Identification of novel antiplatelet agents by targeting Glycoprotein VI: A combined virtual screening study.

Cardiovascular diseases are the primary reason for deaths in the world. However, antiplatelet drugs in the market have limitations in use because of the risk of increased bleeding and other side effects that impair primary homeostasis. Therefore, safe and effective antithrombotic drugs are needed for the treatment of plaque formation in blood vessels. Glycoprotein VI (GPVI) is a platelet major collagen receptor and a target for potent and safe antithrombotic therapy. We designed this study based on the molecular interaction pattern of previously published GPVI receptor antagonists within the reported binding site. We selected sixteen hit compounds from a large chemical database that contains>6 million in-stock compounds by following a combined virtual screening. Then, we evaluated their inhibitory effects on platelet aggregation induced by GPVI receptor agonists (collagen, collagen related peptide (CRP), convulxin) and the most potent platelet agonist, thrombin, in vitro by using washed human platelets. IC50 values of compounds 1 and 2 are, respectively, 0.35 µM and 1.01 µM for collagen, 0.80 µM and 1.92 µM for CRP, 195.2 and 7.24 µM for convulxin and 81.38 and 51.74 µM for thrombin. We identified compounds 1 and 2 as the most promising antiplatelet agents out of sixteen compounds. Additionally, compounds 1 and 2 may serve as promising starting points and shed light on the design of new, potent and selective GPVI receptor antagonists.

Risk Factors for Graft-Versus-Host Disease and Survival in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Single-Center Experience.

OBJECTIVES: Graft-versus-host disease is still one of the most important complications after hematopoietic stem cell transplantation. The risk factors remain unclear, with effects of graft-versus-host disease on survival varying among different centers. We aimed to determine risk factors that may affect development of graft-versus-host disease and the corresponding patient survival rates at a single pediatric hematopoietic stem cell transplant unit. METHODS: Our study included 104 of 118 pediatric patients who underwent allogeneic hematopoietic stem cell transplant at our institute between 2005 and 2018. Patient characteristics, clinical information, pretransplant and posttransplant factors, and laboratory parameters were obtained from the database. RESULTS: Acute graft-versus-host disease was seen in 19 pediatric patients. Chronic graft-versus-host disease, which was seen in 13 of our pediatric study patients, occurred more often in those with peripheral blood stem cell than in those with bone marrow transplant (odds ratio of 9.969; 95% CI, 1.040-95.547; P = .046). Female donor-to-male recipient transplant was significantly associated with incidence of chronic graft-versus-host disease (odds ratio of 8.51; 95% CI, 1.323-54.843; P = .024). Later neutrophil engraftment was associated with incidence of acute graft-versus-host disease (odds ratio of 1.107; 95% CI, 1.012-1.212; P = .02). CONCLUSIONS: Although there are some known risk factors for graft-versus-host disease in adult patients, little is known about risk factors in children. In our comprehensive study in pediatric patients, we found that peripheral blood stem cell transplant, female-tomale transplant, and later neutrophil engraftment were associated with incidence of graft-versus-host disease. Although peripheral blood as a source of stem cells and female-to-male transplant are known risk factors, later neutrophil engraftment was a new finding as a possible risk factor for acute graft-versushost disease. This finding requires further verification in future prospective studies.

The contribution of neurocognitive situation, physical capacity and daily life activities to quality of life in childhood acute lymphoblastic leukemia survivors

Background/aim: There are no extensive studies on the QL in children who completed acute lymphoblastic leukemia (ALL) treatment and currently living without any disease in Turkey. Our study aimed to analyze both the QL and the effects of physical, neurocognitive capacities on QL in childhood ALL survivors aged 7­12 years at the time of recruitment. Materials and methods: PedsQL cancer module 3.0 child and proxy report, for ages 5­7 and 8­12 years, WeeFIM scale, BOTMP Short Form, RPM, reading, writing, and mathematics assessment tools, sociodemographic information form were carried out to the children and their family. Results: There was no effect of the months since the completion of therapy on pain, anxiety, cognitive problems, perceived physical appearance, and the total QL scores of children and proxy reports (p > 0.05). Children's physical capacities were significantly worse than healthy controls and have not reached the level of healthy children even after a long time since completion of ALL therapy. There was a significant association between physical capacity and daily independent living status (p < 0.001). Reading, writing, and mathematical skills were significantly associated with the mean time off-treatment (p < 0.001), and the total score of RPM and PedsQL of those with mathematical difficulties were significantly lower than those without any difficulty (p < 0.05). Conclusion: The months after the treatment (off-treatment time) have not affected total and subunit QL scores. As motor skills difficulties will lead to low academic achievement, early recognition direct the parents for immediate intervention. lead to low academic achievement, early recognition could direct the parents for immediate intervention. Planning psychosocial support programs for physical activity and age-appropriate development of patients from the initiation of treatment will increase the QL in childhood ALL with a survival rate of 80% or more.

Regulatory consideration on preparation and clinical use of COVID-19 convalescent plasma.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), spreading from Wuhan to worldwide has been emerged since December 2019. Although scientists and researchers have been racing to develop specific therapeutic agents or vaccines against SARS-CoV-2 since the identification of the agent, either a drug or a vaccine has not been approved to treat or to prevent COVID-19 up to date. On the base of historical experiences, Convalescent Plasma (CP), a passive antibody therapy, has been evaluated as a hopeful and potential therapeutic option since the beginning of the COVID-19 outbreak. Immune plasma had been used previously for the treatment of H1N1 influenza virus, SARS-CoV-1 and MERS-CoV epidemics successfully. In this scope competent authorities are responsible to set up certain principles and criteria for the collection and clinical use of COVID-19 Convalescent Plasma (CCP). This document has been prepared to aid both for the convalescent plasma suppliers and the clinicians. The first part encompasses the supply of CCP and the second part lead the clinical use of CCP for the treatment of patients with severe COVID-19 infection. Turkish Ministry of Health developed a guide on collection and clinical use of CCP and created a web-based monitoring system to follow-up the patients treated with convalescent plasma in universal. This follow-up process is thought to be crucial for the creation and development of current and future treatment modalities. This guide would be a pathfinder for clinicians and/or institutions those eager to conduct CCP treatment more effectively.

Inherited coagulation disorders in Turkish children: A retrospective, single-center cohort study.

OBJECTIVE: This study aims to investigate the distribution, clinical characteristics and outcome of inherited coagulation disorders (ICD) in Turkish children. SUBJECTS AND METHODS: Data from all children (age<18 years) with ICD examined in our center were retrospectively reviewed. RESULTS: There were 403 children with ICD (233 males and 170 females) with a median age of four years at diagnosis. The percentages of von Willebrand disease (vWd), hemophilia and rare bleeding disorders (RBD) were 40 %, 34 % and 26 %, type-1, type-2 and type-3 vWd were 63 % 17 % and 20 %, hemophilia A and B were 84 % and 16 %, and severe, moderate and mild hemophilia were 48 %, 30 % and 22 %, respectively. Factor VII and FXI deficiencies were the most prevalent, comprising 56 % and 22 % of all children with RBD, respectively. Parental consanguinity rates were 72 % in type-3 vWd and 61 % in severe RBD. The overall prevalence of gastrointestinal bleedings was 4.5 % (18/403), intracranial bleeding (ICB) was 4.96 % (20/403), mortality from ICB was 30 % (6/20) and the overall mortality rate was 1.49 % (6/403). No life-threatening bleeding was seen during regular prophylaxis. Chronic arthropathy prevalence in severe hemophilia was 8 % with primary prophylaxis and 53 % with demand therap. Inhibitor prevalence was 14 % in hemophilia-A and 5 % in hemophilia-B. CONCLUSIONS: These data show that vWd is the most common ICD, type-3 vWd and RBD are prevalent due to frequent consanguineous marriages and diagnosis of ICD is substantially delayed in Turkish children. Prophylactic replacement therapy prevents occurrence of life-threatening bleedings and reduces the development of hemophilic arthropathy.

The Role of Human Parvovirus B19 in the Pediatric Patients with Pancytopenia?

BACKGROUND: Parvoviruses are small DNA viruses causing erythema infectiosum, which is known as the fifth disease. The aim of this study was to investigate the presence of Parvovirus B19 DNA by Real-Time-PCR retrospectively in clinical samples of children diagnosed as acute leukemia and aplastic anemia when investigating the cause of pancytopenia and to investigate its relationship with the clinical manifestations. METHODS: The study samples were collected between March 2014 and March 2018 in Gazi University, Faculty of Medicine, Department of Pediatric Hematology. Sixty pediatric patients; 37 males and 23 females, were included in the study. Nucleic acid isolation was performed by using MagNA-Pure Compact Nucleic Acid Isolation Kit (Roche, Germany). Extracted DNA was studied with LightCycler® 2.0 using the Real-Time PCR method and LightCycler® Parvovirus B19 Quantification Kit (Roche, Germany), and the results were evaluated quantitatively. Parvovirus B19 DNA detection interval of the kit was 101 - 106 copies/mL. RESULTS: Sixty serum samples were investigated and 8.3% (5/60) Parvovirus B19 DNA positivity was determined. Of the five patients with Parvovirus B19 DNA positivity, three had acute lymphoblastic leukemia and two were diagnosed as aplastic anemia. Regarding viral load; 2/5, 1/5, 1/5, and 1/5 of the samples had a viral load of 102, 103, 104, and 105 copies/mL, respectively. Parvovirus B19 DNA positivity was detected in samples from March (2/5), April (2/5), and August (1/5). CONCLUSIONS: Patients with acute leukemia and aplastic anemia in childhood using immunosuppressive drugs, blood, and blood products during chemotherapy, encounter Parvovirus B19 infections in the follow-up period and are diagnosed by serological and molecular methods. As a result of the study, we suggest that the detection of Parvovirus B19 DNA by Real-Time PCR method in children being admitted with pancytopenia and diagnosed as acute leukemia and aplastic anemia is useful in the follow-up and treatment.

Risk factors for bacteremia in children with febrile neutropenia

Background/aim: Bacteremia remains an important cause of morbidity and mortality during febrile neutropenia (FN) episodes. We aimed to define the risk factors for bacteremia in febrile neutropenic children with hemato-oncological malignancies. Materials and methods: The records of 150 patients aged ≤18 years who developed FN in hematology and oncology clinics were retrospectively evaluated. Patients with bacteremia were compared to patients with negative blood cultures. Results: The mean age of the patients was 7.5 ± 4.8 years. Leukemia was more prevalent than solid tumors (61.3% vs. 38.7%). Bacteremia was present in 23.3% of the patients. Coagulase-negative staphylococci were the most frequently isolated microorganism. Leukopenia, severe neutropenia, positive peripheral blood and central line cultures during the previous 3 months, presence of a central line, previous FN episode(s), hypotension, tachycardia, and tachypnea were found to be risk factors for bacteremia. Positive central line cultures during the previous 3 months and presence of previous FN episode(s) were shown to increase bacteremia risk by 2.4-fold and 2.5-fold, respectively. Conclusion: Presence of a bacterial growth in central line cultures during the previous 3 months and presence of any previous FN episode(s) were shown to increase bacteremia risk by 2.4-fold and 2.5-fold, respectively. These factors can predict bacteremia in children with FN.

Successful application of CytoSorb® hemadsorption in an immunocompromised teenager with collapsing glomerulopathy, acute respiratory distress syndrome, and sepsis.

OBJECTIVE: CytoSorb® hemadsorption is an adjunctive therapy in order to reduce elevated cytokine levels of interleukin-6, interleukin-1, and tumor necrosis factor alpha. Here we present a successful administration of CytoSorb® hemadsorption in an immunocompromised pediatric patient with collapsing glomerulopathy, acute respiratory distress syndrome, and sepsis. DATA SOURCES: Clinical observations of one patient. STUDY SELECTION: Case report. DATA EXTRACTION: Data sources are clinical observation during patient management and patient's medical records if needed. The patient's consent was obtained prior to the study. DATA SYNTHESIS: A 17-year-old male with diarrhea was admitted to the hospital and was later found to have elevated creatinine levels and proteinuria. The renal biopsy was consistent with collapsing glomerulopathy and treatment with multi immunosuppressive agents including corticosteroids, mycophenolate mofetil, and rituximab coupled with several courses of hemodialysis and plasmapheresis were administered. During the hospital stay, Stenotrophomonas maltophilia bacteremia from the blood and the catheter cultures were identified. No clinical response was achieved, and patient developed severe sepsis despite antibiotics, intravenous immunoglobulin, and supportive management including albumin, platelet and erythrocyte concentrations, and fresh frozen plasma. CytoSorb® hemadsorption was then added to the ongoing treatment for three consecutive days. Subsequent to CytoSorb® hemadsorption, immediate laboratory and clinical response were observed. CONCLUSION: This is the successful clinical report of an immunocompromised teenager with collapsing nephropathy, sepsis, and multi-organ dysfunction syndrome treated with a combination of renal replacement therapy and CytoSorb® hemadsorption. The usage of CytoSorb® hemadsorption represents a novel approach to improve survival of the patients with multiple organ dysfunction and sepsis.

An adolescent case of extensive Behçet`s disease successfully treated with Infliximab.

Isiyel E, Bakkaloglu S, Oguz D, Yenicesu I, Boyunaga Ö, Özdemir Y, Damar Ç, Kandur Y, Akçaboy M, Aslan AT, Sismanlar T, Hasanoglan E, Buyan N. An adolescent case of extensive Behçet`s disease successfully treated with Infliximab. Turk J Pediatr 2019; 61: 585-588. Cardiac involvement is an uncommon and life-threatening complication of Behçet`s Disease. We present a 14-year-old boy, admitted to our hospital for recurrent hemoptysis. In his radiologic evaluation, a right ventricular thrombus and pulmonary arterial aneurysm were identified. He was diagnosed with Behçet`s Disease, and then he received prednisone and cyclophosphamide. However, his cardiac thrombus enlargened. After his treatment was replaced with infliximab, the pulmonary aneurysms regressed, and the cardiac thrombus disappeared. In conclusion, infliximab should be considered as a reliable option for vascular Behçet`s Disease resistant to conventional treatment.

Parvovirus B19 seroprevalence in Turkish blood donors

Background/aim: Parvovirus risk in blood transfusion has become a popular research topic since there are limited data on parvovirus seroprevalence in blood donors in Turkey. The aim of this study was to investigate parvovirus seroprevalence in blood donors in Turkey. Materials and methods: Blood samples of 988 blood donors admitted to a university blood bank were obtained for parvovirus B19 IgM and IgG detection. The samples were analyzed using the ELISA method. Results: IgM positivity of 3.92% and IgG positivity of 58.9% was detected in the blood samples. Parvovirus IgM positivity was found to be the highest in the age group of 41-50 years (P = 0.045) and IgG positivity was detected to be the highest in the age group of 31-40 years (P < 0.001). Parvovirus IgG positivity was significantly higher in women (P = 0.041). However, there was no difference regarding parvovirus IgM positivity in terms of sex (P = 0.245). Conclusion: Although this study does not represent the whole country, it is still the largest investigation carried out on the topic in Turkey and the obtained results are generally similar to those of European countries. Therefore, it is thought that the results obtained from this study may be supportive for the first steps regarding plasma fractionation, which will soon begin in Turkey.

A child with atypically subtle clinical presentation of acute arterial ischaemic stroke in the middle cerebral artery.

Arterial ischaemic stroke in the paediatric population is considered a rare disease, and its diagnosis is often delayed due to the subtlety and variability of clinical symptoms, especially in younger patients. The clinical presentation and imaging features of ischaemic stroke in the paediatric population are variable depending on the underlying cause, affected artery and patient's age. Literally, acute occlusion of the middle cerebral artery shows significant clinical signs and symptoms, and riotous imaging findings due to the size of the territory. Here, we present a case of a 15-year-old boy who unusually had subtle and intermittent clinical symptoms in spite of a complete acute occlusion in his right middle cerebral artery.

Hematologic Findings of Inherited Metabolic Disease: They are More Than Expected.

Inherited metabolic diseases are pathologic conditions that generally develop as a result of impairment of the production or breakdown of protein, carbohydrate, and fatty acids. Early determination of hematological findings has a positive effect on the prognosis of metabolic diseases. Three hundred eighteen patients who were being followed-up within the previous 6 months at Department of Pediatric Nutrition and Metabolism, Gazi University, Turkey, were included in the study. The hematological findings were classified under 7 main groups: anemia of chronic disease, iron deficiency anemia, vitamin B12 deficiency anemia, hemophagocytosis, leukocytosis, and thrombocytosis. Nine hundred twenty-two hematological examinations of the 319 patients were included in the study, and 283 hematological findings were determined, 127 anemia of chronic disease, 81 iron deficiency anemia, 56 cytopenia, and 4 vitamin B12 deficiency anemia. Leukocytosis (n=1), thrombocytosis (n=5), and hemophagocytosis (n=9) were also observed. It was determined that, although anemia of chronic disease and nutritional anemia are the most common hematological findings, these may be diagnosed late, whereas neutropenia, thrombocytopenia, pancytopenia, and hemostasis disorders may be diagnosed earlier. Our study is the most comprehensive one in the literature, and we think it would positively contribute to the monitoring and prognosis of congenital metabolic diseases.

Relationship between obesity and iron deficiency anemia: is there a role of hepcidin?

OBJECTIVES: Iron deficiency is common in obese children although the underlying mechanism is unclear. The aim of this study was to investigate the associations between iron parameters, leptin, hepcidin and adiponectin levels in obese children. METHODS: A total of 237 children, ranging in age from 5 to 18 years, 180 with primary obesity and 57 healthy children and adolescents, were enrolled. Complete blood count, serum iron levels, iron-binding capacity, ferritin levels, leptin, hepcidin and adiponectin levels were studied. RESULTS: White blood cell and platelet count, iron-binding capacity, high-sensitive C-reactive protein, leptin and hepcidin values in the obese group were higher than those of the control group (p < 0.001, p = 0.002, p < 0.001, p < 0.001, p < 0.001 and p < 0.001, respectively). However, mean corpuscular volume, adiponectin and transferrin saturation values in the obese group were lower than in the control group (p = 0.026, p = 0.003, and p < 0.001, respectively). No significant differences were found in terms of hemoglobin, serum ferritin, iron and IL-6 levels. CONCLUSIONS: Our study suggests that hepcidin levels do not contribute to the development of iron deficiency anemia in pediatric obese individuals.

Juvenile Myelomonocytic Leukemia in Turkey: A Retrospective Analysis of Sixty-five Patients.

OBJECTIVE: This study aimed to define the status of juvenile myelomonocytic leukemia (JMML) patients in Turkey in terms of time of diagnosis, clinical characteristics, mutational studies, clinical course, and treatment strategies. MATERIALS AND METHODS: Data including clinical and laboratory characteristics and treatment strategies of JMML patients were collected retrospectively from pediatric hematology-oncology centers in Turkey. RESULTS: Sixty-five children with JMML diagnosed between 2002 and 2016 in 18 institutions throughout Turkey were enrolled in the study. The median age at diagnosis was 17 months (min-max: 2-117 months). Splenomegaly was present in 92% of patients at the time of diagnosis. The median white blood cell, monocyte, and platelet counts were 32.9x109/L, 5.4x109/L, and 58.3x109/L, respectively. Monosomy 7 was present in 18% of patients. JMML mutational analysis was performed in 32 of 65 patients (49%) and PTPN11 was the most common mutation. Hematopoietic stem cell transplantation (HSCT) could only be performed in 28 patients (44%), the majority being after the year 2012. The most frequent reason for not performing HSCT was the inability to find a suitable donor. The median time from diagnosis to HSCT was 9 months (min-max: 2-63 months). The 5-year cumulative survival rate was 33% and median estimated survival time was 30±17.4 months (95% CI: 0-64.1) for all patients. Survival time was significantly better in the HSCT group (log-rank p=0.019). Older age at diagnosis (>2 years), platelet count of less than 40x109/L, and PTPN11 mutation were the factors significantly associated with shorter survival time. CONCLUSION: Although there has recently been improvement in terms of definitive diagnosis and HSCT in JMML patients, the overall results are not satisfactory and it is necessary to put more effort into this issue in Turkey.

Monoclonal B-cell lymphocytosis in blood donors in Turkey.

OBJECTIVES: Monoclonal B-cell lymphocytosis (MBL) is a precursor state of chronic lymphocytic leukemia (CLL) with peripheral lymphocytosis below 5 × 109/l. The diagnostic criteria exclude the presence of lymphadenopathy, organomegaly, infections, autoimmune diseases or any sign of a lymphoproliferative disorder. This prospective study was designed in order to evaluate the frequency of MBL in blood donors in Turkey. METHODS: The diagnosis of MBL was identified by flow cytometry method based on the International Familial CLL Consortium Report. A total of 999 volunteers [median age 34 (18-78) years; male/female: 705/294] were included in the study. RESULTS: Monoclonal B-cell lymphocytosis was demonstrated in 18 cases (1.8%). A total of 16 cases (1.6%) was evaluated as CLL-like MBL, while 2 (0.2%) had a non-CLL-like phenotype. The subjects were divided into three groups according to age, as <40 years, 40-60 years and >60 years. The prevalence of MBL was 1.1% below 40 years, 0.6% between 40 and 60 years and 0.1% in cases over 60 years, without statistical significance (p > 0.05). DISCUSSION: The sensitivity of the flow cytometry method is essential and may be responsible for the variations in the prevalence of MBL in different populations which can also be attributed to study design, higher detection rates in the elderly and families with genetic predisposition to CLL. CONCLUSION: Large population-based studies and standardized laboratory methods are needed to determine the potential risk factors of progression to CLL, including molecular markers and genetic profile.

Utility of 18-fluorodeoxyglucose positron emission tomography in children with relapsed/refractory leukemia.

OBJECTIVE: Few data are available on the clinical significance of 18-fluorodeoxyglucose positron emission tomography (FDG-PET/CT) results in patients with leukemia. We investigated the utility of FDG-PET/CT at the time of relapsed/refractory disease in pediatric patients with leukemia. METHODS: Medical records of 28 children with suspected leukemia progression or recurrence during/after chemotherapy or allogeneic stem cell transplantation (allo-SCT) were retrospectively reviewed to determine the utility of FDG-PET/CT. RESULTS: Twenty-two of the 28 patients have documented abnormal imaging findings during clinical follow-up, while six had were interpreted as not demonstrating signal consistent with active leukemia. Of the 22 patients with abnormal FDG-PET/CT studies 14 were found to have FDG-PET/CT reported as consistent with active leukemia and increased leukemia blasts on bone marrow biopsy. Regarding the eight patients without positive FDG-PET/CT and proven leukemia relapse, four had discordant findings on FDG-PET/CT and biopsy, and four had FDG-PET/CT reported as infection. Mean maximum standardized uptake values (SUVmax) were significantly higher among patients whose FDG-PET/CT findings were positive for leukemia as opposed to infectious disease (p < .05). Mean SUVmax was also significantly higher among patients with multifocal lesions on FDG-PET/CT than among those with diffuse lesions (p < .05). CONCLUSIONS: The findings suggest that FDG-PET/CT may be a complementary imaging modality that could be combined with bone marrow examination to improve detection of subtle leukemic infiltration in children with suspected leukemia progression or recurrence after chemotherapy or allo-SCT.

Investigation of an algorithm for anti HCV EIA reactivity in blood donor screening in Turkey in the absence of nucleic acid amplification screening.

PURPOSE: In this study we aimed to propose an algorithm for initial anti HCV EIA reactive blood donations in Turkey where nucleic acid amplification tests are not yet obligatory for donor screening. METHODS: A total of 416 anti HCV screening test reactive donor samples collected from 13 blood centers from three cities in Turkey were tested in duplicate by Ortho HCV Ab Version 3.0 and Radim HCV Ab. All the repeat reactive samples were tested by INNO-LIA HCV Ab 3.0 or Chiron RIBA HCV 3.0 and Abbott Real Time HCV. Intra-assay correlations were calculated with Pearson r test. ROC analysis was used to study the relationship between EIA tests and the confirmatory tests. RESULTS: The number of repeat reactive results with Ortho EIA were 221 (53.1%) whereas that of microEIA, 62 (14.9%). Confirmed positivity rate was 14.6% (33/226) by RIBA and 10.6% (24/226) by NAT. Reactive PCR results were predicted with 100% sensitivity and 95% specificity with S/CO levels of 8.1 with Ortho EIA and 3.4 with microEIA. CONCLUSIONS: Repeat reactivity rates declined with a second HCV antibody assay. Samples repeat reactive with one HCV antibody test and negative with the other were all NAT negative. All the NAT reactive samples were RIBA positive. None of the RIBA indeterminate or negative samples were NAT reactive. Considering the threshold values for EIA kits determined by ROC analysis NAT was decided to be performed for the samples above the threshold value and a validated supplemental HCV antibody test for the samples below.

Association of CYP3A5 Expression and Vincristine Neurotoxicity in Pediatric Malignancies in Turkish Population.

Vincristine is a widely used chemotherapeutic agent in the treatment of childhood malignancies. Neuropathy is the most common adverse effect. CYP3A4 and CYP3A5 enzymes of cytochrome p450 enzyme system are responsible in vincristine metabolism. Genetic polymorphism may alter the vincristine metabolism and the neurotoxicity rate. In this study, distribution of CYP3A5 alleles among Turkish children with malignancies, relation between CYP3A5 genotype and neurotoxicity rates, as well as severity and duration of neuropathy and total vincristine doses were investigated. Patient group consisted of 115 patients (age, 1 to 17 y) with acute lymphoblastic leukemia and solid tumors, who were treated with vincristine consisting chemotherapy protocols. Control group consisted of 50 children without any neurological symptom or disorders. All patient files were reviewed for presence and severeness of neurotoxicity symptoms. Blood samples were obtained and CYP3A5 genotypes were analyzed. Neurotoxicity occurred in 20.8% of patients. Although it was found to occur more frequently after 4 doses of vincristine, and rates were higher in the low-dose vincristine group suggesting other contributing factors. Although neurotoxicity rate in the CYP3A5*1/*3 genotype was 17.6%, it was 21.6% in the CYP3A5*3/*3 genotype and the difference was not statistically significant (P<0.05). This study suggested that vincristine-related neurotoxicity is dose-independent and genotype is not the only causative factor in the occurrence of neurotoxicity in these patients.

Successful total hip replacement with sequential administration of bypassing agents in an adolescent boy with hemophilia A and high inhibitor titers.

: There are only a few reports of total hip replacement in patients with hemophilia A and inhibitors. We performed total hip replacement in an 18-year-old adolescent boy who had high inhibitor titers since infancy. Recombinant factor VIIa (NovoSeven) was used as a bypass agent during the surgery. There was no excessive introperative bleeding; however, postsurgical bleeding occurred and was controlled by sequential administration of recombinant factor VIIa and activated prothrombin complex concentrate (FEIBA). This is the first report of this treatment modality in such a major surgery. Sequential bypassing agent therapy can be effective for treating refractory bleeding in hemophilia patients who have high inhibitor titers but require major surgery.

Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia.

OBJECTIVE: High-dose methotrexate (HD-MTX) is widely used in the consolidation phase of childhood acute lymphoblastic leukemia (ALL), but the roles that polymorphisms in folate-related genes (FRGs) play in HD-MTX toxicity and prognosis in children with ALL are not understood. The aims of this study were to investigate the frequencies of polymorphisms in the genes for thymidylate synthase (TS), methionine synthase reductase (MTRR), and methylene tetrahydrofolate reductase (MTHFR) in Turkish children with ALL and to assess associations between these polymorphisms and HD-MTX-related toxicity and leukemia prognosis in this patient group. MATERIALS AND METHODS: FRG polymorphisms were assessed by real-time polymerase chain reaction. Survival status, MTX levels, and toxicity data were retrieved from 106 patients' charts. RESULTS: The allele frequencies for the FRG polymorphisms were as follows: TS 2R 41.0%, 3R 57.0%, and 4R 2.0%; MTRR 66A 42.4% and 66G 57.6%; MTHFR 677C 59.3% and 677T 40.7%; and MTHFR 1298A 58.1% and 1298C 41.9%. At the 48th hour of HD-MTX infusion, serum MTX was significantly higher in patients who had TS 2R/3R/4R variants as compared to those with wild-type TS (p<0.05). No significant differences were detected with respect to event-free survival or toxicity between wild-type and other FRG variants. CONCLUSION: The frequencies of FRG polymorphisms in Turkish children with ALL are similar to those reported in other Caucasian populations. This is the first published finding of the TS 3R/4R variant in the Turkish population. The results indicate that HD-MTX can be tolerated by leukemic children with some polymorphic variants of FRG; thus, it may prevent future risk of leukemic relapse.