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.

Hematopoietic stem cell transplantation activities and HRQOL of refugee or asylum seeker children in Turkey: A multicenter study.

BACKGROUND: Refugee or asylum seekers (RAS) children are at increased risk of physical, developmental, and behavioral health issues. The aim of this study was to evaluate clinical and psychosocial outcomes of hematopoietic stem cell transplantation (HSCT) in RAS children and compare health-related quality of life (HRQOL) to those of Turkish peers. METHODS: This retrospective study included patients who underwent HSCT aged 0-18 years and completed 100-day post-transplant. The PedsQL 4.0 Generic Core Scale was used in children over 5 years old to compare HRQOL. RESULTS: A total of 166 RAS patients (M/F: 106 /60) underwent 174 HSCTs (six patients had two, and one had three HSCT) compared to 66 Turkish patients. The mean age of the patients in the RAS group was 7.8 ± 4.9 years and similar to controls. A total of 124 patients (75%) were from Syria, and 49 (25%) were from other countries in the Middle East and Africa. The cause of migration was war in 121 (74%) RAS patients. Complications of HSCT were no different between the groups. However, the rate of neutropenic sepsis was significantly higher in the RAS group (p = 0.004). The total scores of HRQOL were not different between RAS and controls. In the RAS group, ratings of social functioning were lower in patients with consanguinity or non-malignant disease or who had match-related donors. DISCUSSION: Identifying areas of difficulty in subscales of HRQOL may help physicians to classify patients who need additional supportive care. Regular monitoring and supporting physical needs may result in better functional outcomes after HSCT.

Results of multicenter registry for patients with inherited factor VII deficiency in Turkey.

INTRODUCTION: Inherited factor VII (FVII) deficiency (FVIID) is the most common of inherited rare bleeding disorders. Other determinants of clinical severity apart from FVII level (FVIIL) include genetic and environmental factors. We aimed to identify the cut-off FVIILs for general and severe bleedings in patients with FVIID by using an online national registry system including clinical, laboratory, and demographic characteristics of patients. METHODS: Demographic, clinical, and laboratory data of patients with FVIID extracted from the national database, constituted by the Turkish Society of Hematology, were examined. Bleeding phenotypes, general characteristics, and laboratory features were assessed in terms of FVIILs. Bleeding rates and prophylaxis during special procedures/interventions were also recorded. RESULTS: Data from 197 patients showed that 46.2% of patients had FVIIL< 10%. Most bleeds were of mucosal origin (67.7%), and severe bleeds tended to occur in younger patients (median age: 15 (IQR:6-29)). Cut-off FVIILs for all and severe bleeds were 16.5% and 7.5%, respectively. The major reason for long-term prophylaxis was observed as central nervous system bleeding (80%). CONCLUSION: Our data are consistent with most of the published literature in terms of cut-off FVIIL for bleeding, as well as reasons for prophylaxis, showing both an increased severity of bleeding and younger age at diagnosis with decreasing FVIIL. However, in order to offer a classification similar to that in Hemophilia A or B, data of a larger cohort with information about environmental and genetic factors are required.

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.

Increased Endothelial Cell Density in Childhood Patients With Thalassemia Major.

PURPOSE: We aimed to compare specular microscopy, biometric, refractive, and anterior segment topographic parameters in children with thalassemia major (TM) with normal children of the same age. MATERIAL METHOD: This cross-sectional study included 55 eyes of 55 patients with TM and 63 eyes of 63 age-sex-matched healthy children; all patients with TM were receiving treatment with blood transfusions every 3 to 4 weeks and an oral iron chelator deferasirox (DFX) (ICL670) tablet. A comprehensive ophthalmic examination was performed, including refraction (spherical equivalent), best-corrected visual acuity, slit-lamp bio microscopy, specular examination, optical biometry, intraocular pressure, anterior segment topography, and fundus examination. RESULTS: Endothelial cell density (ECD) was 3,138 in the TM group and 2,996 in the control group (P=0.003). The mean central corneal thickness was significantly thinner in the TM group (P=0.010). Flat keratometry (K1) was 43.5 D in the study group and 42.9 D in the control group (P=0.039). The mean anterior chamber depth (ACD) was shallower in the TM group (P=0.004); axial length (AL) was significantly shorter in the TM group (P=0.002). CONCLUSION: This study shows that there are differences in ECD, AL, keratometry values, ACD, and anterior segment parameters of pediatric patients with TM compared with healthy controls.

Tissue Plasminogen Activator Use in Pediatric Patients: A Single Center Experience.

INTRODUCTION: Thrombosis is rare in children and antithrombolytic treatment is controversial. Most commonly used thrombolytic agent is tissue plasminogen activator (t-PA) in pediatrics. In this study, we report our experience in the use of thrombolytic treatment. METHODS: Eighteen patients who had received systemic t-PA between January 2006 and December 2013 were recorded. The response to t-PA was evaluated as complete, partial, and no. The bleeding complication during t-PA administration was graded as minor or major. RESULTS: There were 18 patients (2 mo to 12 y) who received systemic t-PA. Three patients had venous, 14 patients had arterial, and 1 patient had intracardiac thrombosis. Thrombosis was related to cardiac catheterization (61.1%), central venous catheterization (16.7%), cardiac surgery (11.1%), and arrhythmia (5.5%). In 1 patient thrombosis occurred spontaneously (5.5%). Eighteen patients received 25 courses of systemic t-PA (0.15 to 0.3 mg/kg/h). A total of 55.6% of cases had complete, 27.8% had partial, and 16.6% showed no resolution. CONCLUSION: t-PA infusion at doses of median 0.2 mg/kg/h (0.15 to 0.3) seems effective and safe. There is still no consensus on indications and dosing of antithrombolytic treatment in children but in selected patients it decreases long-term complications due to thrombosis.

Investigation of Dynamic Thiol/Disulfide Homeostasis in Children With Acute Immune Thrombocytopenia.

Oxidative stress may play a role in the pathogenesis of immune thrombocytopenia (ITP), but the role of dynamic thiol/disulfide homeostasis has not been studied. The objective of this study was to assess whether there is a change in thiol/disulfide homeostasis in children with acute ITP. A total of 40 children with acute ITP and 50 healthy age-matched and sex-matched controls were included in this study. Serum total thiol and native thiol levels have been measured with a novel automatic spectrophotometric method. The amount of dynamic disulfide bonds and related ratios were calculated from these values. The average total thiol and native thiol levels of the patient group were found to be significantly lower than those levels of controls (P<0.01). However, intravenous immunoglobulin (IVIG) treatment with 1 g/kg/d prevented these reductions. disulfide level was slightly, but not significantly, depressed in ITP patients, but it recovered following IVIG treatment. We detected no marked changes in disulfide/total thiol, disulfide/native thiol, and native thiol/total thiol ratios between groups. These results are the first to demonstrate that thiol/disulfide homeostasis plays a role in ITP pathogenesis, and IVIG treatment can prevent the reduced thiol levels in children.

Refugee children with beta-thalassemia in Turkey: Overview of demographic, socioeconomic, and medical characteristics.

AIM: Since the beginning of the Syrian civil war, more than 3.5 million Syrians have been under temporary protection status in Turkey. Because beta-thalassemia (BT) is a prevalent disorder in the Mediterranean countries, we decided to estimate the prevalence of and make an overview of the demographic, socioeconomic, medical characteristics, and healthcare problems of refugee children with BT. PATIENTS: Eighteen Turkish Pediatric Hematology Oncology Centers (PHOC) with 318 refugee children from 235 families participated in the study. The mean age of the patients was 8.1 ± 4.8 years (0.5-21 years). The mean time after immigration to Turkey was 2.5 ± 1.5 years (range, 0.1-7 years). Seventy-two (22.6%) of them were born and diagnosed with BT in Turkey. On physical examination, 82 patients (26%) were underweight and 121 patients (38%) were stunted. The appearance of a thalassemic face was reported for 207 patients (65.1%). Hepatomegaly and splenomegaly were reported in 217 (68.2%) and 168 (52.8%) patients, respectively. The median ferritin level was 2508 ng/mL (range, 17-21 000 ng/mL) at the first admission, and 2841 ng/mL (range, 26-12 981 ng/mL) at the last visit after two years of follow-up in a PHOC (P > 0.05). The most frequently encountered mutation was IVSI-110 (G>A) (31%). Before immigration, only 177 patients (55.6%) reported the use of chelators; after immigration it increased to 268 (84.3%). CONCLUSION: Difficulties in communication, finding a competent translator capable in medical terminology, nonregular use of medications, and insensitivity to prenatal diagnosis were preliminary problems. The current extent of migration poses emerging socioeconomic and humanitarian challenges for refugee patients with BT.

Toxicity of Vincristine Combined With Posaconazole in Children With Acute Lymphoblastic Leukemia.

BACKGROUND: Vincristine (VCR) is one of the main drugs of acute lymphoblastic leukemia (ALL) treatment. Azole antifungal medications are used for treatment or prophylaxis of invasive fungal infections in acute leukemia. Coadministration of these drugs increases the risk of VCR toxicity. OBSERVATIONS: We presented a girl with ALL using posaconazole prophylaxis. She developed VCR toxicity that included tubulopathy, high blood pressure, neuropathic pain, difficulty walking, diffuse muscular weakness, constipation, abdominal pain. CONCLUSIONS: There are limited data in children with ALL for posaconazole prophylaxis. We recommend that VCR side effects should be evaluated by careful monitoring of the patients who are on this combination therapy.

Secondary Hemophagocytic Lymphohistocytosis in a Child With Brucellosis.

Hemophagocytic lymphohistocytosis (HLH) is a potentially fatal hyperinflammatory syndrome that is characterized by proliferation of histiocytes and hemophagocytosis in different organs. The diagnostic criteria include fever, hepatosplenomegaly, bicytopenia, high serum ferritin level, decreased natural killer cell activity, elevated soluble CD25 level, high serum fasting triglyceride level or low fibrinogen level, and hemophagocytosis in the bone marrow, spleen, or lymph nodes. HLH can be classified as primary and secondary. Secondary HLH can be related to infections. Here we report a case of Brucella-related HLH, which has been rarely reported in the literature.

Effects of respiratory viruses on febrile neutropenia attacks in children.

Respiratory tract viruses have an important effect on morbidity and mortality in patients with febrile neutropenia (FN). The aim of this study was to determine frequency and clinical influence of viral respiratory viruses as potential etiologic agents in episodes of FN in children. A total of 100 children (62 boys, 38 girls) with 166 FN episodes were included in this prospective study. Nasopharyngeal aspirate samples were analyzed for respiratory viral agents using multiplex real-time polymerase chain reaction. The origin of the fever could be defined in 111 (67%) of the episodes. We detected viral agents in 86 (51.8%), bacterial agents in 19 (11.4%), and fungal agents in 5 (3%) of the episodes. The most common detected viruses were rhinovirus (n= 27), respiratory syncytial virus (n=17), and coronavirus (n=16). Parainfluenza virus, influenza A and B, adenovirus, human metapneumovirus, enterovirus, bocavirus and parechovirus were the remaining detected agents. More than one virus positivity occurred in 13 FN episodes. Forty-three patients had multiple FN episodes. Only four patients had the same viral agent in consecutive attacks. Respiratory symptoms (cough, nasal discharge and congestion, sneezing, wheezing), physical examination signs (rales and rhonchi) and radiological findings were significantly more common in viral agent positive patients (p < 0.05). This study showed that respiratory viruses make a substantial contribution on the etiology of FN episodes in children. Identifying viral agents may help to constitute individualized infection-management algorithms in these patients.

An unusual case of neuroblastoma: a 17-year-old adolescent presented with bilateral diffuse lung metastasis at initial diagnosis.

Neuroblastoma (NB) is the most frequently diagnosed neoplasm during infancy and its incidence declines within the first 3-5 years of life. It can be rarely diagnosed in adolescents and young adults. Adolescents have advanced stage of disease, higher frequency of uncommon metastatic sites such as lungs, and worse outcomes. Herein, we describe an unusual case of NB in a 17-year-old adolescent presented with lung metastasis at diagnosis. The patient was diagnosed with stage IV NB. Thorax high-resolution computed tomography (HRCT) scan revealed irregular septal thickening with ground glass opacity consistent with pulmonary parenchymal metastases. After the first cycle of chemotherapy he developed pulmonary hemorrhage and respiratory distress. He required ventilation support and mechanical ventilation was started. Metastatic nodules were determined on second thorax HRCT. We lost the patient due to septic shock and multiple organ failure 2 months after diagnosis. In conclusion, adolescents with NB have unfavorable prognosis. These patients may have lung metastases at diagnosis. Therefore, detailed chest imaging at initial diagnosis is crucial.

Prognostic impact of RUNX1 and ETV6 gene copy number on pediatric B-cell precursor acute lymphoblastic leukemia with or without hyperdiploidy.

The ETV6/RUNX1 fusion gene is a valuable prognostic marker that is frequently observed in B-cell precursor acute lymphoblastic leukemia (B-cell ALL). However, the clinical significance of copy number aberrations in these genes remains unclear. In this study, the effects of various aberrations inETV6 and RUNX1 gene copy number on disease prognosis were evaluated in 21 pediatric patients diagnosed with B-cell ALL with/without t(12;21). The prognostic significance of changes in gene copy number of ETV6 or RUNX1 in the presence or absence of hyperdiploidy, trisomy 21, and t(12;21) translocation were also evaluated. RUNX1 gene copy number amplifications were detected in 83 % of the patients who lacked t(12;21) and in all of the patients with hyperdiploidy. Trisomy 21 was detected in 78 % of the patients with hyperdiploidy. Changes in ETV6 gene copy number were detected in patients who lacked both the t(12;21) translocation and RUNX1 gene copy number amplifications. However, RUNX1 gene copy number amplification and ETV6 deletion were observed in all of the patients with t(12;21). RUNX1 gene copy number amplification was associated with hyperdiploidy, but not with t(12;21). Thus, the evaluation of distinct FISH and cytogenetic patterns in patients with B-cell ALL may strengthen the prognostic significance of changes in gene copy number.

Idiopathic Pulmonary Hemosiderosis With Allergic Asthma Diagnosis in a Pediatric Patient.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disorder with unknown pathogenesis that usually presents in the first decade of life. As a result of diffuse alveolar hemorrhage, respiratory symptoms such as cough attacks, hemoptysis, dyspnea, and recurrent and refractory iron-deficiency anemia (IDA) are observed. We present an 8-year-old girl who was followed up with recurrent IDA and allergic asthma and later diagnosed with IPH. IPH was confirmed by the presence of hemosiderin-laden macrophages in bronchoalveolar lavage obtained by bronchoscopy and exclusion of the secondary causes of pulmonary hemosiderosis. Glucocorticoids and iron supplementation were started. Clinical and laboratory improvement was observed with therapy. Our case illustrates that refractory/recurrent IDA with any pulmonary symptoms may be the only presenting feature of IPH.

Rheumatic silent carditis: echocardiographic diagnosis and prognosis of long-term follow up.

BACKGROUND: Rheumatic fever and rheumatic heart disease continue to be an important public health problem in developing countries. Doppler echocardiography is now widely used for early detection and recurrence of clinical evident carditis (CC) and silent (subclinical) carditis (SC). The aim of this study was to determine the frequency of SC and to compare clinical and echocardiographic features of CC and SC. METHODS: A total of 156 consecutive patients diagnosed with acute rheumatic fever were included in the study. The patients without clinical evidence but with echocardiographic findings of carditis were diagnosed as having SC. RESULTS: Acute rheumatic fever was diagnosed in 156 patients, and 103 of these (66%) had carditis. The prevalence of SC was 28.2% among these 103 patients. Seventy-four of the patients with carditis were followed up for >1 year, and 20 of those had SC. Valvular regurgitation disappeared completely in 18.5% and improved in 45.5% of the CC patients. The recovery and improvement rates in the SC group were 15% and 30%, respectively. CONCLUSION: It is suggested that Doppler echocardiography be performed in all patients with suspected acute rheumatic fever for early detection of SC. Echocardiography should be used as a diagnostic criterion in order not to miss a diagnosis of SC.