Search Results (611)

Background: Outcomes in chronic myeloid leukemia (CML) remain heterogeneous despite effective BCR::ABL1 tyrosine kinase inhibitors (TKIs). Somatic mutations in epigenetic regulators, particularly additional sex combs-like 1 (ASXL1), have been implicated in adverse prognosis, but their clinical impact in CML has not been systematically defined. Methods: A systematic review was conducted using CINAHL, EMBASE, MEDLINE Ultimate, and PubMed from inception through August 2025. A total of 1339 records were identified; the eligible studies included adult and pediatric patients with chronic and advanced-phase (accelerated or blast) CML. After duplicate removal and screening, 11 studies met the inclusion criteria; these included adult patients only and were included in a qualitative synthesis and meta-analysis. ASXL1 mutation status was assessed using validated molecular methods. The outcomes included the molecular response, cytogenetic response, survival, and treatment resistance. Random-effects models were used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. Results: Across the included studies, ASXL1 mutations were detected in approximately 15% of patients. At 12 months, patients with ASXL1 mutations had significantly lower odds of achieving a major molecular response (MMR) compared with ASXL1-wildtype patients (OR 0.29; 95% CI 0.16–0.51; p < 0.0001; I² = 30%). No statistically significant difference was observed in the complete cytogenetic response (CCyR) (OR 0.30; 95% CI 0.02–5.31; p = 0.41; I² = 68%). Compared with patients harboring other non-ASXL1 somatic mutations, an ASXL1 mutation was not associated with a significant difference in MMR (OR 0.49; 95% CI 0.23–1.05; p = 0.067; I² = 0%). Conclusions: ASXL1 mutations may be associated with an inferior molecular response to TKI therapy in CML, supporting their role as an adverse prognostic biomarker. These findings highlight the potential value of incorporating myeloid mutation profiling into future CML risk-stratification strategies. Full article

Background/Objectives: Long non-coding RNAs (lncRNAs) have been identified as potential biomarkers for cancer diagnosis and prognosis. In the present study, we proposed the analysis of four lncRNAs as a diagnostic support candidate for the follow-up of leukemia patients. The aim of this study was to characterize the expression of BALR6, LINC-PINT, MEG3, and ZEB1-AS1 in patients with B-cell acute lymphoblastic leukemia (B-ALL) at diagnosis and at the end of remission induction therapy. Methods: B-ALL diagnosis and MRD assessment were performed by flow cytometry, while lncRNA expression levels were quantified using TaqMan probe-based assays. Results: Fifteen pediatric patients with B-ALL were followed longitudinally. MRD evaluation identified seven refractory and eight remitted patients. Significant expression changes were observed for MEG3 in remitted patients and for BALR6 and LINC-PINT in refractory patients. No statistically significant differences were detected for ZEB1-AS1. Conclusions: Changes in MEG3, LINC-PINT, and BALR6 lncRNA expression are associated with treatment response and MRD status in pediatric B-ALL, supporting their potential role as complementary biomarkers to conventional MRD monitoring. Full article

Background: Multiparameter flow cytometry is widely used in the diagnosis of acute leukemia, allowing for rapid identification of leukemic cells based on their immunophenotype. The EuroFlow Acute Leukemia Orientation Tube was designed as a standardized screening tool to support early diagnostic orientation and guide further, more targeted testing. In this study, we assessed the diagnostic performance of the ALOT panel in pediatric patients with suspected acute leukemia. Methods: A total of 254 pediatric patients (0–18 years) with suspected acute leukemia were analyzed. Bone marrow samples were assessed using multiparameter flow cytometry with the EuroFlow ALOT panel, comprising eight markers (MPO, cyCD79a, CD34, CD19, CD3, cyCD3, CD7, and CD45). Final diagnoses were established using extended immunophenotypic panels and additional diagnostic methods when required. Samples were processed according to EuroFlow standard operating procedures and acquired on FACSCanto II and FACSCanto 10-color flow cytometers (BD Biosciences). Diagnostic performance was assessed by calculating sensitivity, specificity, precision, accuracy, and negative predictive value. Results: Among 254 patients, 234 were diagnosed with hematologic disorders, while 20 had normal bone marrow findings. The ALOT panel correctly identified all pathological samples and did not misclassify any normal sample, resulting in 100% sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for discrimination between abnormal and normal samples. In terms of exact diagnostic orientation, ALOT correctly classified 244 of 254 cases (96.1%) using a single-tube approach. The remaining 10 cases (3.9%), including rare entities such as Burkitt leukemia, chronic myeloid leukemia, and transient myeloproliferative syndrome, required extended immunophenotypic evaluation. Importantly, these cases were not false negative results, as all were correctly identified as abnormal. Conclusions: The EuroFlow ALOT panel is a reliable screening tool for rapid diagnostic orientation in pediatric acute leukemia. Its implementation facilitates targeted selection of extended immunophenotypic panels, improving the efficiency and cost-effectiveness of diagnostic workflows. Full article

Background: Thromboembolism is a serious complication in acute lymphoblastic leukemia (ALL). This systematic review and meta-analysis evaluated thrombosis incidence and risk factors across populations receiving asparaginase-based therapy. Methods: From 214 studies (1994–2026), 58 met inclusion criteria, totaling 23,655 adult, pediatric, and mixed-population patients. Searches included Ovid MEDLINE, Embase, Cochrane CENTRAL, PubMed Central, and Google Scholar. Eligible studies were observational cohorts or clinical trials reporting thrombosis in ALL patients treated with asparaginase. Risk factors assessed included study design, asparaginase formulation, immunophenotype, gender, treatment phase, corticosteroid use, mediastinal mass, ABO blood group, body weight, and age. Random-effects models were used for meta-analysis, and risk of bias was assessed using ROBINS-I and RoB-2. Results: Adults had significantly higher thrombosis rates than children (p < 0.0001). Study design, asparaginase formulation, immunophenotype, and treatment phase differed significantly across age groups (p < 0.0001). T-cell ALL showed higher thrombosis rates than B-cell ALL (p < 0.0001). Significant pediatric risk factors included age ≥ 10 years, mediastinal mass, non-O blood type, and overweight/obesity (all p ≤ 0.0004). Gender and corticosteroid use were not significant predictors. Findings were limited by substantial heterogeneity across included studies. Conclusions: Thrombosis risk was multifactorial. Adults and older children had higher risk, and pediatric patients with overweight/obesity, mediastinal mass, or non-O blood type were particularly vulnerable. Thromboprophylaxis is advised for high-risk groups. This review was not registered and received no external funding. Full article

Background: Chronic myeloid leukemia (CML) is a rare disease in children and adolescents. Discrepancies have been reported regarding the outcomes of adolescents, most of whom have been studied with younger or older patients not separately. Methods: The International Registry of Pediatric CML (I-CML-Ped Study) retrospectively and prospectively enrolled 614 patients less than 18 years old. Data from adolescents (15–18 years) with CML in chronic phase (CML-CP) were analyzed and compared to data from children less than 15 years old enrolled during the same period. Results: In total, 132 out of 144 adolescents presented with CML-CP: palpable spleen was reported in 67%, and the median leukocyte count was 181 G/L [interquartile range, 70–327]. Responses to treatment and outcome were analyzed in 124 adolescents with imatinib as first-line treatment: the cumulative incidence of major molecular responses (MMR) at months 12 and 36 was 33.4% (95% confidence interval CI, 24.9–41.9) and 79.8% (95% CI, 71.8–87.7), respectively. With a median follow-up of 4 years (95% CI: 3.5–4.9), 49 (40%) of these 124 patients were switched to another treatment, 11 (9%) patients progressed to the advanced phase, and the five-year overall survival rate was 95.2% (95% CI, 90.8–99.9%). We did not find significant statistical differences between these adolescents and younger children receiving imatinib in terms of response (complete cytogenetic response, MMR) and outcome (progression-free survival, overall survival). Conclusions: Response to treatment and outcomes in adolescents with CML-CP in the tyrosine kinase inhibitor era are satisfying without statistically significant difference from results observed in younger children. Full article

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