Search Results (157)

Background: In childhood acute lymphoblastic leukemia (ALL), in addition to classical chromosomal abnormalities, loss of heterozygosity (LOH), including copy-neutral LOH, is also observed. While LOH has been described in the literature, its clinical relevance in pediatric ALL remains unclear. The aim of this study is to identify and analyze patterns of LOH, assess their frequency, and evaluate their association with clinical characteristics and early treatment response during the induction phase of the ALL protocol. Methods: The study included 853 pediatric ALL patients, of whom 120 had B-ALL LOH+ and 58 had T-ALL LOH+. LOH was analyzed using CytoScan HD SNP microarrays. Patients were stratified using multiple correspondence analysis (MCA) and hierarchical clustering on principal components (HCPC), which identified three genetically and clinically distinct clusters. Results: In B-ALL, two clusters with extensive LOH—particularly involving chromosome 9—were associated with poor prognosis and suboptimal response to therapy. In contrast, Cluster 2, characterized by CDKN2A duplication and rare LOH, showed a favorable clinical course. In T-ALL, Cluster 1 had LOH in CDKN2A but favorable outcomes; Cluster 2 exhibited biallelic CDKN2A deletion and aggressive disease; Cluster 3 lacked CDKN2A alterations and showed a genetically stable profile. LOH was common on chromosomes not typically affected by trisomy and rare on those gained. Conclusions: Our study indicates that LOH profiling can positively influence patient stratification by identifying high-risk subgroups, inform prognosis by highlighting unfavorable genetic alterations, and help predict poor treatment response in specific clinical profiles. Full article

Despite the successes achieved in recent years in the treatment of childhood acute lymphoblastic leukemia (ALL), high-risk ALL in particular still represents a considerable challenge, with poorer outcomes. The PI3K/AKT/mTOR signaling pathway is frequently constitutively activated in ALL and consequently leads to unrestricted cell proliferation, without showing frequent mutations in the most important representatives of the signaling pathway. Recent studies have shown that fine balanced protein expression is a common way to adjust oncogenic B cell directed receptor signaling and to mediate malignant cell proliferation and survival in leukemic cells. Too low expression of inhibitory phosphatases can lead to constitutive signaling of kinases, which are important for cell proliferation and survival. In contrast, marked high expression levels of key phosphatases enable cells with distinct pronounced oncogenic B cell directed receptor signaling to escape negative selection by attenuating signal strength and thus raising the threshold for deletion checkpoint activation. One of the most important B cell receptor-dependent signaling cascades is the PI3K/AKT signaling pathway, with its important antagonist SHIP1. However, recent data show that the inositol-5-phosphatase SHIP1 is differentially expressed across the heterogeneity of the ALL subtypes, making the overall therapeutic strategy targeting SHIP1 more complex. The aim of this article is therefore to provide an overview of the current knowledge about SHIP1, its expression in the various subtypes of ALL, its regulation, and the molecules that influence its gene and protein expression, to better understand its role in the pathogenesis of leukemia and other human cancers. Full article

B-cell precursor acute lymphoblastic leukemia (B-ALL) is characterized by a constellation of somatic pathogenic variants associated with malignant transformation. These variants have implications for clinical management by providing clinical biomarkers. Most B-ALL cases have a sporadic presentation. However, some patients may present the disease as the neoplastic manifestation of cancer predisposition syndromes caused by germline pathogenic variants. In these cases, genetic counseling and personalized oncologic management is mandatory, considering the patient’s sensitivity to conventional therapies. In this review, we have summarized current knowledge on the biological role and clinical relevance of somatic and germline pathogenic variants associated with B-ALL, and discuss three aspects of their application as biomarkers: (1) their usefulness to determine specific molecular subtypes, predicting prognosis and response to specific therapies, (2) their influence in genetic counseling and therapy adaptation for B-ALL in the context of underlying cancer predisposition syndromes, and (3) their detection and interpretation through methodologies. We also included a brief discussion on the need to reclassify variants of uncertain significance to clarify their clinical relevance. Finally, we discuss cases illustrating the impact of somatic and germline pathogenic variants in personalized medicine. Full article

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Good overall survival rates of about 90% are the result of improvements in risk stratification and risk-adapted therapy, intensive chemotherapy regimens, hematopoietic stem cell transplantation, and better supportive care. Background and Objectives: The aim of this study is to review the epidemiology, prognostic factors, and causes of death in pediatric ALL patients treated at a tertiary care center, and to identify risk factors influencing clinical outcomes. Materials and Methods: A retrospective study was conducted at the Department of Pediatric Hematology and Oncology, University Hospital Centre Zagreb, including 302 children (0–18 years) diagnosed with ALL between January 2001 and December 2015. Results: Two hundred fifty-one children survived (5-year overall survival 83%). Relapse occurred in 13.6% of patients. Relapse rates were higher for B-cell precursor (Bcp)-ALL than for T-cell ALL (14.3% vs. 10.4%), and no patient with relapsed T-cell ALL survived. The main causes of death were refractory/relapsed disease (43% of patients), followed by infections (35%) and GVHD (8%). The most frequent causes of infectious death were Pseudomonas aeruginosa and Aspergillus fumigatus. The most critical treatment periods were the induction and reinduction phases, especially the de-escalation of corticosteroids. The time of relapse and risk group were independent factors in predicting the outcome. Conclusions: Relapse and infections were the leading causes of death in children with ALL, with the highest mortality observed during induction and reinduction phases. Survival was significantly influenced by relapse timing and risk group, with no survivors among relapsed T-ALL patients. Full article

Background/Objectives: Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children. Contemporary antitumor treatment protocols provide long-term survival rates in over 90% of patients with ALL. High effectiveness of the treatment has been achieved as a result of chemotherapy optimization, use of targeted drugs, up-to-date genetic information, and detection of minimal residual disease (MRD). Current highly sensitive methods for MRD detection have advantages and disadvantages, and the challenge is to distinguish between false-positive and false-negative tests. Methods: A comprehensive search through MEDLINE, PubMed, Scopus, and ScienceDirect using the MRD-related keywords was performed, and included a final set of 72 academic articles. Results: At present, flow cytometry for MRD detection provides the necessary sensitivity of 10⁻⁴ and allows for reliable prediction of ALL dynamics and effective therapeutic strategies. However, even multicolor flow cytometry (MFC) cannot avoid cases of false-positive or false-negative results. Highly sensitive and productive genomic methods in addition to MFC may enhance the accuracy of MRD evaluation. On the other hand, overwhelming efforts to reach the highest sensitivity of the detection methods may lead to the detection of clinically insignificant manifestations of minimal residual disease and, subsequently, to unjustified escalation of antitumor therapy. Conclusions: The necessary ground for an adequate sensitivity of the MRD detection methods could ensure the fine line between false-positive and false-negative MRD results in patients with childhood ALL to develop an appropriate therapeutic strategy. Full article

MicroRNAs are key regulators of lymphoid differentiation, exhibiting a pivotal role in acute lymphoblastic leukemia (ALL) biology and prognosis. The initial steps of canonical miRNA biogenesis involve the microprocessor complex processing the primary miRNA transcripts into precursor miRNAs via Drosha. DROSHA polymorphisms have been implicated in pediatric ALL and linked with cancer risk. This study investigated the role of rs642321, rs3805500, and rs10035440 DROSHA polymorphisms in ALL susceptibility, relapse, and outcomes in children and adolescents of Greek descent. The study included 252 children and adolescents (115 ALL cases and 137 controls). Genotyping was performed using RT-qPCR and the TaqMan Genotyping Assay. Homozygotes for the minor allele in DROSHA rs642321 were nominally associated with ALL susceptibility (TT vs. CC+CT; OR 4.5; 95% CI: 1.2–21.2; p_adj = 0.034). Likewise, homozygotes for the minor allele in rs3805500 were linked with ALL risk (GG vs. AA+AG; OR 2.7; 95% CI: 1.3–6.1; p_adj = 0.012). A suggestive association was observed between the rs3805500 AG genotype and both relapsed (OR 5.8; 95% CI: 1.6–24.3; p_adj = 0.011) and deceased cases (OR 5; 95% CI: 1.1–26.3; p_adj = 0.038). Patients with the rs3805500 AG and GG genotypes showed a trend toward poorer overall survival rates. In summary, certain haplotypes of DROSHA polymorphisms may be modestly associated with the occurrence of childhood ALL and its outcomes, although these findings require validation in larger, independent cohorts. Full article

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 Full article

Background: Although thromboembolic complications are recognized in the treatment of acute lymphoblastic leukemia (ALL), ischemic strokes are rare but severe events. These life-threatening complications not only pose an immediate risk but can also result in long-term neurological deficits, significantly impacting a patient’s quality of life. Identifying high-risk patients and implementing effective prophylaxis strategies are crucial for improving patient outcomes. In addition to strokes, these patients are also at risk of other embolic and thrombotic events, which can occur in up to 35% of patients. Despite this, there are still no clear guidelines for prophylactic management in pediatric patients treated for oncologic diseases. Results: Using the example of a 14-year-old male treated for ALL who suffered an ischemic stroke, we conducted a review of the literature on embolic and thrombotic events, neurological complications, methods of prevention, and ways to monitor and detect patients with an increased risk of such difficulties. We outlined our approach to the monitoring of prothrombotic factors, the interpretation of their levels, and the subsequent adjustment to prophylactic management based on these findings. As a result of this review, we reached two basic conclusions. First, thromboembolic episodes are not uncommon complications in pediatric patients and can cause long-lasting consequences, even after the cancer is cured. Secondly, despite such an urgent problem, clinicians are still struggling with the question of monitoring prothrombotic factors, the choice of drug, and the duration of prophylaxis. Their decisions depend on the experience of the treating center. Conclusions: The pediatric population being treated for malignant disease urgently requires the establishment of guidelines that standardize the management of thromboembolic events. Full article

Acute lymphoblastic leukemia (ALL) accounts for approximately 25% of childhood cancers and 20% of leukemia cases in adults, with a higher prevalence in males than females. It is characterized by symptoms such as fatigue, fever, and bone pain and poses a significant risk of mortality if left untreated. While chemotherapy and stem cell transplantation are standard treatments, their efficacy declines in relapsed or refractory cases, highlighting the need for innovative therapeutic approaches. CAR T-cell therapy has emerged as a transformative technology, offering the potential to overcome these challenges and deliver durable remissions. CAR T-cell therapy demonstrates significant advantages, including targeting specific antigens, overcoming high-risk genetic mutations, and achieving sustained remissions in both pediatric and adult patients. However, notable challenges remain, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In this review, we focus on neurological symptoms associated with CAR T-cell therapy in treating ALL and discuss current and future strategies aiming at reducing their risk. Full article

B-type acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Despite significant advancements in treatment, chemotherapy resistance and relapse remain major challenges to be overcome. Oxidative stress markers, including lipoperoxides, have emerged as potential biomarkers in B-ALL patients under treatment. This study evaluated lipoperoxide levels in the peripheral blood of pediatric B-ALL patients during the induction phase of chemotherapy using high-sensitivity chemiluminescence and analyzed their association with clinical prognostic factors and patient outcomes, including definitive hospital discharge, disease relapse, and patient death. Lower lipoperoxide levels were observed in patients over 10 years old, those who achieved remission and were discharged from the hospital, and those with central nervous system (CNS) involvement. In contrast, significantly higher lipoperoxide levels were found in patients who relapsed, died, or had platelet counts exceeding 50,000/mm³. Receiver operating characteristic (ROC) curve analysis suggests that lipoperoxides may serve as potential biomarkers during the induction phase of chemotherapy, distinguishing B-ALL patients undergoing treatment from those not in treatment (sensitivity: 92.31%; specificity: 71.43%). These findings highlight the potential utility of lipoperoxides as prognostic biomarkers in B-ALL patients. Full article

Childhood leukemia survivors are at risk of long-term complications. Data on bone remodeling in childhood acute lymphoblastic leukemia (ALL) are limited. This 2-year prospective longitudinal study investigated bone remodeling and bone turnover markers at diagnosis, during treatment, and until stopping treatment, in ALL patients < 18 years, to clarify the influence of leukemia itself and/or chemotherapy on bone. Methods: A total of 22 ALL children (12 males, age 5.5 ± 3.6 years) underwent blood sampling at the 5 time point (T0−T4). Osteoprotegerin (OPG), receptor-activator-NF-B-ligand (RANKL), osteocalcin (OC), C-terminal-telopeptide-type-I-collagen (CTX), bone-alkaline-phosphatase (bALP), tartrate-resistant acid-phosphatase-5b (TRACP5b), procollagen-type-I-N-terminal-propeptide (P1NP), Dickkopf-1 (DKK-1), and sclerostin were assessed. Data from patients at T0 were compared to a control group of healthy children. We used the principal component analysis (PCA) for statistics. Results: Levels of CTX, OC, P1NP, and bALP resulted lower in ALL children than controls (p = 0.009 for CTX and p < 0.001 for the others), also DKK1 and sclerostin (p < 0.0001 and p = 0.023). RANKL ed OPG were higher in patients. During T0−T4, CTX, OC, P1NP, TRACP5b, and bALP showed a significant increase, in particular at T0−T1 (end-of-induction). Less evident changes were detected onwards. Conclusions: The onset of leukemia has been revealed as a key point in determining a slowing of bone remodeling in ALL children. Full article

Measurable Residual Disease (MRD) assessment in pediatric acute lymphoblastic leukemia (ALL) is crucial for relapse prediction and treatment guidance. Multiparameter flow cytometry (MFC) enhances detection but faces limitations due to insufficient leukemia-associated immunophenotypes (LAIPs) and antigen modulation. This study explores new markers to improve MFC-based MRD detection in B-cell precursor ALL (BCP-ALL). Expression-patterns of seven aberrancy markers, i.e., CD44, CD304, CD73, CD86, CD123, CD99, CD58, and one B-cell maturation marker, CD22, were studied in 143 samples with leukemic-blasts from sixty-one childhood BCP-ALL patients and in hematogones of 20 non-leukemic bone marrow (BM) samples using fourteen-color MFC. The highest relative frequences of LAIPs amounted to 82.50%, reported for CD99 and CD58, followed by CD44 (81.10%), CD73 (76.20%), CD22 (73.40%), CD304 and CD86 (68.50%), while the lowest relative frequence was CD123 (44.40%). Differential expression of CD58, CD304, and CD73 in diagnostic samples was highly significant (p < 0.01) between pre-B-I, pre-B-II, immature B cells, and BCP-ALL blasts. In MRD-positive samples CD73 showed significantly high (p < 0.01) differential expression between all stages of hematogones and residual blasts, followed by CD304, CD58, and CD22. CD73 and CD304 were identified as the most reliable among the tested markers for distinguishing both diagnostic and MRD blasts from normal B cell precursors. Full article

Analysis of tumoral RNA from bone marrow (BM) biopsy is essential for diagnosing childhood B-cell acute lymphoblastic leukemia (B-ALL), risk stratification, and monitoring, by detecting fusions and gene expression patterns. However, frequent BM biopsies are invasive and traumatic for patients. Small extracellular vesicles (sEVs) circulating in blood contain a variety of biomolecules, including RNA, that may contribute to cancer progression, offering a promising source of non-invasive biomarkers from liquid biopsies. While most EV studies have focused on small RNAs like microRNAs (miRNAs), the role of longer RNA species, including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), remains underexplored despite their demonstrated potential for risk-based patient stratification when starting from BM biopsies. We used immuno-purification to isolate sEVs from peripheral blood at diagnosis in B-ALL patients and cell model-based conditioned culture medium (CCM) with ETV6::RUNX1 and TCF3::PBX1 fusions. Using whole-transcriptome sequencing targeting transcripts over 200 nt and a novel data analysis pipeline, we identified 102 RNA transcripts (67 mRNAs, 16 lncRNAs, 10 circRNAs, 4 pseudogenes, and 5 others) in patient-derived sEVs. These transcripts could serve as biomarkers for two distinct molecular subgroups of B-ALL, each with different risk profiles at diagnosis. This is the first study characterizing the long transcriptome in blood-derived sEVs for childhood B-ALL, highlighting the potential use of circulating RNAs for improved risk-based stratification. Full article

Background: Exposure to pesticides has been associated with an increased risk of developing childhood leukemia. However, the impact of pesticides on childhood leukemia survival has not been examined. We investigated the associations between residential pesticide use during key developmental periods and 5-year survival in children treated for acute lymphoblastic leukemia (ALL). Methods: Residential use of insecticides, herbicides, rodenticides, and flea control products from preconception up to 12 months prior to diagnosis and sociodemographic characteristics were collected via parental interview among 837 children diagnosed with ALL between 1995 and 2008 in California, USA. Data on clinical features were abstracted from medical records. Vital status was obtained through linkage to the National Death Index (NDI) up to 2020. Cox proportional hazards regression models were used to estimate hazard ratios (HRs), adjusting for sociodemographic factors and clinical risk group. Results: A total of 108 children with ALL (~13%) died within 5 years of diagnosis. Exposure to any pesticides pre- and/or postnatally was slightly higher among deceased compared to alive children (95.4% vs. 91.5%; p = 0.23), while use of rodenticides was significantly higher in children who died (25.0%) vs. those who survived (15.5%; p = 0.02). In fully adjusted models, exposure to rodenticides was associated with an increased risk of mortality (HR 1.70; 95% confidence interval (CI) 1.08–2.64; p = 0.02), especially when the child was exposed during pregnancy (HR 1.90; 95% CI 1.15–3.16; p = 0.01) and possibly 12 months before diagnosis (HR 1.60; 95% CI 0.98–2.61; p = 0.06). Increased hazards of death were also observed with other types of pesticides during pregnancy, but those associations were not statistically significant. Conclusions: This study is the first to report reduced survival among children with ALL previously exposed to rodenticides, particularly during pregnancy, underscoring the need to further evaluate mechanisms by which environmental exposures during key developmental stages may later impact cancer outcomes. Full article

Acute lymphoblastic leukemia (ALL) is a malignant neoplasm with the highest incidence in the pediatric population. Although the 5-year overall survival is greater than 85%, in emerging countries such as Mexico, the mortality rate is high. In Mexico, B-ALL is the most common type of childhood cancer; different characteristics suggest the presence of the disease; however, the prognosis is dependent on clinical and laboratory features, and no adverse prognostic molecular marker for B-ALL has yet been identified. The present research aimed to identify the prognostic value of HMMR expression in pediatric patients with B-ALL. The differential expression profile of B-ALL cells was determined via in silico analysis, and HMMR expression was subsequently measured via qRT–PCR and immunocytochemistry. The results were statistically analyzed via the ROUT test, Kolmogorov–Smirnov Z test, and Mann–Whitney U test. ROC curves and the Youden index were constructed, and Kaplan–Meier curves were plotted. We found that HMMR expression was increased in B-ALL patients (p < 0.0001). We observed that high expression was related to poor prognosis (p < 0.05). We observed that high expression was related to poor prognosis (p < 0.05). The increase in HMMR expression could be a potential early molecular prognostic marker and/or a new target in childhood B-ALL patients. Full article