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.

ST2 and Reg3α: Can they predict aGvHD, steroid refractoriness and transplant-related mortality in pediatric patients after HSCT?

BACKGROUND/AIM: There are several complications of hematopoietic stem cell transplantation. Without any doubt, most important of these is aGvHD that increases transplant-related mortality. The aim of this study is to investigate whether ST-2 and Reg3α levels measured at an early stage in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation can be individual biomarkers identifying future GvHD and predicting treatment response. MATERIALS AND METHODS: From January 2019 to January 2021, 27 patients undergoing hematopoietic stem cell transplantation for primary immunodeficiency or hematopoietic diseases formed the study group. During their follow-up, the patients were classified into two groups as those developing and those not developing aGvHD. Nineteen healthy volunteers from a similar age group who needed their blood samples drawn for other reasons and who did not have any history of chronic disease, infection or medication use formed the control group. Blood samples of patients scheduled to have allogeneic HSCT were obtained before the administration of the preparative regimen, on Day +7 post-transplant and on the day of diagnosis if they developed aGvHD. Serum samples were stored at -20ºC until the day of processing. ST2 and Reg3α levels were measured using the ELISA method. RESULTS: For patients who developed aGvHD (n = 13), ST2 levels obtained before the transplantation, on Day +7 post-transplant and on the day of aGvHD diagnosis (in patients developing GvHD) were significantly higher compared to the healthy Control Group (p-value <0.05). As regards to the samples obtained on the same days, ST2 levels did not differ significantly among patients who developed and those who did not develop GvHD (n = 14; p-value >0.05). ST2 levels of samples obtained on the days that acute skin and gastrointestinal tract GvHD developed did not differ significantly between these two groups (p-value >0.05). Reg3α levels of the pre-transplant samples, on Day +7 after the transplantation and on the day of aGvHD diagnosis did not show any difference between any of the groups (p-value >0.05). As only two patients died after transplantation, thus correlation of ST2 and Reg3α levels with transplant-related mortality could not be proven. CONCLUSION: The results of this study suggest that ST2 and Reg3α levels are neither diagnostic nor prognostic or predictive biomarkers of aGvHD, steroid resistance or transplant-related mortality in pediatric patients. This study can be regarded as a pilot study because of the small patient population; more research involving a larger patient population is required.

Exploring Multiple Endocrinological Issues and Dysautonomia in a Rare Case: Hypoparathyroidism in MIRAGE Syndrome.

MIRAGE syndrome is a rare multisystemic disorder characterized by various manifestations, such as myelodysplasia, susceptibility to infections, growth retardation, adrenal hypoplasia, genital anomalies, and enteropathy. In the literature, there have been rare cases of dysautonomia. We present a 6.5-year-old girl, who was first admitted to our department with short stature. On follow up, she exhibited multiple endocrinological issues, including transient hypothyroidism, primary hypoparathyroidism and dysautonomia, along with multisystem involvement. Further investigations revealed recurrent moniliasis, low IgM levels, and transient monosomy 7 in the bone marrow. Whole exome sequencing revealed a heterozygous pathogenic variant of SAMD9 (c.2159del; p.Asn720ThrfsTer35). Additional complications observed during follow-up included medullary nephrocalcinosis, hypomagnesemia, hypermagnesiuria, hypophosphatemia, decreased glomerular filtration rate, and nephrotic proteinuria. The patient also developed hyperglycemia, which was managed with low-dose insulin. This case highlights the diagnostic challenges and the diverse phenotypic presentation observed in MIRAGE syndrome.

Successful Treatment with Ascorbic Acid in a Case of Methemoglobinemia Due to Glucose-6-Phosphate Dehydrogenase Deficiency.

Cite this article as: Karaçoban G, Gurbanov A, Özen H, Gün E, Çakmakli HF, Kendirli T. Successful treatment with ascorbic acid in a case of methemoglobinemia due to glucose-6-phosphate dehydrogenase deficiency. Turk Arch Pediatr. 2024;59(1):112-113.

The effect of granulocyte colony stimulating factor on genotoxicity in allogeneic peripheral blood stem cell transplantation donors: a prospective case-control study.

BACKGROUND: Every year, thousands of donors are exposed to granulocyte-colony stimulating factor (G-CSF) for stem cell mobilization in hematopoietic stem cell transplantations (HSCT). Previous studies about the genotoxicity of G-CSF were inconclusive. In this study, the genotoxic effects of G-CSF in peripheral blood stem cell (PBSC) donors were evaluated prospectively by using three different validated and reliable methods for the first time in the literature to the best of our knowledge. METHODS: Donors of PBSC transplantation (n=36), who received G-CSF were evaluated for genotoxicity by micronucleus test (MNT), nuclear division index (NDI), and comet assay (CA). Genotoxic effects are expected to cause an increase in MNT and CA values and decrease in NDI. Blood samples were collected at three timepoints (TP): before starting G-CSF (TP1), after G-CSF for five days (TP2), and one month after the last dose (TP3). Sixteen controls were included for baseline comparison of genotoxicity tests. CD34 cell counts and hemograms were also analyzed. RESULTS: MNT and CA parameters; comet and tail length, tail DNA%, and tail moment, showed no change in time whereas another CA parameter, Olive`s tail moment (OTM) was increased significantly at TP3 compared to both baseline and TP2 (p=0.002 and p=0.017, respectively). Nuclear division index decreased significantly at TP2 (p < 0.001), then increased above baseline at TP3 (p=0.004). Baseline comparison with controls showed higher MN frequency in donors without statistical significance (p=0.059). Whereas, CA results were significantly higher in controls. CD34 cell count showed moderate positive correlation with white blood cell count at TP2 (Pearson R=0.495, p=0.004). CONCLUSIONS: Our results showed the genotoxic effect of G-CSF in healthy donors, in two of the three tests performed, short-term effect in NDI, and long-lasting effect in OTM. So, this study provides novel information for the debate about the genotoxicity of G-CSF and supports the need for further studies with a larger sample size and longer follow-up.

Pediatric Invasive Aspergillosis: a Retrospective Review of 59 Cases.

Invasive aspergillosis (IA) is a major cause of morbidity and mortality. This study aimed to present our 10-year IA experience at a single center. Fifty-nine pediatric patients with IA were included in this study. The male-to-female ratio was 42/17. The median age was 8.75 years. Hematologic malignancy was present in the majority of the patients (40/59, 68%). The mean neutropenia duration was 18.5 days. Cytosine arabinoside was the most common immunosuppressive therapy directed at T cells during IA diagnosis. IA cases were categorized as proven (27%), probable (51%), or possible (22%) according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. The lungs (78%) were the most common site of IA, and nodules were the most frequent radiological findings (75.5%). In 38 patients (64.4%) receiving antifungal prophylaxis, prophylactic agents included fluconazole (30.5%), liposomal amphotericin B (23.7%), posaconazole (8.5%), and voriconazole (1.7%). Initial treatment was most commonly administered as monotherapy (69.5%). The median antifungal treatment duration was 67 days. Eleven deaths (18.6%) were due to aspergillosis. With the increased use of corticosteroids, biological agents, and intensive immunosuppressive chemotherapy, IA will most likely continue to occur frequently in pediatric patients.

SARS-CoV-2 infection showing signs of cerebral sinus vein thrombosis in the infantile period.

The clinical manifestations of SARS-CoV-2 infection mainly involve the respiratory system. However, there is increasing evidence that this virus can affect other organs, causing a wide range of clinical symptoms. This is the report of a 40-day-old patient who presented with sepsis and had no risk factors other than SARS-CoV-2 infection, whose radiological findings were compatible with cerebral sinus vein thrombosis.

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.

The role of galactomannan test results in the diagnosis of pediatric invasive aspergillosis.

BACKGROUND: Invasive aspergillosis (IA) is an important cause of morbidity and mortality in immunosuppressed children. Early detection of the infection can improve prognosis in this patient population. OBJECTIVES: To investigate the utility of Aspergillus galactomannan antigen assay (GM-EIA) as a diagnostic tool for IA in at-risk paediatric patients. PATIENTS/METHODS: For the study, 659 GM-EIA results from 59 patients diagnosed with IA and 3368 GM-EIA results from 351 subjects without evidence for IA (controls) were reviewed retrospectively. Three cut-off values (i.e. ≥0.5, ≥1, ≥1.5) were specified to determine GM-EIA positivity. RESULTS: The median age was 6.3 years for boys and 14.5 years for girls. There was a significant difference between the girls and boys in terms of age (p < 0.01). For proven/probable/possible IA patients, sensitivity of 67.8% and specificity of 59.8% were detected when the ≥0.5 cut-off value was used for GM-EIA-positivity. The specificity increased to 80% at the cut-off of ≥1 and to 88% at the cut-off of ≥1.5. False positivity rates were 9.14, 3, and 1.45% at the ≥0.5, ≥1 and ≥1.5 cut-offs respectively. In the proven/probable IA group, sensitivity and negative predictive values were 86.9 and 97.2% at the ≥0.5 cut-off, 85.7 and 97.9%, at the ≥1 cut-off and 84.2 and 98.1% at ≥1.5 cut-off respectively. The positive likelihood ratio was 7.57 and the odds ratio was 42.67 at ≥1.5 cut-off. CONCLUSION: The GM-EIA may be used for both screening and diagnostic purposes in paediatric patients using a cut-off value of ≥1.5 for GM-EIA positivity.

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.

Outcomes of Eltrombopag Treatment and Development of Iron Deficiency in Children with Immune Thrombocytopenia in Turkey

Objective: Immune thrombocytopenia (ITP) is a rare autoimmune disease and hematologic disorder characterized by reduced platelet counts that can result in significant symptoms, such as bleeding, bruising, epistaxis, or petechiae. The thrombopoietin receptor agonist eltrombopag (EPAG) is a second-line agent used to treat chronic ITP purpura in adults and children. Materials and Methods: The present retrospective study evaluated the efficacy, safety, and side effects of EPAG treatment in pediatric patients with acute refractory and chronic immune thrombocytopenia, particularly focusing on iron-deficiency anemia. Results: The diagnosis was chronic ITP in 89 patients and acute refractory ITP in 16 patients. The mean age of patients was 9.5±4.5 years (minimum-maximum: 1.2-18 years) at the beginning of EPAG treatment. The overall response rate was 74.3% (n=78). The mean time for platelet count of ≥50x109/L was 11.6±8 weeks (range: 1-34 weeks). The treatment was stopped for 27 patients (25.7%) at an average of 6.8±9 months (range: 1-38 months). The reason for discontinuation was lack of response in 18 patients, nonadherence in 4 patients, and hepatotoxicity in 2 patients. Response to treatment continued for an average of 4 months after cessation of EPAG in 3 patients. Conclusion: Results of the current study imply that EPAG is an effective therapeutic option in pediatric patients with acute refractory and chronic ITP. However, patients must be closely monitored for response and side effects during treatment, and especially for iron deficiency.

Macrocytic anemia in Lesch-Nyhan disease and its variants.

PURPOSE: Lesch-Nyhan disease is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study was  to describe macrocytic erythrocytes as another common aspect of the phenotype. METHODS: The results of 257 complete blood counts from 65 patients over a 23-year period were collected from 2 reference centers where many patients are seen regularly. RESULTS: Macrocytic erythrocytes occurred in 81-92% of subjects with Lesch-Nyhan disease or its neurological variants. After excluding cases with iron deficiency because it might pseudonormalize erythrocyte volumes, macrocytosis occurred in 97% of subjects. Macrocytic erythrocytes were sometimes accompanied by mild anemia, and rarely by severe anemia. CONCLUSION: These results establish macrocytic erythrocytes as a very common aspect of the clinical phenotype of Lesch-Nyhan disease and its neurological variants. Macrocytosis is so characteristic that its absence should prompt suspicion of a secondary process, such as iron deficiency. Because macrocytosis is uncommon in unaffected children, it can also be used as a clue for early diagnosis in children with neurodevelopmental delay. Better recognition of this characteristic feature of the disorder will also help to prevent unnecessary diagnostic testing and unnecessary attempts to treat it with folate or B12 supplements.

Expression of Survivin and Its Splice Variants in Pediatric Acute Lymphoblastic Leukemia.

Aims: Survivin is involved in the inhibition of apoptosis and the regulation of cell division. In addition to wild-type survivin (survivin-wt), at least four splice variants with differential functions (ΔEx3 and 3B antiapoptotic, and 2α and 2B proapoptotic) have been identified. Survivin is highly expressed in several cancers, including hematological malignancies. Although acute lymphoblastic leukemia (ALL) is the most frequent malignancy in children, studies that investigated survivin expression in ALL are limited, and there is no study on 3B and 2α expression in ALL. Therefore the expression of survivin-wt and its splice variants was investigated in pediatric B-cell ALL patients. Materials and Methods: The expression of survivin-wt and its four splice variants was investigated by quantitative real-time polymerase chain reaction in archival RNA samples of 35 pediatric B-cell ALL patients. Patients were divided into high- and standard-risk groups according to age, white blood cell count, extramedullary involvement, and genetic risk factors; expression of survivin variants was compared between these two risk groups. Results: We found that the ratio of survivin-ΔEx3/wild type (WT) expression was higher in the low-risk group than in the high-risk group. Conclusion: Comparative analysis between the high- and low-risk B-cell ALL groups indicated that the survivin-ΔEx3/WT expression ratio could potentially be used in risk classification for pediatric B-cell ALL.

Evaluation of engraftment syndrome in children following full-matched related donor hematopoietic stem cell transplantations.

The term "ES" has been widely used for describing a clinical condition consisting of skin rash, fever, and weight gain that occur during neutrophil recovery period following HSCT. In this study, the incidence, clinical features, risk factors, and outcomes of ES were evaluated in 169 children following allogeneic HSCT from full-matched related donor according to the Spitzer criteria. Seventeen patients (10.1%) presented with clinical conditions suggesting ES. In both univariate and multivariate analysis underlying malignant disease and early release of monocytes to the PB, and in univariate analysis using only CsA for GVHD prophylaxis were found to be the significant risk factors for the development of ES. Patients with ES experienced significantly higher incidence of acute and chronic GVHD and propensity toward a higher rate of TRM. OS did not differ between the patient groups. Thirteen of 17 patients received steroid therapy, and all but one patient responded to therapy. Monitoring for early detection of ES and early intervention with steroid therapy is the key for recovery. The most crucial approach for this purpose mainly is to find out and use the most useful and feasible diagnostic criteria for routine medical practice.

Portal Vein Thrombosis of a Newborn with Corrected Total Anomalous Pulmonary Venous Return.

Total anomalous pulmonary venous return (TAPVR) is a rare and frequently isolated defect identified in 1% to 3% of all congenital heart diseases. To the best of our knowledge, portal vein thrombosis (PVT) associated with TAPVR has not been reported in the literature. We report a successfully managed PVT in a newborn with infracardiac-type TAPVR and review the literature. Anticoagulation therapies were used during the neonatal period to prevent thrombus progression. PVT should be kept in mind in TAPVR patients who have open heart repair with total correction. The treatment in each neonate should be individualized with consideration of the risk/benefit ratio.

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.

The impact of donor age and sex on the nucleated cell count and CD34 count in healthy bone marrow donors.

BM remains an important source of stem cells. The BM characteristics change with age but the estimation of CD34 calculation of one CD34+ cell per 100 nucleated cells is used for all donors including pediatric donors in the operating room before getting the actual CD34 count. In order to see whether this formula is applicable for pediatric donors, we designed a retrospective study to see the affect of the age and sex on the BM NCC, CD34 count, and CD34/NCC ratios. Ninety-eight BM collections from 91 related donors were evaluated retrospectively (median age: nine yr [1.5-54 yr]; M/F: 41/50). A significant negative correlation was found between the donor age and NCC (r = -0.229, p < 0.05), CD34 count (r = -0.563, p < 0.01), and CD34/NCC (r = -0.664, p < 0.01). The negative correlation for CD34 count and CD34/NCC persisted in female and male donor groups. When donors younger than 16 yr of age were compared with the older donor group, the median NCC, median CD34 count, and CD34/NCC were significantly lower in the older group (p < 0.01). Age and sex have to be taken into consideration to avoid unnecessary high-volume collections and increased operating room time in the younger donors.

Advanced sclerosis of the chest wall skin secondary to chronic graft-versus-host disease: a case with severe restrictive lung defect.

Pulmonary chronic graft-versus-host disease (cGvHD) is one of the most common causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). Herein, we describe a patient with severe restrictive lung defect secondary to cGvHD. A 21-year-old male patient was admitted to our pediatric intensive care unit (PICU) with pneumonia and respiratory distress. He had a history of aHSCT for chronic myelogeneous leukemia at the age of 17 years. Six months after undergoing aHSCT, he had developed cGvHD involving skin, mouth, eye, lung, liver, and gastrointestinal tract. At the time of PICU admission he had respiratory distress and required ventilation support. Thorax high-resolution computed tomography was consistent with bronchiolitis obliterans. Although bronchiolitis obliterans is an obstructive lung defect, a restrictive pattern became prominent in the clinical course because of the sclerotic chest wall skin. The activity of cGvHD kept increasing despite the therapy and we lost the patient because of severe respiratory distress and massive hemoptysis secondary to bronchiectasis. In conclusion, pulmonary cGvHD can present with restrictive changes related with the advanced sclerosis of the chest wall skin. Performing a fasciotomy or a scar revision for the rigid chest wall in selected patients may improve the patients ventilation.

Purpura fulminans as the presenting manifestation in a patient with juvenile SLE.

We present a 12-year-old girl with systemic lupus erythematosus and associated antiphospholipid syndrome who developed an unusual manifestation of purpura fulminans in an accelerated fashion. The patient improved after prompt treatment with anticoagulants, aggressive immunosuppressive drugs and plasmapheresis. This is the first pediatric case of purpura fulminans due to secondary antiphospholipid syndrome of systemic lupus erythematosus. We suggest that SLE patients with lupus anticoagulant should be followed closely for similar complications.