Emel Ünal

Objective: Anthracycline-based chemotherapy is used in 50%-60% of childhood cancers despite well-known cardiotoxicity. The authors evaluated dexrazoxane (DEX) as a cardioprotective agent in children receiving anthracyclines. Methods: The authors retrospectively analyzed 142 children aged 0-18 years treated for childhood cancer. The control group comprised 87 patients who received anthracycline alone (2009-2019) and the case group 55 patients who received DEX + anthracycline (2019-2022, after DEX was licensed in Türkiye). Cardiac dysfunction was defined as a left ventricular ejection fraction (LVEF) below 50%. Results: Baseline LVEF was comparable. Mean LVEF fell by 0.71 Å} 6.55 points with DEX vs. 6.44 Å} 9.76 in controls (Time Å~ Group interaction F(1,140) = 14.77, P < .001), and the difference persisted after adjustment for follow-up duration and treatment covariates (β = +4.60, 95% CI = 1.10-8.10, P = .010). Cardiac dysfunction developed in 11 of 87 controls (12.6%) and in none of the 55 DEX patients (P = .007; log-rank P = .040); this held in a 36-month landmark analysis (0 of 52 vs. 4 of 25, P = .009). Mortality was higher in controls (21.8% vs. 5.5%, P = .009) and in patients with cardiac dysfunction (54.5% vs. 17.1%, P = .012). Conclusion: Dexrazoxane attenuated the early decline in LVEF and reduced the incidence of anthracycline-induced cardiotoxicity, and this persisted after adjustment for the difference in follow-up duration. With a median DEX follow-up of only 22.8 months, these data support early cardioprotection; longer follow-up is needed to assess protection against late-onset cardiotoxicity.

Inborn errors of immunity (IEI) are caused by deficiencies or functional abnormalities in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and/or malignancies. Primary hemophagocytic lymphohistiocytosis (HLH) arises from genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer (NK) cells, while secondary HLH is triggered by infections, malignancies, rheumatologic disorders, or immune deficiencies. Treatment consists of remission induction, control of triggers, maintenance of remission, rescue treatment and HSCT as approach curative steps. The aim of this study is to evaluate the clinical and laboratory features, as well as the outcomes, of primary HLH patients who were diagnosed and treated in a multidisciplinary manner over the past 25 years. From 2000 to 2025, 30 HLH cases with primary HLH/IEI who were diagnosed and treated at the departments of pediatric hematology, immunology and oncology of Ankara University School of Medicine Children Hospital and Bone Marrow Transplantation Unit were included in this study. Of the 30 patients, 18 were boys and 12 were girls. The mean age at the onset of the first symptom was 10 months (range: 0.5-204 months), while the mean age at the time of admission to our center was 12.5 months (range: 1-204 months). Pedigree analysis showed that 21 patients were born to consanguineous parents. All patients had a fever lasting longer than five days, with a mean duration of 13.30±14.05 days (range: 5-60 days). Splenomegaly was detected in 29 patients (96.6%), and hepatomegaly in 25 patients (83%). Anemia was observed in 27 patients (90%), neutropenia in 23 patients (76.6%), and thrombocytopenia in 30 patients (100%). Genetic evaluation was performed in all patients, and a causative gene was identified in 19 out of 30 cases (63%). The most common genetic diagnosis was perforin deficiency (FHLH2), detected in 8 patients (26,6%), followed by UNC13D gene defect (FHLH3) in 4 patients (13,3%). HSCT was performed in 17 patients (56,6%), with 6 receiving transplants from matched related donors (MRD), 4 from matched sibling donors (MSD), 5 from matched unrelated donors (MURD), and 2 from mismatched related donors (MMRD). 13 patients remain alive, with a mean survival of 119.89 months. 17 patients (56.6%) died, primarily from mortality included multi-organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), HLH reactivation, septic shock, and heart failure. HSCT patients had a significantly longer survival (mean 165.6 months) compared to non-HSCT patients (45.36 months, p <0.01). PICU admission, organ failure, and neurological involvement were identified as adverse prognostic factors, all significantly associated with higher mortality (p < 0.05). Given the increasing recognition of HLH as a possible manifestation of IEIs, comprehensive immunological and genetic evaluations should be pursued without delay in suspected cases. Our findings, in line with national and international cohorts, confirm that HSCT remains the only curative option for familial HLH, and should be performed as early as possible after achieving disease remission. Improving access to early diagnostics and HSCT could significantly enhance outcomes, particularly in genetically predisposed populations.

Objective: In our study, we aimed to share the clinical experiences of our center regarding osteosarcoma cases, the most common primary malignant bone tumor in children and adolescents. Materials and Methods: With approval from the Clinical Research Ethics Committee of our center, the data of 59 pediatric patients who were followed up in our center with the diagnosis of osteosarcoma between 2007 and 2021 were evaluated retrospectively. Results: The mean time between the onset of symptoms and diagnosis was 3 months. Although not statistically significant, patients with a diagnostic delay of 3 months or less had a higher rate of recurrence and mortality. 59.3% of patients had metastatic disease, and the presence of metastases was associated with higher rates of recurrence and mortality. Significant number of patients had multiple surgical operations. Amputation as the first operation and the need for multiple surgeries were associated with higher mortality. Pathologically poor response to chemotherapy is associated with mortality. 42.4% of patients died, and the 5-year overall and disease-free survival rates were 47.5% and 30.5%, respectively. Survival rates were highest in non-metastatic and non-relapsed patients, and lowest in metastatic patients and patients with poor response to chemotherapy. Renal problems and cardiotoxicity were most frequently treatment-related complications. Conclusion: Significant improvements have been achieved in the survival and quality of life in osteosarcoma cases compared to previous years; however, there is still a long way to go, and more multicenter and multidisciplinary studies are needed on osteosarcoma. Cite this article as: Altıntaş M, Cabi Ünal E, Taçyıldız N, İncesoy Özdemir S, Dinçaslan HU. Clinical and prognostic characteristics in childhood osteosarcoma: A single-center experience in Türkiye. Turk Arch Pediatr. 2024;59(5):461-468.

Background: Long-term survivors of Hodgkin lymphoma (HL) are at risk of developing a range of late effects, with a second malignant neoplasm and cardiovascular diseases being the leading causes of death in these patients. The present study aims to evaluate the late side effects in children with HL. Materials and Methods: Out of 53 HL patients, we assessed the long-term effects of childhood HL survivors (HLSs; n = 50) diagnosed between 1998 and 2019. Patient data related to chronic health conditions, and sociodemographic characteristics were compared with their siblings ( n = 56). Results: The cumulative overall survival (OS) at 1, 5, and 10 years from diagnosis was 98.1 ± 1.9%, 93.3 ± 3.8%, and 93.3 ± 3.8%, respectively. Groups of HLSs and their siblings were matched according to age and gender. Compared with siblings, survivors had will be changed as ‘a higher frequency of nephrotoxicity ( P = 0.02)’, cardiotoxicity ( P = 0.12), thyroid dysfunction ( P = 0.001), health care service usage ( P < 0.01), limitation of physical function ( P = 0.01), and pulmonary disease ( P = 0.01). The control group of siblings had a higher incidence of marital status ( P < 0.01), parenthood ( P = 0.01), and smoking habit ( P = 0.03). Thyroid dysfunction was associated with neck radiotherapy ( P < 0.01). No secondary neoplasm was detected. In relapsed, refractory setting ( n = 10), autologous transplantation ( n = 9) is performed after a complete remission. Brentuximab vedotin with or without bendamustine and rituximab is also used in selected patients. Conclusions: Increased number of chronic health conditions and social problems point to the significance of long-term follow-up of HLSs. We are currently preparing a survivorship guideline appropriate for Turkey’s conditions. Implications for Cancer Survivors: Renal, heart, pulmonary impairment, thyroid dysfunction, limitation in physical functioning, and deterioration in social status (marriage, having children, education).

Here we report an adolescent boy diagnosed with ectopic ACTH (Adrenocorticotropin hormone) syndrome (EAS) caused by atypical bronchial carcinoid. The patient was evaluated multidisciplinaryly: he had surgery and took chemotherapy and radiotherapy treatments afterward. The patient is still under our follow-up. Until today eighteen pediatric and adolescent patients with EAS because of bronchial carcinoid tumors were reported in 13 case reports and literature reviews. Ectopic ACTH syndrome caused by bronchial carcinoids is very rare in children and adolescents. Careful diagnostic evaluation and rapid treatment should be started immediately. Although complete remission is possible in bronchial carcinoids, atypical carcinoids have a more aggressive nature. A multidisciplinary approach and follow-up will improve quality of life and survival.

Hereditary forms of Medullary thyroid carcinoma (MTC) are rare. Different phenotypes with the same mutation may be due to differences in the timing of RET activation steps, additional mutations in other regions of the gene, or the co-occurrence of germline and somatic mutations, which is an infrequent possibility. Here, we aim to present the different features and difficulties in the follow-up of three family members with the same germline mutation. A 4-year-old male patient with respiratory distress was diagnosed with MTC and found to have a heterozygous germline mutation C.2671T>G(S891A) in the RET gene (classified as intermediate risk according to ATA). As the tumor was inoperable, treatment with a tyrosine kinase inhibitor (sorafenib) was initiated. Sorafenib has prevented tumor progression for seven years. Whole exome sequencing (WES) did not identify additional mutations. Segregation analysis showed the same mutation in the asymptomatic mother and sister. In our case, thyroid tissues were examined for somatic mutations, and SDHA c.1223C>T (p.S408L) was found. The clinical presentation of rare mutations such as RET p.S891A differed among family members carrying the same germline mutation. Our index case's more severe clinical presentation may be due to an additional somatic mutation. Sorafenib treatment can be an option for advanced MTC and may prevent disease progression.

A 7-year-old boy with known diagnosis of hereditary spherocytosis and ulcerative colitis was referred for F-18-fluorodeoxyglucose (F-18-FDG) positron emission tomography/computed tomography after detection of a 28 mm lesion suspicious for malignancy in spleen on upper abdomen magnetic resonance imaging (MRI). As an incidental finding, a moderately increased uptake of F-18-FDG was observed in periportal region with no definable mass. MRI revealed compatible findings with "periportal cuffing" as described on ultrasonography.

Inherited forms of medullary thyroid carcinoma (MTC) can cause serious problems in diagnosis and follow-up. Family screening is performed, and prophylactic thyroidectomy at an appropriate age can be life-saving. This study aimed to investigate the diagnostic, clinical, laboratory characteristics, and treatment methods of cases with rearranged during transfection (RET) mutation in the childhood age group. Patients diagnosed with hereditary MTC and patients who were evaluated by detecting MTC and/or RET mutations in their families were included in this study. Nine cases from 6 families were included in the study. Seven patients were evaluated as a result of screening, whereas 2 patients, one of whom was MEN2B, were symptomatic. Prophylactic thyroidectomy was performed in 7 cases. Medullary microcarcinoma was found in all, and additional papillary thyroid carcinoma in one. An inoperable tumor was detected in one patient, and sorafenib treatment was applied. A very heterogeneous clinical presentation can be seen in a group of pediatric patients with RET mutation. In rare RET mutations, the genotype-phenotype relationship is still unclear, and different clinical pictures can be seen. Although prophylactic thyroidectomy is life-saving, it can cause iatrogenic hypothyroidism and hypoparathyroidism. Concomitant papillary microcarcinomas may occur in very young children with germline RET mutation.

Neurotrophic tyrosine receptor kinase (NTRK) gene rearrangements have been recently identified and developed as one of the biomarkers that have been utilized as new targets for cancer therapy. NTRK gene fusions have taken their place in individualized targeted therapy by being used as a predictive (diagnostic) biomarker as well as a treatment target. Selective inhibitors of NTRK fusion proteins have potent efficacy in the treatment of NTRK fusion-positive solid tumors. Detection of these fussions have become important since the finding of new drugs for which U.S. Food and Drug Administration (FDA) granted approval are used on the treatment of patients who has NTRK fussions positive cansers. Clinical trials have shown that first generation tyrosine receptor kinase (TRK) inhibitors, larotrectinib (Vitrakvi, Bayer HealthCare Pharmaceutical Inc, New Jersey, U.S.) and entrectinib (Rozlytrek, Genentech Inc, California, U.S.), have potent efficacy in the treatment of NTRK fusion positive cancers. In the future, with the increase in the number of comprehensive studies on these drugs further information will become available and beneficial.