BACKGOUND:The DICER1 gene located on chromosome 14q, essential for the maturation of miRNAs, is commonly associated with multinodular goiter and thyroid carcinomas. We aimed to systematically search the literature and identify mutations in the DICER1 gene associated with thyroid cancer in children and adolescents. METHODS:The study was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement through four databases (Pubmed, Web of Science/Scopus/Google Scholar). The quality of the studies was assessed using the ROBINS-1 tool. RESULTS:A total of 1672 articles were retrieved through databases. After applying the inclusion/exclusion criteria, 32 original studies were systematically reviewed. Genomic mutations in the DICER1 gene lead to DICER1 syndrome, which is more commonly associated with multinodular goiter than with thyroid carcinomas. The most common type of thyroid cancer in the setting of DICER1 gene mutations is papillary thyroid carcinoma, followed by follicular thyroid carcinoma and poorly differentiated thyroid cancer. Additionally, other rare histological types may occur. These mutations have been associated with capsular invasion and do not often metastasize to lymph nodes or distant organs. CONCLUSION:Mutations in the DICER1 gene appear to be more commonly associated with thyroid cancer in children than in adults, particularly with differentiated thyroid carcinoma. IMPACT:The impact of this study is to provide a systematic analysis of DICER1 mutations in pediatric and adolescent thyroid cancer, summarizing its prevalence, clinical significance and molecular mechanisms in this specific population group. By integrating current evidence, this study highlights the role of DICER1 gene in tumorigenesis and supports future research and clinical decision-making in thyroid cancer among children and adolescents.

BACKGROUND:Invasive fungal disease remains a major cause of morbidity and mortality among children with malignancies and those undergoing hematopoietic stem cell transplantation (HSCT). Real-world data that describe antifungal prescribing practices in pediatric hematology-oncology units are very limited. METHODS:A national prospective observational study from June 2016 through December 2019 in 5 pediatric hematology-oncology units and the single pediatric HSCT unit in Greece was conducted. The first 15 children per month admitted to these units who required initiation of new antifungal agents for prophylaxis or treatment were recorded. Demographics, presence of a central venous line, type of underlying disease, absolute neutrophil count on the first day of antifungal therapy, presence of invasive fungal disease, days of therapy, microbiologic findings and outcomes were recorded. RESULTS:Among 1838 anti-infective courses, 737 (40.1%) involved antifungal agents. Antifungal use was predominantly prophylactic (47.6%) or empiric (50.7%), with targeted therapy accounting for only 1.5%. Prophylaxis was more common in the HSCT unit, whereas empiric therapy predominated in pediatric hematology-oncology units. Fluconazole was the most frequently used prophylactic agent, followed by micafungin and voriconazole. Proven fungemia was uncommon; Candida albicans was the most frequently isolated pathogen. Overall mortality was 1.8%, with slightly higher mortality among patients receiving antifungal therapy. CONCLUSIONS:Antifungal use in pediatric oncology and HSCT settings was extensive and heterogeneous, characterized by heavy reliance on prophylactic and empiric strategies and minimal targeted therapy. These findings support the need for structured antifungal stewardship programs to optimize antifungal exposure while preserving favorable outcomes.

Respiratory viral infections (RVIs) have been described traditionally as clinically important infectious complications in pediatric patients with immunosuppression, particularly in those with malignancies (hematological or solid) and recipients of hematopoietic cell or solid organ transplantation. Specifically, advances in the field of cancer therapy and novel immune-based pharmaceuticals have significantly expanded the population of children with prolonged and complex immunosuppression, whereas the widespread use and availability of molecular diagnostics have increased the detection of respiratory viruses. Additionally, these developments have improved the etiologic identification of RVIs, while introducing important challenges in clinical interpretation, mainly in differentiating incidental viral identification from clinically significant diseases. Furthermore, RVIs in immunocompromised children are characterized by heterogeneous and diverse clinical manifestations, with a range from mild upper respiratory tract involvement to severe lower respiratory tract disease, which can lead to substantial morbidity and mortality. Diagnostic strategies in this field are primarily based on nucleic acid amplification tests, requiring careful interpretation because of the possible prolonged viral shedding, co-detection, and overlapping infectious syndromes. Beyond direct clinical consequences, viral detection has an impact on infection control measures, antimicrobial stewardship decisions, and the timing of therapies. In this literature review, we offer an overview of current evidence on the epidemiology, clinical manifestations, diagnostic approaches, and management of RVIs in immunocompromised pediatric populations, underscoring the unmet need for structured, risk-adapted integration of virologic data into pediatric oncology care.

PURPOSE:Fever in neutropenia (FN) is a potentially lethal complication of chemotherapy for cancer. Prompt administration of broad-spectrum antibiotics is standard of care. Despite conflicting results on the association of time to antibiotics (TTA) with outcomes, TTA limits are used as FN quality measure both in adult and pediatric oncology. This individual patient data (IPD) meta-analysis studied the association between TTA and outcomes in pediatric patients with FN. PATIENTS AND METHODS:IPD on TTA in pediatric patients with FN receiving chemotherapy for any malignancy was collected internationally. Three-level mixed binomial logistic regression analyzed the association of TTA with safety relevant events (SRE; death, admission to intensive care unit [ICU], bacteremia), primarily in patients with severe disease at presentation and secondarily in all patients. RESULTS:Data on 4006 FN episodes in 2073 patients, diagnosed 2016-2023, were reported from 15 study sites in eight countries. Median TTA was 61 min overall and 53 min in the 345 (8.6%) episodes with severe disease at presentation. Among these with severe disease, an SRE was reported in 119 (34%) episodes. Longer TTA (> 60 vs. ≤ 60 min) was associated with less SRE (odds ratio, 0.41; 95% CI, 0.24-0.70). This primary finding was confirmed in secondary and additional exploratory analyses. CONCLUSION:This large, international and adequately powered IPD meta-analysis found no association between shorter TTA and improved clinical outcomes in pediatric patients with FN. This finding was consistent across analyses. These results challenge the continued use of TTA limits as a quality measure for pediatric oncology centers.

Objective: Autoimmune cytopenias (AIC) may be associated with positive antinuclear antibodies (ANA) and can precede the onset of systemic lupus erythematosus (SLE). This study assessed ANA as a predictive factor for progression to SLE in adolescents with AIC. Methods: Medical records from a paediatric haematology referral centre were retrospectively reviewed. Presence of ANA (titer>1:80) was recorded in 90 adolescents and children with AIC. Possible progression to SLE was evaluated in the group. Results: A total of 90 patients with AIC were included, with a median age of 9 years and a predominance of ITP (67/90). ANA positivity was identified in 35/90 patients with AIC, most frequently in females (25/35). Among ANA-positive patients, 6/35 eventually developed SLE, whereas none of the ANA-negative patients progressed to SLE. Of the patients who developed SLE, the majority were female (5/6), with 5/6 initially diagnosed with autoimmune thrombocytopenia and 1 with Evans syndrome. The median age at AIC onset for those who later developed SLE was 10.4 years, and the median time interval between AIC diagnosis and SLE onset was 2.5 years. Additionally, 10/35 ANA-positive patients met high-risk criteria for future SLE according to Lambers et al. (2020), despite not fulfilling EULAR/ACR-2019 criteria for SLE at the time of review. Conclusions: Persistent ANA positivity in patients with AIC strongly predicts subsequent SLE, particularly in females older than 10 years with ITP. This finding warrants further investigation in larger, prospective studies, including follow-up of patients transitioning to adult care, as SLE may manifest later in adulthood.

Acute Lymphoblastic Leukemia (ALL) is a highly heterogeneous hematological malignancy characterized by diverse genetic alterations. Advances in genomic and transcriptomic profiling have enabled refined ALL classification, improving clinical management and patient outcomes. This review provides a comparative evaluation of RNA sequencing methodologies for studying gene expression in ALL. Specifically, bulk RNA sequencing enables transcriptome-wide profiling at the population level, while targeted RNA sequencing provides enhanced sensitivity for detecting clinically relevant alterations. Moreover, single-cell RNA sequencing offers cellular-resolution analysis of leukemic heterogeneity and clonal architecture, whereas spatial transcriptomic analyses further reveal leukemic cell types within their microenvironment. Together, these transcriptomic methodologies have transformed the understanding of leukemia biology and enabled improved disease classification, risk stratification, and personalized medicine. Furthermore, integrating multi-omics approaches has the potential to reshape the clinical management of ALL by shifting treatment from broad chemotherapy to precision medicine. The future of transcriptomic profiling in ALL depends on the strategic integration of existing methodologies to achieve a comprehensive and clinically actionable understanding of leukemic biology.

Invasive fungal diseases (IFDs) have been documented among the causes of post-chimeric antigen receptor-T (CAR-T) cell immunotherapy complications, with the incidence of IFDs in CAR-T cell therapy recipients being measured between 0% and 10%, globally. IFDs are notorious for their potentially life-threatening nature and challenging diagnosis and treatment. In this review, we searched the recent literature aiming to examine the risk factors and epidemiology of IFDs post-CAR-T infusion. Moreover, the role of antifungal prophylaxis is investigated. CAR-T cell therapy recipients are especially vulnerable to IFDs due to several risk factors that contribute to the patient’s immunosuppression. Those include the underlying hematological malignancies, the lymphodepleting chemotherapy administered before the treatment, existing leukopenia and hypogammaglobinemia, and the use of high-dose corticosteroids and interleukin-6 blockers as countermeasures for immune effector cell-associated neurotoxicity syndrome and cytokine release syndrome, respectively. IFDs mostly occur within the first 60 days following the infusion of the T cells, but cases even a year after the infusion have been described. Aspergillus spp., Candida spp., and Pneumocystis jirovecii are the main cause of these infections following CAR-T cell therapy. More real-world data regarding the epidemiology of IFDs and the role of antifungal prophylaxis in this population are essential.

Fungal infections, either invasive and disseminated or cutaneous and superficial, are an important and increasing cause of morbidity [...]

Background/Objective: Radiotherapy for leukemia, the most common childhood malignancy, often exposes patients to radiation, increasing the risk of second malignancies, including thyroid cancer. To assess the incidence and survival outcomes of thyroid cancer after childhood acute lymphoblastic leukemia (ALL). Methods: We systematically reviewed articles reporting the incidence of thyroid cancer in childhood leukemia survivors (age at diagnosis < 18 years) published between 2000–2024 in Science Direct, PubMed, Google Scholar, CENTRAL, and EMBASE. The Newcastle Ottawa Scale was utilized to appraise the methodological quality of the included studies. Descriptive statistics and calculations of incidence were performed using Microsoft Excel. Results: The literature search yielded 1265 articles, of which 18 met the inclusion criteria. Data from 135,861 childhood cancer survivors, among whom 102,070 had a confirmed diagnosis of childhood leukemia, including ALL. The crude incidence of secondary malignancies after childhood leukemia was 10.1 per 1000 patients. Among these, 1.5 per 1000 patients developed second thyroid carcinomas. Overall, 14.6% of the second malignancies in childhood leukemia survivors were thyroid carcinomas, mostly of the papillary type. Survival rates after second thyroid cancer were 100% in all 11/18 studies reporting this outcome. Radiotherapy had been used as part of ALL treatments in 17/18 studies. The use of radiotherapy, female sex, and younger age at the diagnosis of primary ALL emerged as important risk factors for thyroid cancer. Conclusions: Thyroid carcinomas account for ~15% of secondary malignancies after childhood leukemia, with radiation remaining a significant risk factor despite its overall reduced use for the treatment of ALL in the last few decades. Importantly, survival rates remain high. Further research is warranted to determine the incidence and outcomes of thyroid cancer in childhood ALL survivors

The treatment strategy for children and adolescents with chronic myeloid leukemia in the chronic phase (CML-CP) has evolved from allogeneic hematopoietic stem cell transplantation (HSCT) to tyrosine kinase inhibitors (TKIs). With the advent of next-generation TKIs and new targeted therapies in the CML field, an international pediatric CML expert panel provides recommendations based on the medical literature (including previous pediatric guidelines), national standards, and treatment principles used in adults with CML-CP. Recommendations include diagnosis of the disease and details on managing the initial steps of care of children and adolescents with newly diagnosed CML-CP, including complications such as leukostasis. The treatment recommendations are based on the initiation of therapy with a first- or second-generation TKI according to the allocated European Treatment and Outcome Study (EUTOS) long-term survival score risk group of the patient. The subsequent steps are based on the results of recommended monitoring which can justify a switch to another TKI or a drug in development if there is resistance or toxicity. The panel also provides recommendations regarding the discontinuation criteria for TKIs in children and adolescents in sustained deep molecular response. Allogeneic HSCT is not recommended as the first-line of treatment for children with CML-CP but is to be considered in case of progression to the advanced phase or failure of several lines of treatment. The present treatment and management recommendations are intended to provide advice to clinicians in view of optimizing the care and the outcome of children and adolescents with CML-CP.

Background/Objectives: Down syndrome (DS), affecting 1 in 1000 births, has been linked to an increased risk of acute leukemia (AL). Patients with DS–acute lymphoblastic leukemia (DS-ALL) have historically had inferior outcomes when they have received risk-adapted therapy. Transient abnormal myelopoiesis (TAM) constitutes a transient leukemia with spontaneous remission in the neonatal period or represents a preleukemic state, preceding DS–acute myeloid leukemia (DS-AML). DS-AML has a better prognosis than that of AML without DS (NDS-AML) due to genetic and biological underlying features, a better response to chemotherapeutic agents, and a lower frequency of relapses. Methods: This retrospective cohort study presents the DS-AL outcomes from a nationwide survey in pediatric oncology centers. A total of 20 patients were studied, 10 with DS-ALL, 4 with DS-AML, 5 with TAM, and 1 with DS-AML after TAM, at median follow-ups of 9.25 (0.6–17.42) years and 7.25 (0.25–18.25) years for DS-ALL and DS-AML, respectively. Results: The median age at diagnosis was 4.7 (1.16–13.83) and 1.92 (1.25–3) years for ALL and AML, respectively. All DS-ALL patients had B-cell precursor ALL and achieved complete remission (CR). One patient relapsed and succumbed due to a severe infection. Three DS-AML patients had AMKL. All DS-AML patients achieved CR. One patient with TAM demanded treatment, all achieved CR, and one progressed to DS-AML. The overall survival (OS) was 70% and 80% for DS-ALL and DS-AML. Conclusions: The improved survival rates of our patients have been due to new protocols with less toxic therapies and better supportive care.

Immune thrombocytopenia (ITP) in pediatric patients is a common cause of isolated thrombocytopenia. Various pathophysiological mechanisms are implicated in ITP pathogenesis, including the production of autoantibodies against components of platelets (PLTs) by B-cells, the activation of the complement system, phagocytosis by macrophages mediated by Fcγ receptors, the dysregulation of T cells, and reduced bone marrow megakaryopoiesis. ITP is commonly manifested with skin and mucosal bleeding, and it is a diagnosis of exclusion. In some ITP cases, the disease is self-limiting, and treatment is not required, but chronic-persistent disease can also be developed. In these cases, anti-CD20 monoclonal antibodies, such as rituximab and thrombopoietin (TPO) receptor agonists, can be used. TPO agonists have become standard of care today. It has been reported in the published literature that the efficacy of TPO-RAs can be up to 80% in the achievement of several end goals, such as PLT counts. In the current literature review, the data regarding the impact of TPO agonists in the pathogenesis of ITP and treatment outcomes of the patients are examined. In the era of precision medicine, targeted and individualized therapies are crucial to achieving better outcomes for pediatric patients with ITP, especially when chronic refractory disease is developed.

We analyzed data of pediatric invasive fungal diseases of the central nervous system (CNS-IFDs) reported by five of total eight Pediatric Hematology-Oncology Departments in Greece for 15 years (2007-2022). A total of twelve patients (11 boys, median age: 9.5yrs range: 2-16) were reported suffering from CNS-IFDs. Underlying malignancy was acute lymphoblastic leukemia in 9/12, and acute myeloid leukemia, Ewing sarcoma and rhabdomyosarcoma in one each. Eleven patients presented with CNS-related symptoms (i.e seizures, headache, cerebral palsy, ataxia, hallucination, seizures, blurred vision, amaurosis). All patients had pathological MRI findings. Multifocal fungal disease was observed in 6/12 patients. Nine proven and three probable CNS-IFD cases were diagnosed. Causative pathogens in proven cases were Aspergillus spp. and Candida albicans (n=2 each), Mucor spp., Rhizopus arrhizus, Absidia spp., Fusarium oxysporum and Cryptococcus neoformans (n=1 each). Causative pathogens in probable cases were Aspergillus spp. (n=2) and Candida spp. (n=1). All patients received appropriate antifungal therapy (median duration: 69.5 days, range 19-364). Two patients underwent additional surgical treatment. Six patients admitted to ICU due to complications. Three patients (25%) died, two due to IFD and one due to underlying disease. Early recognition and prompt intervention of CNS-IFDs may rescue the patients and improve overall survival.