Gülyüz Öztürk

The effect of steroid and intravenous immunoglobulin on thrombopoietin levels in pediatric patients with immune thrombocytopenic purpura

Thrombopoietin (TPO), which is the main regulator of megakaryo/thrombopoiesis, has been recently cloned and purified, and shown to be useful in discriminating thrombocytopenia due to decreased production or increased platelet destruction. However, there are no detailed investigations about the drug effects on TPO levels during childhood. This study was conducted to measure the TPO levels of children with immune thrombocytopenic purpura (ITP) during steroid and immunoglobulin treatment. Twelve patients with acute ITP were treated with high-dose methyl prednisolone and five patients were treated with intravenous immunoglobulin. Neither steroids nor immunoglobulin were found to have any effect on TPO levels.

Novel plasminogen gene mutations in Turkish patients with type I plasminogen deficiency.

The plasminogen (Plg) protein is the inactive proenzyme form of plasmin that dissolves fibrin thrombi by a process called fibrinolysis. It has been shown that homozygous or compound-heterozygous deficiency of this protein is a major cause of a rare inflammatory disease affecting mainly mucous membranes found in different body sites. In this study, five individual Turkish patients and nine Turkish families with type 1 Plg deficiency were investigated for PLG gene mutations. All of the coding regions of the PLG gene mutations were screened for mutations using denaturing high-pressure liquid chromatography (DHPLC). Samples showing a different DHPLC profile were subjected to DNA sequencing analysis. Here, we described five novel mutations namely, Cys49Ter, +1 IVS6 G>A, Gly218Val, Tyr283Cys, and Gly703Asp. Previously identified five nonsynonymous (Lys38Glu, Glu180Lys, Gly420Asp, Asp453Asn, Pro763Ser), five synonymous (330 C>T, 582 C>T, 771 T>C, 1083 A>G, 2286 T>G), and a 3′ untranslated region (3′ UTR) mutation (c.*45 A>G) were also reported in this present study. In this study, we have identified a total of eight mutations, five of which are novel. The mutations/polymorphisms identified in eight of the patients do not explain the disease phenotype. These cases probably carry other pathological mutations (homozygous or compound heterozygous) that cannot be detected by DHPLC.

Outcome of autologous hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory Hodgkin's lymphoma.

This study evaluates the outcome of 66 pediatric patients with rrHL who underwent autoHSCT. Twenty‐nine patients experienced early relapse, and 19 patients experienced late relapse. Of 18 newly diagnosed with HL, 13 were primary refractory disease and five had late responsive disease. At the time of transplantation, only 68% of the patients were chemosensitive. The majority of patients received BCNU + etoposide + ara‐C + melphalan for conditioning (45/66), and peripheral blood (56/66) was used as a source of stem cells. After a median follow‐up period of 39 months, 46 patients were alive. At five yr, the probabilities of OS, EFS, the relapse rate, and the non‐relapse mortality rate were 63.1%, 54.3%, 36.4%, and 9.1%, respectively. The probability of EFS in chemosensitive and chemoresistant patients at five yr was 72.3% and 19%, respectively (p < 0.001). Multivariate analysis showed that chemoresistant disease at the time of transplantation was the only factor predicting limited both OS (hazard ratio = 4.073) and EFS (hazard ratio = 4.599). AutoHSCT plays an important role for the treatment of rrHL in children and adolescents, and survival rates are better for patients with chemosensitive disease at the time of transplantation.

High MN1 expression increases the in vitro clonogenic activity of primary mouse B-cells

The MN1 (Meningioma 1) gene is overexpressed in certain subtypes of acute myeloid leukemia (AML) and high levels of MN1 expression in mouse bone marrow cells results in myeloid leukemia. We showed that compared with control bone marrow (BM) MN1 expression was increased (2-fold or more) in 29 out of 73 (40%) pediatric B-cell acute lymphoblastic leukemia (B-ALL) patient BM. Additional analysis of MN1 expression in sub-groups within our cohort carrying different chromosome translocations showed that carriers of the good prognostic marker t(12;21)(TEL-AML1) (n=27) expressed significantly more MN1 than both healthy controls (n=9) (P=0.02) and the group carrying the t(9;22)(BCR-ABL) (n=9) (P=0.001). In addition, AML1 expression was also upregulated in 31 out of 45 (68%) B-ALL patient BM compared with control and there was a significant correlation between MN1 and AML1 expression (r=0.3552, P=0.0167). Retroviral MN1 overexpression increased the colony forming activity of mouse Pro-B/Pre-B cells in vitro. Our results suggest that deregulated MN1 expression contributes to the pathogenesis of pediatric B-ALL. Further investigation into the clinical and biological significance of elevated MN1 expression in TEL-AML1(positive) leukemia might provide insight into additional molecular mechanisms contributing to B-ALL and may lead to improved treatment options for patients.

Best treatment option for infantile chronic myeloid leukemia patients: Imatinib or hematopoietic stem cell transplantation?

We were interested in the article by Alchalby and his colleagues about the hematopoietic stem cell transplantation (HSCT) and imatinib therapy in pediatric patients with chronic myeloid leukemia (CML). Philadelphia chromosome (Ph)-positive CML is extremely rare in infants (1). That is why the treatment strategies for infantile CML remain controversial. Treatment with tyrosine kinase inhibitors (TKIs) has replaced HSCT in children especially without a matched sibling donor (MSD) (2). On the other hand, clinical observations in adult patients with CML yielded imatinib as front-line therapy (3). We disagree that this is true for children. The progression to accelerated phase under TKI therapy (4), potential long-term side effects (3) such as osteoporosis and pulmonary hypertension and also higher cost in developing countries (5) are major drawbacks. A 16-month-old girl presented with abdominal distension and anorexia lasting for a month. She had prominent hepatosplenomegaly. Complete blood count showed hemoglobin of 9.4 g/dL, platelet count of 349 9 10/L, and total leukocyte count of 229 9 10/L with a differential count of 17% promyelocyte, 10% myelocyte, 40% stab/ neutrophil, 11% eosinophil, 6% monocyte, 1% basophil, and 15% lymphocyte. Bone marrow aspirate showed no blasts. Leukocyte alkaline phosphatase score was five (range: 20–137), and fetal hemoglobin level was normal. Karyotypic study revealed Ph positivity (46, XX, t(9;22)(q34; q11). RT-PCR showed presence of both b3a3 and b2a2 variants of bcr-abl fusion gene. Imatinib was started at the dose of 340 mg/m. Hematological response was achieved with imatinib therapy at one month. FISH analysis performed after three months showed bcr-abl variants fusion positive in 8.7% b3a3 and 7.4% b2a2 (partial response). After six months of therapy, RT-PCR showed presence of BCR/ABL positivity (0.1006%) (optimal response). She underwent HSCT from matched unrelated donor (MUD) after seven months of imatinib. The patient experienced acute GvHD (grade II) and CMV infection, which were treated successfully. She was fully chimeric, and t(9;22) was negative after HSCT. Chronic GvHD (skin and liver) was detected on +195th day, and CMV pneumonia was diagnosed on +332nd day. She was intubated and admitted to the intensive care unit. But unfortunately, she died due to ARDS on +343th day. Just after the best therapeutic response with TKI in the chronic phase, HSCT with MSD/ MUD is the treatment of choice for children with CML (6, 7). But the high risk of morbidity and mortality even from MSDs should also be taken into account. It has been proposed that imatinib therapy would be more appropriate therapy for patients withoutMSD. Some authors recommend that allo-SCT in children should be postponed until the disease becomes refractory to imatinib (3). To the best of our knowledge, our patient was one of the youngest patients to undergo HSCT in the literature. Although she died of CMV pneumonia, which is one of the complications of HSCT, we still believe that the best curative option for pediatric/infantile CML patients is HSCT until novel drugs with less toxicity and higher efficacy are produced.