Search Results (605)

Background/Objectives: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Understanding its epidemiological characteristics is essential for guiding public health strategies. In this study, we characterized the epidemiological profiles that may contribute to the risk of ALL in children in southern Brazil. Methods: Clinical and epidemiological data from 71 children (1–15 years old) admitted and newly diagnosed with ALL at four hospitals in Curitiba, Paraná, Brazil, were retrieved and analyzed. Results: Among the 71 children with ALL, the majority were male (n = 43, 60.6%), with an age range of 1–3 years (n = 26, 36.6%), self-identified as White (n = 47, 66.2%), and were born in Paraná state (n = 61, 85.9%). Nearly half had a family history of cancer (n = 33, 46.5%), primarily among grandparents (n = 36, 61%). Parental environmental exposures included smoking (n = 30, 42.3%) and occupational exposure to chemicals or radiation (n = 17, 23.9%). At diagnosis, most patients (n = 43, 60.5%) had a bone marrow blast count > 70%, and 27 patients (38%) had a peripheral blood blast count > 70%. B-cell ALL was the predominant subtype (n = 61, 85.9%). In B-cell ALL cases, the most frequent molecular subtype was high hyperdiploidy (n = 17, 23.9%). White blood cell counts differed significantly between the B-cell ALL and T-cell ALL groups (p = 0.029). Conclusions: Our findings provide insights into ALL epidemiology in southern Brazil and highlight regional differences across the country. Full article

Foundation models (FMs) are increasingly proposed as general-purpose solutions for computational pathology, with the potential to simplify clinical artificial intelligence deployment by reducing the need for task-specific architectures. However, their reliability across cancer domains with distinct morphological characteristics remains unclear, limiting confidence in real-world clinical use. We benchmarked seven general-purpose pathology FMs and three domain-specific FMs across eleven patch-level datasets spanning three clinically relevant domains: pediatric hematology, prostate cancer, and breast cancer, using both linear probing and last-layer fine-tuning adaptation strategies. By jointly evaluating pediatric leukemia, male-predominant prostate cancer, and female-predominant breast cancer, this study is, to our knowledge, the first to explicitly examine specialist-versus-generalist FM behavior across age- and sex-stratified cancer populations. Performance differences were strongly domain dependent. In hematology, the specialist FM DINOBloom matched and, in several datasets, marginally exceeded leading generalist models (AUC 0.990–0.999 vs. GigaPath 0.981–1.000), suggesting advantages for highly distinctive cellular morphology. In prostate cancer grading, the generalist FM UNI2-h consistently outperformed the specialist HistoEncoder (AUC 0.956–0.977 vs. 0.908–0.964). In breast cancer, UNI2-h achieved the best overall performance across all tasks. No publicly available breast-cancer-specific FM currently exists for direct comparison; therefore, breast cancer results characterize general FM transferability rather than specialist-versus-generalist differences. Importantly, cross-dataset experiments revealed substantial performance degradation under dataset shift in both prostate and breast cancer, indicating that current FMs are not yet robust enough for heterogeneous multi-site clinical use. These findings support the use of generalist FMs as efficient backbones for well-characterized single-site, patch-level tasks, while challenging the assumption that high benchmark performance necessarily reflects true clinical readiness and demonstrating that pathology FMs are not uniformly superior to specialist models. Full article

Background/Objectives: Inherited variants in IKZF1 and CDKN2A/2B are among the most consistently reported germline susceptibility markers for childhood acute lymphoblastic leukemia (ALL). Nonetheless, effect sizes differ across ancestry groups, age ranges, and immunophenotypic subtypes, making well-characterized population-specific replication studies valuable for refining ancestry-specific evidence. This study examined two sentinel variants with historical relevance, IKZF1 rs4132601 and CDKN2A rs3731217, within a pediatric Greek cohort. Methods: A case–control study with retrospective case ascertainment and control recruitment through routine pediatric visits was conducted, comprising 50 children and adolescents with ALL and 91 healthy controls from Crete, Greece. Constitutional DNA was isolated from peripheral blood samples collected during remission in cases, while controls provided peripheral blood for targeted germline genotyping. Genotyping was performed using PCR-restriction fragment length polymorphism analysis. We evaluated Hardy–Weinberg equilibrium and genotype and allele distributions and analyzed the data using logistic regression models. Results: Control minor allele frequencies were broadly compatible with public European reference data. Neither IKZF1 rs4132601 nor CDKN2A rs3731217 showed a significant association with susceptibility to childhood ALL under either genotype-based or additive models. Results remained consistent after excluding T-cell ALL cases. Exploratory genotype-phenotype analyses did not reveal robust associations with clinical or molecular features. Conclusions: In this first Greek pediatric assessment of IKZF1 rs4132601 and CDKN2A rs3731217, no significant association with ALL susceptibility was observed. Within the constraints of limited statistical power, these negative findings provide population-specific evidence, refine regional allele-frequency and effect-size estimates, highlight the limitations of relying on single historical sentinel single-nucleotide polymorphisms (SNPs), and support future ancestry-informed and polygenic approaches in southeastern European cohorts. Full article

Background/Objectives: Although gingivitis is the most common oral disease in children, periodontitis accompanied by alveolar bone resorption may develop in patients with severe congenital neutropenia. However, no reports to date have focused on changes in the alveolar bone of these patients during long-term follow-up. Case Summary: A girl aged 8 years and 5 months who developed leukemia due to severe neutropenia was admitted to the hospital and referred to the pediatric dentistry department for oral care. Panoramic radiographs at the first visit revealed significant alveolar bone resorption and mobility in the remaining deciduous teeth. We provided oral care, and the patient later underwent a hematopoietic stem cell transplant. No oral mucositis was observed. Measurement of alveolar bone thickness in the anterior and posterior regions revealed that the ratio increased as the patient’s systemic condition improved, showing a relative increase in alveolar bone thickness in the posterior region. Conclusions: Although this report is descriptive and observational, the patient’s alveolar bone loss with severe congenital neutropenia improved as the patient’s systemic condition improved. In addition, improvement of alveolar bone loss was observed along with systemic recovery and tooth eruption. Full article

Pediatric acute myeloid leukemia (pedAML) is a childhood malignancy with relapse rates of approximately 30%. CD68, a macrophage marker involved in phagocytosis and macrophage recruitment, may contribute to AML biology. We analyzed CD68 expression using the TARGET database and performed survival analyses, mRNA/protein profiling, and functional assays in AML cell lines, pedAML samples, and cord blood samples. High CD68 transcript levels correlated with KMT2A-rearrangements and inversion 16. Survival analysis showed that high CD68 predicted worse event-free survival, though not independently in a multivariate analysis. Flow cytometry confirmed higher CD68 expression in 7/8 pedAML samples compared to cord blood samples. Functionally, CD68 knockdown reduced proliferation and increased drug sensitivity, while overexpression promoted growth and resistance. Gene set enrichment analysis (GSEA) indicated enrichment of MAPK signaling, AP-1–mediated stress response, and epithelial–mesenchymal transition (EMT)/migration-associated pathways in CD68-high models. Together, these findings suggest that CD68 contributes to a pro-tumorigenic and stress-adaptive phenotype in pedAML and may represent a biologically relevant therapeutic target. Full article

Importance: A comprehensive analysis of childhood cancer and cancer predisposition syndromes (CPSs) incidence can provide insights that lead to improvements and modifications in treatment protocols through personalized therapy, thereby reducing toxicity. Purpose: This study aimed to analyze age-specific hospital-based childhood cancer rates and the distribution of CPSs in a 20-year pediatric cohort from the region. Materials: A total of 2190 patients, aged from birth to 17 years, diagnosed with any type of neoplasm classified by ICD-10 codes at Karol Jonscher’s Clinical Hospital of Poznan University of Medical Sciences (KJCH PUMS) between 1 January 2000, and 31 December 2019, were included, with 193 (8.8%) having an underlying CPS. Results: The pediatric population of the Greater Poland Region has declined over the past two decades. The most common diagnoses can be grouped into three main categories: (1) leukemias, involving 704 patients (32.1%); (2) central nervous system (CNS) tumors, represented by 382 children (17.4%); and (3) lymphomas, including 279 patients (12.7%), together accounting for 1353 cases (61.8%). The age-specific hospital-based case rate for childhood cancer (all types combined) peaked in the 0–28 days age group at 71.8 per 100,000 person-years (95% CI: 52.2–96.4), with a trend to decrease with age and a slight increase among adolescents aged 16–17 years (13.6 per 100,000, 95% CI: 12.0–15.4). The age-specific incidence of CPS-positive cancers declined from 18.0 (95% CI: 8.2–29.4) per 100,000 person-years in the first month of life to 0.7 (95% CI: 0.3–1.2) in 16–17-year-olds. CPS-positive children were diagnosed at significantly younger ages for four cancer types: liver and intrahepatic bile duct tumors (C22: A = 0.097, adjusted p < 0.001), myeloid leukemia (C92: A = 0.179, adjusted p < 0.001), lymphoid leukemia (C91: A = 0.309, adjusted p = 0.007), and renal tumors (C64: A = 0.335, adjusted p = 0.013). Conclusions: CPSs likely play a significant and underestimated role in pediatric cancers, especially during early childhood. Improving access to genetic testing could greatly enhance risk assessment, personalized treatment, and long-term outcomes in pediatric oncology. Full article

Doxorubicin (Dox) is a cornerstone in the treatment of pediatric acute lymphoblastic leukemia (ALL), but its use is limited by dose-dependent cardiotoxicity. Oxidative stress, arising from mitochondrial dysfunction, enzymatic generation of reactive oxygen species, and cardiotoxic metabolites, has been implicated as a central mechanism, with interindividual variability partly influenced by genetic factors. This study evaluated oxidative DNA damage 8-hydroxy-2′-deoxyguanosine (8-OHdG) as an integrative marker of redox-related pathways in Dox-induced cardiotoxicity. In a prospective case–control study, 93 pediatric patients with ALL treated with Dox and 63 controls were included. Cardiotoxicity was assessed by serial echocardiography, and 8-OHdG levels were measured by ELISA. Genotyping of ABCC1 rs3743527, NCF4 rs1883112, and CBR3 rs1056892 was performed, and multivariable analyses were conducted. Dox-treated patients showed higher 8-OHdG levels than controls, and patients with cardiotoxicity (n = 11) had higher levels than those without. A higher frequency and severity of cardiotoxicity was observed in female patients, although this finding should be interpreted cautiously. Although allele frequencies did not reach statistical significance, distinct distribution patterns were observed between groups. These findings suggest that 8-OHdG may function as an integrative marker of redox dysfunction associated with Dox-induced cardiotoxicity. Full article

Modern scientific research increasingly views olive leaf extract (OLE) not merely as a simple supplement, but as a sophisticated chemical orchestra where a wide array of phytochemicals works in natural harmony to provide therapeutic benefits. While olive oil is the most famous product of the Olea europaea tree, it is important to emphasize that the leaves are actually a far richer and more concentrated reservoir of bioactive molecules, often containing phenolic levels several times higher than those found in the fruit or oil. This whole plant extract often proves more biologically effective than isolated compounds because its components target multiple cellular pathways simultaneously. Many beneficial effects have been ascribed to OLE including anti-inflammatory, anti-oxidant, anti-microbial, anti-viral, neuroprotective, and anti-tumoral effects. In this review, we focused on the latter activity, especially in the field of pediatric tumors such as acute leukemias and neuroblastoma. This issue was discussed starting from the definition of OLE and its components describing the main biological activities, passing through the OLE roles on the immune system, moving on to the anti-cancer functions, and ending with future perspectives. Full article

Cutaneous hematologic neoplasms in children are relatively rare and encompass a wide range of lymphoproliferative and myeloproliferative disorders. This review explores and updates the classification, clinical presentation, diagnostic challenges, histopathology, and management of pediatric lymphomas, lymphoproliferations, and leukemias that may be seen in the skin. The most frequent of them are lymphomatoid papulosis (LyP) and mycosis fungoides (MF), and are discussed first, with a particular focus on differential diagnosis and overlaps with benign lesions—mainly pityriasis lichenoides—which raises questions regarding the delineation of these entities and their potential interconnection. It is important to underline that most cutaneous lymphoproliferations are indolent in children: primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, subcutaneous panniculitis-like T-cell lymphoproliferation (non-associated with HAVCR2 mutations), primary cutaneous marginal zone lymphoproliferative disorder, and EBV-related lymphoproliferative disorders. However, aggressive hematologic malignancies, although rarer, must not be missed; these are mostly leukemias (but not all forms) and blastic plasmacytoid dendritic cell neoplasm. We emphasize the importance of clinical–pathological correlation, with clonality studies playing a crucial role in some cases. Management strategies are briefly reviewed, ranging from skin-directed therapies like phototherapy and corticosteroids to systemic treatments for more aggressive forms of leukemia cutis and lymphomas. Full article

Background/Objectives: Acute myeloid leukemia (AML) comprises genetic subclasses with distinct gene expression profiles. While AML gene expression studies have mainly focused on protein-coding genes, our understanding of expression patterns of long intergenic noncoding RNAs (lincRNAs) remains incomplete. This is due to limited sample sizes, as well as incomplete annotation of lncRNAs with context-dependent expression. Methods: To address this gap, we developed the bioinformatic pipeline LIRA (long intergenic noncoding RNA annotator) to identify novel lincRNAs using stringent criteria, including spliced and intergenic transcripts, and algorithms to exclude coding potential. Results: By applying LIRA to RNA-sequencing data from 878 pediatric and adult AML cases and 20 healthy controls, we identified 1560 novel lincRNAs, expanding the GENCODE v38 lincRNA catalog by 27%. Integration of in-house-generated CAGE- and ChIP-sequencing data from KMT2A::MLLT3 samples revealed that 80% of the novel lincRNAs are 5′ capped, and at least 67% harbor activating epigenetic marks at their transcription start sites. Unsupervised analysis of the 1000 most variable known and newly identified lincRNAs uncovered subclass-specific expression patterns, mirroring those observed for protein-coding genes. Weighted Gene Co-expression Network Analysis identified 17 lincRNA expression modules associated with AML subclasses. Notably, expression of these modules decreased upon degradation of the leukemogenic onco-fusion proteins KMT2A::MLLT3 and PML::RARA, indicating that lincRNA expression is responsive to oncogenic signaling. Conclusions: This comprehensive analysis shows that lincRNAs exhibit similar subclass-specific expression patterns as protein-coding genes and establishes a valuable resource for future studies on genetically defined AML subclasses, with potential implications for biomarker discovery and therapeutic targeting. Full article

RUNX1 alterations contribute to pediatric myeloid malignancies through both germline predisposition syndromes and somatic leukemogenic events, but their clinical and biological significance in children remains incompletely defined. This retrospective single-center study evaluated six pediatric patients with myelodysplastic syndromes or acute leukemias harboring RUNX1 variants, integrating clinical, cytogenetic, and targeted next-generation sequencing data, with germline status confirmed using non-hematopoietic tissues. Three patients carried germline RUNX1 variants, characterized by antecedent cytopenias, dysplastic features, and increased treatment-related toxicity, including severe infections, persistent cytopenias, and transplant-related mortality. In contrast, somatic RUNX1 alterations were associated with overt high-risk disease, frequently accompanied by complex cytogenetics or monosomy 7, and demonstrated heterogeneous outcomes ranging from sustained remission to post-transplant relapse. Mixed-phenotype acute leukemia was observed in both groups. These findings support a model of RUNX1-driven leukemogenesis, in which germline and somatic alterations represent distinct yet interconnected trajectories, while highlighting the importance of distinguishing variant origin for risk stratification, donor selection, and therapeutic decision-making in pediatric myeloid malignancies. Given the small cohort size, the findings remain descriptive and require validation in larger prospective studies. Full article

Survival rates in pediatric cancer have increased substantially over recent decades. However, children and survivors frequently experience treatment-related alterations in physical function, body composition, bone health, and metabolic regulation. Chemotherapy, glucocorticoid exposure, physical inactivity, nutritional imbalance, and inflammatory and neuroendocrine disturbances may contribute to reduced lean mass, decreased bone mineral density, sarcopenic obesity, and long-term cardiometabolic risk. This narrative review critically summarizes current evidence on multimodal exercise and nutritional interventions in pediatric oncology, with particular attention to their effects on physical function, body composition, nutritional status, and metabolic health. Literature searches were conducted in PubMed, Scopus, and Web of Science up to April 2026, combining contextual evidence with studies evaluating combined exercise and nutritional strategies. Current evidence suggests that structured and supervised exercise, particularly resistance and combined aerobic–resistance training, is feasible and safe, and may improve cardiorespiratory fitness, muscle strength, functional capacity, and body composition. Nutritional care should be individualized, prioritizing adequate protein intake, micronutrient status, periodic reassessment of energy requirements, and body composition rather than relying on BMI alone. Nevertheless, available findings remain limited by small sample sizes, heterogeneous protocols, variable supervision, inconsistent outcome assessment, and limited long-term follow-up. Integrating exercise, nutrition, and regular monitoring into pediatric oncology care may help mitigate treatment-related functional and metabolic complications. Future studies should prioritize adequately powered randomized trials, standardized intervention protocols, objective monitoring of exercise intensity, harmonized body composition and functional outcomes, and longer follow-up to define clinically applicable multimodal care models. Full article

Background: Childhood cancer survival now approaches 80% in high-income countries, yet most survivors face lifelong toxicity. This review examines the interplay between treatment efficacy, relapse prevention, and therapy-related complications. Methods: Narrative synthesis of landmark pediatric oncology trials (2000–2026), including AALL1731 (blinatumomab), ELIANA/PLAT-02 (CAR T-cell), and GD2-CART01 (neuroblastoma), with comparative analysis of efficacy and toxicity. Results: In AALL1731, adding blinatumomab to chemotherapy improved 3-year disease-free survival from 87.9% to 96.0% (HR = 0.39, 95% CI: 0.27–0.56, p < 0.001), but increased sepsis from 5.1% to 14.8%. Comparison between AALL1731 (front-line blinatumomab) and ELIANA (CAR T-cell in relapsed disease) reveals that earlier immunotherapy deployment yields better outcomes: 96% DFS vs. 48% 3-year EFS, respectively. In GD2-CART01, early use (after 1–2 prior lines) achieved 89% 5-year survival vs. 43% with delayed use (HR = 0.31). Approximately 95% of survivors experience ≥1 late effect, with 60–90% carrying chronic conditions into adulthood. Conclusions: Immunotherapy transforms outcomes, but timing is critical, as earlier deployment dramatically improves survival. Toxicity remains pervasive, requiring systematic mitigation strategies. Full article

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes—PTPN11, NRAS, KRAS, NF1, or CBL—establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention. Full article

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and genomic profiling has become increasingly vital for risk stratification. We conducted a retrospective single-center study including 96 newly diagnosed pediatric patients with ALL and mixed phenotype acute leukemia to characterize the genomic landscape using conventional and molecular cytogenetics, multiplex ligation-dependent probe amplification and targeted next-generation sequencing and to evaluate associations with treatment response and survival. Mutation co-occurrence analysis revealed a NRAS/KRAS/JAK cluster and an ETV6::RUNX1 cluster characterized by relative mutational exclusivity, with additional associations between NOTCH1–CDK4 and CDK4–CCND3 alterations. DelCDKN2A/CDKN2B alterations showed a trend toward higher day-15 minimal residual disease (MRD) levels and inferior 2-year event free survival rate (EFS). DelIKZF1-positive cases showed lower 2-year EFS. In contrast, ETV6::RUNX1 and high hyperdiploidy were associated with favorable early response and EFS. DelPAX5 did not independently influence outcome. ZNF384 positive cases showed higher early MRD levels despite excellent survival outcomes. NRAS/KRAS mutations were significantly associated with higher positive day-15 MRD (Wilcoxon, p = 0.0067) and remained independently associated after adjustment for white blood cell count and cytogenetic subgroup. Intermediate risk (IR) and high-risk groups showed comparable 2-year EFS, indicating limited discrimination by conventional risk stratification. The IR group displayed a heterogeneous genomic profile, with NRAS/KRAS, Ph-like mutations and delCDKN2A/CDKN2B among the most frequent alterations. These observations highlight the potential of integrated genomic profiling to refine risk stratification, particularly by identifying clinically relevant subgroups within the IR category. Full article