) patients died, and the 5-year overall survival rate was 70 ± 8%. Patients older than 5 years old at ALL diagnosis had significantly worse overall survival than cases younger than 5 years old. In conclusion, children and adolescents who survive ALL have an increased risk of developing SPM compared with healthy populations, and physicians following these patients should screen for SPMs at regular intervals.

COVID-19 disease in children and adolescents following allogeneic hematopoietic stem cell transplantation: A report from the Turkish pediatric bone marrow transplantation study group.

BACKGROUND: Data on the risk factors and outcomes for pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited. OBJECTIVES: The study aimed to analyze the clinical signs, risk factors, and outcomes for ICU admission and mortality in a large pediatric cohort who underwent allogeneic HSCT prior to COVID-19 infection. METHOD: In this nationwide study, we retrospectively reviewed the data of 184 pediatric HSCT recipients who had COVID-19 between March 2020 and August 2022. RESULTS: The median time from HSCT to COVID-19 infection was 209.0 days (IQR, 111.7-340.8; range, 0-3845 days). The most common clinical manifestation was fever (58.7%). While most patients (78.8%) had asymptomatic/mild disease, the disease severity was moderate in 9.2% and severe and critical in 4.4% and 7.6%, respectively. The overall mortality was 10.9% (n: 20). Deaths were attributable to COVID-19 in nine (4.9%) patients. Multivariate analysis revealed that lower respiratory tract disease (LRTD) (OR, 23.20, p: .001) and lymphopenia at diagnosis (OR, 5.21, p: .006) were risk factors for ICU admission and that HSCT from a mismatched donor (OR, 54.04, p: .028), multisystem inflammatory syndrome in children (MIS-C) (OR, 31.07, p: .003), and LRTD (OR, 10.11, p: .035) were associated with a higher risk for COVID-19-related mortality. CONCLUSION: While COVID-19 is mostly asymptomatic or mild in pediatric transplant recipients, it can cause ICU admission in those with LRTD or lymphopenia at diagnosis and may be more fatal in those who are transplanted from a mismatched donor and those who develop MIS-C or LRTD.

Incidence and Management of Thromboembolism in Patients with Acute Leukemia.

Thromboembolic events (TE) in childhood are relatively rare but, serious complications of acute leukemia. The aim was to define the incidence and risk factors of thrombosis in children with leukemias. The electronic files of pediatric denovo/relapsed acute leukemia patients aged below 18 years, treated between 2011 and 2021 were retrospectively evaluated for thrombotic attacks. Thirty out of 469 patients developed 35 thrombotic events. The median age at the time of the TE was 11.8 (2-17.6) years, and the median time from diagnosis to TE was 9 (0-58) months. The frequency of TE was found at 7.4% (n = 35/469). When catheter related (n = 13) events, superficial venous events (n = 10), and arterial central nervous system thrombosis (n = 1) were excluded, the frequency of TE was decreased to 2.3% (n = 11/469). Children older than 10 years old (13.8%; n = 21/152) had significantly higher thromboembolic events than the others (4.4%; n = 14/317) (p = 0.03). The majority of attacks were symptomatic 66% (n = 23/35). The most common complaints were local pain, swelling, and redness 52% (n = 12/23). The majority of attacks in patients with relapsed (75%; 6/8) and newly diagnosed acute lymphoblastic leukemia (40%; 10/25%) developed during the induction phase. Thrombosis recurred in 13.3% (n = 4/30) of cases more than once. Thrombotic attacks were successfully treated with low molecular weight heparin 60% (n = 21/35), and recombinant tissue plasminogen activator 17% (n = 6/35). None of the children were lost due to thrombosis. Thrombosis is an important complication during acute leukemia treatment. Successful results are obtained with early diagnosis and treatment attempts by creating awareness.

Central nervous system thrombosis in pediatric acute lymphoblastic leukemia in Turkey: A multicenter study.

BACKGROUND: In patients with acute lymphoblastic leukemia (ALL), the risk of thromboembolism increases due to hemostatic changes secondary to the primary disease and due to treatment-related factors. In this multicenter study, we aimed to research the frequency of central nervous system (CNS) thrombosis occurring during treatment, hereditary and acquired risk factors, clinical and laboratory features of patients with thrombosis, treatment approaches, and thrombosis-related mortality and morbidity rates in pediatric ALL patients. PROCEDURE: Pediatric patients who developed CNS thrombosis during ALL treatment from 2010 to 2021 were analyzed retrospectively in 25 different Pediatric Hematology Oncology centers in Türkiye. The demographic characteristics of the patients, symptoms associated with thrombosis, the stage of the leukemia treatment during thrombosis, the anticoagulant therapy applied for thrombosis, and the final status of the patients recorded through electronic medical records were determined. RESULTS: Data from 70 patients with CNS thrombosis during treatment, out of 3968 pediatric patients with ALL, were reviewed. The incidence of CNS thrombosis was 1.8% (venous: 1.5 %; arterial: 0.03%). Among patients with CNS thrombosis, 47 had the event in the first 2 months. Low molecular weight heparin (LMWH) was the most commonly used treatment with a median of 6 months (min-max: 3-28 months). No treatment-related complications occurred. Chronic thrombosis findings occurred in four patients (6%). In five (7%) patients who developed cerebral vein thrombosis, neurological sequelae (epilepsy and neurological deficit) remained. One patient died related to thrombosis, and the mortality rate was 1.4%. CONCLUSION: Cerebral venous thrombosis and, less frequently, cerebral arterial thrombosis may develop in patients with ALL. The incidence of CNS thrombosis is higher during induction therapy than during other courses of treatment. Therefore, patients receiving induction therapy should be monitored carefully for clinical findings suggestive of CNS thrombosis.

Successful Treatment of Central Nervous System Involvement in Posttransplant EBV-related Lymphoproliferative Disease With Intrathecal Rituximab Therapy.

The posttransplant lymphoproliferative disease is a severe cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Central Nervous System involvement in EBV-related PTLD is rare, and there is no standard treatment recommendation. We present our patient and discuss other previously reported cases of EBV-associated PTLD with CNS involvement.

The Evaluation of Central Venous Catheter-related Complications in Pediatric Acute Leukemia Patients: Single Center Experience.

Central venous catheters (CVCs) are important for maintenance of childhood leukemia treatment but CVCs may develop complications. The aim of this study was to retrospectively evaluate the CVC-related complication rate, complication types, and outcome in children with acute leukemia. Complications developing in 310 CVCs (ports n=250, Hickman catheters n=60) inserted in 262 patients were evaluated. A total of 225,296 catheter days were screened. Median (range) CVC in-dwelling time was 661.5 (1 to 2636) days. In total, 157 complications developed of which 91 (58%) were infectious complications, 35 (22.3%) were vascular, 19 (12.1%) were surgical, and 12 (7.6%) were mechanical. Hickman catheters had a higher complication rate and were more prone to mechanical complications ( P <0.01) but there was no difference for other complications. A lower absolute neutrophil count at insertion was observed in children with infectious complications ( P <0.01). Seventy-eight of 136 catheters (57.3%) had to be removed prematurely. The overall complication rate was 0.65 per 1000 catheter days. In multivariate analysis, relapse leukemia, Hickman catheter and low absolute neutrophil count increased complication risk by 4.00, 1.97, and 1.92 times, respectively. Five (1.9%) deaths occurred because of catheter complications. Safe use of CVCs can be improved by early detection of complications and an experienced catheter care team.

Central Nervous System Fungal Infections in Children With Leukemia and Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines. MATERIALS AND METHODS: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 ). RESULTS: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae. CONCLUSION: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes.

Assessment of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Multicenter Study From Turkey.

Assestment of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) is of utmost importance both for risk classification and tailoring of the therapy. The data of pediatric ALL patients that received treatment with Berlin-Frankfurt-Münster (BFM) protocols were retrospectively collected from 5 university hospitals in Turkey. Of the 1388 patients enrolled in the study 390 were treated according to MRD-based protocols. MRD assestment was with real time quantitative polymerase chain reaction (qPCR) in 283 patients and with multiparametric flow cytometry (MFC)-MRD in 107 patients. MRD monitoring had upstaged a total of 8 patients (2%) from intermediate risk group to high-risk group. Univariate analysis revealed age 10 years or above, prednisone poor response, PCR-MRD ≥10-3 on day 33 and on day 78 as poor prognostic factors affecting event-free survival (EFS). Detection of >10% blasts on day 15 with MFC (MFC-high-risk group) was not shown to affect EFS and/or overall survival (log-rank P=0.339). Multiple logistic regression analysis revealed PCR-MRD ≥10-3 on day 78 as the only poor prognostic factor affecting EFS (odds ratio: 8.03; 95% confidence interval: 2.5-25; P=0.000). It is very important to establish the infrastructure and ensure necessary standardization for both MRD methods for optimal management of children with ALL.

Hepatitis-Associated Aplastic Anemia: Etiology, Clinical Characteristics and Outcome.

Hepatitis-associated aplastic anemia (HAA) is a form of acquired aplastic anemia (AA) in which bone marrow failure develops after an acute attack of hepatitis. Bone marrow failure leading to AA is generally severe in cases of HAA and fatal if left untreated. This retrospective multicenter study investigated clinical and laboratory characteristics, possible causes, treatment, and outcome of HAA in children. Twenty patients from 8 centers were included in the study. Aspartate aminotransferase and alanine aminotransferase were <3 to 5×upper limit of normal (ULN) in 2 patients, <5 to 10×ULN in 2 patients, and >10×ULN in 16 patients. Acute liver failure developed in 5 (29%) patients. Pancytopenia was simultaneously present in 6 of 20 (30%) patients. Eleven of the 20 patients (55%) were alive, in remission and transfusion free. Those who were alive either had undergone hematopoietic stem cell transplantation and/or immunosuppressive treatment, except 1 patient who had received no treatment. Patients with the diagnosis of acute hepatitis should be evaluated and followed up carefully for presence of cytopenia, so that definitive treatment of AA can be initiated in a timely and appropriate manner when needed.

Invasive Fungal Infections in Children with Leukemia: Clinical Features and Prognosis

Objective: The incidence of invasive fungal infections (IFIs) has increased due to intensive chemotherapy in childhood leukemia. The aim of this study was to evaluate the incidence, risk factors, causative pathogens, and impact on survival of IFIs among pediatric leukemia patients. Materials and Methods: The hospital records of 307 children with acute lymphoblastic leukemia (ALL, n=238), acute myeloid leukemia (AML, n=51), and relapsed leukemia (n=18) between January 2010 and December 2015 were retrospectively evaluated. Results: A total of 1213 febrile neutropenia episodes were recorded and 127 (10.4%) of them were related to an IFI. Of 307 children, 121 (39.4%) developed IFIs. The mean age was significantly older in the IFI group compared to children without IFIs (p<0.001). IFIs were defined as possible, probable, and proven in 73.2%, 11.9%, and 14.9% of the attacks, respectively. Invasive aspergillosis (81.9%) was the most frequent infection, followed by invasive candidiasis (13.4%) and rare fungal diseases (4.8%). The majority of IFI attacks in both ALL and AML occurred during the induction phase. In total, the death rate was 24% and the IFI-related mortality rate was 18%. The mortality rate among children with IFIs was found to be significantly higher than that of children without IFIs (p<0.001). Overall and event-free survival rates at 5 years were also found to be significantly lower in the IFI group (p<0.001). Relapse (odds ratio: 8.49) was the most effective risk factor for mortality, followed by developing an IFI episode (odds ratio: 3.2) and AML (odds ratio: 2.33) according to multivariate regression analysis. Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode

Thrombolysis with Systemic Recombinant Tissue Plasminogen Activator in Children: A Multicenter Retrospective Study

Objective: This study aimed to evaluate systemic thrombolysis experiences with recombinant tissue plasminogen activator (rtPA). Materials and Methods: Retrospective data were collected from 13 Turkish pediatric hematology centers. The dose and duration of rtPA treatment, concomitant anticoagulant treatment, complete clot resolution (CCR), partial clot resolution (PCR), and bleeding complications were evaluated. Low-dose (LD) rtPA treatment was defined as 0.01-0.06 mg/kg/h and high-dose (HD) rtPA as 0.1-0.5 mg/kg/h. Results: Between 2005 and 2019, 55 thrombotic episodes of 54 pediatric patients with a median age of 5 years (range: 1 day to 17.75 years) were evaluated. These patients had intracardiac thrombosis (n=16), deep vein thrombosis (DVT) (n=15), non-stroke arterial thrombosis (n=14), pulmonary thromboembolism (PE) (n=6), and stroke (n=4). The duration from thrombus detection to rtPA initiation was a median of 12 h (range: 2-504 h) and it was significantly longer in cases of DVT and PE compared to stroke, non-stroke arterial thrombosis, and intracardiac thrombosis (p=0.024). In 63.6% of the episodes, heparin was initiated before rtPA treatment. LD and HD rtPA were administered in 22 and 33 of the episodes, respectively. Concomitant anticoagulation was used in 90% and 36% of the episodes with LD and HD rtPA, respectively (p=0.0001). Median total duration of LD and HD rtPA infusions was 30 h (range: 2-120 h) and 18 h (2-120 h), respectively (p=0.044). Non-fatal major and minor bleeding rates were 12.5% and 16.7% for LD and 3.2% and 25.8% for HD rtPA, respectively. At the end of the rtPA infusions, CCR and PCR were achieved in 32.7% and 49.0% of the episodes, respectively. The most successful site for thrombolysis was intracardiac thrombosis. HD versus LD rtPA administration was not correlated with CCR/PCR or bleeding (p>0.05). Conclusion: Systemic thrombolytic therapy may save lives and organs effectively if it is used at the right indications and the right times in children with high-risk thrombosis by experienced hematologists with close monitoring of recanalization and bleeding.

Different Kinetics and Risk Factors for Isolated Extramedullary Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Leukemia.

Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most frequent cause of post-transplantation mortality. Isolated extramedullary (EM) relapse (iEMR) after HSCT is relatively rare and not well characterized, particularly in pediatric patients. We retrospectively analyzed 1527 consecutive pediatric patients with acute leukemia after allo-HSCT to study the incidence, risk factors, and outcome of iEMR compared with systemic relapse. The 5-year cumulative incidence of systemic relapse (either bone marrow [BM] only or BM combined with EMR) was 24.8%, and that of iEMR was 5.5%. The onset of relapse after allo-HSCT was significantly longer in EM sites than in BM sites (7.19 and 5.58 months, respectively; P = .013). Complete response (CR) 2+/active disease at transplantation (hazard ratio [HR], 3.1; P < .001) and prior EM disease (HR, 2.3; P = .007) were independent risk factors for iEMR. Chronic graft-versus-host disease reduced the risk of systemic relapse (HR, 0.5; P = .043) but did not protect against iEMR. The prognosis of patients who developed iEMR remained poor but was slightly better than that of patients who developed systemic relapse (3-year overall survival, 16.5% versus 15.3%; P = .089). Patients experiencing their first systemic relapse continued to have further systemic relapse, but only a minority progressed to iEMR, whereas those experiencing their iEMR at first relapse developed further systemic relapse and iEMR at approximately similar frequencies. A second iEMR was more common after a first iEMR than after a first systemic relapse (58.8% versus 13.0%; P = .001) and was associated with poor outcome. iEMR has a poor prognosis, particularly after a second relapse, and effective strategies are needed to improve outcomes.

Posterior Reversible Encephalopathy Syndrome in Childhood Hematological/Oncological Diseases: Multicenter Results.

The aim of the study was to analyze the characteristics of posterior reversible encephalopathy syndrome (PRES) cases treated at 10 different institutions in our country. Fifty-eight patients diagnosed with PRES were included in this study. The data of PRES cases from 10 departments of pediatric hematology/oncology were analyzed. The mean age of the patients at the time of diagnosis of PRES was 8.95±3.66 years. Most patients (80.4%) had a primary diagnosis of acute leukemia. Patients received chemotherapy (71.4%) and/or used steroids within 14 days before the diagnosis of PRES (85.7%). Hypertension was found in 83.9% of the patients. Twenty-six patients had infections and 22 of them had febrile neutropenia. The most common electrolyte disorders were hypocalcemia, hypomagnesemia, and hypopotassemia. Six patients had tumor lysis syndrome and 4 had inappropriate antidiuretic hormone syndrome. Magnetic resonance imaging was used for diagnosis in all patients. The most commonly involved regions by magnetic resonance imaging were occipital (58%), parietal (51%), and frontal lobes (45%), respectively. Twenty-five patients required intensive care and 7 patients were intubated. In conclusion, PRES may develop during the follow-up and treatment of hematological diseases. In addition to steroid and intense combined chemotherapies, immunosuppressive agents and hypertension are also factors that may be responsible for PRES.

A comprehensive update of ICET-A Network on COVID-19 in thalassemias: what we know and where we stand.

A review of the literature on COVID-19 pandemic in patients with thalassemias is presented. Globally, the prevalence of COVID-19 among  ß-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.

Preliminary Data on COVID-19 in Patients with Hemoglobinopathies: A Multicentre ICET-A Study.

OBJECTIVES: This study aims to investigate, retrospectively, the epidemiological and clinical characteristics, laboratory results, radiologic findings, and outcomes of COVID-19 in patients with transfusion-dependent ß thalassemia major (TM), ß-thalassemia intermedia (TI) and sickle cell disease (SCD). DESIGN: A total of 17 Centers, from 10 countries, following 9,499 patients with hemoglobinopathies, participated in the survey. MAIN OUTCOME DATA: 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 in 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. Six patients had pneumonia, and 4 needed oxygen therapy. Increased C-reactive protein (6/10), high serum lactate dehydrogenase (LDH; 6/10), and erythrocyte sedimentation rate (ESR; 6/10) were the most common laboratory findings. 6/10 patients had an exacerbation of anemia (2 with SCD). In the majority of patients, the course of COVID-19 was moderate (6/10) and severe in 3/10 patients. A 30-year-old female with TM, developed a critical SARS-CoV-2 infection, followed by death in an Intensive Care Unit. In one Center (Oman), the majority of suspected cases were observed in patients with SCD between the age of 21 and 40 years. A rapid clinical improvement of tachypnea/dyspnea and oxygen saturation was observed, after red blood cell exchange transfusion, in a young girl with SCD and worsening of anemia (Hb level from 9.2 g/dl to 6.1g/dl). CONCLUSIONS: The data presented in this survey permit an early assessment of the clinical characteristics of COVID 19 in different countries. 70% of symptomatic patients with COVID- 19 required hospitalization. The presence of associated co-morbidities can aggravate the severity of COVID- 19, leading to a poorer prognosis irrespective of age.

[Evaluation of Micafungin Use in Children]. / Çocuklarda Mikafungin Kullaniminin Degerlendirilmesi.

Micafungin is recommended especially in patients with liver and kidney failure and in the presence of other side effects due to antifungals apart from its known priority indications such as invasive candidiasis. The aim of this study was to evaluate the children who have received micafungin treatment. In the study, 125 children who were hospitalized in the pediatric wards and intensive care units of our hospital and had used micafungin between November 2016 and January 2019 were analyzed retrospectively. Clinical data, micafungin indication, blood values on the first and fourth days of the treatment, side effects of the drug and efficacy were evaluated. Sixty percent (75/125) of the patients were male and the mean age of all the patients were 58 ± 67 (0-215, 30) months. Approximately half of the cases (48%) had malignancy and 13% of them were premature. Sixty-two percent (n= 37) of the malignencies were hematological (27 acute lymphocytic leukemia, nine acute myeloid leukemia, one myelodysplastic syndrome) and 38% (n= 23) were oncological (six neuroblastoma, four Hodgkin lymphoma, two Non-Hodgkin's lymphoma, five sarcomas, one hepatoblastoma, five others) malignencies. The major cause of hospitalization was sepsis (53%). The patients had several risk factors like immunosuppressive therapy (n= 68, 54%), neutropenia (n= 61, 49%), central venous catheter (n= 102, 82%), nasogastric tube (n= 63, 50%), endotracheal intubation tube (n= 49, 39%), urinary catheter (n= 14, 11%) and total parenteral nutrition (n= 81, 65%). Thirteen percent (n= 16) of the cases were post-operative patients. Candida species were cultivated in 97 clinical specimens (blood, endotracheal aspirate, sputum, urine, etc.) among 23 (18%) of the patients. Thirteen (10%) of the patients had candidemia and 62% of them were non-albicans strains. In all candidemias, strains were echinocandin susceptible, and blood cultures were negative within four days. When all the patients (n= 125) were evaluated, a significant decrease in C-reactive protein, an increase in sodium, and a decrease in alanine aminotransferase were observed on the fourth day of micafungin treatment (p<0.05). A total of 39 (31%) patients underwent various antifungal treatments for median seven (1-60) days prior to micafungin treatment. Fourteen (36%) of these 39 patients, had elevated liver function tests (LFT), 10 (26%) of them had hypokalemia, and five (13%) of them had elevated renal function tests. Ten (26%) patients had antifungal-induced hypokalemia previously; and potassium levels were normalized after micafungin treatment (p= 0.0001). The patients for which micafungin treatment was chosen due to elevated liver function tests (n= 47, 38%), whether the antifungalinduced or not; alanine aminotransferase and aspartate aminotransferase levels were decreased after micafungin treatment (p= 0.0001 and p= 0.0001, respectively). Nineteen (15%) of the patients have died within the first 30 days of micafungin treatment and one of them had candidemia. No micafungin treatment related significant side effects were observed in any of the patients. Our study showed that micafungin could be a safe and effective option in pediatric cases including newborns with high liver and kidney function tests.

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.