Serap Aksoylar

Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma

This study aimed to investigate the association of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms with serum drug levels and toxicities after high-dose methotrexate (MTX) infusion. The study included 37 children with acute lymphoblastic leukemia or non-Hodgkin lymphoma. Serum MTX levels and toxicities of bone marrow, liver and kidney were analysed. Genotype analysis of the C677T and A1298C gene polymorphisms from genomic DNA of the subjects was performed by real-time PCR. Subjects with MTHFR polymorphism for C677T (CT, TT) had significantly higher MTX levels at 24 h (p = 0.009), and these genotypes did not seem to cause toxicity. Subjects with MTHFR polymorphism for A1298C (AC, CC) had significantly higher MTX levels at 48 h (p = 0.02), and had more grade III/IV anemia (p = 0.02), thrombocytopenia (p = 0.0001), elevated AST levels (p = 0.04) and frequent febrile neutropenic episodes (p = 0.004). The present study suggests that A1298C gene, but not C677T polymorphism is associated with MTX-related toxicity.

Evaluation of sponging and antipyretic medication to reduce body temperature in febrile children

Two hundred and twenty‐four children aged 6 months to 5 years, with rectal temperatures greater than or equal to 39°C (104°F), were randomly treated with sponging alone or with medication including a single oral dose of aspirin 15 mg/kg, or paracetamol 15 mg/kg, or ibuprofen 8 mg/kg. Twenty‐three children were excluded from the final analysis because they did not complete the study. Demographic characteristics of the patients were found to be comparable in all groups. Rectal temperatures were recorded every 30 min for a 3 h period. During the first 30 min of intervention, sponging was found to be more effective than all of the three medications. After 60 min, the effects of each medication became superior to sponging with tepid water in reducing body temperature. Twenty‐three children were excluded from the final analysis because they did not complete the study. Comparing the effect of the three different medications, it was seen that the antipyretic efficacy of aspirin and ibuprofen were significantly more than paracetamol 3 h after intervention (P < 0.05). For the management of fever over 39°C, it is therefore recommended to give children an antipyretic drug, preferably ibuprofen, and at the same time to begin sponging to provide a rapid and sustained antipyresis.

Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching

Haematopoietic stem cell transplantation (HSCT) remains the best therapeutic option for many acquired and inherited paediatric haematological disorders. Unfortunately, the probability of finding an HLA matched donor is limited. An alternative technique is PGD combined with HLA matching, which offers the possibility of selecting unaffected embryos that are HLA compatible with the sick child, with the aim of possible use of stem cells from the resulting baby in future. Since the first successful report for Fanconi anaemia a decade ago, the therapeutic success of this technique was reported in a few cases and for a limited number of disorders. Here, we report full recovery of 44 sick children who received HSCT from healthy infants conceived after pre-implantation HLA matching for the following 10 indications; beta-thalassaemia, Wiskott-Aldrich syndrome, Fanconi anaemia, sickle cell anaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, Glanzmanns thrombasthaenia, Diamond-Blackfan anaemia, X-linked adrenoleukodystrophy and mucopolysaccharidosis type I. No serious complications were observed among recipients and donors. Graft failure occurred in four children with beta-thalassaemia where a second HSCT was planned. Preimplantation HLA matching is a reliable technique and provides a realistic option for couples seeking treatment for an affected child when no HLA-matched donor is available.

Meropenem Plus Amikacin Versus Piperacillin-Tazobactam Plus Netilmicin as Empiric Therapy for High-Risk Febrile Neutropenia in Children

The aim of this study was to evaluate the efficacy and safety of meropenem plus amikacin compared with piperacillin-tazobactam plus netilmicin for initial empirical antibiotic treatment of high-risk febrile neutropenia in children with cancer. Patients with hematologic malignancy (leukemia or stage III/IV non-Hodgkin lymphoma) who presented with fever and neutropenia (ANC < 500/mm3) and patients with solid tumors who presented with fever and severe neutropenia (ANC < 100/mm3) were considered to be at high risk and eligible for this study. In this prospective study, 33 patients with 50 febrile neutropenic episodes received iv meropenem (20 mg/kg every 8 h) plus amikacin (15 mg/kg/d in 2 divided doses) (in 31 episodes) or piperacillin/tazobactam (100 mg/4 mg/kg every 8 h) plus netilmicin (7 mg/kg every 24 h) (in 19 episodes). Clinical response was determined at 72 h and at completion of the therapy. The groups were comparable in terms of age, sex, initial ANC, use of growth factors, and classification of the infections. An infection was documented microbiologically in 12 episodes (39%) in the meropenem plus amikacin group and in 8 episodes (42%) in the piperacillin/tazobactam plus netilmicin group. Of the 22 microbiological isolates, 37% were gram-positives, 45% were gram-negatives, and 18% were fungi. Most of the clinically documented infections were of lower respiratory tract, gastrointestinal mucosa, or urinary tract origin. The mean duration of neutropenia was 9 days in both groups. Fever persisted for 1–30 days (mean 3 vs. 5 days). The success rate with initial empiric therapy was 52% in the meropenem plus amikacin and 42% in the piperacillin/tazobactam plus netilmicin group, respectively (p= .5). Total success rate (with or without modification) was 97% vs. 90% in the episodes. Three patients died due to infection (1 vs. 2 patients). No major adverse effects were observed in each group. Empirical therapy with meropenem plus amikacin or piperacillin/tazobactam plus netilmicin for high-risk febrile neutropenia is equally effective and safe in pediatric cancer patients.

Comparison of tropisetron and granisetron in the control of nausea and vomiting in children receiving combined cancer chemotherapy.

Tropisetron and granisetron are selective serotonin (5-HT 3 ) antagonists that have been proven effective in the prevention of nausea and vomiting in adults and children receiving cancer chemotherapy. This prospective, randomised study was designed to compare the efficacy of the two agents in the prevention of vomiting and nausea in children receiving highly emetogenic chemotherapy for various malignancies. A total of 51 children (mean age: 7.7 - 4.8 year) were studied in 133 chemotherapy cycles. In 66 chemotherapy cycles, the children received tropisetron as an antiemetic agent in a dose of 0.2 mg/kg/24 h intravenously and, in 67 cycles, they received granisetron 40 w g/kg/24 h intravenously before cytotoxic drug administration during the days they received chemotherapy. The response per 24 h of chemotherapy was defined as complete (no nausea and vomiting), partial (1-4 events of vomiting and/or nausea), and failure (more than 4 events o fvomiting and/or nausea). Efficacy of antiemetic therapy was evaluatedas acute (Day 1) and overall was based on the worst day during the chemotherapy. Complete control of acute vomiting was achieved in 74% of tropisetron and 88% of granisetron patients ( P = 0.04), and complete control of acute nausea in 56% and 82% respectively ( p = 0.002). Overall response by means of complete control of both vomiting and nausea during the whole therapy period was 29% of tropisetron group and 55% of granisetron group ( p = 0.007). The statistical analysis (depending on the emetogenicity of the chemotherapy cycles) showed increased efficacy of granisetron in highly (grade 3) emetogenic chemotherapy cycles ( p = 0.002), whereas there was no differencein the very highly emetogenic cycles ( p = 0.7). Also, granisetron was found to be more effective than tropisetron, especially in patients heavier than 25 kg ( p = 0.02). The adverse reactions were few and mild. There were no differences in the tolerability of the two antiemetic therapy modalities. In conclusion, granisetron was found to be more effective than tropisetron in controlling nausea and vomiting in children receiving highly emetogenic chemotherapy. This increased antiemetic efficacy of granisetron might have been related to maximal dose differences according to body weight.

Prospective Evaluation of Whole Genome MicroRNA Expression Profiling in Childhood Acute Lymphoblastic Leukemia

Dysregulation of microRNA (miRNA) expression contributes to the pathogenesis of several clinical conditions. The aim of this study is to evaluate the associations between miRNAs and childhood acute lymphoblastic leukemia (ALL) to discover their role in the course of the disease. Forty-three children with ALL and 14 age-matched healthy controls were included in the study. MicroRNA microarray expression profiling was used for peripheral blood and bone marrow samples. Aberrant miRNA expressions associated with the diagnosis and outcome were prospectively evaluated. Confirmation analysis was performed by real time RT-PCR. miR-128, miR-146a, miR-155, miR-181a, and miR-195 were significantly dysregulated in ALL patients at day 0. Following a six-month treatment period, the change in miRNA levels was determined by real time RT-PCR and expression of miR-146a, miR-155, miR-181a, and miR-195 significantly decreased. To conclude, these miRNAs not only may be used as biomarkers in diagnosis of ALL and monitoring the disease but also provide new insights into the potential roles of them in leukemogenesis.

Evaluation of telomerase mRNA (hTERT) in childhood acute leukemia

Human telomerase reverse transcriptase (hTERT) is the catalytic component of telomerase enzyme and has been shown to be associated with telomerase activity (TA). Although many studies in adult leukemia have established the importance of TA, very few have been reported in the children. In this study hTERT levels in childhood leukemia was evaluated and compared with the prognostic factors described before. The LightCycler instrument was used (online real-time PCR) for the quantification of hTERT in peripheral blood and bone marrow in 23 cases with acute lymphoblastic leukemia (ALL) and in 8 cases with acute myeloblastic leukemia (AML). Ten cases with normal peripheral blood (PB) and bone marrow (BM) were selected as control group. Cytogenetic analyses were available in 21 patients with leukemia. In all cases with acute leukemia and in control group, peripheral blood (PB) hTERT levels correlated significantly with bone marrow (BM) hTERT levels. Before treatment, patients with ALL had significantly higher hTERT levels than that of AML patients and control cases. Among patients with ALL, higher hTERT levels were observed in patients with pre-B leukemia, followed by B cell and T cell leukemia patients. Initially increased hTERT levels decreased to the nearly normal levels during remission in cases with ALL. No correlation was observed between the initial hTERT levels and the known prognostic factors except cytogenetic findings. Higher hTERT levels were detected in patients having karyotypic abnormalities which indicate poor prognosis. hTERT levels are significantly high in childhood ALL with the highest level of pre-B cell leukemia before treatment. Those high levels of hTERT decrease to almost normal levels in remission. hTERT levels might be useful in monitoring of leukemia in children.

The Association of minor congenital anomalies and childhood cancer.

Although the association of some congenital malformations and specific genetic syndromes is well understood, the association between minor anomalies and cancer is not well known. In recent years some researchers have reported studies establishing this association in different types of cancer. In this study, we aimed to investigate the prevalence and patterns of age‐independent minor anomalies in childhood cancer patients.

Diverse phenotypic and genotypic presentation of RAG1 mutations in two cases with SCID.

Severe combined immunodeficiencies (SCID) comprise a spectrum of genetic defects that involve both humoral and cellular immunities. Defects in recombinating activating gene 1 (RAG1), RAG2, Artemis, or LIG4 can disrupt V(D)J recombination. Defective V(D)J recombination of the T and B cell receptors is responsible for T−B−NK+SCID. Amorphic mutations in RAG1 and RAG2 cause T−B−NK+SCID, whereas hypomorphic mutations cause an immunodeficency characterized by oligoclonal expansion of TCRγδ T cells, severe CMV infection and autoimmunity. First patient is a typical T−B−NK+SCID with clinical and immunologic findings while the second is atypical with normal immunoglobulin levels, CD4 lymphopenia, elevated TCRγδ T cells, persistent CMV infection, and autoimmune hemolytic anemia. These cases are presented to emphasize that mutations in RAG1 gene may lead to a diverse spectrum of clinical and immunologic findings while hypomorphic mutations may be related with autoimmunity and refractory CMV infection during infancy.

Combined cord blood and bone marrow transplantation from the same human leucocyte antigen‐identical sibling donor for children with malignant and non‐malignant diseases

Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)‐identical sibling can be used for transplantation of patients with malignant and non‐malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non‐malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 107/kg and median follow‐up was 41 months. Sixty‐days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade‐II‐IV acute and chronic graft‐versus‐host disease (GVHD) were 19% and 10%, respectively. Four‐year overall survival was 90% (68% malignant; 97% non‐malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA‐identical sibling donor is an effective treatment for children with malignant and non‐malignant disorders with high overall survival and low incidence of GVHD.