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.

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.

The relationship between the care burden and quality of life of parents who have children with hematological problems and their perceived social support.

PURPOSE: The purpose of this study was to examine the interrelationship of the caregiver burden, perceived social support, and quality of life of parents who have children with hematological problems. DESIGN AND METHODS: The design and methods included a descriptive study with 141 parents of children with hematological problems. The introductory information form, the Zarit Burden Interview (ZBI), multidimensional scale of perceived social support (MSPSS), and the EUROHIS-QOL.8 (WHOQOL-8) scale were used as data collection tools. The data obtained were analyzed using descriptive statistics and structural equation models. RESULTS: As a result of the conducted correlation analysis, it was determined that there was a positive correlation between parents' perceptions of social support and their quality of life, and a negative correlation between their perceptions of social support and the caregiver burden (p < 0.05). As a result of the structural equation model, it was determined that the social support received by the parents had a significant effect on their caregiver burden (ß = -0.40; p < 0.05), and their quality of life (ß = 0.42; p < 0.05). CONCLUSIONS: The conclusion formed was that it can be said that parents' perceptions of social support affect their caregiver burden and quality of life. Parents with high perceptions of social support perceive the burden of caregiver to be low and their quality of life to be high. PRACTICE IMPLICATIONS: The practice implications are that healthcare professionals can contribute to reducing the caregiver burden and improving the quality of life of parents, by strengthening the social support systems of parents with sick children.

Erythrocyte transfusion restored heart rate variability in children with thalassemia major.

Thalassemia major (TM) is a severe transfusion-dependent anemia. Regular erytrocyte transfusion is required for the treatment of thalassemia patients. However, repeated transfusion may result in impairements in heart function. In this study, we aimed to investigate short-term effects of erythrocyte transfusion on autonomic control of heart in children with thalassemia major. For that purpose heart rate variability (HRV), which is a non-invasive method used to evaluate the effects of the autonomic nervous system on the heart rhythym, was measured before and after erythrocyte transfusion and compared to the healthy controls. Children diagnosed with TM (n = 17) and sex and age matched healthy children (HC, n = 30) were included in the study. HRV values of TM patients were measured 5 min before erythrocyte transfusion (BET, n = 17) and 5 min after erythrocyte transfusion (AET, n = 17). Parameters of time-domain and frequency-domain of HRV were evaluated in all participants. Heart rate (HR) was higher in the BET than AET (P = 0.002) but there was no difference between AET and HC groups (P > 0.05). HRV parameters were lower in BET than AET (P < 0.05) but there were no statistical difference between AET and HC (P> 0.05). The data suggest that, in thalassemia major patients, erythrocyte transfusion restores HR and HRV parameters to the levels observed in healthy controls and, thus, in short-terms, appears to be beneficial for the autonomic control of the heart.

Hearing status in vitamin B12-deficient children.

AIM: The aim of this study is to investigate the effects of vitamin B12 deficiency on hearing in school-aged children by pure-tone audiometry. METHODS: Forty-three vitamin B12-deficient children and 37 age-matched control subjects were enrolled in the study. Tympanometric evaluations and pure-tone audiometry including high frequencies were performed on the subjects. The results were compared between the two groups. RESULTS: Both right and left ear pure-tone hearing thresholds (PTHTs) at 0.25-4 kHz, and four-frequency pure-tone average values were significantly better in the control group compared with the patient group (P < 0.05). However, PTHTs at 8-16 kHz were not different between the two groups (P > 0.05). Vitamin B12 level also did not show any significant correlation with the PTHTs at 0.25-16 kHz (P > 0.05). CONCLUSION: This study indicates that vitamin B12 deficiency may contribute to hearing impairment at low frequencies as a possible aetiological factor in children.

Muscle strength, motor performance, cardiac and muscle biomarkers in detection of muscle side effects during and after acute lymphoblastic leukemia treatment in children.

Muscle side effects have not been frequently assessed in childhood acute lymphoblastic leukemia (ALL) patients. Our objective was to determine the early and late muscle side effects during childhood ALL treatment. To this end, we examined the early muscle side effects in 15 newly diagnosed "therapy patients" (group I), and the late side effects in 18 ALL survivors "off therapy patients" (group II). Muscle side effects were assessed by measuring hand grip strength (HGS), the "timed up and go" (TUG) test, creatine phosphokinase, myoglobin, plasma electrolytes, cardiac troponin I before and after induction chemotherapy in group I. The same parameters and cranial radiotherapy dose were examined in group II at a single timepoint. Cumulative doses of chemotherapy were calculated, and echocardiograms were obtained for each group. As a result, we found that the HGS and TUG measures of group I at the end of induction were poorer than measures of the first admission, control subjects, and group II. Low HGS measures had been normalized over time, but the TUG measures remained poor. Overt rhabdomyolysis and pyomyositis were not detected in any of the patients. These results suggested that muscle side effect monitoring might be helpful in the follow-up of children with ALL.

Biochemical, radiologic, ultrastructural, and genetic evaluation of iron overload in acute leukemia and iron-chelation therapy.

Iron overload in hereditary hemochromatosis and hematologic malignancy has unfavorable effects on morbidity. Herein, 53 children (age 108.4±58.3 mo, 25 girls and 28 boys) with acute myeloblastic and lymphoblastic leukemia, who received 4 different chemotherapy protocols, were evaluated for iron overload throughout chemotherapy. Iron overload arose: (1) before chemotherapy, which was dependent on neither chemotherapy nor packed red blood cell transfusions and (2) after chemotherapy, which was dependent on the duration and nature of chemotherapy and partially on transfusion of packed red blood cells. Iron overload was documented in 75% of patients with a ferritin level >1000 ng/mL, by liver and heart magnetic resonance imaging, and they were administered iron-chelation therapy with success. Three of 10 radiologically iron-overloaded patients were heterozygous for H63D mutation. Aminolevulinic acid and porphobilinogen levels were normal. Light microscopic examination of the bone marrow revealed increased iron granules in erythroblasts, platelets, and megakaryocytes, iron-laden macrophages, free iron in the matrix, dyshematopoiesis, and apoptotic cells. Electron microscopic examination revealed iron-laden secondary lysosomes and autolysosomes in normoblasts and iron-laden primary granules in promyelocytes, irrelevant to the ferritin level, implying autophagia due to chemotherapy as a source of the excess iron. We think that iron overload, which is an important complication of acute leukemia, should be evaluated separately from "transfusion overload," and the management principles specific to leukemia should be implemented.

Risk factors for acute symptomatic seizure in children with cerebral sinovenous thrombosis: Experience from a tertiary center.

OBJECTIVE: To investigate the risk factors for acute symptomatic seizure (ASS) in children with Cerebral Sinovenous Thrombosis (CSVT) and to evaluate the effect of ASS on outcome. METHODS: Cross-sectional, single-center, hospital-based retrospective analysis of 42 children with neuroimaging-confirmed CSVT recorded between December 2009 and January 2023. ASS was defined as a seizure occurring within 7 days after CSVT. Predictors for ASS were analyzed by univariate and multivariate logistic regression. Functional outcomes were evaluated using the Pediatric Stroke Outcome Measure (PSOM). RESULTS: The average age of the 42 patients included in the study sample was 105.36 ± 63.1 months. Almost one-third (28.6 %) of patients with CSVT developed ASS. In univariate analysis, factors associated with seizure risk were young age, low Glasgow Coma Scale at admission, long hospital stay, headache, change of consciousness, focal neurological findings, cerebral hemorrhage, motor deficit and high D-dimer level (p=0.018, p<0.001, p= 0.016, p= 0.001, p=0.014, p<0.001, p<0.001, p=0.019 and p=0.013, respectively). In multivariate analysis young age, focal neurological findings and D-dimer levels were potential predictors of ASS (p=0.004, p=0.003, p=0.036, respectively). Receiver operating characteristic (ROC) analysis for D-dimer diagnostic accuracy in patients with CSVT revealed D-dimer > 498 ng/mL (AUC=0.743). In both cohorts, PSOM scores at last follow-up were worse in those with acute seizures compared to those without (p<0.001). CONCLUSION: Acute seizures occurred in approximately one-third of our cohort. Young age, focal neurological findings, and high D-dimer levels are potential predictors of ASS in children. Children with ASS had worse outcomes than those without.

Thromboembolism in Children.

OBJECTIVE: To study pediatric patients who were diagnosed with thrombosis between January 2009 and March 2020. METHODS: Patients were evaluated with respect to thrombophilic risk factors, localization of the thrombus, response to treatment, and recurrence rates during the last 11 y. RESULTS: Among 84 patients, 59 (70%) had venous thrombosis and 20 (24%) had arterial thrombosis. The number of documented thrombosis amongst hospitalized children in authors' hospital has increased over the years. It has been observed that the annual incidence of thromboembolism has increased after 2014. Thirteen patients were recorded between 2009 and 2014 and 71 patients between 2015 and 2020 (until March 2020). Exact thrombosis localization could not be detected in 5 patients. The median age of patients was 8 ± 5.95 (range 0-18). Fourteen children (16.9%) had a history of familial thrombosis. Genetic and/or acquired risk factors were detected in 81 (96.4%) of the patients. Overall, 64 patients (76.1%) had acquired risk factors such as infection (20.2%), catheterization (13.1%), liver disease (11.9%), mastoiditis (8.3%), liver transplantation (6%), hypoxic-ischemic encephalopathy (4.8%), dehydration (3.6%), trauma (3.6%) and cancer (2.4%). As genetic risk factors, the most common genetic mutations were PAI-1 4G>5G, MTHFR C677T, and MTHFR A1298C mutations. Twenty-eight (41.2%) patients had at least one genetic thrombophilic mutation. At least one homozygous mutation in 37 patients (44%) and at least one heterozygous mutation in 55 patients (65.4%) were detected. CONCLUSIONS: The annual incidence of thrombosis has increased over the years. Genetic predisposition and acquired risk factors play an important role in etiology, treatment, and follow-up in children with thromboembolism. Especially, genetic predisposition is common. Thrombophilic risk factors should be investigated and optimal therapeutic and prophylactic measures should be promptly taken in children with thrombosis.

Clinical Characteristics and Outcomes of Cancer Cases Among Syrian Refugees From Southern Turkey.

Importance: Cancer was a common noncommunicable disease in Syria before the present conflict and is now a major disease burden among 3.6 million Syrian refugees in Turkey. Data to inform health care practice are needed. Objective: To explore sociodemographic characteristics, clinical characteristics, and treatment outcomes of Syrian patients with cancer residing in the southern border provinces of Turkey hosting more than 50% of refugees. Design, Setting, and Participants: This was a retrospective hospital-based cross-sectional study. The study sample consisted of all adult and children Syrian refugees diagnosed and/or treated for cancer between January 1, 2011, and December 31, 2020, in hematology-oncology departments of 8 university hospitals in the Southern province of Turkey. Data were analyzed from May 1, 2022, to September 30, 2022. Main Outcomes and Measures: Demographic characteristics (date of birth, sex, and residence), date of first cancer-related symptom, date and place of diagnosis, disease status at first presentation, treatment modalities, date and status at last hospital visit, and date of death. The International Statistical Classification of Diseases and Related Health Problems, Tenth Revision and International Classification of Childhood Cancers, Third Edition, were used for the classification of cancer. The Surveillance, Epidemiology, and End Results system was applied for staging. The diagnostic interval was defined as the number of days from first symptoms until the diagnosis. Treatment abandonment was documented if the patient did not attend the clinic within 4 weeks of a prescribed appointment throughout the treatment. Results: A total of 1114 Syrian adult and 421 Syrian children with cancer were included. The median age at diagnosis was 48.2 (IQR, 34.2-59.4) years for adults and 5.7 (IQR, 3.1-10.7) years for children. The median diagnostic interval was 66 (IQR, 26.5-114.3) days for adults and 28 (IQR, 14.0-69.0) days for children. Breast cancer (154 [13.8%]), leukemia and multiple myeloma (147 [13.2%]), and lymphoma (141 [12.7%]) were common among adults, and leukemias (180 [42.8%]), lymphomas (66 [15.7%]), and central nervous system neoplasms (40 [9.5%]) were common among children. The median follow-up time was 37.5 (IQR, 32.6-42.3) months for adults and 25.4 (IQR, 20.9-29.9) months for children. The 5-year survival rate was 17.5% in adults and 29.7% in children. Conclusions and Relevance: Despite universal health coverage and investment in the health care system, low survival rates were reported in this study for both adults and children with cancer. These findings suggest that cancer care in refugees requires novel planning within national cancer control programs with global cooperation.

False positive result of the direct antiglobulin test (DAT): the role of the elevated level of immunoglobulin G.

Direct antiglobulin test (DAT) is a test that shows antibodies bound to the surface antigens of erythrocytes. In this article, our aim was to investigate whether a correlation exists between a DAT positive test and serum immunoglobulin (Ig) levels. In our clinic, all DAT positive patients were retrospectively studied. Patients who had not received a blood transfusion within the last three months and who were evaluated for Ig levels were enrolled in the study (n = 15). Of these subjects, 15 showed a DAT positive result. Ten patients did not show any clinical or laboratory signs of hemolysis, while five patients exhibited signs and symptoms of autoimmune hemolytic anemia (AIHA). While all subjects showed a DAT positive test result (Ig G ± C(3)), four patients without AIHA, and three patients with AIHA showed a positive indirect antiglobulin test (IAT). In patients with a higher level of immunoglobulin G (IgG), the treatment of the concomitant disease resulted in normalization of the IgG level and led to a negative DAT test. The conditions that lead to an elevation of Ig should be reviewed in patients who displayed a DAT positive test without hemolysis and who had not previously received a blood transfusion.

H1N1-Associated Encephalitis in a Child with Acute Myeloblastic Leukemia and Bacteremia due to Klebsiella Pneumoniae.

Herein we present a neutropenic 16-year-old female with acute myeloblastic leukemia that developed recurrentgeneralized seizures while receiving antimicrobial therapy (including oseltamivir) due to pneumonia, bacteremiaof Klebsiella pneumoniae, and H1N1 infection. The patient's seizures were controlled using assisted ventilation.Electroencephalography showed that the patient had encephalopathy. Cranial computed tomography (CT), magneticresonance imaging (MRI), and MRI angiography findings were normal. The patient fully recovered without sequelae.This case indicates that during pandemics of influenza-like diseases H1N1 infection should always be a consideration.

Intensive chemotherapy perturbs heart rate variability in children with cancer.

OBJECTIVES: In children, cancer chemotherapy may impair the functioning of the cardiac autonomic nervous system. Moreover, it is not known whether there are any differences between intensive and maintenance phases of chemotherapy. Therefore, the aim of the current study was to assess autonomic nervous system activity using heart rate variability, in children receiving intensive or maintenance cancer chemotherapy. METHODS: For that purpose, children who were healthy (healthy control, n = 30), receiving intensive chemotherapy (chemotherapy, n = 30), and receiving maintenance chemotherapy (maintenance, n = 25) were included in the study. Autonomic nervous system activity was measured by means of heart rate variability. Electrocardiogram recordings were used to calculate time- and frequency-domain heart rate variability parameters. RESULTS: Time-domain parameters such as standard deviation of NN intervals and frequency-domain parameters such as total power were lower during the intensive chemotherapy but not during maintenance phase (standard deviation of NN intervals: 50±5, 33±3, and 48±3 ms, and total power: 2613±504, 1379±296 and 2295±264 ms2, respectively for healthy control, chemotherapy and maintenance groups, P<0.001 for both standard deviation of NN intervals and total power). DISCUSSION: The present results indicate that intensive chemotherapy perturbs the function of heart rate variability in children, with recovery during the maintenance phase. This suggests that intensive chemotherapy is likely to affect the autonomic nervous system but this effect does not appear to be permanent.

Thalassemia-free and graft-versus-host-free survival: outcomes of hematopoietic stem cell transplantation for thalassemia major, Turkish experience.

We report the national data on the outcomes of hematopoietic stem cell transplantation (HSCT) for thalassemia major (TM) patients in Turkey on behalf of the Turkish Pediatric Stem Cell Transplantation Group. We retrospectively enrolled 1469 patients with TM who underwent their first HSCT between 1988 and 2020 in 25 pediatric centers in Turkey. The median follow-up duration and transplant ages were 62 months and 7 years, respectively; 113 patients had chronic graft versus host disease (cGVHD) and the cGVHD rate was 8.3% in surviving patients. Upon the last visit, 30 patients still had cGvHD (2.2%). The 5-year overall survival (OS), thalassemia-free survival (TFS) and thalassemia-GVHD-free survival (TGFS) rates were 92.3%, 82.1%, and 80.8%, respectively. cGVHD incidence was significantly lower in the mixed chimerism (MC) group compared to the complete chimerism (CC) group (p < 0.001). In survival analysis, OS, TFS, and TGFS rates were significantly higher for transplants after 2010. TFS and TGFS rates were better for patients under 7 years and at centers that had performed over 100 thalassemia transplants. Transplants from matched unrelated donors had significantly higher TFS rates. We recommend HSCT before 7 years old in thalassemia patients who have a matched donor for improved outcomes.

Hematogones in immune thrombocytopenic purpura: diagnostic implication.

Hematogones (HGs) are benign immature B cells in bone marrow with a variety of benign and malignant conditions, including idiopathic thrombocytopenic purpura, leukemia, lymphoma, red blood cell aplasia, iron deficiency anemia, amegakaryocytosis, regenerative bone marrow following viral injury, chemotherapy or bone marrow transplantation, copper deficiency, autoimmune cytopenias, neuroblastoma, and acquired immunodeficiency syndrome (AIDS). HGs may cause diagnostic problems because of their morphologic and immunophenotypic similarities to neoplastic lymphoblasts. Herein, two patients with thrombocytopenia and three lineage dysplasias in the bone marrow suggesting myelodysplastic syndrome (MDS) with excess blasts are presented. Light microscopic evaluation of marrow from both patients revealed periodic acid-Schiff (PAS)-negative blasts However, flow cytometric analysis revealed excessive HGs in both patients, implying that the cells that were considered as blasts were actually large HGs. Thus, the patients were diagnosed as immune thrombocytopenic purpura due to the isolated thrombocytopenia, large platelets on blood and bone marrow smears and increased megakaryocytes in the bone marrow. These cases emphasize the importance of distinction of hematogone-rich conditions from leukemia and MDS for accurate diagnosis and treatment, and the reliability of multiparameter flow cytometry for the differential diagnosis.

Conus medullaris syndrome and acute colonic pseudoobstruction in a child with acute lymphoblastic leukemia.

A 5(3/12)-year-old boy with Philadelphia chromosome (+) pre-B acute lymphoblastic leukemia (ALL) without extramedullary involvement did not achieve remission after induction therapy. His family stopped therapy, but he was readmitted eight months later due to pyoderma, pneumonia and active leukemia with leukocytosis. During cytoreductive and antibiotic therapy, he developed progressive abdominal distension, pain, globe vesicale, tachypnea, and respiratory alkalosis. Bowel sounds could not be auscultated. Dilation, mainly in the large intestine, was detected radiologically. His neurological examination revealed absence of superficial reflexes and hypoesthesia along with normal motor strength and deep tendon reflexes in the lower extremities, consistent with conus medullaris syndrome, which was thought to give rise to acute colonic pseudo-obstruction.